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==== Front Support Care Cancer Support Care Cancer Supportive Care in Cancer 0941-4355 1433-7339 Springer Berlin Heidelberg Berlin/Heidelberg 7536 10.1007/s00520-022-07536-y Research Therapeutic yoga reduces pro-tumorigenic cytokines in cancer survivors Patel Darpan I. pateld7@uthscsa.edu 123 Almeida G. J. 4 Darby N. T. 5 Serra M. C. 3 Calderon T. 3 Lapetoda A. 6 Gutierrez B. 6 Ramirez A. G. 26 Hughes D. C. 26 1 grid.267309.9 0000 0001 0629 5880 Biobehavioral Research Laboratory, School of Nursing, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive M/C 7975, San Antonio, TX 78229 USA 2 grid.267309.9 0000 0001 0629 5880 Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX USA 3 grid.267309.9 0000 0001 0629 5880 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX USA 4 grid.267309.9 0000 0001 0629 5880 School of Health Professions, University of Texas Health Science Center at San Antonio, San Antonio, TX USA 5 Nydia’s Yoga Therapy Studio, The Open Hand Institute, San Antonio, TX USA 6 grid.267309.9 0000 0001 0629 5880 Institute for Health Promotion and Research, University of Texas Health Science Center at San Antonio, San Antonio, TX USA 15 12 2022 2023 31 1 3329 7 2022 9 12 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Introduction Chronic inflammation can remain many years after the completion of cancer treatment and is associated with cancer recurrence. The purpose of this study was to examine how a 16-week therapeutic yoga program (TYP) modulates the cytokine profile in heterogeneous cancer survivors. Methods Eligible participants were 18 years of age or older and clinically diagnosed with cancer. Consenting participants were asked to attend three, 75-min sessions weekly of TYP with meditation. Seventeen patients provided blood samples at baseline and end of study. Eight cytokines (interferon (IFN)-γ; interleukin (IL)-1b, IL-1ra, IL-4, IL-6, IL-8, IL-10; and tumor necrosis factor (TNF)-α), three receptors (sIL-6R, sTNFRI, sTNFRII), and C-reactive protein (CRP) were quantified. Results Patients were 59.6 ± 7.3 years old; over half (56%) were overweight or obese BMI ≥ 25 kg/m2); majority were female (71%) and breast cancer survivors (65%), of which 44% were Hispanic. Marked reductions were observed in all cytokines except IL-4, with significant reductions (p < 0.05) found in IL-1b (− 13%) and IL-1ra (− 13%). No significant changes were observed in soluble cytokine receptors or CRP. Conclusions TYP led to significant reduction in circulating cytokines associated with chronic inflammation in a heterogeneous sample of cancer survivors. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-022-07536-y. Keywords Recurrence Survivorship Physical activity Immunology Body composition http://dx.doi.org/10.13039/100000054 National Cancer Institute CA054174 CA054174 CA054174 CA054174 CA054174 CA054174 CA054174 Patel Darpan I. Almeida G. J. Serra M. C. Lapetoda A. Gutierrez B. Ramirez A. G. Hughes D. C. http://dx.doi.org/10.13039/100006108 National Center for Advancing Translational Sciences UL1-RR024982 UL1-RR024982 Patel Darpan I. Hughes D. C. issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction The American Cancer Society predicts that there will be over 1.9 million new cancer cases diagnosed and 609,360 cancer deaths in the USA in 2022 [1]. Survival rates are increasing due to earlier detection coupled with better treatments, which has shifted the paradigm of the cancer diagnosis of a fatal disease to a chronic disease [1, 2]. However, once a diagnosis of cancer occurs, even though treated and in remission, the possibility of recurrence plays heavy in the minds of cancer survivors and is a concern for the treating oncologist [3]. Multiple factors play a role in cancer recurrence, including obesity and systemic inflammation [4–6]. Elevated body mass index (BMI) is associated with increased systemic concentrations of inflammatory and pro-tumorigenic cytokines [7]. Further, the elevations of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-1β, have been targeted because of their multifactorial impact on tumor progression, as well as many secondary events, such as fatigue and sarcopenia [8–10]. Many studies have demonstrated feasibility of implementing a yoga program to improve quality of life and emotional, physical, and mental well-being in patients with cancer [11–20]. There is also evidence that yoga can attenuate systemic inflammation associated with increase risk of cancer onset and recurrence [13, 21]. There is a growing interest in studying the effects of therapeutic yoga in cancer survivors because it can offer a tailored and individualized approach. What remains to be understood is the immunologic response to yoga in a heterogeneous sampling of cancer survivors and how it presents in an ethnically diverse sample. Furthermore, the multiple approaches to implementing a yoga program provide opportunities to better understand whether the practice of yoga can impact physiological outcomes. The purpose of this study was to determine how 16 weeks of therapeutic yoga can influence the inflammatory cytokine profile of cancer survivors using a single-arm, self-controlled, pilot, exploratory study design. We hypothesized that 16-weeks of therapeutic yoga would significantly modify cytokines associated with chronic inflammation and cancer recurrence in a diverse cancer survivor cohort. Methods Study design and participants A single-arm, self-controlled, block enrollment study design was used. Participants were recruited from January 2020 to March 2020. Participants were recruited from the surrounding community using advertisements and word of mouth. Flyers were placed throughout the University of Texas Health San Antonio’s (UTHSA) Mays Cancer Center. The flyer included a contact number to request information. Individuals that expressed interest were screened for eligibility. The study inclusion criteria were the following: at least 18 years of age, had been given a diagnosis of any cancer in their lifetime (active treatment or post-treatment), had access or use of a mobile phone or computer to complete surveys and respond to text messages, were able to speak and understand English or Spanish, and were oriented to time and place. Participants were excluded if they were currently enrolled in a competing protocol or presented with any absolute contraindication to exercise testing as detailed by the American College of Sports Medicine Guidelines on Exercise Testing and Exercise Prescription [22]. Once contact with the potential participants were made, the coordinator assigned a unique subject identification number. The participants were given a scripted brief explanation of the study in their language of choice (English or Spanish). Participants were told that after accrual reached the cohort target of thirty, the study would start. A list of 43 interested participants was collected. In numerical order, the first thirty participants who passed screening for eligibility were invited to participate in the study and were scheduled for baseline assessments at the Holistic Exercise Advancement Laboratory (HEAL) at the UTHSA Mays Cancer Center. Out of the 30 invited, 29 provided informed consent and completed baseline assessments (Fig. 1).Fig. 1 Therapeutic yoga program CONSORT diagram Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted approval by the Institutional Review Board of the UTHSA (date: December 17, 2019; No: 20190637HU). Informed consent was obtained from all individual participants included in the study. Demographics and patient characteristics After consenting to the study, height, weight, blood pressure, demographic information, and medical history were collected. BMI was calculated as weight [kg]/(height [m])2. Yoga protocol Study participants were asked to participate in a 16-week therapeutic yoga program three times per week on-site at the Mays Cancer Center at UTHSA. Each session lasted 75 min and included structured sequence of combined yoga postures (asanas), breathing practice (pranayama), and loving-kindness meditation (LKM), referred to as the therapeutic yoga protocol (TYP) developed by an experienced and certified yoga instructor as previously described [23]. The TYP was developed to increase mobility of extremities and torso (specifically thoracic mobility), increase overall strength and muscular endurance, improve overall function, guide participants in safe transition to the floor and back up, reduce stress, improve focus and concentration, introduce meditation with breath as a focus during the movement practices, and introduce LKM during the resting portion of the practice. During participation in the TYP, postures were held for 3 slow and controlled breaths. The breath was used as a focus for concentration and to determine the individual participants’ tolerance to the yoga activities. The practice began with introduction, Therapeutic Sun Salutation, transition to quadruped and prone postures, transition to standing postures, transition to floor for seated postures, transition to supine postures, transition to supported modified inversion to final resting posture in supine for LKM. The Therapeutic Sun Salutation is a modified version of the traditional Sun Salutation poses that allow for individuals with balance issues, joint or mobility issues, and individuals with limited hamstring flexibility, to progress through the poses without the risk of injury. The COVID-19 outbreak forced changes to the protocol after the first week of program initiation. The live on-site therapeutic yoga class practices were discontinued to meet the health and safety concerns for this high-risk population. The TYP protocol was transitioned to a virtual implementation. Livestream TYP coupled with video recordings were made available to study participants via the BlueJay Telehealth portal (Pleasanton, CA) in order to complete the 16-week protocol. Each participant was given an individual username and password for accessing the Telehealth portal and was able to attend live sessions of the TYP or view recorded sessions to complete the TYP asynchronously. Cytokine, receptor, and stress hormone evaluation Baseline and end-of-study blood samples were collected into K2-EDTA tubes and centrifuged to separate and aliquot plasma for subsequent cytokine protein analysis. The samples were analyzed in duplicate using the FlexMap 3D platform system (Luminex, Austin, TX) with the MILLIPLEX MAP Human Cytokine Panel A (HCYTA-60 K-08 with TNF-α, IL-1ra, IL-1β, IL-4, IL-6, IL-8, IL-10, and IFN-γ), Human Soluble Cytokine Receptor Panel (HSCRMAG-32 K-03 with sTNFRII, sTNFRII, and sIL-6R) and Milliplex-Human CVD Panel 3 with CRP (HCVD3MAG-67 K-01). Multiplex analysis was performed by the Bioanalytics and Single-Cell Core Laboratory in the Department of Molecular Medicine at UTHSA. Statistical analysis Study data were collected and managed using the REDCap electronic data capture tools hosted at UTHSA [24]. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources. Per-protocol analysis was employed, and only those who completed the study protocol were included. All continuous variables were evaluated for normality using the Kolmogorov–Smirnov test. The effect of the intervention was evaluated by calculating changes in circulating cytokine concentrations between baseline and at the end of the intervention. Percentage changes in biomarkers concentrations from baseline to end of study were calculated as follows: [mean baseline − mean end of study]/[mean baseline] × 100. Within-group differences in cytokine concentrations were evaluated using the Wilcoxon rank-sum test. Data are presented as median (interquartile range). The significance level was set at p < 0.05. The primary outcome was changes in cytokine concentrations after the completion of the 16-week TYP. The analysis was restricted to only the individuals that provided both baseline and end-of-study samples because many individuals chose not to return for the end-of-study visits due to the onset of the COVID-19 pandemic. All analyses were conducted using GraphPad Prism version 9.3.1 (San Diego, CA). Results Participant demographics and clinical characteristics Twenty-two of the twenty-nine consented participants completed the end of study visit, and 17 of those 29 participants provided both baseline and end-of-study blood samples for the analysis of circulating cytokines. These participants were 59.6 ± 7.3 years old (range: 47–69), mostly overweight/obese (56% with BMI ≥ 25 kg/m2) female (71%) breast cancer survivors (65%) with 8 of the 17 participants being Hispanic (see supplemental file for full demographics details). For the 5 participants that did not have a complete blood set, the reasons included hemolysis of samples, short draws, or not willing to provide blood samples. Cytokine, cytokine receptor, and CRP response to therapeutic yoga Biomarker data is presented in Table 1. Significant decreases in concentrations were found only for IL-1β (p = 0.003) and IL-1ra (p = 0.02), with a trend observed in IL-8 (p = 0.07). No significant changes were observed in soluble cytokine receptors; however, sTNFRI was trending towards significance (p = 0.052).Table 1 Changes in circulating cytokines in cancer survivors who completed a 16-week online yoga intervention. Data is presented as pg/ml Pre Post △ p-value Cytokine Median (IQR) Median (IQR) IFN-γ 2.42 (1.95, 3.35) 2.15 (1.90, 3.07)  − 11% 0.12 IL-1b 6.88 (6.32, 9.79) 5.96 (5.14, 8.14)  − 13% 0.003 TNFα 15.42 (13.76, 18.80) 15.95 (13.76, 18.75) 3% 0.5 IL-4 1.67 (1.12, 3.17) 1.48 (1.23, 2.99)  − 11% 0.46 IL-10 12.28 (9.36, 25.97) 13.07 (8.58, 24.13) 6% 0.13 IL-1ra 4.66 (3.18, 11.34) 4.05 (2.98, 10.38)  − 13% 0.02 IL-6 1.74 (1.06, 3.42) 1.89 (1.31, 2.23) 9% 0.32 IL-8 2.56 (2.23, 3.73) 2.16 (1.87, 2.70)  − 15% 0.07 Cytokine receptors sIL-6R 5234 (4389, 5825) 5264 (4545, 5958)  − 1% 0.31 sTNFRI 332.2 (283.7, 412.3) 388.7 (299.7, 449.2) 17% 0.052 sTNFRII 1216 (978, 1591) 1258 (946, 1534) 3% 0.43 Inflammation hormone CRP 2.59 (1.11, 17.18) 3.30 (0.87, 9.44) 27% 0.32 Discussion For cancer survivors, the rumination of threat of cancer recurrence can negatively impact health-related quality of life (HR-QOL). Behavioral and lifestyle modifications are associated with reduced rates of cancer recurrence [25, 26], though mechanisms underlying these benefits are inconclusive and warrant continued investigation. Yoga is a low impact physical activity intervention that has been reported to improve function, fatigue, and quality of life in cancer survivors [11–15, 17–21, 27–30]. The primary objective of this pilot, exploratory study was to determine the effects of 16-week TYP on circulating cytokines. Results from this self-controlled study partially support our hypothesis that yoga can lead to significant reductions in concentrations of inflammatory cytokines that are associated with chronic inflammation and tumor recurrence in a heterogeneous sample of cancer survivors. Specifically, we observed significant reductions in circulating concentrations of IL-1β and IL-1ra. Trends for increased sTNFRI were also observed following the 16-week TYP. The mixed results of our study are indicative of the complexity in studying inflammatory cytokines in older participants with cancer, who may have many other factors that may influence the concentrations of the proteins measured in our study. For example, the simple aging process is associated with increased inflammation, term inflammaging [31], that may have underlying effects on the results of our study. In our study, 55% of participants were above the age of 60 years. Two proteins of interest in our study, CRP and TNF-α, were not significantly lower when compared to baseline, which contradicts a recent systematic review published by Koshravi et al. in which the overall effects of exercise on circulating cytokine concentrations were interpreted [32]. The studies included in this systematic review were overwhelmingly inclusive of aerobic exercise with only two papers including yoga as an exercise modality [21, 29]. Those two studies showed no effect of yoga on CRP or TNF-α, thus, suggesting that CRP and TNF-α response may be dependent on dose and type of intervention. Our study results support several other yoga studies that have reported varying effects on circulating inflammatory cytokines [12, 13, 21, 29]. For example, a 12-week Iyengar yoga intervention also found no significant changes in CRP, sTNFRII, a marker of TNF-α activity, or IL-6 [21]. However, our results indicated a significant reduction in IL-1ra following 16 weeks of our TYP, while similar results were not observed following 12 weeks of Iyengar yoga [21]. Interestingly, the inflammatory cytokine concentrations were either stable or slightly elevated in the Iyengar yoga participants, whereas most of the measured cytokines in our study demonstrated reductions after the yoga program, though some were not statistically significant. This could be perhaps due to the inclusion of breathing practice (pranayama) and loving-kindness meditation in this study, which incorporates mindfulness-based practices which can reduce stress, thereby, reducing cytokine concentrations [33]. In another study, yoga following either mastectomy or breast reconstruction surgery in breast cancer survivors found a significant reduction in TNF-α concentrations [29], while other published studies found no significant changes in inflammatory cytokines concentrations in similar patient populations [12, 34]. Further, given that we found no significant changes in TNF-α concentrations, it should be expected that sTNFRII concentration remain unchanged as it is a marker for TNF-α activity [35]. Briefly, IL-1ra consists of three isoforms and inhibits IL-1-mediated tumor progression [36]. The reduction in IL-1ra concentration in our study may be in part due to feedback mechanisms due to reductions in IL-1β. IL-1β is a product of blood monocytes, tissue macrophages, and dendritic cells that only appears when stimulated by other cytokines, such as TNF-α [37]. Since no significant differences in TNF-α were observed, we can hypothesize that the TYP can overcome the autoinflammatory effects of TNF-α to reduce both IL-1β and IL-1ra. Further research needs to be done to determine the exact mechanism of this action. The tendency for increased sTNFRI is intriguing. The pleiotropic nature of sTNFRI complicates our understanding of the intervention effect on this protein. sTNFRI is not only involved in inducing apoptosis [38], but can also transduce cell survival signals [39]. While the signaling pathways are well defined for sTNFRI, the regulation of life/death signaling is still poorly understood. Future research with a powered sample size will help provide insights into the role of yoga on sTNFRI concentrations. The impact of our intervention on IFN-γ concentrations, although not statistically significant, contradicts previous studies in cancer survivors that have reported an increase in IFN-γ concentrations following structured yoga programs [13, 40]. IFN-γ has been found in different studies to have protective effects on tumor growth and suggestive of a strong immune response [41]. Specifically, low serum IFN-γ levels have been inversely associated with tumor stage [42] and tumor size [43] though the specific mechanism attributed to this benefit is still unknown. Our continued interest in understanding the physiological response underlying the benefits of yoga on cancer survivors was formed with the premise that in healthy individuals, yoga is promoted as an anti-inflammatory intervention [27, 28, 30]. Given the significant role that cytokines, such as TNF-α [44], IFN-γ [45], IL-6 [46], and other interleukins and cytokine receptors, play in cancer onset and progression [47, 48], there is a significant need to better understand if yoga can be effectively used as an “anti-cancer exercise intervention.” However, due to the mixed results currently presented in the scientific literature, there is no established consensus on these effects. Interpretation of our study results is made with caution given the number of limitations to our study design. First, the single group comparison limits our ability to clearly define the effects TYP may have in modulating the inflammatory cytokines measured in this study. Second, the heterogeneous sample of cancer survivors, inclusive of both males and female with varying cancer diagnoses and years of survivorship, though useful for generalizability, may have impacted the levels of inflammatory cytokines. Third, our small sample size likely impacted the non-significant differences observed in concentration of inflammatory cytokines that had marked decreases at the end of the study. Lastly, the impact of the COVID-19 pandemic impacted our studies retention and our study results. Though none of the participants tested positive for COVID-19 while the study was implemented, the stress of the social distancing protocols implemented to limit the spread of the virus may have impacts that are immeasurable. In conclusion, the results of our pilot, exploratory, single-arm, pre-post study suggest that a 16-week TYP can reduce the concentration of cytokines associated with chronic inflammation. Despite the limitations, the results of this study have set a precedent for continued research using more rigorous study design models, such as randomized controlled studies, with powered samples to better understand the effects of yoga on mechanisms important for secondary cancer prevention. Supplementary Information Below is the link to the electronic supplementary material.Supplementary file1 (CSV 2 KB) Acknowledgements The authors would like to acknowledge the study participants that generously volunteered their time to participate in this study, despite the COVID-19 pandemic. Without their unwavering sacrifice, we would not have been able to complete this study. Author contribution All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Darpan Patel, Gustavo Almeida, Bianca Gutierrez, Angelika Lapetoda, and Daniel Hughes. The first draft of the manuscript was written by Darpan Patel, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Funding for this project was provided by the Mays Cancer Center’s P30 Cancer Center Support Grant from the National Cancer Institute (CA054174). Funding for the REDCap database was provided to the Institute for Integration of Medicine and Science (UL1-RR024982). Availability of data and materials The data and materials that support the findings of this study are available from the corresponding author, DP, upon reasonable request. Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted approval by the Institutional Review Board of the UTHSA (Date: 12/17/2019; No: 20190637HU). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. American Cancer Society Cancer Facts & Figures 2022 2022 Atlanta American Cancer Society 2. 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10.1007/s00520-022-07536-y

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==== Front Environ Sci Pollut Res Int Environ Sci Pollut Res Int Environmental Science and Pollution Research International 0944-1344 1614-7499 Springer Berlin Heidelberg Berlin/Heidelberg 24724 10.1007/s11356-022-24724-9 Energy, Environment and Green Technologies for the Future Sustainability Investigation of combustion and emission characteristics of an SI engine operated with compressed biomethane gas, and alcohols http://orcid.org/0000-0003-0788-215X Meena Pradeep Kumar pradeep_2k18phdme08@dtu.ac.in 1 Pal Amit 1 Gautam Samsher 2 1 grid.440678.9 0000 0001 0674 5044 Department of Mechanical Engineering, Delhi Technological University, Delhi, India 2 grid.510441.5 0000 0004 7705 4947 Harcourt Butler Technical University, Kanpur, India Responsible Editor: Philippe Garrigues 15 12 2022 111 8 9 2022 7 12 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Alternative fuels in spark-ignition engines significantly reduce engine exhaust emissions and improve fuel efficiency. This research investigates the performance of a multicylinder SI engine using 10%, 20% (ethanol, methanol, methyl acetate), and 100% compressed biomethane gas (CBG) as alternative fuels. Engine performance parameters (BTE, ITE, ME, BP), BSFC, ISFC, FF, combustion phenomenon (cylinder pressure, crank angle, cylinder volume, mass fraction burned, net heat release, mean gas temperature, cumulative heat release, rate of pressure rise), and emission characteristics (HC, CO, CO2, NOx) are measured. CBG achieved a maximum BTE of 23.33% compared to all other fuels. Minimum fuel consumption rate of 1.72 kg/h at maximum rpm achieved BSFC value of 0.44 kg/kWh and ISFC value of 0.261 kg/kWh. The highest cylinder pressure of 6.79 bar was achieved in the G90M10 with a cylinder volume of 48.58 cc. NHR of 3.08 j/deg was found in the G80M20 at a crank angle of 376°, and the maximum MGT was 390.20 °C in the G80E20. The highest CHR values of 0.12 kJ at crank angles of 432°, 420°, 422°, and 427° were achieved in the G100, CBG, G80E20, and G90E10. G90M10 reached a maximum value of 0.14 bar/degree of rate of pressure rise at a crank angle of 374°. Average minimum emission gas was found in CBG at a minimum and maximum RPM, indicating that CBG gives the best emission result with engine performance compared to all alternative fuels. Keywords Alcohols Engine performance CBG, Emission Biogas ==== Body pmcIntroduction The global economy has weakened following COVID-19. To compensate, gasoline and diesel prices steadily rise in practically all emerging countries. Due to the energy crisis, global warming, high fossil fuel costs, and rigorous emission rules, renewable oxygenated fuels have received greater attention in recent decades (Awad et al. 2018a), (Gülüm and Bilgin 2018). So, the globe is transitioning to a sustainable energy period, focusing on energy efficiency and renewable energy sources (Chauhan et al. 2010). In reality, fossil fuels remain the primary source of global energy, with global energy consumption expected to climb by around 33% by 2050 (Hosseini and Wahid 2013), (Saidur et al. 2011). In recent years, the hunt for alternative fuels that offer a harmonious relationship with sustainable development, energy-saving, efficiency, and environmental protection has intensified. Biofuels have the potential to provide a viable solution to the global petroleum dilemma. Automobiles that run on gasoline or diesel also substantially contribute to greenhouse gas emissions. Furthermore, the increasing number of circulating diesel and petrol cars accounts for roughly 20% of global greenhouse gas (GHG) emissions (Iodice et al. 2016), (Rajesh Kumar and Saravanan 2016). Energy policy, planning, and associated issues have become a significant public agenda item in most industrialized and developing countries in recent years. As a result, governments support using alternative fuels in automobile engines. Several alternative fuels, such as gasoline and diesel with natural gas (CNG/CBG), ethanol, methanol, methyl acetate, butanol, and hexanol, have been judged acceptable and cost-effective alternatives for conventional fuels based on these criteria. Because of their excellent physicochemical qualities, ethanol, methanol, butanol, methyl acetate, and other alcohols are essential renewable fuels when blended with pure gasoline among the renewable energies available for spark-ignition (SI) engines (Awad et al. 2018b). “Some of the experimental studies are as follows: Four-stroke spark-ignition engine, the effects of ethyl alcohol blended fuel with different blending ratios (10, 20, and 30% by volume) on engine performance and exhaust emissions were explored, and the results showed that combining ethanol with gasoline improves BTE and BSFC and lowers exhaust gas temperature, as well as lower CO and HC exhaust emissions, while NOx emissions are higher” (Vivek Pandey and Gupta 2016). As ethanol blends were utilized in lower quantities, engine torque increased by 2.31–4.16%, and BP increased by 0.29–4.77%, while BSFC increased when the ethanol percentage grew from 5.17 to 56.0% (Thakur et al. 2017). “Methanol (M5, M7.5, M10, M12.5, M15) was tested for the performance and combustion characteristics of a four-cylinder, four-stroke, spark-ignition engine (SI). According to the experiments’ results, adding methanol enhanced the engine’s performance. It was also discovered that increasing methanol concentration lowered CO and HC emissions while increasing CO2 and NOx emissions” (Shayan et al. 2011). In terms of methanol mixtures (0–15%), there has been a rise in gasoline octane rating, an increase in BTE and ITE, and a drop in knocking (Mallikarjun and Mamilla 2009). “When the compression ratio for the methanol/gasoline blend was increased from CR8 to CR10, the peak pressure and NHR value increased by 27.5% and 30%, respectively, at a speed of 1600 rpm. At a compression ratio of 10:1, the performance results demonstrate a good agreement of improvisation with a 25% rise in BTE and a 19% reduction in BSFC. CO and HC emissions were reduced by 30–40% at a more excellent compression ratio of 10:1, and the same trend was detected at all speeds; however, NOx emissions rose with increasing CR” (Nuthan Prasad et al. 2020), (Jhalani et al. 2021). “At varied loads of 104, 207, 311, and 414 kPa, methyl acetate is used in a single-cylinder spark-ignition engine, which is fueled with base gasoline, M5 (95% base gasoline + 5% methyl acetate), and M10 (90% base gasoline + 10% methyl acetate). According to these findings, adding methyl acetate to base gasoline boosts BSFC while lowering the engine’s BTE. Additionally, it was discovered that while methyl acetate does not significantly influence HC emissions, it did reduce CO and increase CO2. Adding methyl acetate to the NOx data showed a significant increase in NOx emissions” (Cakmak et al. 2018). Biogas (BG), also known as an alternative or renewable fuel, has been recommended to solve the problem since it has numerous advantages over natural gas, often utilized as a car fuel. BG is mainly a mixture of CH4 and CO2 and other gases formed in anaerobic conditions. Both agricultural and industrial wastes can be used to make BG (Holm-Nielsen et al. 2009), (Pradeep Kumar Meena and Sumit Sharma 2022). Removing CO2 and H2S from raw biogas and compressing pure biogas at high pressure can be used in the automobile sector and power generation (Larsson et al. 2016). Because CBG possesses qualities similar to CNG, biogas has a great potential to replace natural gas (Subramanian et al. 2013). Furthermore, biomethane might be compressed into a fuel tank as CBG for transportation fuel in a CNG vehicle, which is easy to store and reduces transportation expenses (D. Deublein 2008). “CBG was utilized in a multicylinder engine compared to CNG at 50% maximum load and engine speed (1500–3500 rpm). Results suggest that the engine run with CBG has higher thermal efficiency and reduced NOx and HC emissions. As a result, CBG fuel can replace CNG in spark-ignition engines as an alternate fuel” (Limpachoti and Theinnoi 2021). Many researchers have worked on alcohol fuels, but very little research has shown the effects of ethanol, methanol, and methyl acetate alcohols on engine performance and emissions. This research has used three types of alcohol fuels: ethanol, methanol, and methyl acetate mixed with 10% and 20% gasoline fuels and 100% CBG. So, here is a comparison of the performance and emission parameters of the multicylinder SI engine using four alternate fuels. Material and method Fuels properties In this experimental process, three types of alcohol blends of ethanol, methanol, and methyl acetate have been used with gasoline fuel, which is pure fuel up to 98–99%. It is a volatile, colorless liquid with a distinct aroma and flavor resembling alcohol. And by making BG from solid organic waste (fruit, vegetable wastes) and removing CO2 and H2S composition, pure biogas is compressed at 200 bar pressure and filled in a high-pressure bar cylinder. Different fuel properties of these fuels are given in Table 1.Table 1 Fuel properties (ethanol, methanol, methyl acetate, and CBG) Fuel properties Unit G100% E10% E20% M10% M20% MA10% MA20% CBG Chemical formula - C5-C12 C2H5OH C2H5OH CH3OH CH3OH C3H6O2 C3H6O2 CH4 Density at 40 °C kg/m3 721 734 735 723 736 737 757 0.90 Lower heating value MJ/kg 44 42.38 40.76 41.59 39.18 41.75 39.5 48.5 RON - 94.5 96.3 98.5 97.1 98.8 99.5 107.5 127 MON - 84.3 84.5 86.2 84.2 86.1 97.3 104.8 119 Stoichiometric air/fuel ratio - 14.8 14.3 13.5 14.1 13.3 13.9 13.1 17.2 Reid vapor pressure at 38 °C - 55.7 56.3 57.1 94.5 95.8 54.2 52.7 - Flash point °C - 26.3 30.5 29.8 28.2 27.5 21.5 18.1 - Fire point °C - 25.1 28.9 29.7 29.9 31.5 28.3 31.48 - Methane (CH4) % - - - - - - - 96.6 Hydrogen sulfide (H2S) % - - - - - - - 0.0 ppm O2 % - - - - - - - 0.4 CO2 % - - - - - - - 3.0 Experimental setup Experimental setup used is a Maruti Wagon R with a maximum power of 47.70 kW @ 6200 rpm. It is a four-cylinder, four-stroke, variable speed, water-cooled, and petrol engine, whose details are given in Table 2. Various alcohols such as ethanol, methanol, and methyl acetate have been tested by mixing 10% and 20% (G90E10, G80E20, G90M10, G80M20, G90MA10, G80MA80) with gasoline. Gasoline and alcohol blend readings were taken in a burette tube at an interval of 60 s. Experiment data has been taken by setting the load from the dynamometer to 4 kg and varying the speed from 2000 to 4500 rpm. And pure CBG has also been studied on the same parameters. Using CO2 and H2S scrubbers to purify the raw biogas, pure biogas, i.e., up to 96.6% CH4, is obtained, whose composition is checked with a biogas analyzer.Table 2 Details of experimental setup Engine specification Details Stroke length 72.00 (mm) Cylinder bore 68.50 (mm) Connecting rod length 112.50 (mm) Compression ratio 9.2:1 Swept volume 265.34 (cc) Engine type Maruti Wagon R 4 strokes 4 cylinders No. of cylinders 4 Maximum power output at 6200 rpm 47.70 kW Cooling system Water cooling close system Orifice diameter 40 mm Dynamometer arm length 210 mm Fuel pipe diameter 33.90 mm Number of cycles 10 For use, the CBG is fed into a high-pressure cylinder using a compressor. For safety features, a gas stop valve, pressure gauge, gas conversion kit, and gas filter have also been installed, which are shown in Fig. 1b. During the experiment, water is supplied from cooling waters used to cool the engine setup, whose flow is adjusted by rotameters. Compression studies of gasoline, alcohol blends, and CBG fuels have been performed. The resulting combustion parameters include cylinder pressure, rate of pressure rise, mass fraction burned, pressure volume, net heat release, mean gas temperature, and cumulative heat release. Thermal efficiencies, BSFC, ISFC, etc., have been studied in performance parameters. All experimental data was saved from the NI unit to the computer with the help of IC Engine software, shown in Fig. 1a. Apparatus used for studying these fuel blends and the different properties of CBG are given in Table 1. CO2, CO, HC, and NOX gases from the AVL emission apparatus were also checked (Table 3).Fig. 1 a Experimental setup with parameters measuring instruments. b Schematic diagram of experimental setup Table 3 Apparatus used during experiment Apparatus Name of the company Biogas analyzer OX-300B, Nunes Instruments Biogas compressor Italy tech Viscometer Anton Paar Junkers calorimeter H. L. Scientific Industries Emission gas analyzer AVL Results and discussion Engine parameters have been studied at 4 kg constant load and different speeds. Given below are various parameters such as engine performance (BP, BTE, ITE, ME), BSFC, ISFC, FF, and combustion phenomena (cylinder pressure, crank angle, crank angle, cylinder volume, mass fraction burned, NHR, mean gas temperature, cumulative heat release, rate of pressure rise) and emission parameters (HC, CO, CO2, NOX) have been studied. Engine performance Figure 2a shows that at a constant load of 4 kg, the engine speed was 2000 rpm, and the brake power value was 1.73 kW; at that time, the highest brake thermal efficiency of 23.33% CBG was achieved. Compared to gasoline, CBG has a higher octane rating and more excellent knock resistance. CBG burns more efficiently than gasoline or diesel, and very little of it remains unburned. As a result, engines designed explicitly for CBG have more excellent compression ratios and hence higher stated efficiency. BTE of CBG from a minimum rpm of 2000 to a maximum rpm of 4500 was superior than the other fuels. G100 fuel had a BTE value of 21.76% at 2000 rpm, and the highest BTE value of 17.28% in the alcohol fuel was obtained in the G80E20, and the lowest value was 13.25% in the G90M10. At a maximum of 4500 rpm, the BTE value of CBG was 16.76%, 15.63% for G100, and 14.69% for G90M20. Alternative fuels G90M20, G80MA20, and CBG have BTE values higher than the G100 at 2500 and 3000 rpm, meaning all these alternative fuels have the potential to replace gasoline fuels. Similarly, in a study, BTE values of G90E10 and G80E20 and G70E30 blends in a four-stroke engine at 2000 to 3000 rpm were found to be 16.2%, 18.9%, and 21.2% (Vivek Pandey and Gupta 2016). The BTE value of methanol blend G88M12% is achieved at 18.5% at 2000 rpm, 21.5% at 2500 rpm, and 23.5% at 3000 rpm (Mohammed Kamil and Ibrahim Thamer Nazzal 2016). G90MA10 blend at constant 1500 rpm has achieved BTE values ranging from 10 to 28% at effective pressure (104 to 414 kPa) (Cakmak et al. 2018).Fig. 2 a Brake thermal efficiency, brake power varies w.r.t Speed. b Indicated thermal efficiency, brake power varies w.r.t speed. c Mechanical efficiency, brake power varies w.r.t speed Figure 2b shows that at 2000 rpm, the maximum value of ITE was achieved at 48.52% in G100, 38.65% in alcoholic fuel (G80E20), and 31.09% in CBG. CBG has a higher calorific value than gasoline and alcohol fuel, and the fuel flow rate is also higher at minimum rpm and constant load. Hence, the value of ITE at low speed was lower in CBG. At a maximum of 4500 rpm, the highest ITE value was obtained in CBG at 28.35%, G100 gained 17.8%, and the ITE value in the alcohol fuel (G90M20) was reached at 16.64%. As the rpm increases from 2000 to 4500, the value of ITE decreases in G100 and other alcohol blends, but the value of ITE in CBG has increased compared to other fuels. At higher speeds, CBG consumes less fuel rate than other fuels, due to which the value of ITE was found to be higher in CBG at higher speed. In Fig. 2c, CBG has less friction loss at low rpm than other fuels, and the difference between indicated power and brake power is less. Hence, the value of ME (75.04%) at low rpm was found to be higher in CBG. And as the speed increases, the friction loss also increases in CBG, so the ME value is found to be less at higher rpm than in other fuels. In contrast, the friction loss in gasoline and alcohol blends decreases, so the ME value was lower in CBG and higher in gasoline and alcohol blends. Brake specific fuel consumption (BSFC) and indicated specific fuel consumption (ISFC) Figure 3a shows that in the alcohol G90M10, the highest FF value was obtained at 1.13 kg/h at 2000 rpm, and the G100 value was 0.65 kg/h. The lowest FF value at the lowest rpm was 0.88 kg/h and 0.55 kg/h in G80E20 blends and CBG, respectively. Fuel ITE with a higher flow rate will have higher BSFC and lower BTE value. In BSFC at 2000 rpm, G100 found 0.38 kg/kWh; the lowest BSFC value in the alcohol blend was 0.51 kg/kWh in the G80E20 and the highest at 0.97 kg/kWh in the G90MA10. A value of 0.32 kg/kWh was achieved in CBG, the lowest value among all the fuels overall, due to which the BTE value of CBG was achieved the highest. At the maximum rpm, i.e., at 4500 rpm, the value of FF in the G100 is 2.03 kg/h. The lowest value of 2.29 kg/h in alcohol blends is found in G90E10, and the highest is 2.5 kg/h in G80MA20. FF in the CBG value is obtained at 1.72 kg/h, which is the lowest compared to other fuels. At same rpm, the BSFC in CBG was 0.44 kg/kWh, while the G100 got 0.52 kg/kWh and G90M10 and G90MA10 got 0.6 kg/kWh. CBG consumes less fuel than other fuels at higher engine speeds, thereby increasing the engine’s efficiency. Gasoline, G90E10, and G80E20 at 2000 to 2500 rpm have BSFC values in the range of 0.375 to 0.4 kg/kWh. As the RPM increases, the value of BSFC will also increase to a limit (Vivek Pandey and Gupta 2016). The BSFC value in G88M12 blends from 2000 to 3000 rpm has been found in the range of 0.42 to 0.4 kg/kWh (Mohammed Kamil and Ibrahim Thamer Nazzal 2016). At constant 1500 rpm and brake mean effective pressure (104 to 414 kPa), the MA5 and MA10 have obtained BSFC values between 0.9 and 0.3 kg/kWh (Cakmak et al. 2018).Fig. 3 a Fluid flow, brake specific fuel consumption varies w.r.t speed. b Fluid flow, indicated specific fuel consumption varies w.r.t speed In Fig. 3b, the ISFC value in the G100 was achieved at the minimum speed, i.e., 0.168 kg/kWh at 2000 rpm. Among alcoholic fuels, the IFSC was found to be 0.293 kg/kWh at the highest FF value in G90M10. The IFSC value of 0.228 kg/kWh was obtained in G80E20 at the lowest value of FF. CBG had the lowest value of FF compared to other fuels, while IFSC had a value of 0.239 kg/kWh. IFSC value at 4500 rpm in G100 was found to be 0.461 kg/kWh. In alcohol fuel G80MA20, the IFSC value was found to be 0.568 kg/kWh at the maximum FF value. IFSC value of 0.261 kg/kWh in CBG at maximum rpm was obtained, which was the lowest fuel consumption among all the fuels. Combustion phenomenon Figure 4a shows the start of burning (SOB) fuel in G100 and alcohol fuel when cylinder pressure is between 3 and 4 bar, and the crank angle is 335° before TDC. In CBG, SOB starts when cylinder pressure is 4.25 bar, and crank angle is 335° before TDC.Fig. 4 a Cylinder pressure vs crank angle, b cylinder pressure vs cylinder volume, c mass fraction burned vs crank angle Experimental setup for CBG testing is started on gasoline fuel; when the engine cylinder pressure reaches 4 bar, SOB is started on CBG fuel. So, in gasoline and alcohol blends, the SOB starts above 3 bar pressure, while in CBG, the SOB starts above 4 bar pressure. The SOB of a 100% gasoline and all alcohol mixture is started between 3 and 4 bar/335°. Whereas in the case of CBG, it began at 4.25 bar/335°, as the engine has to run at a higher speed than pure gasoline before running on CBG fuel, the cylinder pressure value also increased in the case of CBG. Cylinder pressure is calculated by taking an average of 10 cycles for each fuel. Ten percent fuel burn in all fuels starts just after TDC when cylinder pressure is 6 to 6.5 bar at a crank angle of 375°, and 90% fuel burn occurs in all fuels when cylinder pressure is 5 to 5.75 bar, and the crank angle is 415°. Maximum cylinder pressure was up to 6.79 and 6.76 bar, respectively, in the G90M10 and G90M20, and the lowest cylinder pressure achieved was 5.54 bar in the G80MA20 fuel when the crank angle was 385° after TDC. Maximum cylinder pressure in CBG is 6.06 bar at a 377° of crank angle after TDC, and its end-of-burning (EOB) fuel starts when cylinder pressure reaches 2.75 bar at a crank angle of 415° after TDC. In G100 and other alcohol fuels, when the cylinder range gets 1.25 bar at a crank angle of 450° after TDC, EOB starts in these fuels. CBG completes the EOB cycle earlier than gasoline, and alcohol blends because unburned particles are negligible in CBG, and the combustion cycle ends earlier. Whereas gasoline and alcohol blends contain more unburned particles, their EOB cycle is longer than CBG. In Fig. 4b, the highest cylinder pressure value was found at 6.79 bar in the G90M10 when the cylinder volume was 48.58 cc, and in the G90M20, with a cylinder volume of 49.86 cc, the pressure value was 6.76 bar. Maximum cylinder pressure in G100 was 5.84 bar when the cylinder volume was 49.86 cc, and in CBG, the maximum pressure was 6.06 bar at a cylinder volume of 39.97 cc. Among all the fuels, the G80MA20 raised the lowest cylinder pressure to 5.54 bar when the cylinder volume value was 46.15 cc. Piston advances from TDC to BDC with the intake valve already open. As the piston completes its stroke, the volume keeps growing. When the piston is at BDC, the maximum volume is attained. Because the piston action creates volume and the vacuum effect draws air into the cylinder, the pressure is below atmospheric pressure throughout the stroke. Compression stroke starts once the piston has passed BDC. Volume begins to fall, and the pressure rises during this phase. Intake valve is still open even after the piston has passed BDC because it takes some time for the pressure inside the cylinder to exceed the pressure outside. Pressure progressively rises as the piston approaches TDC. When the ignition is started, the pressure increases until it reaches its peak. Since the cylinder’s high pressure pushes the piston, the volume increases, and the pressure gradually decreases. Piston is back at the BDC after the power stroke. Once more, the cylinder’s volume is at its maximum value, and its pressure is similar to the atmosphere. Cumulative heat release to total heat release ratio is known as MFB. Apparent heat release can be roughly calculated if the MFB is known as a function of crank angle. Value of MFB in CBG was lower than in gasoline and alcohol, as there is complete combustion in CBG. In Fig. 4c, before TDC, at a crank angle of 165 to 124°, G100 and alcohol fuel are just fuel-burning, whereas, in CBG, combustion starts when the crank angle is 89°. G100 and alcohol blends have a 5% MFB crank angle at 138.2 to 108.82° before TDC, while the CBG has this value at 79.55°. And when the crank angle is 138 to 93.76° before TDC, the G100 and alcohol blends burn 10% of the fuel, while the CBG burns when the crank angle is 67.27°. Fifty percent of MFB was found in G100 and rest alcohols at 9.08 to 2.91° after TDC, whereas in CBG, it was located at 16.95°. After TDC, 90% of MFB was detected in G100 and the rest in alcohols at 38.85 to 28.26°, while CBG was found at 38.16°. EOB in G100, alcohol blends, and CBG were located at 71 to 28.26° after TDC. Conversion of chemical energy from the reactants in the charge into thermal energy is measured by the NHR profile, which is estimated from the cylinder pressure trace. Heat and mass transfer are not taken into account by the NHR profile. As shown in Fig. 5a, the maximum NHR value of the average ten cycles in the G100 was 2.47 j/deg at a crank angle of 387°; similarly, the CBG averaged an NHR value of 2.41 j/deg at a crank angle of 388°. And the highest NHR value among alcohol blends was 3.08 j/deg at a crank angle of 376° in the G80M20 mixture. NHR value of the average cycle across all fuels was the highest at a crank angle of 376 to 388°. Figure 5b shows that the maximum mean gas temperatures in G100, G80E20 alcohol blends, and CBG with crank angles of 412°, 406°, and 411° were 384.2 °C, 390.20 °C, and 388.17 °C, respectively. The lowest MGT, 324.97 °C, was achieved in the G80MA20 at a 406° of crank angle. CBG and alcohol fuels are highly flammable as compared to gasoline fuels. In addition to raising exhaust gas temperature and having a slower flame propagation speed than gasoline, CBG also has a higher auto-ignition temperature than other fuels. Therefore, CBG and alcohols G100E80 were found to have higher MGT values. In Fig. 5c, the highest CHR values of 0.12 kJ were found in the G100, CBG, G80E20, and G90E10 at crank angles of 432°, 420°, 422°, and 427°, respectively. And the lowest CHR value of 0.10 kJ is found in G80MA20 and G90MA10 at the crank angles of 419° and 418°. Due to CBG and ethanol blends are highly inflammable, the flame consumes the unburned mass. Hence, the maximum value of CHR was found in these fuels, whereas in methyl acetate, it got a minimum value of CHR due to low flame.Fig. 5 a Net heat release vs crank angle. b Mean gas temperature vs crank angle. c Cumulative heat release vs crank angle. d Rate of pressure rise vs crank angle Figure 5d shows that the G100, CBG, and G90M10 had maximum RPRs of 0.12, 0.13, and 0.14 bar/degree at 344°, 348°, and 374° of crank angles, respectively. At 344° and 346° of crank angles, the lowest RPR value of 0.11 bar/degree was achieved in G90MA10 and G80MA20. Gasoline, CBG, and methanol blends found the most significant increase in gas pressure during combustion, due to which the RPR value was higher in these fuels. Methyl acetate was found to have the lowest pressure increase during combustion, due to which the value of RPR was found to be the lowest in these blends. Emission characteristics Figure 6a presents that at 2000 rpm, the highest 20% and 22% CO2 were obtained in the blends G90M10 and G90M20, respectively, and the lowest 3% was obtained in CBG. And at the highest 4500 rpm, G100 and G80M20, CO2 yielded were 13% and 21%, respectively, while CBG produced 6% CO2, which means CBG green energy is considered the best alternative fuel of all fuels. Atoms of carbon and hydrogen constitute gasoline. CO2 is created during combustion when oxygen is from the air and carbon from the fuel mix (CO2). Similarly, in methanol bands and gasoline, the value of CO2 has increased from the minimum speed to the maximum speed, which means that the CO2 emission from methanol blends increases. Due to its low carbon content, CBG burns more cleanly than petroleum-based products. In addition, compared to gasoline and alcohol fuels, CBG emits 10 to 15% less CO2. Maximum amount of CO is due to the burning of G100 fuel, which causes environmental pollution. In Fig. 6b, from the lowest speed to the highest speed, the maximum amount of CO was found in G100, from 1.64 to 2.63%.Fig. 6 a Carbon dioxide vary w.r.t speed. b Carbon monoxide vary w.r.t speed. c Nitrogen oxide vary w.r.t speed. d Hydrocarbon vary w.r.t to speed The highest CO content of 1.45 to 1.08% was found in G90E10 among alcohol blends, and the lowest CO content at the highest speed was 0.232% in CBG. Due to incomplete combustion, a lack of oxygen, inadequate mixing, or all three, gasoline fuel was discovered to have a high CO content. Alcohol benefits engine performance and lowers exhaust since it has a high vaporization heat, octane number, and flammability temperature. Because alcohol is an oxygenate, meaning its molecules include oxygen, it burns efficiently and CO emissions are thus decreased. To assist the alcohol burn thoroughly, the oxygen atoms within it interact with the oxygen molecules in the surrounding air. When combined with alcohol, this extra oxygen makes gasoline burn more efficiently. Due to the low oxygen gas concentration in CBG, relatively little CO gas is generated. As shown in Fig. 6c, the NOX value in fuel G100 and alcohol blends G90M10 and G80M20 was found to be 225 and 1425 PPM at a minimum of 2000 rpm, while in CBG, its value was found to be 70 PPM. At maximum rpm, G80E20, G80MA20, and G100 have NOX values of 2050, 1775, and 1275 ppm, respectively, while CBG has achieved 1125 ppm at the highest RPM, which means CBG emits the lowest NOX from gasoline and other alcohol fuels and pollutes the environment less. Because engine speed affects NOx emissions, when engine speed increases, more fuel is used, temperatures rise, and NOx emissions increase. During combustion, nitrogen is oxidized to NOx. Fuel burns more in the gasoline and alcohol band, which increases combustion temperature, cylinder pressure, and heat release, due to which these fuels were found to have higher NOx values ​​. In contrast, CBG had lower fuel consumption, allowing the engine performance increases, and NOx is also emitted less. Figure 6d shows that the HC values at minimum speed were 265, 258, and 238 PPM, respectively, in G100, G90M10, and CBG. And the HC values at maximum speed were 110, 115, and 65 PPM in the G90MA10, G80MA20, and CBG, respectively. Gasoline and alcohol blends have higher hydrocarbon emissions because the fuel does not burn entirely at low speeds. As the speed of the engine increases, the fuel starts burning well, so the value of HC is obtained less in all the fuels at higher rpm. CBG fuel burns well at minimum RPM to maximum RPM, due to which the HC value in CBG is rarely achieved at all RPMs. In a study found, CO2 values are ranging from 11 to 13% in gasoline at 2000 to 5000 rpm, CO values are ranging from 1.5 to 4.5%, and HC values are ranging from 180 to 450 ppm (Geok et al. 2009). Blends G85M15 and G70M30 at 2000 to 4000 rpm yielded CO values ranging from 0.14 to 0.06%, CO2 in the range of 13.5 to 14.8%, and HC values ranging from 150 to 90 ppm (Shayan et al. 2011). The CO values ranged from 0.5 to 0.75% in blends G90E10 and G80E20 at 2000 to 4500 rpm, and HC values ranged from 145 to 65 ppm (Iodice and Cardone 2021). The CO2 values ranged from 12.5to 13.75% in blend G75E25 at 2000 to 4500 rpm, and the NOx values ranged from 800 to 600 ppm (Thangavelu et al. 2015). In methyl acetate blends G95MA5 and G90MA10, CO values ranged from 0.3 to 3.8% at constant 1500 rpm, while HC values ranged from 80 to 170 ppm and CO2 values ranged from 10.5 to 13% (Cakmak et al. 2018). Conclusion At a constant load of 4 kg, from a minimum speed of 2000 rpm to a maximum speed of 4500 rpm, the FF rate (0.55–1.72 kg/h and BSFC 0.32–0.44 kg/kWh) in CBG fuel has been achieved, which is the lowest compared to gasoline and alcohol fuel blends, resulting in the highest BTE value in CBG at 23.33%. At a cylinder volume of 39.97 cc, the CBG achieved the highest cylinder pressure of 6.06 bar, and the G80MA20 achieved the lowest cylinder pressure of 5.54 bar among all fuels when the cylinder volume was 46.15 cc. At lower rpm, friction loss is higher in G100 and alcohol blends and lower in CBG, resulting in higher ME (75.05%) in CBG at lower rpm. SOB started at all fuels when the crank angle was 335°, and the cylinder pressure was between 3 and 4.50 bar. Its end-of-burning (EOB) began when the crank angle was 415° after TDC. Ninety percent mass of fraction burned in G100, alcohol blends, and CBG fuel after TDC was found at 38.85 to 28.26° of crank angle. In contrast, the EOB mass fraction was between 71 and 28.26° after TDC. All alcohol blends have different properties due to their various characteristics, resulting in the G80M20 having an NHR value of 3.08 j/deg at a crank angle of 376°, which was higher than the NHR values for all fuels. The maximum mean gas temperature value in the G80E20 blends was achieved at 390.20 °C at a crank angle of 406 °C. At 432°, 420°, 422°, and 427° of crank angles, the G100, CBG, G80E20, and G90E10 achieved the highest CHR values of 0.12 kJ. The value of CO2, CO, HC, and NOx emission gases in CBG at minimum speed to maximum speed is deficient compared to other fuels. Due to the low carbon content in CBG, it less pollutes the environment than gasoline and alcohol fuels. And it burns cleaner than petroleum-based products. Therefore, CBG fuel is also the best solution for solid organic waste, is the best alternative to gasoline fuel, and is eco-friendly. Our results suggest that CBG has the best results among all fuels in terms of engine performance, combustion, and emissions. Acknowledgements The authors would like to thank Dr. Anil Kumar for his support in editing this research and the Delhi Technical University Administration for their valuable support. Author contribution All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Pradeep Kumar Meena, Amit Pal, and Samsher Gautam. The first draft of the manuscript was written by Pradeep Kumar Meena, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability Not applicable. Declarations Ethical approval As authors, we would like to tell you that this is our original work, and this paper has not been submitted anywhere except in this journal. Consent to participate Not applicable. Consent for publication Not applicable. Conflict of interest The authors declare no competing interests. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Awad OI Mamat R Ali OM Alcohol and ether as alternative fuels in spark ignition engine: a review Renew Sustain Energy Rev 2018 82 2586 2605 10.1016/j.rser.2017.09.074 Awad OI Mamat R Ibrahim TK Overview of the oxygenated fuels in spark ignition engine: environmental and performance Renew Sustain Energy Rev 2018 91 394 408 10.1016/j.rser.2018.03.107 Cakmak A Kapusuz M Ganiyev O Ozcan H Effects of methyl acetate as oxygenated fuel blending on performance and emissions of SI engine Environ Clim Technol 2018 22 55 68 10.2478/rtuect-2018-0004 Chauhan BS Kumar N Du Jun Y Lee KB Performance and emission study of preheated Jatropha oil on medium capacity diesel engine Energy 2010 35 2484 2492 10.1016/j.energy.2010.02.043 D Deublein AS (2008) Biogas from Waste and Renewable Resources. Wiley-VCH Verlag GmbH & Co KGaA, Weinheim, Germany Geok HH, Mohamad TI, Abdullah S et al (2009) Experimental investigation of performance and emissions of a sequential port injection compressed natural gas converted engine. SAE Tech Pap Gülüm M Bilgin A A comprehensive study on measurement and prediction of viscosity of biodiesel-diesel-alcohol ternary blends Energy 2018 148 341 361 10.1016/j.energy.2018.01.123 Holm-Nielsen JB Al Seadi T Oleskowicz-Popiel P The future of anaerobic digestion and biogas utilization Bioresour Technol 2009 100 5478 5484 10.1016/j.biortech.2008.12.046 19217772 Hosseini SE Wahid MA Feasibility study of biogas production and utilization as a source of renewable energy in Malaysia Renew Sustain Energy Rev 2013 19 454 462 10.1016/j.rser.2012.11.008 Iodice P Cardone M Ethanol/gasoline blends as alternative fuel in last generation spark-ignition engines: a review on co and hc engine out emissions Energies 2021 14 4034 10.3390/en14134034 Iodice P Senatore A Langella G Amoresano A Effect of ethanol–gasoline blends on CO and HC emissions in last generation SI engines within the cold-start transient: an experimental investigation Appl Energy 2016 179 182 190 10.1016/j.apenergy.2016.06.144 Jhalani A Sharma D Soni S Feasibility assessment of a newly prepared cow-urine emulsified diesel fuel for CI engine application Fuel 2021 288 119713 10.1016/j.fuel.2020.119713 Larsson M Grönkvist S Alvfors P Upgraded biogas for transport in Sweden - effects of policy instruments on production, infrastructure deployment and vehicle sales J Clean Prod 2016 112 3774 3784 10.1016/j.jclepro.2015.08.056 Limpachoti T, Theinnoi K (2021) The comparative study on compressed natural gas (CNG) and compressed biomethane gas (CBG) fueled in a spark ignition engine. 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Scrivener Publishing, pp 277–343 Rajesh Kumar B Saravanan S Use of higher alcohol biofuels in diesel engines: a review Renew Sustain Energy Rev 2016 60 84 115 10.1016/j.rser.2016.01.085 Saidur R Abdelaziz EA Demirbas A A review on biomass as a fuel for boilers Renew Sustain Energy Rev 2011 15 2262 2289 10.1016/j.rser.2011.02.015 Shayan SB Seyedpour SM Ommi F Impact of methanol – gasoline fuel blends on the performance and exhaust emissions of a SI engine Int J Automot Eng 2011 1 219 227 Subramanian KA Mathad VC Vijay VK Subbarao PMV Comparative evaluation of emission and fuel economy of an automotive spark ignition vehicle fuelled with methane enriched biogas and CNG using chassis dynamometer Appl Energy 2013 105 17 29 10.1016/j.apenergy.2012.12.011 Thakur AK Kaviti AK Mehra R Mer KKS Performance analysis of ethanol–gasoline blends on a spark ignition engine: a review Biofuels 2017 8 91 112 10.1080/17597269.2016.1204586 Thangavelu SK Chelladorai P Ani FN Emissions from petrol engine fueled gasoline-ethanol-methanol (GEM) ternary mixture as alternative fuel MATEC Web Conf 2015 27 2 5 10.1051/matecconf/20152701010 Vivek Pandey, Gupta VK (2016) Technical assessment of performance emission characteristics of an SI engine using ethanol-gasoline blended fuel. 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==== Front Oper Manag Res Operations Management Research 1936-9735 1936-9743 Springer US New York 328 10.1007/s12063-022-00328-x Article Two years of COVID-19 pandemic: Understanding the role of knowledge-based supply chains towards resilience through bibliometric and network analyses http://orcid.org/0000-0002-0353-1849 Majumdar Abhijit majumdar@textile.iitd.ac.in 1 Agrawal Rohit mailerrohit@gmail.com 2 Raut Rakesh D. rraut@nitie.ac.in 3 Narkhede Balkrishna E. benarkhede@nitie.ac.in 3 1 grid.417967.a 0000 0004 0558 8755 Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, India 2 Operations Management and Quantitative Techniques, Indian Institute of Management, Bodh Gaya, India 3 grid.462559.9 0000 0004 0502 6066 Operations and Supply Chain Management, National Institute of Industrial Engineering (NITIE), Mumbai, Maharashtra India 15 12 2022 117 7 4 2022 9 7 2022 22 9 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Coronavirus disease (COVID-19) catastrophically disrupted most of the global supply chains (SC). Knowledge-based SC can cope with the pandemic disruptions by the efficient use of data, information, knowledge, human intelligence and emerging technologies. This article aims to critically analyse the SC research during the two years of COVID-19 pandemic to understand the role of knowledge-based supply chain towards SC resilience. A review of the 281 shortlisted articles is presented, along with bibliometric and network analyses in order to create an intellectual map of the domain and to identify the emerging knowledge themes. Bibliometric analysis reveals that the knowledge focus during this short span has migrated from COVID-19 pandemic to SC risk management and finally to risk mitigation strategies. The network analysis identifies five emerging knowledge themes, namely impact of COVID-19 on SC; SC risk mitigation and resilience; supply chain viability; sustainable SC strategies; and food SC. This review also elucidates the strategies to mitigate COVID-19 disruptions for incorporating resilience in SC. Future research directions for a knowledge-based sustainable-leagile-resilient (S-leagilient) supply chain have also been propounded. Keywords Bibliometric analysis COVID-19 pandemic Digitisation, Knowledge-based supply chain: network analysis Supply chain resilience Supply chain strategies ==== Body pmcIntroduction The coronavirus disease (COVID-19) was first identified in Wuhan city of China in October 2019. In March 2020, the spread of the virus was so pervasive that the COVID-19 was declared as a global pandemic by WHO (Grinberga-Zalite et al. 2021; Ortiz-Barrios et al. 2021). As of 30th October 2022, 635.37 million COVID-19 positive cases were detected, causing 6.59 million deaths across the world. Most of the countries declared stringent lockdown at different places, specially at markets, malls etc., which led to significant disruption in the supply chain (SC). All businesses faced gigantic challenges due to these unprecedented happenings (Zarghami 2021). Vulnerabilities faced by SC were caused by lack of supply of raw materials and components, demand fluctuations, disruption in the network, non-availability of different modes of transportation (Deshpande et al. 2022). According to a report published in Fortune magazine, among the fortune-1000 companies, 94% reported disruption in their SC (Chowdhury et al. 2021; Ivanov and Dolgui 2021). On the other hand, few supply chains like medicine, personal protective equipment (PPE), facemask, oximeter, and ventilator saw a massive rise in demand (Hu 2022; Omar et al. 2022). Moreover, supply, transportation, and logistics were severely affected because of the closure of international borders, lockdown in countries, restrictions in vehicle movement, shortages of labour, and, most importantly, maintaining social distancing with others (Chowdhury et al. 2021). SC risk management has become a prominent research area in the last two decades (Ivanov and Dolgui 2021). However, COVID-19 pandemic showed some unprecedented disruptions in demand and supply. Due to these debilitating impacts of COVID-19 on SC, the financial market and economy nosedived in many countries, and even the World Trade Organisation announced that the global trade may decrease by about 13–32% (WTO 2020). Looking at the severe impacts of the COVID-19 pandemic on the various activities of SC, researchers renewed their focus towards enhancing the SC capabilities and resiliency to deal with the present and future pandemics (Hosseini et al. 2016; Lusiantoro and Pradiptyo 2022). As a result, a huge proliferation of research articles focussing on SC disruptions during COVID-19 was seen. One of the ways to incorporate resilience in SC is to imbibe the philosophies of a knowledge-based SC that relies on data, information, knowledge, intelligence and uses the advanced technologies like artificial intelligence, machine learning and Industry 4.0 (Frederico et al., 2020). It is imperative for the traditional SCs to transform to knowledge-based SCs so that the untoward consequences of disruptions can be mitigated. Taking cognisance of the disruptions that happened in the SC during COVID-19, many researchers worked on identifying the role of knowledge-based supply chains on resilience. A few review articles are already available on the impact of COVID-19 on SC to map the scientific literature of this domain (Queiroz et al. 2020; Verma and Gustafsson 2020a; Chowdhury et al. 2021; Montoya-Torres et al. 2021; Pujawan and Bah 2021; Cordeiro et al. 2021). Most of these articles present systematic literarture review concentrating on limited number of articles (Queiroz et al. 2020; Chowdhury et al. 2021; Pujawan and Bah 2021) while some others have used bibliometic analysis (Cordeiro et al. 2021). Verma and Gustafsson (2020b) used network analysis based on co-words only whereas Montoya-Torres et al. (2021) used co-occurrence of author keywords to determine major themes of research articles published in 2020. A glance at the aforesaid reviews show that the articles published till the end of 2020 have been covered. This review extends the temporal span of the analysis by including articles published till the end of 2021. Moreover, use of network analysis has been done sparingly; and mapping of emerging knowledge themes with the aid of bibliographic coupling is still missing in existing reviews. As the knowledge themes during this turbulant phase are transitory in nature, it is important to redraw the pattern of scientific literature more frequently. From the ongoing discussion, we posit three research questions and attempt to answer these through our research: RQ1. What are the trends of SC research during COVID-19? RQ2. What are the emerging knowledge themes of SC research during COVID-19? RQ3. What strategies should be adopted in a knowledge-based SC to cope with pandemic disruptions? To answer the aforesaid research questions, this article presents a review of literature, published till the end of 2021, using bibliometric and network analyses. SCOPUS database was considered to identify the articles. A set of 281 articles were shortlisted based on the selected keywords and inclusion/exclusion criteria. Bibliometric and network analyses were performed to create an intellectual map and to identify emerging knowledge themes in this domain. Finally, future research directions are presented to attain a knowledge-based sustainable-leagile-resilient (S-leagilient) SC. Rest of this article is arranged as follows. Section 2 presents the methodology adopted. Section 3 elucidates the results of bibliometric analysis, followed by the results of network analysis in section 4. Section 5 explains the emerging knowledge themes. The discussion on mitigation strategies, managerial implications and future research directions has been elaborated in section 6. Finally, section 7 presents the conclusion. Methodology A systematic literature review (SLR) attempts to answer some specific research questions pertaining to a research field. It enables understanding of the considered field without any bias and provides information about the past and current research work done. It also enables propositions for future research directions. The main aim of a literature review is to identify research gaps by investigating published articles, which further helps in enhancing the scientific body of knowledge in the considered field. This study uses the SLR methodology as shown by (Sharma et al. 2020c). The flow chart used in the SLR methodology is presented in Fig. 1. It starts with selecting suitable keywords in the relevant field, identifying and shortlisting essential articles, and then reviewing shortlisted articles. Fig. 1 The flowchart of analysis Database selection In this work, research articles were analysed in the SC domain in COVID-19. SCOPUS database was considered to identify and shortlist the research article in the selected field. The reason for considering the SCOPUS database is, it has the most extensive database, which includes articles from almost all reputed publishers (IEEE, Elsevier, Emerald insights, Wiley, Springer, Tailor and Francis, and many more). While Web of Science covers 24,952 journals (Web of Science 2020), SCOPUS encompasses 39,237 journals (SCOPUS 2022). Keywords selection The article explores the research work in the field of the SC during COVID-19. The selection of keywords is an essential aspect of selecting relevant articles in the considered field. The considered keywords were fed to the SCOPUS database by using Boolean expression: TITLE (“Supply chain” AND COVID). Inclusion and exclusion of articles This study included only peer-reviewed research and review articles published till December 2021 in the field of SC in COVID-19. Articles written only in the English language were considered in this study. This study excluded conference papers, book chapters, and Erratum because they do not have a stringent peer-review process. Using the keywords and inclusion and exclusion criteria, a set of 281 articles were identified to be considered for this review. Bibliometric analysis This section attempts to address the RQ1 through bibliometric analysis. Bibliometric analysis helps to analyse the statistics of published articles in the considered field. The bibliometric analysis shows the data pertaining to authors, journals, articles, keywords, collaboration networks, country statistics, and so on. Researchers have used various packages to perform the bibliometric study, namely CiteSpace, HistCite, BibExcel, and R package (Sharma et al. 2020c). As the R package is open-source software with an excellent web interface to analyse bibliometric data, it was used in this research to perform the bibliometric analysis. In this study, publication trends, important journals, prolific authors, impactful articles, frequently occurring keywords have been identified to frame an intellectual map of SC research in COVID-19. Publication trends The yearly trend of published articles is presented in Fig. 2. It can be seen from the figure that research started in 2019, where Indonesian researchers published the first article. They emphasised the SC of drug delivery during the COVID-19 scenario. From 2020 to 2021 (till October), a hopping growth (163%) in terms of research articles has been observed. Fig. 2 Year-wise statistics of articles on SC in COVID-19 Top contributing journals The leading journals in the field of the SC in COVID-19 are shown in Table 1. The leading journal publishing articles in the SC during COVID-19 is Sustainability (Switzerland) with 16 articles, followed by International Journal of Logistics Management, International Journal of Logistics Research and Applications, and Operations Management Research with 14, 8, and 8 articles, respectively. Other journals that received top 10 positions in the considered area are International Journal of Operations and Production Management, International Journal of Production Research, Transportation Research Part E: Logistics and Transportation Review, Computers and Industrial Engineering, IEEE Engineering Management Review, and Supply Chain Management. These top 10 journals contribute to 28.5% of the total articles considered in this study. Table 1 Top ten journals in terms of number of articles Sources No. of Articles Sustainability (Switzerland) 16 International Journal of Logistics Management 14 International Journal of Logistics Research and Applications 8 Operations Management Research 8 International Journal of Operations and Production Management 7 International Journal of Production Research 6 Transportation Research Part E: Logistics and Transportation Review 6 Computers and Industrial Engineering 5 IEEE Engineering Management Review 5 Supply Chain Management 5 Author and country statistics The top ten contributing authors in the SC in COVID-19 are presented in Table 2. Ivanov D is the topmost author with 12 articles, followed by Paul SK and Kumar A with 9 and 8 articles, respectively. The countries whose researchers are working on the SC in COVID-19 are presented in Table 3. From Table 3, it is found that USA, India, and China are the major contributing countries with 128, 107, and 71 articles, respectively. It can be seen that, among the top ten countries, 60% are Asian countries. UK and France are the two European countries, which have also contributed to this area. Table 2 Top contributing authors Authors No. of Articles Ivanov D 12 Paul SK 9 Kumar A 8 Ali SM 6 Moktadir MA 6 Gunasekaran A 4 Mangla SK 4 Sharma M 4 Shi X 4 Wang Y 4 Table 3 Top ten countries publishing articles on SC in COVID-19 Country No. of Articles* USA 128 India 107 China 71 UK 58 Australia 31 Iran 27 Bangladesh 21 Pakistan 21 France 18 Indonesia 17 *For articles with authors from multiple countries, the count has been given to all countries Citations statistics of articles Global citation is the citations received by articles globally from the SCOPUS database. The top 10 articles in the descending order of global citations are presented in Table 4. From Table 4, it is found that out of 10 articles, four are from the same author, i.e., Ivanov D. It can also be found that Ivanov (2020a) received the highest global citation of 444, followed by Ivanov and Dolgui (2020) and Hobbs (2021) with 285 and 257 citations respectively. Ivanov (2020a) used simulation tools to predict the impact of COVID-19 on the SC using simulation and optimisation. The study identified both short-term and long-term impacts and conducted sensitivity analysis at different scenarios to open and close facilities at different locations to overcome the COVID-19 outbreak. Ivanov and Dolgui (2020) discussed the viability of SC networks. The study discussed intertwined supply networks and proposed a conceptual model for decision-making in SC viability. Hobbs (2020) discussed the consumer consumption pattern during COVID-19 in the food SC. The study analysed disruptions in the supply side, such as labour shortage, movement of goods, etc., in the pandemic. Table 4 Top ten globally cited articles on SC in COVID-19 Author Title of the paper Total citations Citations per year Ivanov (2020a) “Predicting the impacts of epidemic outbreaks on global supply chains: A simulation-based analysis on the coronavirus outbreak (COVID-19/SARS-CoV-2) case” 444 222 Ivanov and Dolgui (2020) “Viability of intertwined supply networks: extending the supply chain resilience angles towards survivability. A position paper motivated by COVID-19 outbreak” 285 142.5 Hobbs (2020) “Food supply chains during the COVID-19 pandemic” 257 128.5 Ivanov (2020b) “Viable supply chain model: integrating agility, resilience and sustainability perspectives—lessons from and thinking beyond the COVID-19 pandemic” 174 87 Queiroz et al. (2020) “Impacts of epidemic outbreaks on supply chains: mapping a research agenda amid the COVID-19 pandemic through a structured literature review” 157 78.5 Guan et al. (2020) “Global supply-chain effects of COVID-19 control measures” 141 70.5 Govindan et al. (2020) “A decision support system for demand management in healthcare supply chains considering the epidemic outbreaks: A case study of coronavirus disease 2019 (COVID-19)” 132 66 Remko (2020) “Research opportunities for a more resilient post-COVID-19 supply chain–closing the gap between research findings and industry practice” 111 55.5 Singh et al. (2021) “Impact of COVID-19 on logistics systems and disruptions in food supply chain” 95 95 Ivanov and Das (2020) “Coronavirus (COVID-19/SARS-CoV-2) and supply chain resilience: A research note” 83 41.5 Keyword statistics Keyword statistics enables the identification of the most frequently used keywords by authors in the research articles. Table 5 shows the top 20 keywords used in the field of SC in COVID-19. From Table 5, it is found that the keywords are mainly focused on three knowledge domains, namely, SC issues (supply chains, food supply, supply chain management, supply chain resilience, and supply-chain disruptions etc.), COVID-19 pandemic related issues (COVID-19, coronavirus, pandemic, epidemic, and viral disease etc.), and operations management (decision making, and risk management). The word cloud of most frequently used keywords was also developed and is presented in Fig. 3. Table 5 Top twenty keywords used by the researchers on the SC in COVID-19 Words Occurrences Words Occurrences Supply chains 103 Supply chain resilience 12 COVID-19 52 Epidemiology 11 Supply chains management 48 Pandemics 11 Pandemic 28 Economics 10 Human 27 Risk management 10 Food supply 24 Food security 9 Coronavirus disease 2019 20 Industry 9 Decision making 16 Supply-chain disruptions 9 Coronavirus 15 Sustainability 9 Epidemic 13 Viral disease 9 Fig. 3 Word cloud of most frequently used keywords Network analysis Network analysis depicts the association between authors, keywords and articles based on their connections or link strengths. Clusters are formed taking the entities which have more connections. From SCOPUS database, ‘.CSV’ file was extracted and was fed to VOS viewer software for network analysis. In this work, network analysis was performed for keywords and bibliometrically coupled articles. Keyword co-occurrence network Keyword co-occurrence network was developed by considering keywords that appeared at least three times. Out of 1065 identified keywords, only 92 met the criteria, and thus, the keyword co-occurrence network was developed by considering only these 92 keywords. COVID-19, SC management, pandemic, and resilience were identified as the most networked keywords having 84, 67, 67, and 48 links with other keywords and with total link strength of 409, 216, 183, and 110, respectively. A keyword overlay visualisation network, depicted in Fig. 4, was developed to identify the changing trends of keywords with time. Fig. 4 Keyword overlay network The keyword overlay network shows that the keywords related to the COVID-19 pandemic (coronavirus, human, drug industry, pneumonia, virus pneumonia, healthcare policy etc.) were widespread in the early 2020s when the pandemic really broke out across the globe, whereas supply chain risk management (economic impact, risk management, resiliency, etc.) emerged during the mid of 2020s. Finally, keywords related to supply chain risk mitigation strategies (outbound logistics, procurement, inbound logistics, agile manufacturing, blockchain etc.) are emerging in 2021. This implies that global SC is learning and devising strategies to cope with the ongoing and future pandemics. Bibliographic coupling for identifying emerging knowledge themes Bibliographic coupling helps in identifying common knowledge themes among research articles by creating clusters of articles which are connected strongly. When two articles A and B both cite a third common article C in reference, the first two articles i.e., A and B become bibliometrically coupled (Pirri et al. 2020). Unlike co-citation analysis, bibliographic coupling does not put recently published articles at a disadvantage as the latter is based on cited references and not on citations. As the temporal span of this review is just last two years, bibliographic coupling was chosen for identifying emerging knowledge themes. Among considered articles in this study, those articles which have received at least two citations were considered for this analysis. So, the count of articles was reduced to 79. From bibliographic coupling analysis, seven clusters were developed, including 61 articles, while other articles were eliminated due to low connectivity in the network. Figure 5 shows that the largest cluster (red) contains 15 articles, followed by cluster 2 (green), cluster 3 (blue), cluster 4 (yellow), cluster 5 (violet), cluster 6 (sky blue), and cluster 7 (orange) which have 13, 12, 9, 7, 3, and 2 articles respectively. Five major knowledge clusters along with their leading articles (based on the number of links) are presented in Table 6. Discussion on these clusters and related knowledge themes are presented in the following section. Fig. 5 Emerging knowledge themes Table 6 Lead articles from the major knowledge themes Authors Title Year Journal Citation Links TLS Approach Cluster 1 (Red): Food SC Chowdhury et al. (2021) “COVID-19 pandemic related supply chain studies: A systematic review.” 2021 Transportation Research Part E: Logistics and Transportation Review 14 44 169 Presented a review on COVID-19 in SC. The four major research themes identified were COVID-19 impact on SC, the role of technology in SC, resilience strategies, and sustainability in SC. Kumar et al. (2021) “Mitigate risks in perishable food supply chains: Learning from COVID-19.” 2021 Technological Forecasting and Social Change 6 34 70 Analysed risk mitigation strategies of perishable food SC in COVID-19 scenario by using the Fuzzy best-worst method (BWM). Ali et al. (2021) ‘Supply chain resilience reactive strategies for food SMEs in coping to COVID-19 crisis” 2021 Trends in Food Science and Technology 3 23 42 Reviewed SC resiliency strategies for food SC in the COVID-19 scenario. Kumar and Kumar Singh (2021) ‘Strategic framework for developing resilience in Agri-Food Supply Chains during COVID 19 pandemic” 2021 International Journal of Logistics Research and Applications 3 20 38 Analysed the impact of COVID-19 on agri-food SC by using the BWM. The strategies to improve resilience in agri-food SC were also analysed using quality function deployment. Aday and Aday (2020) “Impact of COVID-19 on the food supply chain” 2020 Food Quality and Safety 37 20 36 Presented a review on the impact of COVID-19 on agri-food SC. Cluster 2 (Green): Sustainable SC strategies Nandi et al. (2021) “Do blockchain, and circular economy practices improve post COVID-19 supply chains? A resource-based and resource dependence perspective” 2021 Industrial Management and Data Systems 3 36 109 Recommended adopting circular economy practices and blockchain technologies to enhance the firm’s localisation, agility and digitisation. Karmaker et al. (2021) “Improving supply chain sustainability in the context of COVID-19 pandemic in an emerging economy: Exploring drivers using an integrated model” 2021 Sustainable Production and Consumption 20 32 87 Analysed the drivers of sustainable SC using fuzzy total interpretive structural modeling. Financial support from the government was found to be the topmost driver to enhance the sustainability of SC. Qin et al. (2021) “Investigating the effects of COVID-19 and public health expenditure on global supply chain operations: an empirical study” 2021 Operations Management Research 3 28 87 Assessed the impact of COVID-19 on the global SC by using the random effect and fixed effect approaches. Nikolopoulos et al. (2021) “Forecasting and planning during a pandemic: COVID-19 growth rates, supply chain disruptions, and governmental decisions” 2021 European Journal of Operational Research 26 26 35 Used predictive analytics tools to forecast and plan to overcome the adverse effect of the pandemic. The Deep-learning model was used to forecast the growth rate of COVID-19. Veselovská (2020) “Supply chain disruptions in the context of early stages of the global COVID-19 outbreak” 2020 Problems and Perspectives in Management 8 23 28 Conducted a survey to analyse disruption in SC by collecting responses. Various measures taken by industries to minimise COVID-19 impact were also discussed. Cluster 3 (Blue): SC risk mitigation and resilience Butt (2021) “Strategies to mitigate the impact of COVID-19 on supply chain disruptions: a multiple case analysis of buyers and distributors” 2021 International Journal of Logistics Management 4 41 132 Presented the countermeasures taken by distribution firms to tackle disruption in SC caused due to COVID-19. Semi-structured interviews were conducted with 36 senior managers from nine firms to analyse the buying and distribution strategy. El Baz and Ruel (2021) “Can supply chain risk management practices mitigate the disruption impacts on supply chains’ resilience and robustness? Evidence from an empirical survey in a COVID-19 outbreak era” 2021 International Journal of Production Economics 27 35 112 Analysed the importance of risk management in mitigating the disruption in SC due to COVID-19. A survey was conducted on 470 French firms and followed by structural equation modeling. Xu et al. (2021) “The compounded effects of COVID-19 pandemic and desert locust outbreak on food security and food supply chain” 2021 Sustainability (Switzerland) 3 29 69 Proposed the reactive and proactive approaches for enhancing the resiliency of food SC. Ivanov and Dolgui (2020) “Viability of intertwined supply networks: extending the supply chain resilience angles towards survivability. A position paper motivated by COVID-19 outbreak” 2020 International Journal of Production Research 191 29 153 Discussed the viability of the SC network. The integrity of intertwined supply network and viability were presented, and a decision model was proposed for SC viability. Free and Hecimovic (2021) “Global supply chains after COVID-19: the end of the road for neoliberal globalisation?” 2021 Accounting, Auditing and Accountability Journal 7 22 44 Analysed the drivers of SC vulnerability. A case study of the manufacturing sector was presented to show the global policies for enhancing SC vulnerability. Cluster 4 (Yellow): Impact of COVID-19 on SC Singh et al. (2021) “Impact of COVID-19 on logistics systems and disruptions in food supply chain” 2021 International Journal of Production Research 48 36 95 A simulation model was developed for the public distribution system to showcase disruptions in food SC. The proposed simulation model helps in establishing responsive and resilient SC. Taqi et al. (2020) “Strategies to manage the impacts of the COVID-19 pandemic in the supply chain: Implications for improving economic and social sustainability” 2020 Sustainability (Switzerland) 8 36 70 Identified COVID-19 effect on SC and proposed strategies to mitigate the negative impact of COVID-19. Grey based digraph matrix was used to map the essential strategies. Farooq et al. (2021) “Supply chain operations management in pandemics: A state-of-the-art review inspired by covid-19” 2021 Sustainability (Switzerland) 3 35 155 Presented a systematic review to identify the challenges in SC during COVID-19 and also explored the strategies to overcome those challenges. Grida et al. (2020) “Evaluate the impact of COVID-19 prevention policies on supply chain aspects under uncertainty” 2020 Transportation Research Interdisciplinary Perspectives 8 25 44 Analysed the prevention policies to deal with COVID-19 disruptions. BWM and TOPSIS were used to prioritise the prevention policies. Cai and Luo (2020) “Influence of COVID-19 on Manufacturing Industry and Corresponding Countermeasures from Supply Chain Perspective” 2020 Journal of Shanghai Jiaotong University (Science) 8 19 21 Analysed the impact of COVID-19 on SC and suggested the countermeasures to overcome those impacts. Cluster 5 (Violet): Supply chain viability Ivanov (2021a) “Lean resilience: AURA (Active Usage of Resilience Assets) framework for post-COVID-19 supply chain management” 2021 International Journal of Logistics Management 9 38 242 Proposed an active usage of resilience assets (AURA) model to combat COVID-19 disruptions. The proposed model enhances resiliency and enables value creation. Ivanov (2021b) “Supply Chain Viability and the COVID-19 pandemic: a conceptual and formal generalisation of four major adaptation strategies” 2021 International Journal of Production Research 9 37 176 Identified the adoption strategies used by industries during the COVID-19 pandemic. Four strategies, namely, intertwining, repurposing, substitution, and scalability were discussed. Golan et al. (2020) “Trends and applications of resilience analytics in supply chain modeling: systematic literature review in the context of the COVID-19 pandemic” 2020 Environment Systems and Decisions 48 36 108 Presented a review on SC resiliency. Several future research directions were proposed to enhance the resiliency of SC. Shahed et al. (2021) “A supply chain disruption risk mitigation model to manage COVID-19 pandemic risk” 2021 Environmental Science and Pollution Research 5 29 68 Used two algorithms, namely, genetic algorithm and pattern search, to propose a mathematical model to mitigate the disruptions in the SC. Knowledge-based supply chain: Emerging themes This section deals with the RQ2 by elucidating the emerging knowledge themes in of SC research in COVID-19. The clusters identified through bibliographic coupling were named after studying the articles under each cluster and assimilating the common theme among them. These are: cluster 1-food SC, cluster 2- sustainable SC strategies, cluster 3- SC risk mitigation and resilience, cluster 4- impact of COVID-19 on SC, and cluster 5- SC viability. Food supply chains Food and nutrition is the most essential aspect of life and therefore, it plays a crucial role in the attainment of sustainable development goals (SDGs). Globally one among nine people suffer from hunger and thus, it is a serious concern for every nation (Nordhagen et al. 2021). Ensuring the reachability of proper food and nutrition to all human beings should be the prime motto of food SC. In this regard, a simulation model for the distribution system was presented by Singh et al. (2021) to analyse the disruptions in food SC during the COVID-19 pandemic. Further, the current food SC was analysed by Mor et al. (2020) based on the available reports and predicted the future performance of food SC in the post-COVID-19 scenario. The risk-mitigating strategies of perishable food SC were analysed by Kumar et al. (2021) using the fuzzy BWM. Collaborative management was identified as the top food SC strategy for risk mitigation. Further, the impact of COVID-19 on agri-food SC was analysed by Kumar and Kumar Singh (2021) and explored the potential strategies to enhance the resiliency of agri-food SC. Chenarides et al. (2021) proposed a flexible SC model that enhances stakeholders’ value by improving the flexibility across the SC. Lastly, a survey on 367 agri-food industries was presented by Nordhagen et al. (2021) to analyse the impact of COVID-19 on agri-food SC. The survey showed that 94.3% of the firms reported that their SC was heavily affected, and the sales were also decreased. Sustainable supply chain strategies The COVID-19 pandemic has significantly affected the SC and its long-term sustainability (DeWit et al. 2020). The achievement of sustainable development goals (SDGs) has become questionable because of SC disruptions (Alam et al. 2021; Karuppiah et al. 2021). Therefore, firms need to revisit their existing SC strategies to minimise disruptions from COVID-19. Some researchers suggested that short-term reactive strategies must be adopted to handle disruptions effectively (Butt 2021). Several researchers have suggested that agile production, flexibility in manufacturing, and diversification of supplies sources as potential strategies to deal with disruptions in SC due to the COVID-19 pandemic (Taqi et al. 2020; Butt 2021). The challenges associated with the vaccine SC were analysed using the fuzzy-based DEMATEL method (Alam et al. 2021). The study reveals that a limited number of vaccine manufacturing firms and inappropriate coordination were the topmost challenges in vaccine SC. The lack of social sustainability in the SC of clothing industries was also discussed (Majumdar et al. 2020). The authors reveal that the dominant power of some brands is the main reason for the lack of social sustainability. Also, the unauthorised sub-contracting in the clothing industry is a critical issue for lack of social sustainability. Sharma, Luthra, et al. (2020c) proposed a framework to improve the survivability of sustainable SC in the post-COVID-19 scenario. The study analyses the factors affecting the survivability of sustainable SC using the SWARA method and found that SC network viability is the main driving factor in enhancing the survivability of sustainable SC. The impact of COVID-19 on the environment, economy, and society was analysed by Yu et al. (2021). The study also identified the remedial measures to deal with disruption in SC from COVID-19. Anser et al. (2021) analysed the critical factors that affect the sustainable SC in COVID-19. Karuppiah et al. (2021) analysed the challenges of COVID-19 in the humanitarian SC using the analytical hierarchy process (AHP). The result reveals that the humanitarian SC’s top challenges were short lead time, emergency service, and spread of rumours. Supply chain risk mitigation and resilience Hosseini and Ivanov (2020, 2021) proposed a multi-layer Bayesian model to identify the deviations and to quantify the consequences of disruptions happening in the SC due to COVID-19 pandemic. To cope with such disruptions, three dimensions of SC resilience, namely absorptive capacity, adaptive capacity, and restorative capacity was identified (Hosseini et al. 2019, 2022). Multiple sourcing, geographical separation of suppliers etc. contribute to the absorptive capacity while rerouting enhances the adaptive capacity. Restorative capacity implies the ability of the physical facilities to return to the original state after disruption. It depends on the available protection to the physical facilities and financial capacity of the organisation to fund the restoration work. Risk mitigation and SC resilience have emerged as a dominant knowledge theme during the COVID-19 pandemic. The two major resilience strategies, namely preposition of extra inventory and backup suppliers were also suggested for enhancing the resilience in SC (Moosavi and Hosseini 2021). A mathematical model was presented to minimise disruptions in SC from both supplier and retailer sides due to the COVID-19 pandemic (Shahed et al. 2021). Further, Sid et al. (2021) analysed the short and long-term impact of COVID-19 on the agri-food SC. Detailed analysis on the remedial strategies was conducted to minimise the disruptions in SC. A review on disruptions in SC due to the COVID-19 pandemic was presented by Pujawan and Bah (2021). El Baz and Ruel (2021) surveyed 470 French firms to analysed the risk management in SC to mitigate the disruptions that happened due to COVID-19 using structural equation modelling. Al-Mansour and Al-Ajmi (2020) discussed the implications of COVID-19 on the business strategies and suggested firms revisit business strategies to tackle the disruptions from COVID-19. Simulation models were developed to analyse the exit strategies of SC to combat COVID-19 (Ivanov 2021c). The proposed simulation model helps in the selection of relevant recovery strategies for COVID-19 after effect. Nikolopoulos et al. (2021) forecasted the growth of the COVID-19 pandemic using a deep learning model, which helps in enhancing the production planning to combat COVID-19 disruptions. The countermeasure strategies adopted by distribution firms to minimise disruptions in SC were analysed by Butt (2021). Impact of COVID-19 on supply chain The COVID-19 pandemic has a disastrous impact on most of the supply chains, including automobile, hospitality, aviation etc. (Aigbedo 2021; Belhadi et al. 2021). To minimise COVID-19 impact, the government has taken several precautionary measures such as regional and country-wide lockdown, travel restrictions, and shutdown of various facilities. This step has disrupted SC heavily. In this regard, the effects of SC on economic growth during the pandemic were analysed by collecting data from 130 nations (Goel et al. 2021). Artificial intelligence and machine learning (AI-ML) were seen as affecting technologies to minimise SC disruptions, so the challenges in implementing AI-ML techniques in agriculture SC were analysed using an interpretive structural modelling approach (Nayal et al. 2021). It is found that lack of regulations and data security were the topmost challenges in adopting AI-ML techniques in SC. The impact of COVID-19 was analysed in the literature, and firms’ remedial measures to combat disruptions in SC were also analysed Sharma, Adhikary, et al. (2020a). Further, the impact of COVID-19 in Flemish food SC was also analysed (Coopmans et al. 2021). Many organisations are adopting remedial policies to cope up with damages in SC due to COVID-19. The impact of these remedial policies on the SC was analysed by Grida et al. (2020) using BWM. The impact of COVID-19 on customer satisfaction was analysed by Brandtner et al. (2021) and found a decrease in customer satisfaction due to pandemics. Supply chain viability The COVID-19 has affected human lives, business, and other economic activities such as manufacturing, tourism, and hospitality. This uninterrupted SC has led to delay in deliveries, unpredicted demands, and panic buying (Yuen et al. 2021). It is essential to improve the viability and resiliency of SC to handle these disruptions and challenges faced in the current pandemic. Supply chain viability is defined as “the ability of a supply chain (SC) to maintain itself and survive in a changing environment through a redesign of structures and replanning of performance with long-term impacts” (Ivanov 2020b). The ripple effect of the COVID-19 outbreak was modelled by Ivanov and Das (2020) considering pandemic propagation, market disruption, and declination in demand. Innovations and technology integration in SC generates a competitive advantage. However, the resiliency in the SC may not be enhanced through these innovations and technology integration, and resiliency must be enhanced through adaptive capacity and redundancy in the SC (Golan et al. 2020). A minor delay in any project activity may disrupt the whole network, leading to project resilience, and that’s why the disruption caused during the COVID-19 pandemic damaged the SC activities severely (Golan et al. 2020). Further, Four strategies, namely, intertwining, repurposing, substitution, and scalability, were proposed and discussed (Ivanov 2021b) to enhance the viability and resiliency of SC. Discussion This study intends to analyse the impacts of the current COVID-19 pandemic on SC and how the SC players are learning to cope with this unprecedented disruption by devising various strategies and practices. It is pertinent to mention here that COVID-19 is a high-impact but low-probability event that requires distinct strategies compared to low-impact and high-probability disruptions like natural calamity, supply shortages, demand fluctuations etc. The lean strategies revolving around minimisation of inventory and Just in Time (JIT) philosophy results good efficiency, however, at the cost of SC resilience. Therefore, incorporating resilience in SC to tame pandemic disruptions needs adoption of new philosophies rooted in knowledge-based systems and practices. Research on the impact of COVID-19 on SC gained tremendous momentum from the early 2020s. The trend of research is also found to be highly dynamic as it migrated from COVID-19 pandemic-related issues in early 2020 to SC risk management in mid-2020 and then to risk mitigation strategies in 2021. Among various supply chains, food and pharmaceutical supply chain have received most of the attention from the researchers. Knowledge-based strategies for SC resilience This section deals with the RQ3. Studies showed that the disruption impact of COVID-19 varies based on the complexity of the SC network, such as the number of entities in SC, information and product flows etc. So, it is essential to consider network complexity while devising strategies to cope with the impact of COVID-19 in SC (Duong and Chong 2020). COVID-19 has uncovered the vulnerabilities of lean and efficient SCs. The unrelenting focus on the cost and efficiency has led to the creation of supply chains without the desired flexibility and redundancy. This has worked well when the business environment is stable and predictable. However, disruption from COVID-19 has created renewed attention towards integrating resiliency in SC. While building resilience through absorptive and adaptive capacities has been suggested by some researchers, others have propounded strategies like ‘glocalisation’, i.e., amalgamation of globalisation and localisation in the context of procurement (Sarkis et al. 2020). The development of local suppliers not only reduces the dependence on suppliers located in other geographic locations but also shortens the length of the SC. However, monitoring of not only the tier-1 supplier, but also of tier-2 and tier-3 suppliers on a regular basis has been prescribed as a part of supplier management during the pandemic. It has become important to know the capacity, redundancy, and lead time at every echelon of the SC network. Strategic sourcing that not only ensures minimum cost but also takes care of quality, responsiveness, collaboration, timely delivery etc. has also been accepted by the SC practitioners as an effective way to improve the SC performance during disruptions (Frederico et al., 2021). As strategic sourcing improves the agility and responsiveness of SC, it helps to augment the resilience. Irrespective of natural disaster that happens only to a specific location/area, the COVID-19 has impacted the world. Almost all countries were impacted, and it has led to overall disruption in SC internationally. There is a need to revise the strategies of SC to enhance its resilience. One such option to enhance the resilience in SC is adoption of digital technologies that helps in quick recovery and foresight seen of future pandemics. Use of digital technologies such as artificial intelligence (AI), machine learning (ML) and blockchain can help in smooth monitoring of suppliers (Linton and Bidiya 2020; Nayal et al. 2021). Development of SC digital twin (Burgos and Ivanov 2021), that mimics the physical SC with a computerised model representing the state of network at any given moment in real time by two way information transfer, can be a very potent strategy way to handle disruptions created by pandemics. In this context L-A-D framework (localization-agility-digitization) can really augment the blockchain enabled circular economy adoption in SC in the post COVID-19 era (Nandi et al. 2021). Using the dynamic big data and SC mapping, stress testing can be done under simulated conditions to understand the effect of disruption at one stage of SC on the survivability of the entire network. Based on the ongoing discussion, a framework relating knowledge-based SC and resilience is proposed as shown in Fig. 6. This simple framework illustrates that the use of AI and ML, adoption of blockchain and SC digitisation will lead to knowledge-based supply chain which in turn will augment the SC resilience. Fig. 6 Framework relating knowledge-based SC with resilience The strategies like SC viability propounded by Burgos and Ivanov (2021) and Ivanov (2020b) have attracted the attention of the research fraternity. The SC viability defined as “the ability of a SC to maintain itself and survive in a changing environment through a redesign of structures and replanning of performance with long-term impacts” integrate three philosophies of supply chain, namely agility, resilience and sustainability through a multi-structural (organisation, information, technology, process-function, finance etc.) framework. Therefore, a viable SC should respond with agility to quick changes and also absorb negative impacts of disruptions and recover quickly from it showing resilience. Viability will also require adjustment of capacity utilisation and allocation during long term global disruptions to meet the sustainability goals. Some studies suggested restructuring of SC networks by considering reshoring and nearshoring. However, the challenges associated with SC reconstruction are still largely unexplored (Deaton and Deaton 2020). Agile and flexible manufacturing and quick repurposing have also been proposed as potent strategies to build resilience. Many manufacturing companies have changed their manufacturing facilities to serve a different product line which not only helped them to maintain their revenue but also to serve the society in a better way (Belhadi et al. 2021). In India, some of the major textile and clothing manufacturers have ventured into the manufacturing of masks and personal protective equipment (PPE) by quickly modifying their production lines and by augmenting the capacities for the new products. Many authors have argued in favour of enhancing the sustainability of SC post-COVID-19 disruptions by adopting both short-term and long-term strategies. Short-term strategies to minimise the immediate disruption and long-term strategies to enhance the sustainability of SC to deal with future pandemics. Some of the initiatives suggested by researchers are the adoption of blockchain technology in SC, usage of predictive analytics in demand management, and financial support from the government to enhance the sustainability of the SC. Managerial implications This review on SC in COVID-19 provides various knowledge-based avenues to improve SC resiliency for tackling the current and future disruptions. The strategies to be adopted by the SC managers are going to be crucial for the viability of the SC. This work presents a compendium of supply chain issues, knowledge themes, and mitigation strategies which will help the practicing managers to take a more informed decision while handling pandemic disruptions. Besides, the insights gained from this literature review will help the managers to systematically analyse the critical challenges faced by SC in the current pandemic and also poke them to reflect on the counter strategies, discussed in section 6, to minimise the disruptions in SC. Adopting sustainable practices will enhance the viability and resiliency of the SC and will also help to deal with sudden disruptions or market shifts. These strategies should be a balanced mix of short-term and long-term initiatives. Short-term strategies are needed during sudden disruptions to minimise their immediate effect, whereas long-term strategies are helpful for the post-pandemic recovery and sustainable growth of SC. Various AI and ML based predictive and prescriptive analytics tools should be embraced by the SC managers to cope with the demand fluctuation and uncertainty in supply during pandemic. Proactive managers should develop data-driven supply chain models for simulated stress testing to identify the critical nodes that may cause disruption. More attention should be given and adequate resource allocation should be made by the managers to make these critical nodes robust and absorptive. Overall, the practitioners and managers must revisit their operations strategies to cope with the present pandemic and to deal with future pandemics. Research implications This review identifies various knowledge-based strategies to enhance the SC resilience during pandemic. The insights gained from this review will help the researchers to reflect on and to develop resilient strategies to mitigate such disruptions. Strong emphasis is needed on researches related to supply chain digitisation and the use of artificial intelligence so that end to end visibility in SC is obtained and automated decisions can be taken in case of unprecedented deviations in demand, supply or schedules. A detailed elaboration of future research directions is presented in the following section. Future research directions In the last two years, the research on SC in COVID-19 has received significant attention from the SC and risk research communities. This is mainly due to the unprecedented and deleterious effects of COVID-19 on SC. Looking at the severe impact of the COVID-19 outbreak, researchers and practitioners are shifting their focus towards knowledge-based SC to improve the resiliency and long-term viability. The key question that the researchers are trying to answer is what is the optimum balance between the SC efficiency and SC resiliency? Too much focus on leanness has definitely pushed the resiliency to the back seat. Therefore, COVID-19 has become an eye-opener for the researchers, and it has compelled them to ponder over the issue of integrating resilience in the SC using knowledge-based platforms and technologies. Therefore, the new research paradigm should focus on the development of a sustainable-leagile-resilient (S-leagilient) SC which will not only meet the triple bottom line but also fulfil the lean, agile, and resiliency dimensions. Achieving all these dimensions may seem paradoxical, however, a logical balance of these dimensions can definitely be achieved. The following research propositions are propounded for future research: Proposition 1: Analysing the short-term and long-term impacts of the COVID-19 pandemic on SC and developing knowledge-based counter strategies for mitigation. Proposition 2: Incorporating AI, ML and blockchain based digital technologies to create digital twins for enhancing the resiliency of SC. Proposition 3: Developing a unified framework for a knowledge based sustainable-leagile-resilient supply chain leading to supply chain viability. Conclusion This article presents an overview of SC research trends, knowledge themes, and strategies during the COVID-19 pandemic through bibliometric and network analyses. Bibliometric analysis shows that the research in this area started at the fag end of 2019, however, it exploded in the following two years. The keywords, an important indicator of knowledge themes, revolve around three facets, namely SC issues, COVID-19 related issues, and operations management related issues. The five dominant knowledge themes elicited through bibliographic coupling are food SC, sustainable SC strategies, SC risk mitigation and resilience, impact of COVID-19 on SC, and SC viability. The present literature review also deliberate on the knowledge-based counter strategies that are being adopted by the firms to tackle the current pandemic and to enhance the resiliency of SC. Glocalisation, monitoring of sub-suppliers, adoption of digital technologies (digital twins), L-A-D (localization-agility-digitization), SC viability, SC stress testing etc. are some of the knowledge-based strategies and best practices suggested in contemporary literature to cope with the present and future pandemic disruptions. This article contributes by mapping the knowledge-based SC research in COVID-19 using bibliometric and network analyses. Though the research outputs in this area are increasing at an exponential rate, there is a lacuna in terms of summarising this contemporary research through network analysis and delineating the future strategies for a new SC paradigm. This review presents a compendium of trends and emerging knowledge themes with special focus on disruption mitigation strategies. The several counter strategies taken by the researchers and industrial practitioners to tackle COVID-19 disruptions in SC are succinctly discussed. Finally, this review highlights that there exists a need to develop a unified framework for a knowledge-based sustainable leagilient SC. The study only includes the research articles covered in the SCOPUS database, and conference papers, policy documents, and research reports do not come under the purview of this study. Moreover, this study does not focus on any particular supply chain which may require in-depth analysis through systematic literature review. Data availability The data that support the findings of this study are available from the corresponding author on request. Declarations Conflict of interest statement The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Aday S Aday MS Impact of COVID-19 on the food supply chain Food Qual Saf 2020 4 167 180 10.1093/fqsafe/fyaa024 Aigbedo H (2021) Impact of COVID-19 on the hospitality industry: A supply chain resilience perspective. 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Accessed 1st Mar 2022 WTO (2020) WTO. https://www.wto.org/english/news_e/pres20_e/pr855_e.htm. Accessed 28 Oct 2021 Xu Z Elomri A El Omri A The compounded effects of COVID-19 pandemic and desert locust outbreak on food security and food supply chain Sustain 2021 13 1 17 10.3390/su13031063 Yu Z Razzaq A Rehman A Disruption in global supply chain and socio-economic shocks: a lesson from COVID-19 for sustainable production and consumption Oper Manag Res 2021 10.1007/s12063-021-00179-y Yuen KF, Leong JZE, Wong YD, Wang X (2021) Panic buying during COVID-19: Survival psychology and needs perspectives in deprived environments. Int J Disaster Risk Reduct 62. 10.1016/j.ijdrr.2021.102421 Zarghami SA (2021) A reflection on the impact of the COVID-19 pandemic on Australian businesses: Toward a taxonomy of vulnerabilities. Int J Disaster Risk Reduct 64. 10.1016/j.ijdrr.2021.102496

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==== Front Wireless Netw Wireless Networks 1022-0038 1572-8196 Springer US New York 3141 10.1007/s11276-022-03141-3 Original Paper Psychological factors of sports injury caused by wireless communication of embedded microprocessor in social sports teaching and training Huang Changliang huangchangliang@sdpei.edu.cn 1Changliang Huang graduated from the Shandong Sport University in 2002. He works in Shandong Sport University. His research interests include track and field training and teaching, nutrition in sport. Xu Yuting xuyt@hit.edu.cn 2Yuting Xu graduated from the Shandong Sport University in 2007. She works in of Harbin Intitute of Technology, Weihai. Her research interests include track and field training and teaching, nutrition in sport. 1 grid.443422.7 0000 0004 1762 7109 School of Shandong Sport University, Jinan, Shandong, 250102 China 2 grid.19373.3f 0000 0001 0193 3564 School of Harbin Institute of Technology, Weihai, Shandong, 264209 China 15 12 2022 19 6 9 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. In the process of physical education and training, students’ sports injuries are found, and the laws of injury and psychological factors of injury are discovered from them, to propose targeted preventive measures to reduce the incidence of sports injuries. Based on embedded communication technology, it provides a material means for the sharing of information resources. And the application of the microprocessor makes it very useful in physical education. It is hoped that the incidence of track and field sports injuries of physical education students can be reduced, their potential can be tapped, and their sports life span can be prolonged. This paper establishes the evaluation model of sports injury psychology and emotion, and analyzes the influence of sports injury emotion change on injury rehabilitation and psychological state maintenance cycle in Google data analysis platform. 36 undergraduates from 211 universities were recruited as subjects to show them the introduction information of various sports and ask them to complete the questionnaire. This paper adopts the group design method with psychological quality (high / low) as the independent variable and the choice intention of sports (simple sports / complex sports) as the dependent variable. To select suitable sports for young people to carry out psychological experiments and realize the effective control of scene information. According to the score of psychological quality, the group with high score is regarded as young people with high psychological quality, and the group with low score is regarded as young people with low psychological quality. According to the experimental data, the median score of experiment 1 was 5.00. Those who score higher than 5.0 have high psychological quality, while those who score lower than 5.0 have low learning ability. Taking "psychological quality (high / low)" as the independent variable and "sports project (simple sports / complex sports) choice intention" as the dependent variable, this paper carries out one-way ANOVA with the help of spss22.0. The results show that psychological quality has a significant impact on young people's sports injury. Keywords Physical education Sports injury Mental state Comprehensive development of body and mind Embedded microprocessor Wireless communication ==== Body pmcIntroduction The thorough advancement of body and brain in school actual instruction is as yet lingering behind. The fundamental explanation is that the association between schools and market economy is not sufficiently close. Albeit a few super advanced implies have been utilized in school sports and wellness, the way is moderately single, the gear is maturing, and the level of insight is not high. Indeed, most of the games adopted the normal display mode and confrontation mode, and the study of the psychological nature of sports injuries in the classroom and in the preparation was lacking. In recent years, the application of embedded technology has penetrated into all aspects of people's lives, from mobile phones and handheld computers to smart home appliances such as smart refrigerators and microwave ovens. There are also large-scale CNC machines such as CNC machine tools and CNC centers in the industry. Embedded controller on the device. The development of embedded technology brings great convenience to human production and life, which greatly promotes production and improves people's quality of life. The embedded wireless communication system can use the wireless method to release information and is equipped with a set of software interfaces for product display. The system has a built-in operating system, so that the system functions can be expanded with the increase of application software functions, and it has a wide range of market applications.. Of course, you can observe the psychological changes of students in the training process in real time. Khan S talked about the way of behaving of African-American understudies remaining in school and decided the impact of various social, mental, and different variables. Non-parametric investigation shows that higher feelings of anxiety, youth destitution, absence of parental association or backing, absence of help from mentors, and absence of self-inspiration improve the probability of exiting. The discoveries of this study have significant ramifications for the school standard for the dependability of African American understudies [1]. A large number of studies believe that psychological quality cognitive strategy plays an important role in sports learning. Jin Wook C's research found that for learning behavior, individuals with high interpretation level are more confident in their own learning effects [2]. What is more, letafatkar A's research also shows that individuals have higher expectations of long-distance performance than recent tasks. This means that with the increase of time distance, the task goal of individual choice will become higher [3]. In addition, Richmond s study also found that: the farther the time distance, the more attention individuals pay to the desirability of behavior results; the closer the time distance, the more attention individuals pay to the feasibility of behavior results [4]. Soltyk believes that in a general sense, people with higher self-efficacy have higher psychological quality, and they are more likely to choose more difficult task goals. However, because this experience can not be formed in a short time, the time factor is particularly important for the formation of self-efficacy that is competent for a certain learning task [5]. Vlad R pointed out that at the macro level, we must give play to the regulatory functions of the government and society, strengthen social, cultural, and economic construction, to enhance the awareness of sports participation of the whole society [6]. In recent years, increasingly people begin to classify sports according to the complexity of sports skills. For example, when Beijsterveldt AMV discussed the universality of operational memory ability in sports, he divided motor skills into simple motor skills and complex motor skills and used the index of "ability" to represent the difficulty of motor skill learning, and classified them accordingly [7]. Labella believes that it is necessary to cultivate young people's interest in sports at the micro level, strengthen physical education, and use mass media to enhance young people's interest in participation. However, it is a pity that the above suggestions ignore the important role of young people's own psychological qualities [8]. Ham pointed out that the difficulty of different sports is not the same, so the required psychological quality is also different. It is inferred that young people's choice of sports may be affected by their own psychological qualities [9]. Moreover, the time distance theory proposed by Lee Y S also confirms that people will present different decision-making characteristics when they are faced with making choices immediately or making plans for the future [10]. The above research on the macro analysis of the psychological factors of sports injury, but for people with different psychological quality sports injury with psychological change feedback and lack of data proof, this paper analyzes the psychological changes in specific sports. This paper establishes the evaluation model of sports injury psychology and emotion, and analyzes the influence of sports injury emotion change on injury rehabilitation and psychological state maintenance cycle in Google data analysis platform. 36 undergraduates from 211 universities were recruited as subjects to show them the introduction information of various sports and ask them to complete the questionnaire. This paper adopts the group design method with psychological quality (high / low) as the independent variable and the choice intention of sports (simple sports / complex sports) as the dependent variable. To select suitable sports for young people to carry out psychological experiments and realize the effective control of scene information. The innovation of this paper is that it adopts a group design method with psychological quality as the independent variable and exercise selection intention as the dependent variable. The rest of the paper is categorized as the following content. Related theory introduction Sports metacognition teaching Physical fitness is an eternal topic. Today, with the rapid development of science and technology, people's attention and demand for health has risen to a new height. Fitness is an important way to promote health and improve national physique [11, 12]. The traditional fitness is greatly affected by the venue, way, coach, economy, and time [13, 14]. The classified guidance and personalized guidance for different physical groups are vague, and the tracking evaluation is not in place. Sports training and teaching is a branch industry of training and teaching, which has the function of competition, performance and entertainment and leisure [15, 16]. At present, increasingly trainers are attracted to participate in it. To advance the change and advancement of sports industry, we ought to work on the nature of occasion broadcasting and setting offices, enrich and optimize the service content, to promote the continuous improvement of industrial training [17, 18]. Novel coronavirus pneumonia has been greatly affected by the new crown pneumonia epidemic situation, which has been unable to meet the training needs of trainers. Thusly, how to advance the supported and solid improvement of sports preparing industry under extreme scourge circumstances has turned into a critical issue. In this situation, due to the obstacles of offline training, we can use the Internet platform to implement online training according to the needs of trainers, and promote the smooth progress of training [19, 20]. At the same time, we should strictly supervise, evaluate, and timely the feedback online to ensure the training effect. In terms of fitness and leisure industry, sports, town, and city marathons are in full swing. People keep on partaking in the sports and the travel industry, which animates the development of sports preparing. Under the change of sports training demand, the fitness and leisure industry should actively seek transformation and reshape the business model [21, 22]. Specifically, we can attract trainers to participate in sports training by holding sports training festival activities and issuing sports training coupons, to promote the growth of sports service training. Under the support of policy and science and technology, and guided by the needs of trainers, we focus on the implementation of online and offline integrated development modes [23]. Psychological index simulation model in physical training At present, the management of College Students' Extracurricular fitness is insufficient. There is no professional guidance and supervision for students' extracurricular exercises, which can not avoid the negative impact of unscientific fitness. Students' fitness activities can not achieve the purpose of professional, safe, effective, and convenient, which hinders the formation of lifelong sports awareness and habits. At the same time, there are few full-time fitness coaches in colleges and universities, and most of them come from other sports. The results show that there is a lack of guidance and pertinence for students' fitness, and there is no information management equipment due to backward fitness ways and equipment. This depends on the intervention and integration of intelligent means. Only by combining psychology with fitness can the fitness effect be implemented:1 P=∑j=1k∑h=1k∑t=1nj∑r=1nhyij-yhr2n2u At present, the comprehensive development of physical and mental health in China's coastal provinces is relatively advanced. Rizhao and other cities have been building a comprehensive health club integrating intelligent medical treatment, intelligent fitness, and intelligent rehabilitation. It adopts the whole process information and intelligent means, takes foreign advanced equipment as the carrier, and integrates the body measurement, monitoring, tracking, treatment, and individual planning as one of the intelligent fitness system. However, most of these methods exist in commercial clubs, but they are rarely used in colleges and universities, and they do not meet the requirements of the National College fitness club reform. The purpose of club system reform in colleges and universities is to integrate sports into students' lives, so that students can achieve the purpose of physical fitness and cultivating students' interest in sports through extracurricular sports competition, extracurricular sports exercise, extracurricular sports training, sports performance, sports video watching and other ways:2 IA=Ew+Enb+Et-Ic Use Internet, Internet of things, big data, and other high-tech to create a new fitness management mode. Reasonable optimization of fitness club, several areas, set up fitness test area, scientific fitness area, sports rehabilitation area, health care area, health management service area, college students can, according to their own physique monitoring report data and analysis, understand their body composition and need to strengthen the place, use big data, Internet of things, reasonable development of fitness plan and exercise model for their own physique type:3 Ej=12uj∑i=1nj∑r=1njyji-yjrnj2 According to the students' level and fitness years, the students are divided into junior students, intermediate students, and senior students. A series of activities and competitions are regularly carried out in different levels of student groups, such as health knowledge, competition, fitness one-to-one assistance activities, free fitness, activity planning, strength and speed competition, etc., to enrich the content of fitness activities, increase the interest and participation of fitness, and make the fitness more effective, to promote the development of fitness research system and arouse the enthusiasm of students to explore fitness knowledge, we should make the model more diversified and game oriented, increase the discussion part of audience groups, effectively combine theory with practice:4 Et=∑j=2k∑h=1j-1Gjh(pjsh+phsj)Djh(1-Djh) Add a variety of free sports, combine traditional rhythmic gymnastics with intelligent fitness, such as yoga, Pilates, pedal exercise, aerobic combat, dance, etc. On the operational level, members can register and ask questions through the app and the official websites. After the competition, they can communicate, interact, and share online to improve the influence and sustainability of the activity and facilitate the collection and retention of activity files. All slave cores run the simulation model at the same time to calculate the objective function of psychological state5 M=djh-Pjhdjh+Pjh To consider the uncertainty related to activity duration, K replicates are used to calculate the total cost and duration of the project in each round:6 djh=∫0∞dFh(y)∫0yy-xdFj(y) The last worth of the goal, is not entirely set in stone by the normal aftereffect of K reproduces, which is utilized as the result of the recreation model:7 f(x)=1Nh∑i=1NkXi-xh The result of the reproduction (for example, the wellness upsides of all individuals from the sub-populace) is sent back to the expert hub to perform transformative activities (for example, determination, hybrid, and change) and lastly select the original Pareto front:8 P=σt=1n∑i=1n(FIit-FIit)2FIit Embedded microprocessor and wireless communication (1) Embedded Microprocessor Embedded microprocessors evolved gradually from CPUs to general-purpose computers. Most microprocessors with 64 bits or more have higher processing performance. Unlike computer processors, embedded microprocessors retain only functional components closely related to embedded applications in actual embedded applications, and remove other redundant functional parts. In terms of low power consumption and rich peripheral functions, A good balance has been found to meet the special requirements of embedded product applications. Compared with industrial control computers, embedded microprocessors have the advantages of low power consumption, low cost, light weight, small size, and high reliability. Figure 1 shows the overall layout of the embedded microprocessor core board.Fig. 1 Block diagram of the core board module It can be seen from Fig. 1 that the core board circuit layout is relatively concentrated and the area is small, which not only reduces the cost of the board, but also facilitates the integration of the entire system. The necessary core circuits are concentrated on a core board, which greatly facilitates the design, development, and debugging of the product. At the same time, in some application circuits with strong electromagnetic interference, you can increase the entire the design reliability of the circuit. (2) Wireless Communication. When the fourth-generation (4G) wireless communication system commercial network is rapidly spreading worldwide, the fifth-generation (5G) wireless communication system "facing 2020 and the future" has become a research hotspot in the global wireless communication field. 5G wireless communications will integrate multiple technologies, such as millimeter wave communications, large-scale antenna arrays, full-duplex and ultradense networking, etc., to support multiple business communications, such as virtual reality, augmented reality, Internet of Things, and multimedia applications. Upgrades and advancements to existing innovations to take care of the four fundamental issues of "ceaseless wide-region inclusion", "areas of interest and high limits", "low inertness and high dependability" and "low power utilization and enormous association". All through the times of improvement of remote correspondence frameworks, the restoration of every age of remote correspondence frameworks has been joined by the development of notable various access advancements. To meet the large access and super high limit prerequisites of 5G remote correspondence framework, Non-Orthogonal Multiple Access (NOMA) technology has gradually become one of the candidate technologies for multiple access in 5G wireless communication systems. Figure 2 details the basic principles of the downlink and uplink NOMA technology.Fig. 2 Schematic diagram of the basic principle of NOMA technology As shown in Fig. 2, the transmitter first divides the multiuser signal in the power domain according to user channel conditions, user quality of service (Quality of Service, QoS) requirements, interuser interference and other information, and then divides the multiuser signal in the power domain through superposition coding (SC). Its sending; receiving end uses the serial interference cancellation (Successive Interference Cancellation, SIC) technology to eliminate the interference among the multiuser signals step by step according to the difference in the power of the multiuser signals, until the desired signal is decoded. It can be seen that in NOMA technology, the system transmits multiple user signals overlapping on the same wireless resource with different transmission powers, which can provide wireless transmission services for multiple users at the same time, and realizes the system's new dimension power domain. Multiple access. Psychological factors of sports injury Data model This paper establishes the evaluation model of sports injury psychology and emotion, and analyzes the influence of sports injury emotion change on injury rehabilitation and psychological state maintenance cycle in Google data analysis platform. 36 undergraduates from 211 universities were recruited as subjects to show them the introduction information of various sports and ask them to complete the questionnaire. Steps This paper adopts the group design method with "psychological quality (high / low)" as the independent variable and "sports project (simple sports / complex sports) choice " as the dependent variable. To select suitable sports for young people to carry out psychological experiments and realize the effective control of scene information. Combined with the literature review and according to the difficulty of sports, 15 sports events are selected as the pretest objects. The subjects were asked to evaluate the difficulty of each sport by Likert 5 scale. Among them, 1–5 represent five grades of "very easy to learn to very difficult to learn". To verify the interaction between psychological quality and time distance in influencing the willingness to choose sports events, this paper takes "sports choice" as the dependent variable and "psychological quality and time distance" as the independent variable, and uses (Sports difficulty: high vs low) × (time distance: far) The experimental process is similar to the first step. According to the characteristics of time distance, this study adopts direct manipulation, and the time distance of event occurrence is manipulated to two levels: far and near. On the one hand, according to the actual life situation, such as the length of the swimming training course, the "time distance" is set to 3 days. Psychological factors of sports injury in physical education teaching and training As shown in Fig. 3, due to the lack of experience and competence, people with low psychological quality tend to choose simple sports within their ability and avoid complex sports in the face of recent choices. However, if they are given enough time, the evaluation expectation and confidence of people with low psychological quality to participate in complex sports may be improved. At this time, they pay more attention to the desire to participate in complex sports.Fig. 3 People with low psychological quality lack experience and competence As shown in Table 1, the extension of time distance has a greater impact on the willingness of people with low psychological quality to participate in complex sports. In addition, for people with high psychological quality, in the case of sufficient time, because they have a lot of experience, they are more willing to choose complex sports. However, if the time given is limited, their self-confidence may decrease with the decrease of the level of explanation, and eventually they tend to consider the feasibility of the behavior results, and then choose simple sports, not complex sports.Table 1 The effect of the extension of time distance on the willingness of people Item Mental quality High psychological Low psychological Time Distance Complex sports 3.22 2.57 1.55 1.62 2.47 H2 2.2 2.88 5.94 5.55 5.27 H15 2.99 4.19 3.85 1.16 5.03 Pair 4.94 2.69 2.21 3.46 2.74 Sample 5.28 1.9 3.74 3.54 2.47 As shown in Fig. 4, compared with students with low self-efficacy, students with high self-efficacy prefer mastery goals. Learners with high self-efficacy are more likely to work hard and choose difficult tasks. From this point of view, self-efficacy, as a psychological control factor of psychological quality, has an impact on learners' choice of different difficulty sports. Among them, compared with learners with low psychological quality, learners with high psychological quality are more willing to choose or face complex tasks. To sum up, self-efficacy will not only affect learners' confidence in accepting learning tasks, but also enable learners to choose tasks of different difficulties according to their self-efficacy.Fig. 4 High self-efficacy and preferred mastery goals Single sample t-test was conducted with the mean value of swimming sports injury (M = 3.36, SD = 1.073), running sports injury (M = 1.56, SD = 0.909) and the median score (median = 3). As shown in Fig. 5 the mean value of swimming sports injury was significantly greater than the median (P = 0.051 < 0.1); the mean value of running sports injury was significantly less than the median (P = 0.000). The results show that there is a significant difference between swimming injury and running injury (t = 7.680, P = 0.000, SD = 1.411). In conclusion, this study decided to choose swimming sports injury (corresponding to complex sports) and running sports injury (corresponding to simple sports) as psychological experimental test items.Fig.5 The mean and median of swimming injuries As shown in Table 2, young people with different psychological qualities have significant differences in choosing sports with different difficulties, which proves the conclusion of this paper. Among them, people with high psychological quality are more willing to participate in complex sports than those with low psychological quality, while people with low psychological quality are more willing to choose simple sports than those with high psychological quality. The above results show that young people will unconsciously consider their own psychological qualities when they choose sports. However, it should also be noted that both knowledge and sports learning not only include a series of cognitive activities, but also need the support of time. Therefore, the influence of psychological quality on sports choice intention may also be regulated by time distance.Table 2 There are significant differences in choosing sports of different difficulty Item Sample Mental quality High psychological quality Low psychological quality Sports 2.58 3.57 2.94 5.32 Select 2.84 1.89 4.45 2.23 Simple sports 2.9 3.48 2.5 2.64 Complex sports 2.26 6.54 2.31 3.75 Conclusion The growth of science and technology is changing day by day and the development of information technology is even faster. Embedded technology is the new darling of the development of information technology. The combination of embedded system and wireless communication is the general trend and has high practical value. The system's microprocessing uses a cost-effective and high-performance microcontroller developed by Samsung. Its most prominent feature is that its CPU core uses a 64-bit structure. In the process of developing processor-based embedded systems, how to make the system start up normally and quickly is a key link, including the following contents: setting the interrupt vector table, initializing the memory system, initializing the stack, and calling the program. The system can be used in the analysis of the psychological factors of sports injuries to students in physical education teaching. Sports preparing is the major main thrust for the advancement of sports administration industry, and preparing updating gives an inward source to the change and improvement of the sports administration industry. In view of the issue of "how to advance the improvement of sports administration industry under the foundation of preparing overhauling", this paper examines the cooperation, coordination and imaginative activity of sports administration industry and related businesses from three parts of dynamic instrument, activity component and way component, through the examination of sports preparing strategy plan and execution, sports preparing market advancement and development, sports preparing request change and updating dynamic elements, it further investigates the advancement way of "incorporating sports administration industry assets under approach direction, further developing games administration industry framework under specialized help, and enhancing sports administration industry content under request excitement". Under the realistic background of training upgrading, it is of extraordinary functional importance to investigate the advanced improvement instrument of sports administration industry for the reason of extending the hypothesis. Therefore, this study has achieved an effective breakthrough in both theoretical and practical aspects, which provides an important reference for the development of industrial training and development research. Furthermore, we can dissect the components and meaning of the unique system, activity instrument, and way components of sports administration industry, and recover the vital substance of the improvement of sports administration industry, to really advance the examination progress in the field of sports administration industry. Young people have always been important players in sports. As an important force of economic development, the health of young people is the cornerstone of promoting social development. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Khan S Analysis of social, psychological and other factors on college dropout rates among african american students Advances in Applied Sociology 2017 7 8 319 326 10.4236/aasoci.2017.78020 2. Jin-Wook C Hong-Sun S Eon-Ho K Incidence of sports injury in middle and high school fencers by gender, grade and type during training Kinesiology 2017 19 4 65 72 3. Letafatkar A Rabiei P Farivar N Long-term efficacy of conditioning training program combined with feedback on kinetics and kinematics in male runners Scandinavian Journal of Medicine & Science in Sports 2020 30 3 46 49 10.1111/sms.13587 31487062 4. Richmond S Berg CVD Owoeye O The efficacy of a neuromuscular training injury prevention warm-up program in junior high school students British Journal of Sports Medicine 2017 51 4 379 379 10.1136/bjsports-2016-097372.241 5. Soltyk O The peculiarities of physical education teachers' professional training: Foreign experience Comparative Professional Pedagogy 2017 7 4 154 162 10.1515/rpp-2017-0048 6. Vlad RA Hancu G Popescu GC Doping in sports, a never-ending story? Advanced Pharmaceutical Bulletin 2018 8 4 42 49 10.15171/apb.2018.062 7. Beijsterveldt AMV Richardson A Clarsen B Sports injuries and illnesses in first-year physical education teacher education students Bmj Open Sport & Exercise Medicine 2017 3 1 89 95 8. LaBella Cynthia R Youth sports injury prevention: Keep calm and play on British journal of sports medicine 2017 51 3 145 146 10.1136/bjsports-2016-096648 27919920 9. Hams A Evans K Adams R Epidemiology of shoulder injury in sub-elite level water polo players Physical Therapy in Sport 2019 35 2 127 132 10.1016/j.ptsp.2018.12.001 30551122 10. Lee YS Park DS Oh JK Prediction model for utilization of complementary and alternative medicine for sports injuries among Korean elite collegiate athletes Integrative Medicine Research 2020 9 2 435 439 10.1016/j.imr.2020.02.009 11. Toomas T Staffan J Jenny J Lifetime history of sexual and physical abuse among competitive athletics (track and field) athletes: Cross sectional study of associations with sports and non-sports injury British Journal of Sports Medicine 2018 53 5 74 79 12. Ohmi Y Hirose N Effects of a prevention program focused on hip joint function on the incidence of anterior cruciate ligament injuries in female basketball players British Journal of Sports Medicine 2017 51 4 367 368 10.1136/bjsports-2016-097372.213 13. Bakken A Targett S Bere T Interseason variability of a functional movement test, the 9+ screening battery, in professional male football players[J] British Journal of Sports Medicine 2017 51 14 1081 1089 10.1136/bjsports-2016-096570 27601450 14. 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Jayanthi N The effects of serial sports training risk assessment and counselling in kids track British Journal of Sports Medicine 2017 51 4 334 335 10.1136/bjsports-2016-097372.130 19. Carey DL Blanch P Ong KL Training loads and injury risk in Australian football—differing acute: Chronic workload ratios influence match injury risk British Journal of Sports Medicine 2017 51 16 1215 1220 10.1136/bjsports-2016-096309 27789430 20. Zwolski C Quatman-Yates C Paterno MV Resistance training in youth: laying the foundation for injury prevention and physical literacy Sports Health 2017 78 4 436 443 10.1177/1941738117704153 21. Murray JJ Renier CM Ahern JJ Neuromuscular training availability and efficacy in preventing anterior cruciate ligament injury in high school sports: A retrospective cohort study Clinical Journal of Sport Medicine 2017 27 6 524 529 10.1097/JSM.0000000000000398 27755010 22. Feletti, F., (2017) Extreme sports medicine training and injury prevention strategies in extreme sports, 10(26):337–355 23. Sara Ahmed Shereen Exercise therapy myofascial pain myofascial pain syndrome physical education and training Journal of exercise rehabilitation 2018 14 6 902 910 30656147

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==== Front Clin Transl Imaging Clin Transl Imaging Clinical and Translational Imaging 2281-5872 2281-7565 Springer International Publishing Cham 531 10.1007/s40336-022-00531-7 Systematic Review Myocardial perfusion imaging in the era of COVID-19: a systematic review Hassanzadeh Sara 1 Neshat Sina 2 Heidari Afshin 1 Moslehi Masoud moslehi@med.mui.ac.ir 3 1 grid.411036.1 0000 0001 1498 685X School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 2 grid.417467.7 0000 0004 0443 9942 Research Fellow, Department of Pulmonology, Allergy and Sleep Medicine, Mayo Clinic, Jacksonville, FL USA 3 grid.411036.1 0000 0001 1498 685X Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Hezar-Jarib Sreet, Isfahan, 81746-73461 Iran 15 12 2022 133 18 8 2022 4 11 2022 © The Author(s), under exclusive licence to Italian Association of Nuclear Medicine and Molecular Imaging 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Purpose As COVID-19 was uncovered, it became evident that specific individuals could experience multi-organ complications for quite a while after infection. Among them, there were several cardiovascular complications. Myocardial perfusion imaging single photon emission computed tomography (MPI SPECT) can be utilized to detect and evaluate cardiac problems regardless of whether COVID caused them. By examining all publications relevant to the impacts of the pandemic on SPECT MPI imaging, we aimed to understand how the COVID pandemic affected different aspects of the MPI, how intense these effects were, and what the consequences were. Method On the 6th of June, 2022, a four-domain search strategy was developed and implemented by searching the following databases: PubMed, SCOPUS, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. The retrieved records have been put through two levels of screening. The search for forward and backward citations provided more results. Results This study contained 32 papers, divided into the following three categories: 1. Case reports and series; 2. A comparison of the number of MPIs conducted before and after the pandemic; and 3. SPECT MPI findings. Conclusion We observed through the article review that CT scans performed in combination with MPI are crucial and should be interpreted within the context of COVID, especially during outbreaks. Moreover, we discovered that in the initial months of the pandemic, the number of SPECT MPIs performed globally decreased, with the fall being more significant in some countries, primarily in low- to middle-income regions. Lastly, we found that individuals with a history of COVID-19 may be more prone to having MPIs that demonstrate abnormalities, such as ischemia. Graphical abstract Keywords Myocardial perfusion imaging COVID-19 Systematic review ==== Body pmcIntroduction The first reports of this outbreak focused primarily on typical symptoms of influenza-like illness in patients with COVID-19, such as dry cough, fever, and fatigue [1]. In early 2020, a Chinese case report presented the first COVID-19 patient with cardiovascular injuries who died because of fulminant myocarditis [2]. However, later, researchers and scientists discussed cardiac injuries and their possible pathology and etiology in COVID-19 [3, 4]. There are several imaging modalities for diagnosing and evaluating different cardiovascular injuries caused by COVID-19 [5, 6]. It is still recommended that un-urgent and elective cardiac imaging be postponed in patients who are known cases of COVID-19 or are suspected to be [7, 8]. The use of cardiac imaging in positive or suspicious COVID-19 cases should only be considered if the imaging results affect the patient's management plan [5]. When indicated [9], one of the cardiac imaging modalities used is myocardial perfusion imaging (MPI). MPI, which is done by Single Photon Emission Computed Tomography (SPECT), is the most frequently applied nuclear cardiac imaging technique [10]. There are now 27,180 SPECT scanners worldwide in 141 countries [11]. Major indications of using myocardial SPECT are diagnosing coronary artery disease (CAD), risk stratification in patients with known CAD or after myocardial infarction or before non-cardiac surgeries, and assessment of intervention and myocardial viability before bypass or percutaneous surgery [12]. It can also diagnose ACS in emergency departments, assess ischemia in patients who had successful revascularization but had a recurrence of symptoms [13], and evaluate dyspnea with a possible cardiovascular cause [14]. MPI can be utilized to assess cardiovascular damage in COVID-19 or, as indicated before the pandemic, for non-COVID patients [15]. To perform MPI based on predetermined priorities in the COVID-19 era, it is necessary to take some measurements at various stages as follows: prior to the patient's arrival at the imaging facility, upon entry, during the imaging process, and after that. By taking these measures, infected and suspicious patients, covid-negative patients, and employees can be protected by decreasing their COVID-19 exposure [16–20]. As the back-to-normal situation advances, some of these measures will be adopted [21]. Guidelines for nuclear cardiology advocate against exercise stress testing in MPI in the era of COVID-19. Instead, they should use pharmacological stress tests with vasodilators to minimize droplet exposure to staff and reduce close contact between patients and staff. In addition, it is recommended to employ attenuation-corrected imaging during the COVID-19 pandemic. It is crucial to interpret CT scans taken for attenuation correction in the context of pulmonary COVID findings prior to discharge [19, 22], as COVID-19 pulmonary findings can occur in asymptomatic patients [18]. In light of the published guidelines and best practices to conduct SPECT MPI in the era of COVID-19, some of which were mentioned above, a broad research question has emerged as follows: has the COVID pandemic affected the cardiac nuclear imaging community and their patients? Moreover, what are the likely consequences of such a change if that is the case? The authors' primary searches revealed that, to the best of our knowledge, not all of the effects of the pandemic on the SPECT MPI imaging community had been examined in one broad framework simultaneously. We aimed to address this fundamental question for the following reason : to determine what effects the COVID pandemic had on various aspects of spect MPI and how intense these effects were. This is due to the fact that the COVID pandemic is still ongoing, and there is still a possibility of subsequent waves worldwide or regionally. Material and methods The Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) Statement was followed in the reporting of this systematic review. An electronic version of this systematic review protocol is available in The International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY®) (https://doi.org/10.37766/inplasy2022.4.0063). We included all English studies regardless of their study design, whether they were experimental or observational of all types, both original articles and conference abstracts. Exclusion criteria were as follows:Written in any language other than English. Theses, book chapters, editorials, and letters. In accordance with the PICO framework, participants were defined as anyone who had experienced SPECT MPI anywhere in the world since the COVID-19 pandemic, regardless of their age, gender, race, or health status. The intervention was SPECT MPI in any setting, regardless of whether it was performed at rest or under stress. Other nuclear cardiology imaging methods, such as positron emission tomography (PET), were not included in the study. Moreover, records of SPECT findings outside the myocardium were excluded. The comparators for this study included the number of SPECT MPIs done during the pandemic, the results of MPIs in COVID patients versus those without COVID, or any other aspect of SPECT MPI. The primary outcomes were as follows:Comparing the number of MPIs in multiple regions around the world before and during the pandemic, MPI findings in COVID-19 patients, in long-COVID cases, or in cases that were COVID-positive before. The secondary outcomes were as follows:A comparison of the increasing or decreasing trend among different regions of the world in terms of the number of SPECT MPIs performed Diagnosis of COVID-19 as an incidental finding in attention correction CT with MPI SPECT imaging Any other aspects of SPECT MPI which are influenced by the COVID-19 pandemic and its margins Case series and case reports about any aspect of SPECT MPI in the era of COVID-19. We searched PubMed, Scopus, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials (from Ovid) on June 6th, 2022. Additionally, we searched clinicaltrials.gov to see if any trials were currently underway. We looked for similar reviews in Prospero and Inplasy. Neither date nor language filters was used during these searches. To begin with, we conducted a sensitive PubMed search with four domains using the following components:A: Synonymous terms for COVID-19 and SARS-CoronoVirus-2: “post-acute COVID-19 syndrome” as supplementary concept, “COVID-19” as MeSH, and using title/abstract search filter for the terms: “covid”, “long-covid”, “long-haul covid”, long hauler covid”, “post acute covid”, “persistent covid”, chronic covid”, “sars-cov-2”, “2019-ncov”, corona virus”, “severe acute respiratory syndrome coronavirus”, “post-covid”, and representations synonyms or similar to these terms B: Myocardial perfusion imaging and its analogs: “Myocardial Perfusion Imaging” and “Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography” MeSHes, and using title/abstract search filter for the following terms: “myocardial scintigraphy”, “myocardial perfusion scintigraphy”, myocardial mibg scintigraphy”, “gmps”, myocardial ct perfusion”, “sestamibi myocardial scintigraphy”, “myocardial perfusion single-photon emission computed tomography”, “myocardial perfusion spect”, myocardial first-pass perfusion imaging”, “cardiac-gated spect”, and any terms synonyms or similar to these C: For SPECT and other related terms, we used “Single Photon Emission Computed Tomography” and “Perfusion Imaging” as MeSHes, and synonyms and similar terms for “spect” and “spects” using title/abstract search filters D: Myocardium, as a MeSH term and with the title/abstract search filter. Our search string was A and (B OR (C and D)); Table 1 lists the entire PubMed search string. All authors (AH, SH, and SSN) conducted this primary search string together through a virtual meeting via Google Meet and using the “rain of thoughts” technique; all authors (AH, SH, and SSN) conducted this primary search string together.Table 1 Main search strategy developing Domain Term(s) Search string Number of results (Pubmed) A COVID-19, long-COVID, or SARS-Corona Virus-2 "post-acute COVID-19 syndrome" [Supplementary Concept] OR “COVID-19"[Mesh] OR covid*[tiab] OR covid-19[tiab] OR covid-19[tiab] OR “long-covid*”[tiab] OR “long-haul covid*”[tiab] OR “post-acute covid*”[tiab] OR “persistent covid*”[tiab] OR “long covid*”[tiab] OR “long haul covid*”[tiab] OR “long hauler covid*”[tiab] OR “post acute covid*”[tiab] OR “persistent covid*”[tiab] OR “chronic covid*”[tiab] OR “sars-cov-2”[tiab] OR “2019-ncov”[tiab] OR “corona virus”[tiab] OR “coronavirus”[tiab] OR “novel coronavirus”[tiab] OR “ncov-2019”[tiab] OR “severe acute respiratory syndrome coronavirus”[tiab] OR “postcovid*”[tiab] OR “post covid*”[tiab] OR “post-covid*”[tiab] 277,655 B Myocardial SPECT “Myocardial Perfusion Imaging”[Mesh] OR “myocardial perfusion imaging”[tiab] OR “myocardial perfusion scan”[tiab] OR “myocardial scintigraphy”[tiab] OR “myocardial perfusion scintigraphy”[tiab] OR “myocardial mibg scintigraphy”[tiab] OR gmps[tiab] OR “myocardial ct perfusion”[tiab] OR “sestamibi myocardial scintigraphy”[tiab] OR “myocardial perfusion single-photon emission computed tomography”[tiab] OR “myocardial perfusion spect”[tiab] OR “spect myocardial perfusion”[tiab] OR “myocardial first-pass perfusion imaging”[tiab] OR "Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography”[Mesh] OR “cardiac gated single photon emission computer assisted tomography”[tiab] OR “cardiac-gated spect”[tiab] OR “cardiac gated spect”[tiab] 12,528 C SPECT "Single Photon Emission Computed Tomography Computed Tomography”[Mesh] OR “single photon emission computed tomography”[tiab] OR spect[tiab] OR spects[tiab] OR "Perfusion Imaging"[Mesh] 42,511 D Myocardium “Myocardium"[Mesh] OR myocard*[tiab] 538,990 C and D Myocardial SPECT 10,855 B or (C and D) Myocardial SPECT 16,552 A and (B or (C and D)) COVID-19 (or long-COVID or SARS-CoV-2) and Myocardial SPECT 22 Under the supervision of another author (SH), an author (AH) translated the search strategy from PubMed’s specified advance-search language to other databases’. Appendix A provides all the search strings for all databases. After developing search strings for all databases, on June 6, 2022, one of the authors (AH) retrieved all records from the databases. “Journal of Nuclear Cardiology” and “European Journal of Nuclear Medicine and Molecular Imaging” had the most search results using the Scopus database’s “Source title” filter (12 and 5 records, respectively). We also searched the Web of Science database using the “Publication Titles” filter. Each journal had five records, indicating that the two journals with the most relevant results were the same, each with five related records. As a result, we determined that these two journals contained the most relevant search results. As those journals were registered in PubMed, we ran two more sensitive searches on June 6th, 2022, in PubMed for those two journals, which are available in Appendix B. After adding all results to the resulting pool, one of the authors (AH) imported them to a newly created library in EndNote version 20 and performed an automated duplicate finding with the EndNote default settings. The remaining records were then sorted alphabetically from A to Z in the library, and the first and second authors separately looked through titles (and, if necessary, abstracts and full texts) to eliminate duplicates. The remaining records were imported into Rayyan, a free web tool designed to help researchers with systematic reviews [23], and two of the authors (AH and SH) screened them separately by title and abstract. Any records that did not fit our study questions’ scope were removed. All not-excluded records are tagged as “may be included.” One author (AH) transferred the records extracted from Rayyan to a library in Endnote, titled “maybe included,” and searched for any more probable relevant records in both the references to the records and the articles that cited them using Google Scholar. This approach, called “forward and backward citation search,” was done in 3 days by June 12th, 2022, and more articles were added to the “maybe included” library of Endnote. Following another automated duplicate detection, the library was sent to Rayyan for the second screening step. Records were screened independently by two of the authors (AH and SH) based on full texts provided by another author (SSN). “Included” was tagged to all records that met inclusion criteria and did not have exclusion criteria. Excluded articles were specified with their reasons for exclusion. The two authors talked about their disagreements about screening and tried to develop a consensus-based solution. Any remaining disagreements were brought to the third author (SNN) for a final resolution. In Microsoft Excel, one of the authors (AH) created a data-extraction form containing bibliographic information (title, first author, DOI, year, journal, country, type of article), the study design, as well as the findings, results, and the conclusion of the studies. Having finalized the process of selecting records, two of the authors (AH and SH) filled out the data-extraction form with all selected records, each on one line. The differences between the two were discussed and resolved after finalizing the data entry. In order to assess the risk of bias in all included studies, two authors (AH and SH) independently used critical appraisal tools developed by the Joanna Briggs Institute (jbi.global/critical-appraisal-tools). We evaluated and scored analytical cross-sectional, case–control, case reports, case series, cohorts, and prevalence cross-sectional studies using the JBI Checklists for Analytical Cross-Sectional Studies (8 questions), the Case–Control Checklist (10 questions), and the Case Report Checklist (8 questions), the Case Series Checklist (10 questions), the Cohort Study Checklist (11 questions), and the Prevalence Study Checklist (9 questions), respectively. Considering the heterogeneity of study designs and types included in this review, as well as the different checklists utilized with different maximum scores, we calculated the net score by dividing each paper's score by the maximum score it can achieve based on its checklist. It has been done to make comparisons and reporting easier. Here, low-quality scores are determined as less than 1/3, medium-quality scores are defined as between one-third and two-thirds, and high-quality scores are defined as over two-thirds. Study selection Among the 285 papers included in our record pool, 201 were obtained from searching electronic databases, including 22 records from PubMed, 60 records from SCOPUS, 85 from Embase, 30 from the Web of Sciences, and four from searches of the Cochrane Central Register of Controlled Trials accessed through Ovid. Alongside the search of the main databases, we retrieved 84 records from other sources, including three completed studies on the clinicaltrials.gov website, eight records from the Nuclear Cardiology journal, and 73 records from the European Journal of Nuclear Medicine and Molecular Imaging. A total of 119 duplicate records have been omitted from these 285 records, 115 by the automated duplicate finder in Endnote version 20, and four by hand. We screened the remaining 116 papers according to their title and abstract. One hundred three records were excluded and identified as irrelevant at this stage, and 63 records received approval for inclusion eligibility screening based on review of full texts. Using forward and backward citation methods, we searched through these 63 records, and, as a result, seven new unduplicated papers were added to our pool, making 70 full texts eligible for inclusion screening. In this stage, 38 papers were excluded; of those, 28 were not about SPECT or were about SPECT in an area other than myocardial, four were guidelines and recommendations, two were not about COVID-19, two were study protocols, one was in German, and one we were unable to locate the full text of. In the end, 32 records were finally included. In Fig. 1, the study selection process is summarized.Fig. 1 Prisma flow diagram of study selection Results Twelve of the 32 papers included were cross-sectional analytical studies, while four were cross-sectional prevalence studies. Two articles used a retrospective cohort study design, one utilized a historical cohort, and one used a prospective single-arm cohort design. An article was written as a case control. There were also ten case reports and a case series. Based on JBI critical appraisal tools, 21 papers were categorized as high quality, six as medium quality, and five as low quality. In Table 2, all studies that were finally included are listed, along with their study design, publication type, and quality assessment scores.Table 2 All finally included studies The first author Title Publication type/ Study design Year Journal JBI critical appraisal score Quality assesses* Nappi C Effects of the COVID-19 Pandemic on Myocardial Perfusion Imaging for Ischemic Heart Disease Analytical cross-sectional, Journal article 2020 European Journal of Nuclear Medicine and Molecular Imaging 8/8 High Aksu A Evaluation of Myocardial Perfusion Scintigraphy SPECT and CT Images in Patients with a History of COVID-19 Case–control, Conference abstract 2021 Journal of Nuclear Medicine 4/10 Medium Assante R Impact of COVID-19 Infection on Short-Term Outcome in Patients Referred to Stress Myocardial Perfusion Imaging Retrospective cohort, Journal article 2021 European Journal of Nuclear Medicine and Molecular Imaging 8/11 High Kudryavtsev A Molecular Imaging in Diagnosis of Cardiovascular and Lung Damage in Patients with COVID-19 Case series, Conference abstract 2021 European Journal of Nuclear Medicine and Molecular Imaging 4/10 Medium Salobir G Myocardial Perfusion Scintigraphy During the COVID-19 Pandemic—Findings from the University Teaching Hospital in Slovenia Analytical cross-sectional, Conference abstract 2021 European Heart Journal 2/8 Low Araz M Myocardial Perfusion SPECT Findings in PostCOVID Period Historical cohort, Journal article 2021 European Journal of Nuclear Medicine and Molecular Imaging 7/10 High Hasnie U Prevalence of Abnormal SPECT Myocardial Perfusion Imaging During the COVID-19 Pandemic Analytical cross-sectional, Journal article 2021 European Journal of Nuclear Medicine and Molecular Imaging 7/8 High Kutuk E Prior COVID-19 History Increases the Risk of Ischemia in Myocardial Perfusion CZT Detectors Scintigraphy Analytical cross-sectional, Conference abstract 2021 European Journal of Nuclear Medicine and Molecular Imaging 1/8 Low Scrima G Safety Measures and Clinical Outcome of Nuclear Cardiology Department During COVID-19 Lockdown Pandemic: Northern Italy Experience Prospective single-arm cohort, Journal article 2020 Journal of Nuclear Medicine 7/10 Low Cap M SPECT Myocardial Perfusion Imaging Identifies Myocardial Ischemia in Patients with a History of COVID-19 Without Coronary Artery Disease Analytical cross-sectional, Journal Article 2021 The International Journal of Cardiovascular Imaging 8/8 High Hasnie U Stress Testing and Myocardial Perfusion Imaging for Patients After Recovery from Severe COVID-19 Infection Requiring Hospitalization: A Single-Center Experience Retrospective cohort, Journal article/Brief report 2021 Journal of Nuclear Medicine 6/11 Medium Hindle-Katel W Incidental Finding of COVID-19 Pulmonary Infiltrates on SPECT/CT Attenuation Correction CT Case report 2020 Journal of Nuclear Medicine 7/8 High Malek H Extra-Cardiac Multifocal Lung Uptake of Tc-99 m-Sestamibi in Myocardial Perfusion Imaging: An Asymptomatic Case with Coronavirus Infection Features Case report 2020 Journal of Nuclear Medicine 5/8 Medium Delabie P Increased Lung Signal as a Hint of COVID-19 Infection on Tc-99 m-Sestamibi Myocardial Perfusion Scintigraphy Case report 2020 Journal of Nuclear Medicine 6/8 High Ananthasubramaniam K Lurking in the Shadows: Asymptomatic Bilateral Lung Involvement with Novel Corona Virus 2019 Identified on Myocardial Perfusion SPECT CT: Implications for Interpreting Physicians Case report 2020 Journal of Nuclear Medicine 8/8 High Yousefi-Koma A Multi-Modality Imaging of Inflammation and Ischemia for Assessment of Myocardial Injury in COVID-19 Case report 2020 Journal of Nuclear Medicine 5/8 Medium Kalantari F COVID-19 Manifestation on Tl-201 Myocardial Perfusion SPECT/CT Case report 2021 Iranian Journal of Nuclear Cardiology 8/8 High Cichocki P Mask-Related Motion Artifact on 99mTc-MIBI SPECT: Unexpected Pitfalls of SARS-CoV-2 Countermeasures Case report 2021 Diagnostics 7/8 High Dondi M Reduction of Cardiac Imaging Tests During the COVID-19 Pandemic: The Case of Italy. Findings From the IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID) Analytical cross-sectional, Journal article 2021 International Journal of Cardiology 6/8 High Freudenberg L Global Impact of COVID-19 on Nuclear Medicine Departments: An International Survey in April 2020 Prevalence cross-sectional, Journal article 2020 The Journal of Nuclear Medicine 9/9 High Giammarile F Changes in the Global Impact of COVID-19 on Nuclear Medicine Departments During 2020: An International Follow-Up Survey Prevalence cross-sectional, Journal article 2021 European Journal of Nuclear Medicine and Molecular Imaging 9/9 High Giammarile F Impact of COVID-19 on Nuclear Medicine Departments in Africa and Latin America Prevalence cross-sectional, Journal article 2021 Seminars in Nuclear Medicine 9/9 High Hirschfeld C Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World Analytical cross-sectional, Journal article 2021 JACC: Cardiovascular Imaging 8/8 High Einstein A International Impact of COVID-19 on the Diagnosis of Heart Disease Analytical cross-sectional, Journal article 2021 Journal of the American College of Cardiology 8/8 High O’Sullivan P Impact of COVID-19 on Diagnosis Cardiac Procedural Volume in Oceania: The IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID) Analytical cross-sectional, Journal article 2021 Heart, Lung and Circulation 8/8 High Williams C Impact of COVID-19 on the Imaging Diagnosis of Cardiac Disease in Europe Analytical cross-sectional, Journal article 2021 Open Heart 8/8 High Skali H Clinical and Economic Outcomes of Pharmacological Stress Tests in Patients with a History of COVID-19 Analytical cross-sectional, Conference abstract 2022 Journal of the American College of Cardiology 2/8 Low Bilge O The Effect of Coronavirus Disease 2019 Pneumonia on Myocardial Ischemia Detected by Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging Analytical cross-sectional, Journal article 2022 Nuclear Medicine Communications 8/8 High Koo B.S Mild or Asymptomatic COVID-19 Infection Is Associated with a High Likelihood of SPECT Myocardial Perfusion Abnormalities Even in the Absence of Obstructive Coronary Artery Disease Prevalence cross-sectional, Conference abstract 2022 Journal of the American College of Cardiology 7/9 High Osorio Martinez A SARS-CoV-2-Related Subacute Thyroiditis, Myocarditis, and Hepatitis After Full Resolution of COVID-19 Serum Markers Case report 2021 American Journal of Case Reports 8/8 High Emren Z.Y Spontaneous Right Coronary Artery Dissection in a Patient With COVID-19 Infection: A Case Report and Review of the Literature Case report 2021 Turk Kardiyologi Dernegi Arsivi 4/8 Medium Kunnirickal S Symptomatic Coronary Endothelial Dysfunction After Recovery From COVID-19 Case report, Conference abstract 2021 Journal of the American College of Cardiology 3/8 Low *For ease of comparison, this column’s calculation is based on the results of the JBI critical checklist. Scores below 1/3 are deemed to be of low quality, those between one-third and two-thirds are considered to be of medium quality, and scores above two-thirds are judged to be of high quality To present the results in an orderly and classified manner, all finally included records have been organized into one of these three categories:Case reports and case series, which have three sub-categories:CT-scan findings; Consideration of motion artifacts; Complications of COVID-19; Comparison of the number of performed MPIs before and after the pandemic at three levels:Countries, Continents, Global; MPI findings in active or previous COVID-19 patients. A summary of the results is provided in Table 3. The following explains each category in more detail:Table 3 Summary of findings Category Scope The first author Title Are of study Takeaway Quality assessed Comparing the numbers of performed SPECT MPIs before and after the pandemic Countries Nappi C Effects of the COVID-19 Pandemic on Myocardial Perfusion Imaging for Ischemic Heart Disease Italy Significant reduction of performed MPIs High Salobir G Myocardial Perfusion Scintigraphy During the COVID-19 Pandemic—Findings from the University Teaching Hospital in Slovenia Slovenia MPI numbers reduction in the first wave of COVID-19, which got back to normal in the second wave following reorganizing their schedule Low Hasnie U Stress Testing and Myocardial Perfusion Imaging for Patients After Recovery from Severe COVID-19 Infection Requiring Hospitalization: A Single-Center Experience USA Significant reduction of performed MPIs Medium Kutuk E.S Prior COVID-19 History Increases the Risk of Ischemia in Myocardial Perfusion CZT Detectors Scintigraphy Turkey Significant reduction of performed MPIs Low Countries versus the rest of the world Dondi M Reduction of Cardiac Imaging Tests During the COVID-19 Pandemic: The Case of Italy. Findings From the IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID) Italy vs. RoW and RoE MPI numbers reduction in Italy was more prominent compared to the RoW and RoE High Hirschfeld C Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World USA vs. RoW Reduction in performed MPIs was similar between the U.S and non-U.S. facilities High Continents Giammarile F Impact of COVID-19 on Nuclear Medicine Departments in Africa and Latin America Africa, and Latin America Significant reduction of performed MPIs High O’Sullivan P Impact of COVID-19 on Diagnosis Cardiac Procedural Volume in Oceania: The IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID) Oceania Considerable reduction in performed MPIs, which was less than the global decrease High Williams C Impact of COVID-19 on the Imaging Diagnosis of Cardiac Disease in Europe Europe MPIs numbers reduction, which was more than RoW High Worldwide Freudenberg L Global Impact of COVID-19 on Nuclear Medicine Departments: An International Survey in April 2020 Global Significant reduction of performed MPIs High Giammarile F Changes in the Global Impact of COVID-19 on Nuclear Medicine Departments During 2020: An International Follow-Up Survey Global Significant reduction of performed MPIs High Einstein A International Impact of COVID-19 on the Diagnosis of Heart Disease Global Significant reduction of performed MPIs High SPECT MPI findings Assante R Impact of COVID-19 Infection on Short-Term Outcome in Patients Referred to Stress Myocardial Perfusion Imaging Italy COVID-19 and abnormal MPI both increased cardiac event risk High Araz M Myocardial Perfusion SPECT Findings in PostCOVID Period Turkey The frequency of ischemia on MPI is much higher in patients with a history of COVID-19 High Cap M SPECT Myocardial Perfusion Imaging Identifies Myocardial Ischemia in Patients with a History of COVID-19 Without Coronary Artery Disease Turkey SARS-CoV-2 infection could predict abnormal MPI High Hasnie U Prevalence of Abnormal SPECT Myocardial Perfusion Imaging During the COVID-19 Pandemic USA The number of patients with MPI testing after COVID-19 infection will increase over time High Bilge O The Effect of Coronavirus Disease 2019 Pneumonia on Myocardial Ischemia Detected by Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging Turkey COVID-19 pneumonia could predict ischemia on SPECT-MPI High Koo B.S Mild or Asymptomatic COVID-19 Infection Is Associated with a High Likelihood of SPECT Myocardial Perfusion Abnormalities Even in the Absence of Obstructive Coronary Artery Disease USA Prior SARS-CoV-2 infection ais associated with SPECT MPI defects High Aksu A Evaluation of Myocardial Perfusion Scintigraphy SPECT and CT Images in Patients with a History of COVID-19 Turkey Even during COVID patients’ improvement interval, radiopharmaceutical uptake may be observed Medium Case reports and case-series Hindle-Katel W Incidental Finding of COVID-19 Pulmonary Infiltrates on SPECT/CT Attenuation Correction CT USA Importance of performing and reviewing CATC alongside SPCET MPI imaging during the pandemic High Malek H Extra-Cardiac Multifocal Lung Uptake of Tc-99 m-Sestamibi in Myocardial Perfusion Imaging: An Asymptomatic Case with Coronavirus Infection Features Iran Importance of performing CATC alongside SPCET MPI imaging during the pandemic Medium Delabie P Increased Lung Signal as a Hint of COVID-19 Infection on Tc-99 m-Sestamibi Myocardial Perfusion Scintigraphy France Importance of performing and reviewing CATC alongside SPCET MPI imaging during the pandemic High Ananthasubramaniam K Lurking in the Shadows: Asymptomatic Bilateral Lung Involvement with Novel Corona Virus 2019 Identified on Myocardial Perfusion SPECT CT: Implications for Interpreting Physicians USA Importance of performing and reviewing CATC alongside SPCET MPI imaging during the pandemic High Yousefi-Koma A Multi-Modality Imaging of Inflammation and Ischemia for Assessment of Myocardial Injury in COVID-19 Iran The acute inflammatory response precipitated by COVID might account for the perfusion defect in the rest SPECT Medium Kalantari F COVID-19 Manifestation on Tl-201 Myocardial Perfusion SPECT/CT Iran Importance of performing and reviewing CATC alongside SPCET MPI imaging during the pandemic High Cichocki P Mask-Related Motion Artifact on 99mTc-MIBI SPECT: Unexpected Pitfalls of SARS-CoV-2 Countermeasures Poland Mask-related motion artifacts can create false-positive MPS results High Osorio Martinez A SARS-CoV-2-Related Subacute Thyroiditis, Myocarditis, and Hepatitis After Full Resolution of COVID-19 Serum Markers Mexico When facing patients with cardiovascular symptoms, we should keep COVID and its complication in the post-COVID period in mind High Emren Z.Y Spontaneous Right Coronary Artery Dissection in a Patient With COVID-19 Infection: A Case Report and Review of the Literature Turkey Spontaneous coronary artery dissection may develop as a COVID-19 complication Medium Kunnirickal S Symptomatic Coronary Endothelial Dysfunction After Recovery From COVID-19 USA Some patients may experience endothelial dysfunction and smooth muscles hyperreactivity in the post-COVID period Low Kudryavtsev A Molecular Imaging in Diagnosis of Cardiovascular and Lung Damage in Patients with COVID-19 Russia COVID-19 may cause false-positive results on myocardial SPECT/CT Medium Other Scrima G Safety Measures and Clinical Outcome of Nuclear Cardiology Department During COVID-19 Lockdown Pandemic: Northern Italy Experience Italy The importance and necessity of implementing the published guidelines and best-practices Low Skali H Clinical and Economic Outcomes of Pharmacological Stress Tests in Patients with a History of COVID-19 USA Patients with a history of SARS-CoV-2 infection a year before performing pharmacological stress MPI were more likely to incorporate a reversal agent Low Case reports and case series Of ten case reports, nine were journal articles, and one was a conference abstract. Of those case reports, six were about computed tomography of the thorax and incidental findings; three were about complications of COVID-19, and one discussed the possibility of motion artifacts when patients wear a mask during MPI SPECT (Table 4).Table 4 Case reports and case series Article type The first author Patient no Country Gender, age Reason of referral MPI cardiac findings Pulmonary findings Covid Diagnosis Conclusion Case report Hindle-Katel W 1 USA Male, 65 Clinical suspicious for CAD Normal Abnormal pulmonary GGOs in the bilateral lower lobes in CATC COVID test was positive (doesn’t specify the test technique) With CTAC, it became possible to discover that he had COVID (as an incidental finding). That's why non-cardiac findings are also important in MPI/CTAC Malek H 2 Iran Male, 44 Preoperative risk stratification, had DOE without chest pain Stress-induced apical ischemia, LVEF = 60% Multifocal abnormal uptake in both lungs, corresponding to the CTAC GGOs CT images showed multiple peripherally distributed GGOs, typical of COVID lung involvement. The patient wasn’t tested right away, but was quarantined In regions where the disease has spread extensively, 99 m-Tc-sestamibi uptake in lungs could be considered a feature of pulmonary infection with COVID-19. Identifying and diagnosing COVID can be made easier with CTAC Delabie 3 France Male, 50 Has Had DOE since a month prior Normal In both lungs, high signals observed during thorax reconstruction for quality check. Following that, a chest CT revealed GGOs and crazy paving pattern Positive rtPCR The high lung signal can indicate an asymptomatic COVID-19 infection, especially in a normal LVEF. Also, as per ASNC, nuclear cardiology centers should be organized to identify symptoms of active COVID and prevent stress testing in patients showing them Ananthasubramaniam K 4 USA Male, 47 Risk assessment prior to be listed for kidney transplant Mild perfusion defect, and CTAC showed three vessel coronary calcification Peripheral GGOs in both lungs in CTAC Positive rtPCR COVID can hide in the shadows. Even though he had a bilateral involvement, the patient was asymptomatic. It reminds us of the importance of reviewing CTACs, where there are sometimes critical non-cardiac findings hidden Yousefi-Koma A 5 Iran Female, 69 Dyspnea and chest pain. LBBB in ECG. Echocardiography showed hypokinesis Rest perfusion defects Bilateral GGOs in chest CT Positive rtPCR The acute inflammatory response precipitated by COVID might account for the perfusion defect in the rest SPECT, although this is characteristics of myocarditis. CT images revealed the COVID infection in this case Kalantari F 6 Iran Female, 67 Assessment of IHD Normal Multifocal, bilateral, and peripheral GGOs in lungs, accompanied with fine background uptake of TI-201 According to the chest CT and considering the outbreak, the initial diagnosis was COVID. The patient was recommended to undergo a test, but she declined This case emphasizes the importance of non-cardiac findings in patients who undergo SPECT CT. Also, CTAC should be interpreted in the context of COVID. Before discharge, these images should be interpreted Cichocki P 7 Poland Male, 61 To exclude CAD Initial rest MPI showed a mild perfusion defect, and stress imaging showed stress-induced ischemia. The test was repeated because the result was inconsistent with the patient’s good condition, and the patient stated that his mask was in a bad position. The second stress image showed stress-induced ischemia. The only finding was a mild perfusion defect in the apex and inferoseptal wall of LV (which is common in LBBB) Mask-related motion artifacts can create false-positive MPS results (especially stress) that can lead to invasive procedures for the patient. This case report reminds us of the prominent role of technologists and the importance of matching the patient's bedside with test results Osorio Martinez A 8 Mexico Male, 64 Oppressive chest pain began three weeks after the COVID Normal GGOs in chest CT Positive rtPCR This case is about some possible complications after COVID. Some post-COVID patients might experience myocarditis. We should keep COVID and its complication in the post-COVID period in mind Emren Z.Y 9 Turkey Male, 50 To rule out infarction and ischemia, seven days after COVID diagnosis Myocardial ischemia in the inferior and posterior segments Positive rtPCR This case is about another possible complications of COVID, Spontaneous coronary artery dissection Kunnirickal S 10 USA Male, 65 Shortness of breath and DOE, with a history of COVID infection and intubation three months ago Chest pain during exercise MPI, with a minor apical anterior and septal defect Some patients may experience endothelial dysfunction and smooth muscles hyperreactivity in the post-COVID period. This case emphasizes the importance of physiological and provocative testing in this population Case series Kudryavtsev A 11–20 Russia 6 male, 4 female. 55 to 75 years old Among 10, seven patients had an increased LHR (mean 0.62, SD 0.1) COVID-19 may cause false-positive results on myocardial SPECT/CT in patients with the disease due to increase uptake in pulmonary tissue as well as an increase in the LHR. An FDG PET/CT might be clinically helpful in gathering information about the inflammatory process in the lung parenchyma CT-scan findings A total of six patients (Table 4, patients one to six), four males and two females, have been examined, ranging in age from 44 to 69. The most common previous cardiovascular disease among them was hypertension. All six patients have been found to have grand glass opacities (GGOs) on their chest CT. Patients 1 [24] and 3 [25] were referred for exercise SPECT MPI following dyspnea on exertion (DOE), which was reported to be normal. In the CTAC of patient 1, bilateral GGOs were seen in the inferior lobes. A SPECT acquisition quality check was undertaken by reconstructing the thorax of Patient 3, in which both lungs showed high signals. On chest CT, GGOs and crazy-paving patterns were found. Patients 2 [26] and 4 [27] were referred to MPI for risk assessment before kidney surgery. Patient two had DOE, but his ECG showed no abnormalities, so he underwent MPI for risk stratification before kidney transplant surgery, which revealed stress-induced ischemia without regional septal motion abnormalities and with an LVEF of 66%. Multiple extracardiac uptakes of 99 m-sestamibi were found in CTAC with GGOs. Detection of the SARS-CoV-2 infection in patient two is an incidental finding following CT scanning, as it was for patients 1 and 3. This case report argues that a multi-focal increase in 99-m-sestamibi uptake may indicate SARS-CoV-2 infection. Patient 4 had no general or cardiac symptoms and was referred to MPI for kidney transplant risk assessment. On the MPI, there was mild ischemia along with bilateral GGOs in the CATC, which was interpreted as COVID-19 lung involvement. Patient 2 and 4 CTACs showed SARS-CoV-2 infection involvement as incidental findings. Both authors of the above two case reports concluded that if multi-focal high uptake of sestamibi is reported, COVID-19 may be considered a differential diagnosis since COVID can hide in the shadows. Patients 5 [28] and 6 [29] also suggest that we should reconsider our diagnostic approach in the context of the COVID-19 pandemic when we must pay attention to both the probable COVIDIAn nature of our patients and the importance of noncardiac findings. Both CATC and MPI of patients should be interpreted in terms of the likelihood of SARS-CoV-2 infection and done upon discharge. Kudryavtsev et al. case series [30] findings are in accordance with patient 5. Ten patients with moderate COVID-19 in this case series underwent PET/CT with FDG and SPECT/CT with 99-m-to-mibi. Because of inflammatory changes in lung tissue, seven of the ten had an increased lung-to-heart ratio (LHR). In this case series, presented as a conference abstract, Kudryavtsev and colleagues reported that these changes may look like CAD, where usually diffuse myocardial hypo-perfusion can be the reason for increased LHR. However, myocardial PET/CT did not show any significant FDG uptake, and the greatest increase in uptake of FGF has occurred in areas with GGO involvement and mediastinal lymph nodes. Consolidations, on the other hand, have shown less uptake of FDG. As Kudryavtsev et al. concluded, myocardial SPECT in COVID-19 patients may lead to false-positive diagnoses of coronary artery disease (CAD) because of increased pulmonary tissue uptake and LHR increase; in these instances, FDG PET/CT could provide valuable information regarding inflammation within the lung parenchyma. Consideration of motion artifacts An occupational physician referred patient 7 [31] for the exclusion of CAD. On his initial electrocardiogram, LBBB was detected. He underwent rest MPI, which showed a mild perfusion defect in the inferoseptal wall and left ventricle apex. The patient then underwent stress MPI, which revealed multiple significant stress-induced ischemias. Since this finding did not align with the patient's good health, a nuclear medicine technician performed a quality control test, revealing that his heart was moving along the Z axis throughout the imaging. Additionally, the patient claimed that his mask had slipped into an uncomfortable position and caused him to experience breathing difficulties. After a second stress test was conducted on him, he had nothing but a fixed perfusion defect at the apex and inferoseptal wall, which is common in patients with LBBB. According to the case study, many patients use a mask during nuclear imaging during the pandemic period, which can lead to false-positive results during MPIs. So, nuclear medicine technologists should pay attention to these possible artifacts. Additionally, if the stress or rest imaging results were not in accordance with the patient’s clinical condition, additional data processing is required. Complications of COVID-19 In the last three patients (8, 9, and 10), SPECT MPI was performed to diagnose complications associated with COVID-19. It has been reported that COVID may cause three possible complications since the pandemic’s beginning. These include myocarditis in patient 8 [32], spontaneous coronary artery dissection in patient 9 [33], and post-COVID endothelial dysfunction in patient 10 [34]. As a result of the authors’ reports in these three studies, they assert that physicians should keep an eye out for cardiac and noncardiac complications that could result from SARS-CoV-2 infection. Comparing the number of MPIs before and after the pandemic Two of the 12 articles that compared the number of MPI SPECTs conducted before and after the pandemic were conference abstracts. The remaining nine were journal articles. As shown in Table 5, four of those 12 records dealt with a specific country (the United States, Turkey, Slovenia, and Italy), three focused on continents, and five were global (two were specific to a country versus the rest of the world). According to all of these studies, the number of SPECT MPIs performed following the pandemic was lower than before.Table 5 Comparing the numbers of performed SPECT MPIs before and after the pandemic The first author Area of study Location/Source Imaging technique Comparing pre and post pandemic Interpretation Reduction in Countries Nappi C Italy University of Napoli Federico II Stress SPECT MPI post-pandemic: Between February and May 2020: 123 pre-pandemic: Between February and May 2019: 418 Between February and May 2018: 415 Between February and May 2017: 413 The number of procedures during the pandemic was significantly lower (P < 0.0001) Salobir G Slovenia University Medical center Ljubljana SPECT MPI post-pandemic: Spring 2020 (the first wave): 233 Autumn 2020 (the second wave): 347 pre-pandemic: Spring 2019: 366 Autumn 2019: 349 During the first wave of the pandemic, they performed 40% fewer MPI They reorganized their schedule for COVID’s second wave patient numbers, which were once again comparable to last autumn Hasnie U USA University of Alabama Medical Center at Birmingham SPECT MPI post-pandemic: 2020, per month: 105 pre-pandemic: 2019, per month: 553 When the pandemic restrictions were at their peak, SPECT MPI studies were significantly reduced Kutuk E.S Turkey Ankara City Hospital SPECT MPI post-pandemic: August to November, 2020: 896 post-pandemic: August to November, 2019: 1415 There was a significantly lower number of procedures during the pandemic (P < 0.01) Reduction in a Country Versus the Rest of the World Dondi M Italy vs. RoW and RoE 52 Italian centers, and 909 centers from 198 countries Stress SPECT MPI Reduction of Stress SPECT in March 2020 compared to March 2019: Italy: 66% Rest of the world: 39% Rest of Europe: 46% (P < 0.001) Reduction of Stress SPECT in April 2020 compared to March 2019: Italy: 84% Rest of the world: 73% Rest of Europe: 78% (P = 0.006) There was a significant reduction of performed MPIs in Italy, which was more prominent compared to the rest of the world and the rest of Europe Hirschfeld C USA vs. RoW INCAPS COVID Stress SPECT MPI Reduction in the U.S in April 2020 compared to March 2019: 75% Reductions by U.S. regions: Midwest: 77%, Northeast: 87% South: 68% West: 47% Reduction in other countries in April 2020 compared to March 2019: 74% Early COVID-19 pandemic reductions in cardiovascular testing were similar between the U.S. and non-U.S. facilities. However, the Northeast and Midwest regions in the U.S experienced the greatest reductions in procedure volumes Reduction in Continents Giammarile F Africa, and Latin America Web based questionnaire, through a software hosted by IAEA SPECT MPI Africa: in June 2020: of 23, 70% of centers reported a reduction, 26% standstill in October 2020: of 23, 52% of centers reported a reduction, 13% standstill Latin America: in June 2020: of 61, 85% of centers reported a reduction, 16% standstill in October 2020: of 62, 79% of centers reported a reduction, 8% standstill As a result of pandemic-related challenges, nuclear medicine diagnostics and therapeutics decreased in 2020. A more significant negative impact is felt in low- or middle-income countries like Africa and Latin America. Compared to October, when the situation improved, the decline in June was greater. But still, the number of procedures conducted was lower than pre-pandemic O’Sullivan P Oceania INCAPS COVID Stress SPECT MPI Reduction of tests comparing March 2019 to April 2020: 44.3% Reduction by type of centers*: In metropolitan sites: 41% In regional sites: 48% In public sites: 43% In private sites: 47% In hospitals: 45% In outpatient sites: 43% Teaching centers: 42% Non-teaching centers: 52% *No significant reduction among none of them in the comparison Oceania has had a considerable decrease, which, of course, was less than the global decrease Williams C Europe INCAPS COIVD Stress SPECT MPI Reduction of tests comparing March 2019 to April 2020: Europe: 79% RoW: 73% Reduction by European region: Western: 73% Southern: 83% Eastern: 76% Northern: 77% Comparing the reduction of Europe to the rest of the world, the decline was more significant in Europe (P = 0.002), but there are no significant differences between various regions of Europe (P = 0.112) Worldwide Reduction Freudenberg L Global Web based questionnaire, through a software hosted by IAEA SPECT MPI 66% reduction reported in SPECT MPI studies (Questionnaires made available online from April 16th to May 3rd, 2020) This study shows a worldwide decline in SPECT MPI imaging centers’ activity during the COVID-19 pandemic Giammarile F Global Web based questionnaire, through a software hosted by IAEA SPECT MPI In June 2020: of 244 centers, 79.5% reported a reduction In October 2020: of 244 centers, 64.3% reported a reduction (Questionnaires made available online from November 23rd to 31st December, 2020) This study is a follow-up to the previous survey (Upper row, by Freudenberg L. et. Al). Again, it shows the reduction of nuclear medicine’s diagnostic and therapeutic services worldwide Einstein A Global INCAPS COVID Stress SPECT MPI Worldwide reduction comparing March 2019 to March 2020: 42% Worldwide reduction comparing March 2019 to April 2020: 74% Reduction from March 2019 to April 2020 by type of center: Reduction by type of facility: Hospital inpatient only: 72% Hospital inpatient and outpatient: 75% Hospital outpatient only: 71% Outpatient imaging Center: 77% Outpatient physician practice: 69% Reduction by teaching center status: Teaching: 75% Non-teaching: 73% Reduction by hospital beds: Lowest tertile: 81% Middle tertile: 78% Highest tertile: 70% All non-urgent outpatient procedures reductions: Not canceled: 72% Canceled: 78% During the COVID-19 pandemic, the activity of SPECT MPI imaging centers decreased worldwide The comparison of countries Nappi et al. conducted a comparison of stress SPECT MPIs performed at the Napoli Federico II center, Italy, between February and May 2020 with those performed at the same time in 2017, 2018, and 2019 [35]. The number of SPECT MPI during the pandemic was lower than the average for the preceding three years (P < 0.0001). It has been reported that in those months of 2020, approximately 36% of stress MPIs were abnormal, similar to the corresponding month of the previous three years (P = 0.65). Despite the fact that they had an average of 319 abnormal stress MPIs in the 3 years prior to the pandemic, it dropped to 44 abnormal tests during the pandemic, so Nappi et al. concluded that approximately 68% were missing. According to the study cohort's demographics, many were elderly, had hypertension, or were diabetic. At the University Medical Center Ljubljana in Slovenia, Salobir and colleagues compared MPIs carried out during two periods of the epidemic with those before the outbreak [36]. By spring 2019, during the first wave of the COVID-19 pandemic, the number of MPIs had been reduced to 40%, whereas by autumn 2020, the second wave, the number of MPIs had risen to almost as high as before the pandemic even started. Salobir et al. in that center reset their schedule planning and restored the number of MPIs to the level before the pandemic. Due to the possibility of SARS-CoV-2 virus transmission from asymptomatic patients, they have attempted to follow international community recommendations and increased the number of pharmacological stress MPI tests instead of stress tests. They continued with this approach until the second wave, but they then decided to increase the number of MPIs to reduce the negative impact of the COVID-19 pandemic on non-COVID patients, especially those with coronary artery disease (CAD). Hasnie et al. at the University of Alabama Medical Center in Birmingham, USA, compared the mean number of MPIs performed in 2020 with the mean number performed in 2019, which revealed an 81% decrease [37]. The number of abnormal SPECT MPIs was 31% in 2020 and 27% in 2019. The proportion of abnormal SPECT MPIs did not significantly change between the 2 years (P = 0.4). Based on the same calculation as Nappi et al. [35], Hasnie and colleagues found that about 81% of abnormal studies were missed during the COVID-19 pandemic. Kutuk et al. from Turkey compared the amount of MPI between August and November of 2020 to the same period in 2019 and found that SPECT MPIs in 2020 were significantly lower than in 2019 (P < 0.01) [38]. At the same time, the ischemic MPI rate in 2020 was higher than before the pandemic (42.2 versus 31.0%, P < 0.01). In the pandemic group, patients with a history of SARS-CoV-2 infection had a higher rate of ischemic MPIs than those without (52.4 versus 41.1%, P = 0.049). Therefore, they ultimately concluded that an individual with a history of SARS-CoV-2 infection was 1.5 times more likely to have ischemic MPI results (OR = 1.57, 95%CI, 1.003–2.470, P = 0.048). According to the study conducted by Kutuk and colleagues, infection with COVID-19 may lead to an increased risk of ischemia in patients undergoing SPECT MPI. Continent comparison The International Atomic Energy Agency (IAEA) conducted a survey in April 2020 in order to determine the initial impact of the COVID-19 pandemic on nuclear medicine facilities worldwide [39]. They conducted a follow-up study to further investigate the matter in October 2020 and June 2020 [40]. The Giammarile et al. study highlights that follow-up in Africa and Latin America [41]. The IAEA provided an online questionnaire powered by IAEA software for 6 weeks, from November 23 to December 31, 2020. In June 2020, 71% of 23 centers reported having lower MPI than pre-pandemic, and 26% of those centers had halted operations entirely. By October 2020, 52% of centers reported doing less MPI than before the pandemic, and 13% of centers were at a complete standstill. According to the paper by Giammarile and colleagues, of 61 centers in Latin America in June 2020, 85% performed less MPI than before COVID, and 16% of the centers ceased to operate. In October 2020, of 62 centers in Latin America, 70% of centers reported having less SPECT MPI than before the pandemic, and 8% of facilities stopped working. This study was conducted to examine the impact of the COVID-19 pandemic on nuclear medicine services in lower-middle-income countries. It was revealed that a significant decrease in nuclear medicine facilities' activities had occurred in Africa and Latin America due to the pandemic. Compared to October of the same year, the decline was more pronounced in June 2020, and between the two regions, it was more severe in South America. The non-invasive cardiology protocol survey on COVID (INCAPS COVID) was designed and carried out by the IAEA division of human health. Previously, the IAEA conducted numerous studies on cardiac nuclear imaging, including INCAPS-1, an international multi-center investigation into nuclear imaging activities [42]. INCAPS COVID was an international multi-center investigation designed to assess the impact of the COVID-19 pandemic on nuclear medicine imaging facilities [43]. INCAPS provided web-based questionnaires, and the International Research Integration System (iris.iaea.org) collected the data. These surveys included questions about health facilities, medical staff, personal protective equipment, plans for reopening centers damaged by the pandemic, and variations in the number of cardiac imaging procedures—like SPECT MPI—during the COVID-19 pandemic. These online questionnaires did not collect any personal information about the patients [44]. In addition to reviewing data obtained from facilities, the Data Coordination Committee dealt with mixed, duplicate, and inconsistent data. Ultimately, only one data set from each facility was used in the final analysis [45]. A total of 27 of the 936 questionnaires submitted for this survey were excluded, resulting in data collected from 909 centers in 198 countries [46]. In various papers that used INCAPS COVID data, the statistics of March and April 2020 have been compared with March 2019 as a basis for comparison. O’Sullivan et al. outlined INCAPS COVID data from 63 Oceania centers (including New Zealand, Australia, and Papua New Guinea) [44]. From March 2019 to April 2020, the number of stress SPECT MPIs conducted in Oceania decreased by 44.3%. During the research, the disparities among different facilities were also analyzed. In metropolitan areas, the decrease from March 2019 to April 2020 was 41%, whereas, in regional centers, it was 48%. There was a 43% reduction in public sites, while a 47% reduction was observed in private sites. In hospitals, the decrease was about 45%, while in outpatient facilities, it was 43%. The reduction in teaching and non-teaching centers was 42 and 52%, respectively. Significant reductions were not reported in either category. As reported by O’Sullivan and colleagues, cardiac nuclear facilities’ activities in Oceania and the rest of the world (RoE) have decreased, although the reduction in Oceania was relatively more minor. The authors of this article speculated that part of this reduction was possibly due to recommendations of nuclear imaging associations and legislative action taken by governments to reduce the spread of COVID-19. According to their conclusion, allocating resources to COVID should not result in the neglect of cardiovascular diseases, particularly since COVID can last for months or even years. Finally, the authors argued that this pandemic gave us a unique opportunity to reevaluate our healthcare systems from genesis. By doing this, we will be able to make a significant impact and improve our resource allocation mechanisms. INCAPS COVID findings on Europe were outlined by William et al. [45]. As compared to March 2019, the number of stress SPECT performed dropped by 79%, which is a significant decrease compared to a reduction of 73% from RoW (P = 0.002). They also assessed reductions in different regions of Europe: decreases in western, southern, eastern, and northern regions were 73, 83, 76, and 77%, respectively. Different parts of Europe showed no significant differences (P = 0.112). Global In two stages, an Internet questionnaire was sent to nuclear medicine facilities worldwide following the outbreak of COVID-19 through software hosted by the IAEA. The first stage was conducted between April 16 and May 3, 2020, and 434 responses were received from 72 countries. Freudenberg et al. noted in their paper that there was a 66% reduction in the number of SPECT MPIs performed globally [39]. The study of Giammarile and colleagues focused on the second phase, the first phase follow-up, in which questionnaires were available online for 6 weeks between November 23 and December 31 [40]. Of 505 respondents from 96 countries, data were extracted from 355 questionnaires. Among these, 338 questionnaires were fully completed. According to the prescribed survey, 79.5% of the 244 centers in June 2020 and 64.3% in October 2020 performed fewer MPIs. Throughout the world, nuclear medicine diagnostic and treatment services have declined, as described in this follow-up study by Giammarile et al. This decline was more pronounced in June 2020 than in October 2020. Compared to April 2020, the June 2020 nuclear medicine diagnostic and treatment services number was considerably lower, but not significantly different in the SPECT MPI area. Nevertheless, compared to before the pandemic, these services have decreased by more than 50%. In Einstein and associates’ paper, studies related to the INCAPS COVID executive committee survey are discussed, which included 909 centers from 108 countries [43]. Compared to March 2019, the worldwide reduction in stress SPECT was 42% in March and 74% in April 2020. Considering the differences among the types of centers, the reduction of various centers is also discussed. According to the type of facility, hospitals saw a 71% reduction, outpatient centers saw a 77% decline, and outpatient physician practices saw a 69% decrease. Based on teaching statutes, teaching centers had a 75% reduction, and non-teaching centers had a 73% reduction. According to the number of beds, the stress SPECT decreased 81% in the lowest tertile, 78% in the middle tertile, and 70% in the highest tertile. They conclude that the activity of nuclear medicine facilities worldwide declined following the pandemic’s beginning. The study suggests the need to plan for future pandemics by providing better access to cardiac diagnostic services worldwide, especially in low- and middle-income countries. Among the five studies examining the decline of SPECT MPIs globally, two evaluated a particular country compared to the RoW (Table 5). In a study using results from the IAEA survey, Dondi and colleagues assessed cardiac imaging tests performed in 52 Italian cardiac centers during the pandemic against 909 centers in 108 countries, as well as in other European countries [47]. In March 2020, stress SPECT tests decreased by 66% in Italy, compared to the rest of the world (RoW) and the rest of Europe (RoE), where reduction rates were 39% and 46%, respectively; this indicates that the Italian decrease was significant in comparison to those in RoW and RoE (P < 001). As stated by the authors of this study, in March and April 2020, the Italian health system faced unprecedented pressure due to the spread of COVID-19. Thus, the delivery of routine services was delayed, resulting in a decrease in the number of cardiac imaging procedures in Italy. They conclude that, given the vital importance of cardiac imaging in public health programs, departments in Italy and across the world should be prepared to provide medical services in critical conditions to patients and non-patients without endangering clinical staff. Using data from INCAPS COVID, Hirschfeld et al. compared the United States with the rest of the world [48]. The number of stress SPECTs performed decreased by 75% in April 2020 compared to March of that year in the United States, a decrease that was not statistically significant from the decrease observed in non-US countries (P = 0.062). In this study, different regions of the United States were also compared. In April 2020, compared to 2019, the reduction in stress SPECT test was 77% in the Midwest, 87% in the northeast, 68% in the south, and 47% in the west (P < 0.001). The decline was more pronounced in the northeast and the Midwest. According to this study, cardiovascular imaging tests declined sharply during the pandemic; in that period (between April 2020 and March 2019 as the baseline), there were about three-quarters fewer stress SPECT procedures worldwide, nearly the same number as for the United States. In their study, Hirschfeld et al. suggested that factors such as the spread of COVID, urban centers, outpatient imaging facilities, and staff redeployment resulted in fewer cardiac imaging services in the United States. SPECT MPI findings One of the seven papers published about SPECT MPI findings was a brief report journal article, two were conference abstracts, and the remaining three were journal articles of original research. Records are summarized in Table 6.Table 6 SPECT MPI findings The first author Country Sample size and characteristics Age (years) Male gender %) Study duration Conclusion Assante R Italy 960 patients (with known or suspected CAD) 64 ± 10 (Mean, SD) 67% January 2018–June 2019 During a short-term follow-up of patients undergoing stress MPI, subsequent COVID-19 infection was associated with a significantly higher cardiovascular event rate, independently of other cardiovascular risk factors COVID-19 and abnormal MPI both increased cardiac event risk in these patients CAD patients with COVID-19 infection may suffer a poor outcome due to its effects on the cardiovascular system Araz M Turkey of 179 patients: 85 in study group (confirmed prior COVID-19 infection) 94 in control group (non-COVID) Study group: 58.13 ± 9.07 (Mean, SD) Control group: 58.43 ± 9.42 (Mean, SD) Study group: 50.5% Control group: 55.3% Study group: August 2020-April 2021 Control group: January 2019-September 2019 The frequency of ischemia on MPI is much higher in patients with a history of COVID-19 Angiography, stent implantation, CABG, and medical therapy are also more common in these patients MPI can be used to investigate ischemia in patients presenting with cardiovascular symptoms late in COVID Cap M Turkey of 1888 patients: 340 patients in COVID-19 group 1548 in non-COVID group COVID-19 group: 55.8 ± 10.4 (Mean, SD) Non-COVID group: 56.1 ± 11.5 (Mean, SD) COVID-19 group: 33% Non-COVID group: 35% January 1st 2021-June 30th 2021 COVID-19 patients had higher ischemia rates in MPI than non-COVID-19 patients, and a prior COVID-19 infection could predict abnormal MPI CMD may cause symptoms like chest pain and shortness of breath in post-COVID-19 patients with ischemia in MPI and without critical coronary stenosis Hasnie U USA 15 patients with a history of COVID 60 (51–68) (Median, Range) 67% March 2020-October 2020 The number of patients with MPI testing after COVID-19 infection will increase over time Bilge O Turkey of 266 patients (with a history of COVID): 157 in pneumonia group 109 in non-pneumonia group 57 (50–64) (Median, IQR) 30% January 1st 2021-November 1st 2021 COVID-19 pneumonia could predict ischemia on SPECT-MPI Coronary ischemia may cause chest pain and shortness of breath in COVID-19 pneumonia patients Koo B.S USA 60 patients with a prior COVID infection June 2020-March 2021 Even mild or asymptomatic COVID infections without hospitalization are associated with SPECT MPI defects These SPECT data match cardiac MRI findings previously reported Aksu A Turkey 287 patients with a prior COVID infection October 2020-January 2021 The appearance of improvements in COVID patients’ images may take more than two weeks During this interval, radiopharmaceutical uptake may also be observed Using multivariable Cox analysis, Assante et al. found that abnormal MPI and a history of SARS-CoV-2 infection were predictive factors of CAD events in patients who had undergone SPECT MPI [49]. The annualized event rate among COVID patients with normal or abnormal MPI was not significantly different (P = 0.56). However, abnormal MPI was associated with an increased event rate in patients without past SARS-CoV-2 infection (P < 0.001). In both normal and abnormal TPD, patients with prior COVID infection had a higher event rate than those without previous infection. According to Assante and colleagues, subsequent SARS-CoV-2 infections are associated with increased cardiovascular events in the short term, independent of other cardiovascular factors. Furthermore, a history of COVID and an abnormal MPI were both associated with an increased risk of cardiovascular events among these patients. In conclusion, the COVID effect on the cardiovascular system may contribute to poor outcomes for patients with CAD. In their study, published as a conference abstract, Aksu et al. examined 287 patients with stress SPECT MPI [50]. They classified patients into two groups: those with only GGOs on CT scans and those with both GGOs on CT scans and Methoxy Isobutyl Isonitrile Technetium-99 m (MIBI) involvement. There were GGOs observed in non-diagnostic CT scans of 11 of the 22 patients with a history of COVID-19, and ten patients had Tc-99 m-MIBI involvement along with GGOs. Patients with Tc-99 m-MIBI involvement had a median time between COVID diagnosis and MPI of 50.5 days. In contrast, patients with only GGOs on CT scans had a median time of 63.5 days, indicating no significant difference between the two (P > 0.05). The authors conclude that while imaging models correlated with clinical improvement in patients with a history of COVID-19 usually occur within the first two weeks following infection, they might persist for an extended period following diagnosis. This may also be accompanied by an increase in the uptake of radiopharmaceuticals. The last five papers about SPECT MPI findings in the COVID-19 era all talk about MPI findings in patients who had MPI after the acute stage of COVID and in the post-COVID period. Araz et al. categorized patients with SARS-CoV-2 infection within the past six months as their study group and patients who had not had COVID during that period as the control group [51]. The two groups were matched based on age and gender. According to the analysis of the predominant reasons for MPI referral, dyspnea was more common among the study group patients than among the control group (P < 0.001), but chest pain did not differ significantly between the two groups (P = 0.028). A total of 85 patients (45.4%) had abnormal MPI results. Patients with a history of COVID were more likely to experience ischemia (P < 0.001). It was found that, regardless of MPI results, invasive evaluation with coronary angiography and treatment was more prevalent in the study group (P = 0.006 and P = 0.015). It was the same for the patients with abnormal MPI (P = 0.008 and P = 0.015, respectively). It was, however, not valid for the group with ischemic MPI results (P = 0.29 and P = 0.06, respectively). According to Araz and colleagues, patients with COVID in the last six months are more likely to have ischemia in MPI, require CAG, undergo CABG, and begin medical therapy. According to Araz et al., MPI can be a reliable diagnostic tool for patients exhibiting cardiovascular symptoms in the late stages of COVID. An additional study by Cap et al. examined 1888 patients, of whom 340 had a history of SARS-CoV-2 infection [52]. There were 340 of these patients, 26% (N = 88) of whom had abnormal MPI results showing ischemia (N: 46, TPD > 10%), 64 of whom underwent CAG for coronary stenosis, and 11 had coronary stenosis greater than 50%. While out of 1548 patients without COVID history, 19% (N = 297) had abnormal MPI results showing ischemia (N: 122, TPD > 10%), 192 underwent CAG angiography, and 53 had coronary artery stenosis of more than 50%. To assess the study’s hypothesis, myocardial ischemia in non-obstructive coronaries, Cap and colleagues excluded 64 patients from both groups with coronary stenosis greater than 50%. In the remaining patients of the study, abnormal MPI results were found in 77 patients (23%) with a history of COVID and 242 patients (16%) without; after using Bayesian logistic regression, an essential connection between SARS-CoV-2 infection presence in history and abnormal MPI results was found. When a weakly informative prior was used, the posterior median odds ratio was 1.70 (95% CI, 1.20–2.40), and the estimated risk difference was 9.6% (95% CI, 1.8%–19.7%). Based on the findings of this study, there was a probability of more than 90% for the odds ratio to become more significant than 1. This indicated any level of abnormal MPI risk. According to Cap and colleagues, patients with COVID had a higher ischemia rate than non-COVID patients, suggesting that previously confirmed infection with COVID may be an abnormal MPI predictor. Symptoms such as chest pain and shortness of breath, which can occur post-COVID in some patients, might be due to CMD in patients with ischemia in MPI and without critical coronary stenosis. Hasnie et al. conducted an outpatient study where stress tests were used to evaluate chest pain or shortness of breath [53]. Most patients had normal perfusion, except for one patient (7%) who showed a scar on the left anterior descending artery distribution. The mean LVEF was 55%. Among 11 patients who underwent a pharmacologic stress test, one complained of chest pain after receiving Regadenoson, and more than half reported dyspnea, but other symptoms were not severe. 75% of the patients who underwent exercise tests reported non-limiting shortness of breath, and 25% reported mild chest pain. In their published brief report Hasnie and colleagues concluded that more patients who recover from COVID require MPI to assess myocardial ischemia over time. Because of this, there is a growing need to do more research to come up with official protocols for nuclear imaging in this group. Bilge et al. conducted a study in which patients who had previously been infected with COVID and had a thorax CT scan were included [54]. Based on the CT findings, 157 patients were divided into two groups: those with pneumonia (57%) and those without pneumonia (43%). They were admitted to a hospital's outpatient cardiology department with symptoms of chest pain, shortness of breath, or both. They underwent MPI testing after recovering from COVID. The median time between COVID and MPI was 154 days (IQR, 81–224). It was found that 65 (24%) of these patients had ischemia findings on SPECT MPI. Coronary angiography was performed for 54 of them, and 11 patients had at least 50% stenosis. There were no significant differences between pneumonia and non-pneumonia groups in terms of age, gender, diabetes, hypertension, hyperlipidemia, or smoking. The abnormal SSS score and rate of abnormal SPECT MPI score were higher in the pneumonia group due to ischemia (P = 0.002 and P = 0.017, respectively). Bilge and his colleagues came to the conclusion that COVID-19 pneumonia could be an independent predictor of ischemia in SPECT MPI and that chest pain and shortness of breath in COVID patients might be related to coronary ischemia. During the study of Koo et al. of 80 patients who recovered from COVID and were referred for stress imaging, 36 of whom had never been hospitalized for COVID and had no history of coronary artery disease, were subjected to stress SPECT MPI [55]. Perfusion defects were found in 77.8% of the patients. Among the patients with at least one perfusion defect, 71.4% had a septal perfusion defect, 67.8% had an inferior wall defect, and 35.7% had an anterior wall defect. Twenty of the twenty-one patients (95%) with an abnormal stress SPECT MPI and some angiographic evaluations afterward showed no signs of obstructive CAD. As a result of the study, Koo and colleagues found a high prevalence of defects in stress SPECT MPI in patients with mild or asymptomatic COVID, which correlates with previous findings from cardiac MRI tests. Other papers The study by Scrima et al. also addresses SPECT MPI in the era of COVID-19 [56]. In this study, they designed an imaging protocol based on Regadenoson-stress 99 m-Tc-Tetrofsomin for single-day fast imaging. Patients were contacted by telephone four days before the test. They were asked about their COVID test positivity, their history of contact with an infected or suspected person, and their symptoms, such as coughing, fever, and breathing difficulties. The questionnaire was repeated on the day of the test. For admission to the department, patients must have a fever below 37.5 and be symptom free of SARS-CoV-2 infection on the day of the test. The patients should have worn surgical masks and gloves. Social distance was observed during the test, and healthcare personnel wore personal protective equipment. Sixty-six patients who had imaging from April 7th to May 15th, 2020, did not exhibit COVID symptoms during telephone follow-ups. As of May 18th, all staff members had tested negative for COVID. Using an extensive claims database (Pharmetric Plus), Skali et al. studied patients who had undergone pharmacological MPI between March 2020 and February 2021 [57]. A total of 6372 (3.5% of 179,803 patients) had a history of COVID-19 up to one year before the test. Skali and colleagues concluded that patients with a history of COVID a year before performing pharmacological stress MPI were more likely to incorporate a reversal agent without an increase in subsequent resource utilization or clinically significant costs. There may be no need to worry about pharmacological MPI in patients with a history of COVID-19. Conclusion In the aftermath of the COVID-19 pandemic, it is no longer a secret that the pandemic has changed the world as we knew it. The nuclear medicine imaging modality MPI SPECT has not been exempt from these changes. We realized the value of CT scans accompanied by MPI SPECT and, by reviewing several case reports, the importance of interpreting those CTACs in the context of the possibility of patients having COVID. The CTACs should be interpreted upon discharge, particularly in regions with a high prevalence of COVID. We also found that we should pay attention to the possible complications of COVID and long-COVID in patients with either a recent or distant history of SARS-CoV-2 infection. The importance of COVID history for patients with abnormal MPI was found to be significant since it may predict cardiovascular events. A decrease in MPI procedures caused by the pandemic resulted in diagnostic delays, which will adversely affect patient outcomes in the coming years. This situation demands special attention and preparation from the nuclear medicine community. While SPECT MPIs have declined considerably worldwide, this decline has been even more pronounced in low- and middle-income countries. It appears that the pandemic has magnified the differences that have always existed in access to nuclear medicine imaging facilities. More research is needed in this area. Appendix A search strings for all databases. 1. PubMed search string: results 6th June, 2022 (“post-acute COVID-19 syndrome” [Supplementary Concept] OR “COVID-19”[Mesh] OR covid*[tiab] OR covid-19[tiab] OR covid-19[tiab] OR “long-covid*”[tiab] OR “long-haul covid*”[tiab] OR “post-acute covid*”[tiab] OR “persistent covid*”[tiab] OR “long covid*”[tiab] OR “long haul covid*”[tiab] OR “long hauler covid*”[tiab] OR “post acute covid*”[tiab] OR “persistent covid*”[tiab] OR “chronic covid*”[tiab] OR “sars-cov-2”[tiab] OR “2019-ncov”[tiab] OR “corona virus”[tiab] OR “coronavirus”[tiab] OR “novel coronavirus”[tiab] OR “ncov-2019”[tiab] OR “severe acute respiratory syndrome coronavirus”[tiab] OR “postcovid*”[tiab] OR “post covid*”[tiab] OR “post-covid*”[tiab]) AND ((“Myocardial Perfusion Imaging”[Mesh] OR “myocardial perfusion imaging”[tiab] OR “myocardial perfusion scan”[tiab] OR “myocardial scintigraphy”[tiab] OR “myocardial perfusion scintigraphy”[tiab] OR “myocardial mibg scintigraphy”[tiab] OR gmps[tiab] OR “myocardial ct perfusion”[tiab] OR “sestamibi myocardial scintigraphy”[tiab] OR “myocardial perfusion single-photon emission computed tomography”[tiab] OR “myocardial perfusion spect”[tiab] OR “spect myocardial perfusion”[tiab] OR “myocardial first-pass perfusion imaging”[tiab] OR "Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography”[Mesh] OR “cardiac gated single photon emission computer assisted tomography”[tiab] OR “cardiac-gated spect”[tiab] OR “cardiac gated spect”[tiab]) OR (("Single Photon Emission Computed Tomography Computed Tomography”[Mesh] OR “single photon emission computed tomography”[tiab] OR spect[tiab] OR spects[tiab] OR "Perfusion Imaging"[Mesh]) AND (“Myocardium"[Mesh] OR myocard*[tiab]))). 2. Scopus search string: results 6th June, 2022 (TITLE-ABS-KEY(“post-acute COVID-19 syndrome” OR “covid-19” OR covid* OR covid19 OR “long-covid*” OR “long-haul covid*” OR “post-acute covid*” OR “persistent covid*” OR “long covid*” OR “long haul covid*”OR “long hauler covid*” OR “post acute covid*” OR “persistent covid*” OR “chronic covid*” OR “sars-cov-2” OR “2019-ncov” OR “corona virus” OR “coronavirus” OR “novel coronavirus” OR “ncov-2019″ OR “severe acute respiratory syndrome coronavirus” OR “postcovid*” OR “post covid*” OR “post-covid*”) AND (TITLE-ABS-KEY(“myocardial perfusion imaging” OR “myocardial perfusion scan” OR “myocardial scintigraphy” OR “myocardial perfusion scintigraphy” OR “myocardial mibg scintigraphy” OR gmps OR “myocardial ct perfusion” OR “sestamibi myocardial scintigraphy” OR “myocardial perfusion single-photon emission computed tomography” OR “myocardial perfusion spect” OR “spect myocardial perfusion” OR “myocardial first-pass perfusion imaging” OR "Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography” OR “cardiac gated single photon emission computer assisted tomography” OR “cardiac-gated spect” OR “cardiac gated spect”) OR (TITLE-ABS-KEY(“single photon emission computed tomography” OR spect OR spects OR "Perfusion Imaging”) AND TITLE-ABS-KEY(“Myocardium" OR myocard*)))). 3. Embase search string: results 6th June, 2022 (“long COVID”/exp OR ‘coronavirus disease 2019’/exp OR ‘Severe acute respiratory syndrome coronavirus 2’/exp OR covid*:ab,ti OR covid-19:ab,ti OR covid-19:ab,ti OR “long-covid*”:ab,ti OR “long-haul covid*”:ab,ti OR “post-acute covid*”:ab,ti OR “persistent covid*”:ab,ti OR “long covid*”:ab,ti OR “long haul covid*”:ab,ti OR “long hauler covid*”:ab,ti OR “post acute covid*”:ab,ti OR “persistent covid*”:ab,ti OR “chronic covid*”:ab,ti OR “sars-cov-2”:ab,ti OR “2019-ncov”:ab,ti OR “corona virus”:ab,ti OR “coronavirus”:ab,ti OR “novel coronavirus”:ab,ti OR “ncov-2019”:ab,ti OR “severe acute respiratory syndrome coronavirus”:ab,ti OR “postcovid*”:ab,ti OR “post covid*”:ab,ti OR “post-covid*”:ab,ti) AND ((‘myocardial perfusion imaging’/exp OR ‘nuclear stress test’/exp OR “myocardial perfusion imaging”:ab,ti OR “myocardial perfusion scan”:ab,ti OR “myocardial scintigraphy”:ab,ti OR “myocardial perfusion scintigraphy”:ab,ti OR “myocardial mibg scintigraphy”:ab,ti OR gmps:ab,ti OR “myocardial ct perfusion”:ab,ti OR “sestamibi myocardial scintigraphy”:ab,ti OR “myocardial perfusion single-photon emission computed tomography”:ab,ti OR “myocardial perfusion spect”:ab,ti OR “spect myocardial perfusion”:ab,ti OR “myocardial first-pass perfusion imaging”:ab,ti OR “cardiac gated single photon emission computer assisted tomography”:ab,ti OR “cardiac-gated spect”:ab,ti OR “cardiac gated spect”:ab,ti) OR ((‘single photon emission computed tomography’/exp OR ‘gated single photon emission computed tomography’/exp OR “single photon emission computed tomography”:ab,ti OR spect:ab,ti OR spects:ab,ti OR ‘scintigraphy’/exp) AND (‘cardiac muscle’/exp OR myocard*:ab,ti))). 4. Web of Science search string: results 6th June, 2022 (TS = (“post-acute COVID-19 syndrome” OR “covid-19” OR covid* OR covid19 OR “long-covid*” OR “long-haul covid*” OR “post-acute covid*” OR “persistent covid*” OR “long covid*” OR “long haul covid*”OR “long hauler covid*” OR “post acute covid*” OR “persistent covid*” OR “chronic covid*” OR “sars-cov-2” OR “2019-ncov” OR “corona virus” OR “coronavirus” OR “novel coronavirus” OR “ncov-2019” OR “severe acute respiratory syndrome coronavirus” OR “postcovid*” OR “post covid*” OR “post-covid*”) AND (TS = (“myocardial perfusion imaging” OR “myocardial perfusion scan” OR “myocardial scintigraphy” OR “myocardial perfusion scintigraphy” OR “myocardial mibg scintigraphy” OR gmps OR “myocardial ct perfusion” OR “sestamibi myocardial scintigraphy” OR “myocardial perfusion single-photon emission computed tomography” OR “myocardial perfusion spect” OR “spect myocardial perfusion” OR “myocardial first-pass perfusion imaging” OR "Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography” OR “cardiac gated single photon emission computer assisted tomography” OR “cardiac-gated spect” OR “cardiac gated spect”) OR (TS = (“single photon emission computed tomography” OR spect OR spects OR "Perfusion Imaging”) AND TS = (“Myocardium" OR myocard*)))). 5. Cochrane Central Register of Controlled Trials via Ovid search string: results 6th June, 2022 ((“post-acute COVID-19 syndrome” OR “covid-19” OR covid* OR covid19 OR “long-covid*” OR “long-haul covid*” OR “post-acute covid*” OR “persistent covid*” OR “long covid*” OR “long haul covid*”OR “long hauler covid*” OR “post acute covid*” OR “persistent covid*” OR “chronic covid*” OR “sars-cov-2” OR “2019-ncov” OR “corona virus” OR “coronavirus” OR “novel coronavirus” OR “ncov-2019″ OR “severe acute respiratory syndrome coronavirus” OR “postcovid*” OR “post covid*” OR “post-covid*”).ti,ab AND ((“myocardial perfusion imaging” OR “myocardial perfusion scan” OR “myocardial scintigraphy” OR “myocardial perfusion scintigraphy” OR “myocardial mibg scintigraphy” OR gmps OR “myocardial ct perfusion” OR “sestamibi myocardial scintigraphy” OR “myocardial perfusion single-photon emission computed tomography” OR “myocardial perfusion spect” OR “spect myocardial perfusion” OR “myocardial first-pass perfusion imaging” OR "Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography” OR “cardiac gated single photon emission computer assisted tomography” OR “cardiac-gated spect” OR “cardiac gated spect”).ti,ab OR ((“single photon emission computed tomography” OR spect OR spects OR "Perfusion Imaging”).ti,ab AND (“Myocardium" OR myocard*).ti,ab))). Appendix B more sensitive pubmed search strings for two journals which had most papers among all sources. A. Journal of Nuclear Cardiology search via PubMed: results 6th June, 2022 "J Nucl Cardiol”[jour] AND (covid OR corona) AND (mpi OR myocardial perfusion OR scintigraphy OR spect OR single photon emission computed tomography). B. European Journal of Nuclear Medicine and Molecular Imaging search via PubMed: results 6th June, 2022 "Eur J Nucl Med Mol Imaging"[jour] AND (covid OR corona) AND (mpi OR myocardial perfusion OR scintigraphy OR spect OR single photon emission computed tomography). Funding In order to prepare this paper, the authors declare that they have not received any governmental or non-governmental funding, grants, or other supports during the preparation of the manuscript. Declarations Conflicts of interest There is no conflict of interest reported by the authors. Ethical approval This paper does not contain any studies with human or animal participants performed by any of the authors. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Wu Z McGoogan JM Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention Jama 2020 323 1239 42 10.1001/jama.2020.2648 32091533 2. Varga Z Flammer AJ Steiger P Haberecker M Andermatt R Zinkernagel AS Endothelial cell infection and endotheliitis in COVID-19 The Lancet 2020 395 1417 1418 10.1016/S0140-6736(20)30937-5 3. Fox SE Li G Akmatbekov A Harbert JL Lameira FS Brown JQ Unexpected features of cardiac pathology in COVID-19 infection Circulation 2020 142 1123 1125 10.1161/CIRCULATIONAHA.120.049465 32689809 4. 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Cichocki P Adamczewski Z Kuśmierek J Płachcińska A Mask-related motion artifact on 99mTc-MIBI SPECT: unexpected pitfalls of SARS-CoV-2 countermeasures Diagnostics 2021 11 1426 10.3390/diagnostics11081426 34441360 32. Martínez AO González-Razo VT Navarro-Sánchez V Meiriño CAS Ahumada-Ayala M SARS-CoV-2-related subacute thyroiditis, myocarditis, and hepatitis after full resolution of COVID-19 serum markers Am J Case Rep 2021 22 e932321 e932331 34138828 33. Emren ZY Emren V Özdemir E Karagöz U Nazlı C Spontaneous right coronary artery dissection in a patient with COVID-19 infection: a case report and review of the literature Turk Kardiyol Dern Ars 2021 49 334 338 10.5543/tkda.2021.34846 34106068 34. Kunnirickal S Spatz E Shah S SYMPTOMATIC CORONARY ENDOTHELIAL DYSFUNCTION AFTER RECOVERY FROM COVID-19 J Am Coll Cardiol 2021 77 1965 10.1016/S0735-1097(21)03321-0 35. 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Assante R D’Antonio A Mannarino T Gaudieri V Zampella E Mainolfi CG Impact of COVID-19 infection on short-term outcome in patients referred to stress myocardial perfusion imaging Eur J Nucl Med Mol Imaging 2022 49 1544 1552 10.1007/s00259-021-05619-2 34773166 50. Aksu A Vural Topuz O Yilmaz B Evaluation of myocardial perfusion scintigraphy SPECT and CT images in patients with a history of COVID-19 J Nucl Med 2021 62 3027 51. Araz M Soydal Ç Sütçü G Demir B Özkan E Myocardial perfusion SPECT findings in postCOVID period Eur J Nucl Med Mol Imaging 2022 49 889 894 10.1007/s00259-021-05552-4 34490492 52. Çap M Bilge Ö Gündoğan C Tatlı İ Öztürk C Taştan E SPECT myocardial perfusion imaging identifies myocardial ischemia in patients with a history of COVID-19 without coronary artery disease Int J Cardiovasc Imaging 2022 38 447 456 10.1007/s10554-021-02477-9 34811596 53. Hasnie UA Hawi R Andrikopoulou E Iskandrian AE Hage FG Stress testing and myocardial perfusion imaging for patients after recovery from severe COVID-19 infection requiring hospitalization: a single-center experience J Nucl Cardiol 2021 28 2167 2173 10.1007/s12350-021-02606-w 33904148 54. Bilge Ö Kömek H Kepenek F Taştan E Gündoğan C Tatli İ The effect of coronavirus disease 2019 pneumonia on myocardial ischemia detected by single-photon emission computed tomography myocardial perfusion imaging Nucl Med Commun 2022 10 1097 55. Kim BS Yu A Busch S Lassen J Makaryus JN MILD OR ASYMPTOMATIC COVID-19 INFECTION IS ASSOCIATED WITH A HIGH LIKELIHOOD OF SPECT MYOCARDIAL PERFUSION ABNORMALITIES EVEN IN THE ABSENCE OF OBSTRUCTIVE CORONARY ARTERY DISEASE J Am Coll Cardiol 2022 79 2114 10.1016/S0735-1097(22)03105-9 56. Scrima G D’Amico M Bertuccio G Canavese G De Sanctis P Safety measures and clinical outcome of nuclear cardiology department during Covid-19 lockdown pandemic: Northern Italy experience J Nucl Cardiol 2021 28 331 335 10.1007/s12350-020-02286-y 32737838 57. Skali H Walker D Lima RB Gurumoorthy G Davies K Kimura T CLINICAL AND ECONOMIC OUTCOMES OF PHARMACOLOGICAL STRESS TESTS IN PATIENTS WITH A HISTORY OF COVID-19 J Am Coll Cardiol 2022 79 2095 10.1016/S0735-1097(22)03086-8

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==== Front Int J Diabetes Dev Ctries Int J Diabetes Dev Ctries International Journal of Diabetes in Developing Countries 0973-3930 1998-3832 Springer India New Delhi 1143 10.1007/s13410-022-01143-7 Guidelines RSSDI Guidelines for the management of hypertension in patients with diabetes mellitus Kumar Vasanth 12 http://orcid.org/0000-0002-8889-2626 Agarwal Sanjay agarwalclinic@gmail.com 345 Saboo Banshi 67 Makkar Brij 89 1 grid.428010.f 0000 0004 1802 2996 Apollo Hospitals, Hyderabad, India 2 President. RSSDI, Prune, India 3 Aegle Clinic-Diabetes Care, Pune, India 4 grid.419353.9 0000 0004 1805 9940 Department of Medicine and Diabetes, Ruby Hall Clinic, Pune, India 5 Secretary-General, RSSDI, Pune, India 6 Immediate Past-President, RSSDI, Pune, India 7 grid.477253.0 Dia-Care Hormone Clinic, Ahmedabad, India 8 President-Elect, RSSDI, Prune, India 9 Dr Makkar’s Diabetes & Obesity Centre, A-5B/122, Paschim Vihar, New Delhi, 110063 India 15 12 2022 130 20 5 2022 1 11 2022 © The Author(s), under exclusive licence to Research Society for Study of Diabetes in India 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Hypertension and diabetes mellitus (DM) are two of the leading lifestyle diseases in the Indian and South Asian populations that often co-exist due to overlapping pathophysiological factors. Obesity, insulin resistance, inflammation, and oxidative stress are thought to be some common pathways. Up to 50% of hypertensive cases in India are diagnosed with type 2 diabetes mellitus (T2DM), which defines the need for a comprehensive guideline for managing hypertension in diabetic patients. These RSSDI guidelines have been formulated based on consultation with expert endocrinologists in India and Southeast Asia, acknowledging the needs of the Indian population. Ambulatory blood pressure monitoring and office and home-based blood pressure (BP) monitoring are recommended for the early analysis of risks. Cardiovascular risks, end-organ damage, and renal disorders are the primary complications associated with diabetic hypertension that needs to be managed with the help of non-pharmacological and pharmacological interventions. The non-pharmacological interventions include the nutrition education of the patient to reduce the intake of salt, sodium, and trans fats and increase the consumption of nuts, fresh fruits, vegetables, and potassium-rich foods. It is also recommended to initiate 50 to 60 min of exercise three to four times a week since physical activity has shown to be more beneficial for hypertension control in Indian patients than dietary modulation. For the pharmacological management of hypertension in patients with T2DM, angiotensin II receptor blockers (ARBs) are recommended as the first line of therapy, demonstrating their superiority over other antihypertensive agents such as ACEi. However, most of the global hypertension guidelines recommend initiation with combination therapy to achieve better BP control in most patients and to reduce the risk of adverse events. For combination therapy, calcium channel blockers (CCBs) are recommended to be administered along with ARBs instead of beta-blockers or diuretics to avoid the risk of cardiovascular events and hyperglycaemia. Among the CCBs, novel molecules (e.g. cilnidipine) are recommended in combination with ARBs for better cardiovascular and reno-protection in diabetic hypertensive patients. Keywords Diabetes mellitus Hypertension Macrovascular complication Treatment ==== Body pmcIntroduction Currently, hypertension is a major public health issue in India, causing over 1.6 million annual deaths accounting for 10.8% of the total mortalities and 4.6% of the disability-adjusted life years [1]. Both conditions’ co-existence is common in the middle and older age groups across all geographic and sociodemographic groups in India [2]. A crucial consideration for the management of hypertension in Indian subjects is the management of risk factors, which can be achieved through a combination of treatment approaches [3]. To manage the co-existing diseases, there is a need for detailed guidelines that consider the safety and efficacies of various treatment agents in patients with DM. This guideline by the Research Society for the Study of Diabetes in India (RSSDI) provides a detailed account of the standard, approved, and novel treatment agents to be used in India for controlling hypertension in patients with DM and for managing and reducing the risks of associated complications and organ damage. It also will describe lifestyle modification strategies and dietary approaches recommended for patient education, which is a pressing need for the Indian population [4]. This guideline focusses only on the management of hypertension in diabetic patients. Discussion on the non-pharmacological or pharmacological management of diabetes and special populations like pregnancy may not be in the purview of this guideline. Definition of hypertension Hypertension or systemic arterial hypertension refers to persistently high blood pressure in the systemic arteries beyond 140 mmHg [5]. ACC/AHA guidelines have changed the range to 130/80; however, Indian Guideline of Hypertension IV (IGH IV) guideline defines hypertension as systolic blood pressure (SBP) of ≥ 140 mmHg and/or diastolic blood pressure (DBP) of ≥ 90 mmHg [6]. Classification of blood pressure Blood pressure is defined as the pressure exerted on the blood vessels due to blood flow. Measurement of systolic pressure refers the pressure in arteries when the heart beats while the diastolic pressure refers the pressure in arteries when the heart rests between beats. A pressure below 120/80 mmHg is normal for all age groups. Table 1 shows a classification of normal and elevated blood pressure. When the BP levels of the patient are far beyond the normal and range higher than 180/120 mmHg, they are in a state of hypertensive crisis (as referred by AHA) requiring immediate medical attention [6].Table 1 Various blood pressure categories and definitions of hypertension grade [6] Blood pressure category Systolic mmHg (upper number) Diastolic mmHg (lower number) Normal Less than 120 and Less than 80 Elevated 120–129 and Less than 80 High blood pressure (hypertension) stage 1 130–139 or 80–89 High blood pressure (hypertension) stage 2 140 or higher or 90 or higher High blood pressure (hypertension) stage 3 OR hypertensive crisis Higher than 180 and/or Higher than 120 Other criteria based on office, ambulatory (ABPM), and home blood pressure (HBPM) measurements are shown in Table 2.Table 2 Office, ambulatory (ABPM), and home blood pressure (HBPM) measurements [6] SBP/DBP, mmHg Office BP  ≥ 140 and/or ≥ 90 ABPM    24-h average  ≥ 130 and/or ≥ 80    Daytime (or awake) average  ≥ 135 and/or ≥ 85    Nighttime (or asleep) average  ≥ 120 and/or ≥ 70  HBPM  ≥ 135 and/or ≥ 85 Types of hypertension Based on causative factors Primary or essential hypertension Primary hypertension is mostly asymptomatic and is diagnosed based on repeated BP measurements or community screening [5]. Positive family history because of involvement of multiple genes and their allelic variants [5] Up to 60% of the population above 60 years of age is more susceptible to primary hypertension [7]. Indian patients with primary hypertension are mostly unaware of their status and remain undetected. Hence, the Ministry of Health and Family Welfare Guidelines have advised that patients with positive risk factors such as obesity, diabetes mellitus, previous history of cardiovascular disease, patients above 60 years, and current smokers must be screened regularly [8]. Salt-sensitive hypertension Patients’ response to salt due to the genetic build-up is one of the described factors for the development of essential hypertension. Not all individuals demonstrate a rise in BP due to the intake of a salt-rich diet. Salt sensitivity is a crucial element in the pathophysiology of hypertension. It is involved in both mechanisms of hypertension: (a) increased pulse volume and inability to excrete sodium in the urine and (b) endothelial dysfunction and increased peripheral resistance. Salt-sensitive hypertension is presented by a significant increase or decrease in the BP levels of the patient depending on the salt content of the diet [9]. In Indian patients, salt intake has been a significant barrier to managing hypertension, as the average intake is as high as 13.8 g per day [4]. Approximately 17–30% of cases of hypertension and associated cardiovascular conditions have been attributed to high salt consumption in India [4]. It also increases the risk of endothelial dysfunction and renal function decline [9] The possible mechanism by which excess salt intake contributes to hypertension involves its effects on cardiac output. Excessive salt intake leads to an expansion of extracellular volume in the presence of sodium, which causes an increase in the cardiac output, increasing the cardiac workload. Reduction of dietary salt intake, thus, has a positive effect and is thus recommended in Indian patients [10]. Secondary hypertension Secondary hypertension is often due to an identifiable reason showing sudden worsening of BP. It is secondary to other diagnoses such as aldosteronism, reno-vascular hypertension, renal disease, and obstructive sleep apnea (OSA) [5]. The prevalence of secondary hypertension is about 5–10% of hypertensive cases, wherein 2–3% cases are reno-parenchymal hypertension, and 1–2% are reno-vascular [11]. As per the International Society of Hypertension, the following signs and symptoms should suggest the possibility of secondary hypertension [12]:Muscle weakness/tetany Cramps, arrhythmias Hypokalemia Pulmonary edema Sweating Palpitations Frequent headaches (pheochromocytoma) Snoring, daytime sleepiness (obstructive sleep apnea) Across all adult ages, renal disease, reno-vascular hypertension, aldosteronism, and OSA represent the most common causes of secondary hypertension. In patients with secondary hypertension, besides blood pressure assessment, further investigations should include blood investigations for the sodium, potassium, serum creatinine, estimated glomerular filtration rate (eGFR), lipid profile, and fasting glucose levels, along with urinalysis. Clinical recommendations in practice for the evaluation of hypertension are for early detection of secondary hypertension, for prevention of hypertension-mediated organ damage (HMOD) and associated cardiovascular complications [13]. Young adults prone to secondary hypertension should be assessed for renal parenchymal disease [14]. Based on disease severity Resistant hypertension Patients in whom hypertension remains unmanaged despite being treated with 3 or more antihypertensive medications, including diuretics, are classified to have treatment-resistant hypertension after ruling out non-adherence to treatment and sub-optimal choices in antihypertensive therapy [5]. It affects about 10% of the population and is associated with a high risk of cardiovascular disorders, end-organ damage, and all-cause mortality [12]. Patients with resistant hypertension must be screened for secondary causes with the help of lab investigations that have been outlined above as per guidelines by the International Society of Hypertension. Hypertension in special populations Isolated systolic hypertension In elderly patients, isolated systolic hypertension is the predominant type that carries a significant cardiovascular or cerebrovascular risks, leading to significant morbidity and mortality [15]. Approximately 60% of individuals above the age of 60 years have isolated systolic hypertension, and its prevalence is expected to rise substantially in the future [15]. The incidence of isolated systolic hypertension is lower among generalized adult age groups in India, with 5.1% of men and 3.6% of women being diagnosed in North India as per the findings of a community cross-sectional survey conducted in the year 2010 [16]. However, isolated diastolic hypertension has also been identified in parts of rural India, which has a much higher prevalence of 70%, according to another cross-sectional survey of 3148 adults [17]. Overall, Asian populations have been identified to be at a greater risk of systolic hypertension when compared with Western counterparts putting, which increases the risk of cardiovascular disorders, renal functional decline, and mortality [18]. Gestational hypertension: In pregnant women, hypertension with or without the diagnosis of preeclampsia is termed gestational hypertension, which increases the risk of maternal mortality and fetal abnormalities [19]. Refer to Table 3 for the diagnosis and blood pressure range for various types of hypertension [20].Table 3 Types of hypertension with a blood pressure range [20] Type of hypertension Description Blood pressure range Essential hypertension (most common type) Chronic elevation in blood pressure with no underlying disease Both systolic and diastolic blood pressures are elevated at more than 140/90 mmHg Secondary hypertension (second most common type) Chronic elevation in blood pressure due to underlying pathology (mostly due to renal problems) Both systolic and diastolic blood pressure are elevated at more than 140/90 mmHg Isolated systolic hypertension Common in the elderly due to the loss of elasticity of major arteries The systolic blood pressure is higher than 140 mmHg, while the diastolic blood pressure is close to the normal range Resistant hypertension When more than three different antihypertensive agents are prescribed, including a diuretic, and blood pressure remains elevated Both systolic and diastolic blood pressures are elevated at more than 140/90 mmHg Other sub-types of hypertension White coat hypertension White coat hypertension, also called isolated clinic hypertension, is characterized by elevated office BP readings but normal out-of-the-office values [1]. Ambulatory blood pressure monitoring is recommended for the diagnosis of white coat hypertension. Patients with office BP values at least 20/10 mmHg higher when compared with their ambulatory values are positive for white coat hypertension [21]. In Indian patients, the risk of white coat hypertension is higher among younger populations compared to the elderly [21]. Masked hypertension Masked hypertension, or isolated ambulatory hypertension, refers to a state where the patient has normal office readings but elevated out-of-the-office BP levels [5, 22]. It is diagnosed with the help of office blood pressure monitoring and ambulatory monitoring. The risk of masked hypertension is not related to the age group of patients in the Indian population. Overall, patients who are receiving appropriate treatment for the management of hypertension are at a lower risk of masked hypertension [23]. Refer to Table 4 for the diagnosis of masked and white coat hypertension.Table 4 Criteria for the diagnosis of white coat hypertension and masked hypertension in clinical practice [21] • White-coat hypertension (isolated clinical hypertension)    ○ Untreated patients with elevated office BP ≥ 140/90 mmHg and 24-h ambulatory BP < 130/80 mmHg and       Awake ambulatory BP < 135/85 mmHg and       Sleep ambulatory BP < 120/70 mmHg • Masked hypertension    ○ Untreated patients with office BP < 140/90 mmHg and       24-h ambulatory BP ≥ 130/80 mmHg and/or       Awake ambulatory BP ≥ 135/85 mmHg and/or       Sleep ambulatory BP ≥ 120/70 mmHg • Pseudo- or false-resistant hypertension because of the white-coat effect    ○ Treated patients with elevated office BP ≥ 140/90 mmHg and       24-h ambulatory BP < 130/80 mmHg and       Awake ambulatory BP < 135/85 mmHg and       Sleep ambulatory BP < 120/70 mmHg • Masked uncontrolled hypertension    ○ Treated patients with office BP < 140/90 mmHg and       24-h ambulatory BP ≥ 130/80 mmHg and/or       Awake ambulatory BP ≥ 135/85 mmHg and/or       Sleep ambulatory BP ≥ 120/70 mmHg Global and Indian scenarios of hypertension As per WHO, worldwide, about 1.13 billion people have hypertension. Among them, two thirds are from low- and middle-income countries (LMICs). The percentage of adults having hypertension is higher in LMICs (31.5%) than in high-income countries (28.5%) [24]. A systemic analysis of population-based studies from 90 countries showed the age-standardized prevalence of hypertension was slightly higher in men (31.9%) than in women (30.1%) [25]. As the Global Burden of Diseases 2016, 1.63 million deaths in India were attributed to hypertension. This was 108% higher than in 1990 [26]. The fourth National Family Health Survey reported hypertension in 13.8% of men vs. 8.8% of women aged 15–49 and 15–54, respectively [26]. In India, about 33% and 25% of urban and rural residents, respectively, are hypertensive. Among them, over 50–75% are unaware of their hypertensive state [27]. Prevalence of hypertension in patients with diabetes The prevalence of hypertension is higher in patients with diabetes mellitus (DM), with 50% of cases of hypertension also being diagnosed with type 2 diabetes mellitus (T2DM) [28]. This risk is marked in the elderly population, who are at a greater risk of complications, including macro- and microvascular diseases due to the co-existence of DM and hypertension [29]. In India, an increase in the coexistence of diabetes and hypertension is being reported. Patients with diabetes showed 1.5–2.0 times higher prevalence of hypertension than those without diabetes [30]. Good blood pressure measurement and its significance Office blood pressure measurement Blood pressure measurement in the office or clinic is a standard diagnostic test for hypertension and follow-up. A minimum of 2–3 office visits at 1–4-week intervals (depending on the BP level) is required to confirm the diagnosis of hypertension. Diagnosis must be performed in the first visit if BP is ≥ 180/110 mmHg with an evidence of cardiovascular disease (CVD). Figure 1 shows recommendations for Office BP measurement.Fig. 1 Recommendations for office blood pressure measurement [12] An automated oscillometric upper-arm cuff device (validated) is recommended for BP measurement. To measure BP, the cuff bladder must be wrapped so that it covers 80% of the arm circumference of the patient and 40% of the width. Accurate positioning of the patient is most crucial for precisely monitoring his/her BP levels. AHA recommends measuring blood pressure while the patient sits upright with legs uncrossed and arms supported. The centre of the cuff on the upper arm must be at the level of the right atrium of the patient, which lies at the midpoint of the sternum. Chair positioning and pillows as support must be made to achieve the desired level. Ambulatory blood pressure and home BP measurement Ambulatory BP monitoring (ABPM) provides a 24-h account of the patient’s state and is useful for diagnosing primary and secondary hypertension and differentiating it from the white coat and masked subtypes [31]. ABPM is accurate in predicting the risk of cardiovascular disease and mortality [31]. BP level measurement using home or ambulatory BP monitoring is recommended in patients with office BP classified as high-normal BP or grade 1 hypertension (systolic 130–159 mmHg and/or diastolic 85–99 mmHg) (Table 5).Table 5 Home and ambulatory blood pressure (BP) measurement [32–35] Condition Position Device Cuff Measurement protocol Interpretation Home blood pressure monitoring As for office blood pressure As for office blood pressure Validated electronic (oscillometric) upper-arm cuff device Size according to the individual’s arm circumference Before each visit to the health professional: • 3–7-day monitoring in the morning (before drug intake if treated and the evening) • Two measurements on each occasion after 5 min sitting rest and 1 min between measurements Long term follow-up of treated hypertension: • 1–2 measurements per week or month • 24-h monitoring at 15–30 min intervals during daytime and night-time • At least 20 valid daytime and 7 nighttime BP readings are required. If less, the test should be repeated 24-h ambulatory blood pressure monitoring Routine working day Avoid strenuous activity. Arm still and relaxed during each measurement • Average home blood pressure after excluding readings of the first day ≥ 135 or 85 mmHg indicates hypertension • 24-h ambulatory blood pressure after ≥ 130/80 mmHg indicates hypertension. (Primary criterion) • Daytime (awake) ambulatory blood pressure ≥ 135/85 mmHg and night-time (asleep) ≥ 120/70 mmHg indicated hypertension Blood pressure monitoring in patients with diabetes ABPM is recommended for patients with DM and hypertension to reduce the risk of post-treatment complications and improve BP control [36]. In elderly patients, it is recommended to opt for a standing position during blood pressure monitoring [37]. In a systematic review of 95 randomized control trials (RCTs), it was stated that for patients with hypertension and diabetes mellitus, the blood pressure target must be kept close to 120 to 130 mmHg to reduce the risk of stroke [38]. In a clinical trial of 244 subjects with uncontrolled SBP and DM, it was found that home blood pressure monitoring alleviated the risk of cardiovascular disorders due to the reduction of BP by 9 mmHg and better control of BP fluctuations during the day [39]. More than half of the patients achieved better adjustment of antihypertensives with the help of home blood pressure monitoring [39]. As per the American Diabetes Association (ADA) recommendations, blood pressure must be monitored at every office visit in patients with DM [40]. In patients with elevated BP, multiple readings must be taken to diagnose hypertension [36]. If automated devices are used during office measurement of BP, the machine must be calibrated and validated regularly. Generally, a 5- to 10-mmHg variation from a traditional sphygmomanometer is expected [36]. Digital mediums being used for blood pressure measurement in India Digital semiautomatic and fully automatic devices have been introduced in India for ABPM [40]. While it has the advantage of reducing the risk of human errors, especially in busy clinics, there is a mistrust related to the use of digital monitoring devices among the clinicians, primarily because they are not formally validated and, thus, have a range of error [40]. Population-based studies in India indicate that an aneroid sphygmomanometer must be preferred over digital devices since their readings are more like a traditional mercury-based sphygmomanometer, the most reliable device. However, digital mediums can be preferred for home-based measurement for higher patient comfort, which has a specificity of 80% and a sensitivity of 67.7% in the Indian population [41]. Hypertension and diabetes: the relationship A complex cause–effect relationship between hypertension and diabetes involves obesity, visceral adiposity, and insulin resistance as the probable main pathogenic factors [42] (Fig. 1). Hypertension and diabetes are the consequence of metabolic syndrome. Inflammatory markers such as C-reactive protein are elevated in patients with DM or hypertension, indicating that both the conditions are associated with low-grade inflammation and genetic factors such as single nucleotide polymorphisms [43]. Insulin being a pleiotropic hormone has a role in developing hypertension, diabetes, and metabolic syndrome [44]. In patients with DM and hypertension, the risk of isolated systolic hypertension is the highest due to autonomic neuropathy (Fig. 2) [38]. They have a higher baseline heart rate and are at an increased risk of cardiovascular disorders (CVDs) [37]. Furthermore, nocturnal BP elevation is not significant in these patients, but they face greater day fluctuations [37].Fig. 2 Relationship between hypertension and diabetes The incidence of resistant hypertension (RH) is higher among people with diabetes than in the general or hypertensive population. The peculiar presentation of hypertensive patients with DM reflects the need for specific guidelines. Indian guidelines need to be more comprehensive in terms of patient education and consideration of dietary factors so that the overall risk and burden of hypertensive disorders is reduced in patients with DM. This objective is addressed in present guideline, which provides recommendations related to the use of various antihypertensive combinations and treatments in patients with DM along with dietary and lifestyle changes as well as the need for monitoring. Hypertension-mediated/related conditions Hypertension, diabetes, and cardiovascular disorders Hypertension is common among patients with diabetes mellitus and so is the risk of cardiovascular complications (Fig. 3). Hypertension alleviates the risk of atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications. In subjects with diabetes, ACSVD significantly increases the morbidity and mortality [36].Fig. 3 Diabetes and hypertension predispose to cardiovascular disease [45] It has been observed that the management of hypertension in patients with DM lowers the risk of ASCVD events. With every 10 mmHg decrease in systolic BP, the risk of complications of DM is reduced by 12%, and the associated mortality is reduced by 15%. The risk of MI in these patients is reduced by 11%, and microvascular complications are reduced by 13% [46]. This states the significance of good blood pressure management in patients with DM, especially those at a high risk of cardiovascular complications. Hypertension-mediated organ damage Undesired changes in the structure and function of arteries or organs lead to hypertension-mediated organ damage, a critical marker of cardiovascular (CV) disease. Higher incidences of all-cause death and CV events including ischemic heart disease, ischemic stroke, hemorrhagic stroke, cardiac death, and major adverse cardiac and cerebrovascular events (MACCE) may be observed. Nephropathy is the most common form of organ damage seen in hypertensive patients. European Society of Cardiology guidelines for hypertension recommend basic screening of HMOD in all hypertensive patients [47]. Hypertension and chronic kidney disease Hypertension is closely linked with chronic kidney disease because a sustained state of elevated BP worsens kidney function (Fig. 4) [48]. The pathophysiology of CKD and hypertension is complex. A loss of kidney function worsens blood pressure or vice versa.Fig. 4 Pathophysiological relationship between hypertension and chronic kidney disease [49] Tight control of BP reduces the risk of chronic kidney disease by attenuating the pathophysiological pathways that contribute to eGFR progression and loss of kidney function [49]. Along with antihypertensive medications, dietary management, including salt restriction, forms the mainstay in the management of BP in CKD patients [50], which has been discussed in the dietary recommendations made by RSSDI ahead. Proteinuria/microalbuminuria and end-organ damage Microalbuminuria or proteinuria is a major risk factor for renal disease progression, and it is also a powerful marker of cardiovascular disease and all-cause mortality [51]. For early diagnosis and better management of albuminuria with the help of sensitive tests such as albumin-to-creatinine ratio (UACR) is recommended for the avoidance of these complications [52]. UACR is the key to early diagnosis of chronic kidney disease (CKD) in patients with diabetes mellitus because the patient is generally asymptomatic at this stage, and their glomerular filtration rate (GFR) is also close to normal [52]. American Diabetes Association (ADA), Kidney Disease Improving Global Outcomes (KDIGO), and US Kidney Disease Outcomes Quality Initiative (KDOQI) recommend at least annual screening for UACR in patients with diabetes mellitus [52]. Indian guidelines recommend that all patients with hypertension must be screened for the presence of kidney disease at the time of their diagnosis and regularly thereafter [53]. Along with UACR, serum creatinine measurement and calculation of eGFR are also recommended [54]. Urine protein-to-creatinine ratio (UPCR) is an accurate method to quantify proteinuria for the diagnosis of preeclampsia (PE), the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation [55]. Hypertension and coronary/peripheral artery disease Globally, peripheral arterial disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) are leading causes of morbidity and mortality [56]. Patients with cerebrovascular complications, including ischemic and hemorrhagic stroke, observed increased systolic hypertension more frequently. Post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy (INVEST) demonstrated that among hypertensive CAD patients, concomitant PAD indicates a worse prognosis for adverse cardiovascular outcomes than CAD over a mean follow-up of 2.7 years [57]. Hypertension-associated erectile dysfunction Hypertension and erectile dysfunction (ED) are related diseases with a common denominator, i.e. endothelial dysfunction. Changes in the endothelium-derived factors can lead to an increase in vascular smooth muscle (VSM) contraction [58]. Hypertension induces vascular changes that affect pudendal arteries and penile vasculature leading to reduced blood circulation to the penis [59]. High blood pressure or antihypertensive treatment can also lead to ED. Antihypertensive drugs like diuretics, beta-blockers, and centrally acting agents negatively affect erectile function. At the same time, calcium antagonists and ACE inhibitors are neutral [60]. Hypertension and heart failure There is a direct correlation between increased blood pressure and the risk of developing heart failure. Patients with blood pressure greater than or equal to 160/100 mmHg have a doubled risk of heart failure than those with blood pressure less than 140/90 mmHg [61]. High blood pressure can also lead to high prevalence of atrial fibrillation [62], ventricular arrhythmias [63], and a sixfold greater risk of myocardial infarction [64], and subsequent heart failure with reduced ejection fraction (HFrEF). High BP increases the left ventricular (LV) afterload and peripheral vascular resistance, which causes diastolic dysfunction followed by concentric or eccentric LV hypertrophy (Fig. 5) [65].Fig. 5 Different stages of hypertensive heart disease Hypertensive retinopathy Choroidopathy, retinopathy, and optic neuropathy are hypertension-related ocular diseases [66]. Hypertensive retinopathy occurs because the retinal vessels are damaged due to elevated blood pressure. Angiotensin-converting enzyme allele deletion increases the risk of hypertensive retinopathy [67]. Higher plasma leptin level was reported to be associated with hypertensive retinopathy and vascular endothelium damage [68]. A study showed that serum uric acid (SUA) concentration and hypertensive retinopathy are significantly associated. For every 1 mg/dL increase in SUA, there was a significant 6% higher probability of hypertensive retinopathy [69]. Communities study of atherosclerosis risk showed that the incidence of stroke was two- to fourfold higher in patients with moderate hypertensive retinopathy, independent long-term hypertension, cigarette smoking, and dyslipidemia [70]. Long-term effects of hypertension Patient with hypertension having abnormal BP is at high risk of transient ischemic attack (TIA) [71]. Not only first TIA, but hypertension is also a risk factor for recurrent TIA and stroke. A study in TIA patients (N = 1707) showed that 58% of patients had a history hypertension while 75% of them had SBP > 140 mmHg following the onset of TIA [72, 73]. Normotensive people after stroke can have high blood pressure—acute hypertensive response perhaps due to autonomic nervous system dysfunction and/or abnormal cerebrovascular reactivity [74]. Hypertension might increase the risk of Alzheimer’s disease (AD). The pathology linking hypertension to Alzheimer’s disease is intracranial atherosclerosis, possibly limiting cerebral blood flow and/or dampening perivascular clearance [75]. A cross-sectional study in < 60 years of age group individuals showed all-cause dementia, mixed Alzheimer’s/vascular dementia, and Alzheimer’s disease with elevated SBP and those on antihypertensive medication [76]. For all the above disease situations, recommended BP thresholds for treatment are shown in Table 6.Table 6 Summary of office blood pressure thresholds for treatment [32] *As per NICE guideline (2019) ≥ 150 mmHg [77] Hypertension: risk factors Several factors predisposing hypertension vary from country to country and between urban and rural region of same place. An Indian community-based cross-sectional study reported tobacco and alcohol consumption, overweight, obesity, and abdominal obesity as risk factors associated with HTN [78]. Old age and physical inactivity are independent risk factors for hypertension. Different epidemiologic and clinical studies showed sleep-related breathing disorders (SRBD) (obstructive sleep apnea (OSA) and habitual snoring) as independent risk factors for essential hypertension [79]. Table 7 [80] shows the cardiovascular risk assessment based on risk factors. Patient with grade 1 hypertension can be at low risk to high risk depending upon risk factors. Men above 50 years, non-smoking, and non-obese with grade 1 HTN may be at low risk, whereas smoking men are at moderately to higher risk of HTN. Diabetic patients irrespective of other factors are at high risk of HTN.Table 7 Assessment of cardiovascular risk in patients with hypertension based on the number of risk factors Methodology The RSSDI guidelines for the management of hypertension in diabetics have been formulated in consultation with expert endocrinologists and diabetologists in India and Southeast Asia for making recommendations for the management of hypertension, along with strategies to reduce the risks for HMOD and cardiovascular complications. These recommendations were supported by literature evidence and clinical overview obtained from existing Indian and international guidelines. Literature evidence included data and recommendations from Indian, international, and South Asian journals, gathered based on extensive literature research, primarily conducted in PubMed and Cochrane libraries. After a thorough quality assessment, published RCTs, systematic reviews, meta-analysis papers, cross-sectional studies, cohort studies, and expert opinion papers were considered and included. The first draft having recommendations was prepared and circulated among RSSDI panellists to gather suggestions for improvements. All the authors provided written recommendations for improvements in each section following the rigorous review of the document based on their expertise in the field (Tables 8 and 9). The draft was revised to address the identified gaps and was sent out to the authors for further review and feedback. Since all the expert authors approved the recommendations made in the second draft, it was finalized and sent out for publication.Table 8 Levels of recommendation based on the type of literature evidence Level Type of evidence I Systematic review (with homogeneity) of RCTs OR RCTs with a large sample size depicting significant results II Systematic review (with homogeneity) of cohort studies OR small-scale RCTs with unclear results OR consistent recommendations from multiple consensus guidelines (more than 2 national/international guidelines) OR randomized observational studies III Individual cohort studies or clinical studies without randomization OR “outcomes” research OR cross-sectional studies OR evidence gathered from existing consensus guidelines IV Systematic review (with homogeneity) of case–control studies OR individual case–control studies OR guidelines with improper evidence/lack of consensus OR retrospective analysis of patient data V Case series OR independent case study observations OR expert opinion without explicit critical appraisal based on standard principles or narrative reviews or literature reviews without systematic analysis Table 9 Grades of recommendation for guiding practice implications for the physicians Grade Descriptor Quantifying evidence Implications for practice A Strong recommendation Level I evidence with consistent findings from multiple studies of levels II, III, and IV Clinicians should follow grade A recommendations unless a clear and compelling rationale for an alternative approach is defined B Recommendation Levels II, III, and IV evidence with consistent findings but lack of level I evidence Clinicians should follow grade B recommendation while remaining alert to newly published evidence and sensitive to patient preferences C Option Levels II, III, and IV evidence with inconsistent findings While considering grade C evidence for individual practice, clinicians should be flexible in their decision-making approach, patient preferences and peer opinions should have a substantial influencing role D Option Level V evidence: little or no systematic empirical evidence For grade D evidence, the physician must consider all options in their decision making and be alert to newly published evidence that clarifies the benefit versus harm of the selected approach; patient preference should have a substantial influencing role Management/treatment RSSDI recommendations for the management of hypertension in patients with diabetes mellitus Summary of evidence Dietary and lifestyle recommendations A nutrition education program is recommended for patients with DM and hypertension to reduce the risk of metabolic syndrome complications [81].In the RCT of 51 participants, it was found that the knowledge of food portion control for weight reduction, education about healthier food choices, individualized meal planning, understanding of the glycemic index and glycemic loads of different food items and their importance in blood glucose control, recognition of the food pyramid, and its use in meal planning for BP control assisted in the improvement of metabolic factors in patients with DM [81]. In a systematic review of 198 studies for BP management in diabetic patients in low- and middle-income countries, it was stated that self-management and control through patient education are crucial for managing CVD risk factors [82]. Nutritional interventions that facilitate glycaemic and blood pressure control are recommended [81, 82]. In the RCT of 40 patients with DM and hypertension, it was noted that Dietary Approaches to Stop Hypertension (DASH) diet and increased walking duration helped reduce ABPM values [83]. This dietary plan promotes higher consumption of whole grains, fat-free or low-fat dairy products, fruits, vegetables, poultry, fish, and nuts, along with reduced intake of saturated fat, total fat, cholesterol, and sodium and high intake of potassium, calcium, magnesium, fibre, and protein [79, 84]. DASH diet, in consideration of the taste preferences of Indian patients, is recommended for hypertensive control in DM patients. For the prevention of CVDs in patients with DM and hypertension, it is recommended that physicians must work closely with the patients to identify potential barriers and support them in reaching their target BP and HbA1c goals [84]. Regular exercise or walking is recommended along with dietary control in patients with hypertension and DM [83, 85]. In the RCT of 94 Indian participants, it was affirmed that physical activity had a greater impact on BP control when compared with dietary salt restriction [86]. Therefore, brisk walking for 50 to 60 min, three to four times a week was recommended for effective BP management [86]. Yoga and salt restriction were also effective for Indian patients but had a lower impact than physical activity [86]. Alcohol intake was to be decreased or avoided [54]. Smoking cessation should be advised to all patients. Cessation therapies should be provided for patients who wish to quit smoking [54]. Combining these approaches would achieve maximal benefits for patients with co-existing disease [86]. Worksite interventions are effective for reducing SBP, diastolic blood pressure (DBP), and blood glucose levels in obese Asian subjects at risk of metabolic conditions [87]. These interventions must be planned in the form of multidisciplinary sessions by including physicians, nutritionists, and physical trainers to guide the patient [87]. Recommendations • Pharmacological therapy with lifestyle modifications should be initiated in patients with confirmed office-based BP > 140/90 mmHg • A target value of 120 to 130 mmHg must be achieved in patients with co-existing DM and hypertension through a combination of dietary and lifestyle interventions, including a low sodium diet, plenty of fresh fruits, vegetables, and whole grains along with regular physical activity (grade A) • Brisk walking as a physical form of activity, having sessions for 50–60 min three to four times a week, is more effective than dietary salt restriction and yoga and must be recommended in patients (grade B) • Nutrition education about the role of diet and knowledge of healthy food choices is crucial for self-management of BP in diabetic patients (grade A) Overview of treatment options for the management of hypertension in patients with diabetes mellitus Initial treatment for diabetes depends on the severity of hypertension with a regimen that includes calcium channel blockers (CCBs), angiotensin II receptor blocker (ARB)/ACE inhibitors, and diuretics, beta-blockers for compelling indications [54]. Real-world studies consider ACE inhibitors or ARBs as the first-line treatment agents for diabetic hypertensive patients depending on their treatment response and tolerance profiles [88]. Clinical evidence suggests that single-pill combination (SPC) containing two or more antihypertensive agents (with complementary MOA) offers potential advantages over free drug combinations [89]. Thiazides may also be used for the first-line treatment, but these must be administered alongside ACEi or ARBs [90]. The drug’s clinical effects must be evaluated before the selection of any treatment agents, particularly ARBs [91]. The selection of treatment agents must be based on the patient’s profile, especially in those at the risk of end organ damage due to multiple comorbidities [91]. Antihypertensive drug therapy for the management of hypertension in diabetic patients Blockers of the renin–angiotensin–aldosterone system (RAAS): angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) ARBs and ACEi are the most widely used antihypertensive drugs because of their similar effects on cardiovascular outcomes. ARBs help in reducing the cardiovascular and cerebrovascular risks and renal complications, hence minimizing the morbidity and mortality risks in patients with hypertension [92]. ARBs are safer, tolerant, and more efficacious than ACEi for BP control [89, 92, 93]. In the RCT of 1600 patients, telmisartan facilitated greater BP reduction than ramipril [92]. ARBs have been found to have maximal reno-protective effects when compared with other classes of drugs [26]. The risk towards side effects is also lower with these agents compared with ACEi that induce cough [89]. Therapy having a combination of an ARB and an ACE inhibitor is not recommended as it is associated with an excess of adverse renal events [93]. ARBs are administered in combination with other agents such as calcium channel blockers (CCBs) or thiazide diuretics to reduce the risk of CVDs and renal disorders in patients with DM [89, 93]. In diabetic hypertensive patients, telmisartan and losartan are the most effective choice of ARBs to reduce cardiovascular risk factors [91]. Telmisartan must be selected as the first-line ARB agent in diabetic patients because of its beneficial impacts on fasting blood glucose and insulin levels [91]. In those at a higher risk of stroke, losartan must be preferred, whereas telmisartan is recommended in patients having a history of atrial fibrillation [91]. German registry “EARLY” reported that a significantly greater proportion of patients in the azilsartan group achieved the target blood pressure of < 140/90 mmHg compared to ACEi [94]. In RCT of 204 Indian patients, it was found that the efficacy and safety of azilsartan are like telmisartan. Thus, it can be selected as an alternative drug in patients based on its availability [92]. ACEi may be preferred as first-line treatment agents in patients with diabetic hypertension as an alternative to ARBs [95]. Both these agents effectively reduce the risk of CVDs in high-risk patients, although ARBs are more efficacious [92–96]. Both ARBs and ACEi effectively reduce the risk of end-stage renal disease [97]. Azilsartan is a suitable agent for antihypertensive therapy in CKD patients. A 20-mg dose of azilsartan has demonstrated potent antiproteinuric effects compared with other agents such as candesartan [98]. An 80-mg dose is effective for controlling SBP and DBP in office and ambulatory settings [99]. Azilsartan improved diastolic function of the left ventricle in patients with heart failure with preserved ejection fraction (HFpEF) [100]. While ACEi also achieved this clinical benefit, a more beneficial impact was observed with ARBs [101]. A single-centre study including 133 hypertensive subjects diagnosed with COVID-19 infection showed a lower rate of admission to semi-intensive/intensive care units when patients were treated with RAAS inhibitor (32% using ARBs and 30% using ACEi) [102]. Suppose target blood pressure values are not achieved with either of the therapies. In that case, the addition of a thiazide diuretic is indicated as a second-line agent [95]. A meta-analysis containing 7 studies compared ACEi/ARB alone and in combination therapy with sodium–glucose cotransporter 2 (SGLT2) inhibitors in T2DM patients. The analysis reported that combination therapy with SGLT2 inhibitors could achieve better control of blood pressure and estimated glomerular filtration rate (eGFR) [103]. 2. Beta-blockers Beta-blockers are used for the initial management of BP in diabetic patients in cases with a previous history of CVDs such as myocardial infarction, heart failure, coronary artery disease, or stable angina [95]. Beta-blockers and CCBs are not used independently. They are only indicated as a part of combination therapy with ARBs or ACEi in patients with DM [95]. Recent clinical trial showed that the use of beta-blockers increases the risk of cardiovascular events in patients with DM due to the promotion of a hypoglycemic state. Hence, its use is not recommended in patients with co-existing DM and hypertension unless absolutely indicated [104]. Beta-blockers are combined with other classes of antihypertensive drugs for treating hypertension in specific situations like heart rate control, symptomatic angina, post-myocardial infarction, HFrEF, and as an alternative to RAAS in young hypertensive women with a pregnancy plan or of child-bearing potential [105]. 3. Calcium channel blockers Several RCTs have confirmed that CCBs can reduce cardiovascular morbidity and mortality. CCBs are potent, first-line blood pressure-lowering drugs with minimal contraindications [106]. A meta-analysis including 147 RCTs involving 464,164 participants confirmed a significant reduction in risk of coronary events (20–25%) and stroke (30–45%) with all the five BP lowering agents. CCBs had a more pronounced preventive effect on stroke [107]. CCBs can be used alongside ARBs as a part of combination therapy for the management of hypertension in diabetic patients. The vasodilatory effect of CCBs on vascular smooth muscle cells is attributed to their inhibitory effect on calcium entry through L-type calcium channels. Recently, novel CCBs are preferred due to their added pleiotropic benefits above their antihypertensive action. Certain CCBs block the activity on N- and L-type calcium channels and hence show additional benefits of lowering cardiovascular events and renal injury [106]. The role of the novel CCB — cilnidipine in diabetic hypertension:Cilnidipine is a novel and unique dihydropyridine calcium channel blocker that has inhibitory actions on both L-type and N-type calcium channels. Intracellular Ca2+ overload is associated with atrial fibrillation. Cilnidipine restricts this overload and activates eNOS which regulates cardiac function [108]. CCBs are used alongside ARBs as a part of combination therapy for the management of hypertension in diabetic patients. As per a prospective observational trial, single-pill combination treatment with ARB plus cilnidipine helps in reducing morning home systolic blood pressure (MHSBP), in elderly patients [109]. Cilnidipine is preferred in hypertensive patients with DM because it improves insulin sensitivity through its vasodilator effects [110]. Besides its antihypertensive effect, cilnidipine has improved insulin sensitivity along with various reno-protective and cardioprotective benefits, thus making it the choice of DHP-CCB in hypertension with DM [111]. Refer to Fig. 6 for the mechanism of action of cilnidipine. Amlodipine and cilnidipine are equally efficacious in reducing blood pressure; however, the incidences of pedal edema are lower with cilnidipine associated than amlodipine [112]. When administered at a dosage of 5–20 mg/day, based on the patient’s clinical profile, cilnidipine facilitates BP reduction and helps reduce heart rate and serum triglyceride levels in Indian patients, suggestive of cardioprotective benefit [113]. Independent of blood pressure reduction, 8-week treatment with cilnidipine 5–10 mg/day improved left-ventricular systolic function [114]. Cilnidipine is more tolerable in Indian patients and must be preferred in those with proteinuria or pedal edema [115, 116]. Fig. 6 Mechanism of action of cilnidipine in the lowering of blood pressure in hypertensive patients [117] Thus, cilnidipine should be the preferred CCB in diabetic hypertensives due to its reno-protective and cardioprotective benefits and better safety and tolerability profile (pedal edema) over other CCBs.4. Diuretics Low-dose thiazides have demonstrated their success in mild to moderate cases of hypertension, but its function is depleted if the sodium intake of the patient is above 8 g/day, indicating the relevance of dietary salt restriction and its use [118]. Low doses, i.e. 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide, or 1.25 mg/day of indapamide, minimize metabolic complications and their antihypertensive effects [119]. Hydrochlorothiazide lowers pulse pressure by 4 to 6 mmHg due to the greater effect on systolic than on diastolic blood pressure [120]. Thiazide-like diuretics such as chlorthalidone demonstrated superior blood pressure reduction in patients with resistant hypertension [121, 122]. Diuretics such as hydrochlorothiazide are not recommended in patients with diabetic hypertension because of its potential to elevate fasting blood glucose and HbA1c levels [123]. A systematic review of 26 RCTs indicated that low doses of thiazide might avoid glycemic changes [124]. However, the strength of this finding is low since evidence against low-dose hydrochlorothiazide has been stated by another meta-analysis of 368 studies [125]. While diuretics are not commonly used to manage hypertension in patients with DM, their use is indicated in certain specialized cases [126], such as elderly patients with existing CVDs [118]. In a crossover trial, the use of potassium-sparing diuretics such as spironolactone reduced BP by − 8.7 mmHg for reaching the target levels in patients with resistant hypertension, compared to other two treatments, i.e. doxazosin and bisoprolol [127]. A low dose of spironolactone is recommended in those whose serum potassium is < 4.5 mmol/L and eGFR is > 45 mL/min/1.73 m2 to achieve BP targets [127, 128]. Guideline comparison of blood pressure goals and recommended drug options in different populations has been mentioned in Table 10.5. Combination therapies Drug combinations including ARB plus cilnidipine or ARB plus hydrochlorothiazide effectively reduce nocturnal BP fluctuations [125]. However, due to the risk of glycemic variability, ARB plus cilnidipine must be considered even in patients with nighttime BP fluctuations, rarer in patients with co-existing diabetes and hypertension [123–125]. A combination of ARB and CCB must also be preferred over beta-blockers because of the potential of the latter to cause adverse cardiovascular events (Table 11) [105]. Table 10 Guideline comparison for hypertension treatment [129] Guideline Population Goal BP mmHg Initial management 2014 hypertension guideline Diabetes  < 140/90 ACEi, ARB or CCB, thiazide-type diuretics CKD  < 140/90 ACEi or ARB ESH/ESC 2013 Diabetes  < 140/85 ACEi or ARB CKD no proteinuria  < 140/90 CKD + proteinuria  < 130/90 CHEP 2013 Diabetes  < 130/80 ACEi or ARB with additional CVD risk, ACEi, ARB, thiazide CKD  < 140/90 ACEi or ARB ADA 2013 Diabetes  < 140/80 ACEi or ARB ESC/ESH 2018 CAD, CKD, diabetes  ≤ 140/90 ACEi or ARB + CCB or diuretic-dual combination for CAD) ACEi/ARB + CCB OR ACEi/ARB + diuretic (or loop diuretic-dual combination for CKD) ACEi/ARB + CCB/diuretic-dual combination for diabetes ISH 2020 CKD  < 130/80 mmHg (< 140/80 in elderly patients) RAS inhibitors as first line; CCBs and diuretics can be added KDIGO 2012 CKD no proteinuria  ≤ 140/90 ACEi or ARB CKD + proteinuria  ≤ 130/80 KDIGO 2021 RRT (CKD G1T-G5T)  ≤ 130/80 CCB or ARB Safety considerations for hypertensive management in diabetic patients When treatment agents such as blockers of the renin–angiotensin–aldosterone system (RAAS) are being used to manage BP in patients with DM, close monitoring of kidney functions and the levels of electrolytes are recommended [38]. Frequent monitoring of potassium and creatinine is recommended in patients treated with aldosterone antagonists, such as spironolactone. Monitoring of serum potassium levels in patients on combination therapy is stated to reduce the risk of hyperkalemia [38]. An observational study in diabetes patients concluded that CCB, when added to ACEi/ARBs, is associated with reno-protective and cardioprotective outcomes compared to thiazide diuretics [130]. Recommendations: which treatment therapy to use and when • Individual profile of the patient and their response to the treatment must be evaluated for the selection of the most suitable treatment agent for hypertensive management (grade A) • ARBs, either alone or in combination with CCBs, can be used for BP control in diabetic patients (grade A) • Combination therapy of ARB and CCB is recommended to be initiated in hypertensive patients for better BP control, reducing risks of complications, and better patient adherence (grade B) • ARBs must be preferred over ACEi in diabetic patients with hypertension, telmisartan or azilsartan being selected as the first-line agent (grade B) • In patients at the risk of CVDs, renal disorders, or cerebrovascular disorders, combination therapy must be preferred for the reduction of patient mortality (grade B) • Calcium channel blockers must be preferred over beta-blockers and thiazides in combination therapy with ARBs. Cilnidipine is a comparatively more effective and safer novel molecule as compared to conventional CCBs for Indian diabetic hypertensive patients (grade A) • The use of beta-blockers and thiazide diuretics must be avoided in patients with DM and hypertension because of their potential to cause cardiovascular events and hyperglycaemia, respectively (grade A) • Monitoring of electrolyte levels, serum potassium, and creatinine levels, as well as regular evaluation of kidney function, is recommended for patients with diabetic hypertension based on the choice of treatment agents and their risk profile (grade B) Data on the global approvals of molecules of each class For the selection of the treatment agent necessary on the individual clinical profile of the patient, it is essential to understand the treatment indications of various FDA-approved drug labels, which have been summarized in Tables 11 and 12.Table 11 Major drug combinations with efficacy results Combination Type of patients % Change in relative risk Two RAS blockers/ACE inhibitor 1 ARB or RAS blocker 1 renin inhibitor [131] High-risk diabetic patients More renal events ACE inhibitor and diuretic Stroke or TIA [132]  − 28% strokes (p < 0.001) Diabetes [133]  − 9% micro-/macrovascular events (p = 0.04) Hypertensive; > 80 years [134]  − 34% CV events (p < 0.001) ARB and diuretic Hypertensive; ≥ 70 years [135]  − 28% non-fatal strokes (p = 0.04) CCB and diuretic Hypertensive [136]  − 27% CV events (p < 0.001) ACE inhibitor and CCB Older with isolated systolic hypertension (ISH) [137]  − 37% CV events (p < 0.004) Beta-blocker and diuretic Older with ISH [138]  − 36% strokes (p < 0.001) Older hypertensive [139]  − 40% CV events (p = 0.003) ARB and CCB Older with ISH [140] 14% reduction in BP Hypertensive [141] Lower incidences of CV events (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.70–0.91; p < .001) Table 12 FDA- and DCGI-approved drug labels for hypertension management in diabetic patients Indications FDA-approved drug Telmisartan For hypertensive management in patients with CVD risk factors and diabetes patients with end-organ damage [142] Azilsartan In patients with DM and hypertension for BP control [93] Olmesartan Management of hypertension in diabetic patients with other comorbidities such as chronic kidney disease, cerebrovascular events, heart failure, and ischaemic heart disease [143] Captopril Management of hypertension in patients with impaired renal function, presence of diabetic nephropathy, myocardial infarction, and left ventricular dysfunction [144] DGCI-approved drug [145] Cilnidipine tabs. 5 mg, 10 mg For treatment of mild to moderate hypertension Amlodipine besylate IP Eq. to amlodipine 10 mg + indapamide SR 1.5 mg tablet For the treatment of mild to moderate hypertension Combination drug containing - Cilnidipine:10 mg Olmesartan medoxomil IP (20 mg/40 mg) Chlorthalidone IP (12.5 mg) For the treatment of essential hypertension Combination drug containing - Losartan potassium IP (50 mg) Amlodipine besylate IP Eq. to amlodipine (5 mg) Hydrochlorothiazide IP (12 mg) For the treatment of hypertension in patients who are not managed with the help of dual therapy Combination drug containing - Olmesartan medoxomil (20 mg) Amlodipine besylate (5 mg) For mild to moderate hypertension Combination drug containing - Olmesartan medoxomil (20 mg) Ramipril (5 mg) For treatment of essential hypertension Management of hypertension in patients with CKD In patients at the risk of CKD, it is recommended to maintain blood pressure values below 130/80 mmHg for renal and cardioprotection in patients under 60 years [52]. National Institute for Health 2014 and Care Excellence guideline recommends a goal blood pressure of < 140/90 in a patient with CKD while < 130/80 mmHg in patients with an albumin creatinine ratio of ≥ 70 mg/mmol [146]. 2012 KDIGO guideline recommendation for blood pressure goals in diabetic and non-diabetic patients with non-dialysis dependent CKD is mentioned in Fig. 7 [147]. Combination therapy is mostly recommended for achieving these target BP levels in these patients [115]. It is useful for managing patients who are unresponsive to the use of a single drug agent [148]. SPC with cilnidipine (10 mg) and ARB (80 mg) was seen to be effective in reducing BP values in patients with sympathetic hyperactivity [39]. Control of sympathetic activity is one of the treatment goals in hypertensive patients with DM and CKD to reduce cardiovascular risks. This SPC was also effective in reducing diurnal and nocturnal blood pressure fluctuations in patients with DM. Thus, SPCs are recommended [109, 125]. Cilnidipine has been clinically proven effective for morning hypertension and white-coat hypertension, closely associated with sympathetic overdrive. Due to its N-type calcium channel blockade and unique sympatholytic activity, cilnidipine offers cardiovascular benefits apart from its antihypertensive action. In a study involving hypertensive patients (n = 2920), treatment with cilnidipine and angiotensin receptor blocker showed significant reductions in heart rate, particularly in those with a higher baseline heart rate [149] (Tables 13 and 14). In patients with microalbuminuria/proteinuria, treatment with cilnidipine is recommended when CCBs are used in combination therapy [150, 151]. Compared to other drugs, such as amlodipine, cilnidipine facilitates UACR reduction and helps in decreasing albumin excretion in hypertensive patients [149, 150]. It is a preferred agent in patients with proteinuria, sympathetic overactivity, and pedal edema. It is a better treatment agent than amlodipine for hypertensive patients [109, 150]. In a clinical trial of 50 patients with diabetic nephropathy, it was found that 12-week treatment with cilnidipine led to a significant reduction in estimated GFR values and serum creatinine levels [125]. Six months of treatment with the drug helped significantly control albumin excretion [150, 151]. Thiazide diuretics can be used if GFR is greater than or equal to 40 mL per minute per 1.73 m2, while loop diuretics are used in GFR ≤ 40 to 50 mL per minute per 1.73 m2 [115]. A combination of ACEi and ARBs reduces urinary albumin excretion compared to monotherapy; however, they are associated with a further risk to the kidney and hence are not recommended [152]. Fig. 7 2012 KDIGO guidelines on the management of hypertension in diabetic/non-diabetic CKD patients Table 13 Indications of individual drug classes based on guidelines and clinical studies [6] Compelling indication* Recommended drugs^ Clinical trials basis# Diuretic BB ACEI ARB CCB ALDO ANT Heart failure ■ ■ ■ ■ ■ ACC/AHA Heart failure Guidelines, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES Postmyocardial infraction ■ ■ ■2 ■1 ■ ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS High coronary disease risk ■ ■ ■ ■ ALLHAT, HOPE, ANBP2, LIFE, CONVINCE Diabetes ■ ■ ■ ■ ■ NKF-ADA, Guideline, UKPDS, ALLHAT Chronic kidney disease ■ ■ ■3 KDIGO 2021, NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent stroke prevention ■ ■ ■4 PROGRESS 1Option for patients without heart failure or impaired LV function in patients with contraindications to beta-blockers (Danish Verapamil Infarction Trial II–DAVIT)[153] 2If ACEi not tolerated 3First-line antihypertensive agent in adult kidney transplant recipients 4A meta-analysis of 13 studies with 1789 subjects randomized to CCBs *Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP ^Drug abbreviations: ACEI angiotensin-converting enzyme inhibitor, BB beta-blockers, ARB angiotensin receptor blocker, Aldo ANT aldosterone antagonist, CCB calcium channel blocker #Conditions for which clinical trials demonstrate the benefit of specific classes of antihypertensive drugs Table 14 Indian evidence on the use of antihypertensive agents [154–160] Drug Efficacy data Safety data Indications Adverse events/contraindications Corresponding Indian study Azilsartan • Effective for lowering BP levels by 26–29 mmHg as per a 6-week RCT of 303 patients • Non-inferior to telmisartan • Non-inferior to telmisartan in terms of safety in Indian patients • Well-tolerated with only mild treatment-related side effects First-line therapy in essential hypertension Headache and dizziness [154] Telmisartan • Telmisartan 40 mg is efficacious in reducing DBP by 18.1% compared to Losartan (14.3%) as reported in adult hypertensive male and non-pregnant female patients between 18 and 65 years of age No serious adverse events were reported in this study Patients with clinic blood pressure (BP) levels of systolic BP (SBP) of 140–200 mmHg and diastolic BP (DBP) of 95–114 mmHg No reports [155] • Telmisartan reduces proteinuria in hypertensive patients with chronic kidney disease Well tolerated with no adverse events Patients with CKD (96.36% hypertensive; 63.61% diabetic) No reports [156] Olmesartan Olmesartan 20/40 mg helped in reducing by 34/18 mmHg in 6 months as per the results of an open-label observational study of 8940 Indian patients No serious adverse events were reported in this study Patients with BP values above 140/99 mmHg Few patients complained of dizziness, vertigo, and oedema [157] Cilnidipine Comparable efficacy to amlodipine in lowering BP levels as per the results of an Indian cross-sectional study of 140 mild to moderate hypertensive patients • Superior safety profile than amlodipine • No significant impacts on the heart rate Patients with CVDs No adverse events Previous studies have reported headache, dizziness, and GI symptoms as adverse events [158] Cilnidipine helped in lowering the heart rate and uric acid levels of the patient in addition to their BP management over 24 weeks as per a clinical study of 100 Indian patients Higher safety profile than amlodipine No reflex tachycardia Patients with high uric acid levels and those with CVDs/tachycardia Not reported [159] Cilnidipine helps in reducing the heart rate along with lowering BP levels of patients, as depicted by an Indian RCT of 63 participants Amlodipine also lowered BP but significantly increased heart rate Higher safety over amlodipine due to cardiovascular benefit through heart rate reduction Patients with proteinuria, pedal oedema, and sympathetic overactivity Nausea, decreased appetite, headache, insomnia, and palpitation [160] Oral antidiabetic agents that exert reno-protection:Combining SGLT2 with ACEi + ARB inhibitor reduced composite kidney outcome (CKO) among T2DM patients with CKD [161]. Evidence suggests that DPP-4 inhibitors and SGLT2 inhibitors exert reno-protective effects in patients with diabetes. Management of resistant hypertension Early diagnosis of resistant hypertension with the help of ABPM is recommended to avoid end-organ damage in patients [32, 126]. Initial treatment with ARBs along with CCBs is recommended [126]. In patients with resistant hypertension, additional treatment agents such as diuretics are recommended since patients may be unresponsive to standard combination therapies [5, 126]. Refer to Fig. 8 for treatment selection and management in patients with resistant hypertension. Fig. 8 Therapeutic approach in resistant hypertension [162] Novel concepts in hypertension and future treatment molecules Growing significance of central aortic blood pressure: In the pathogenesis of cardiovascular disease, central (aortic and carotid) pressures are gaining more relevance than peripheral pressures. The left ventricle encounters the aortic systolic pressure during systole (afterload), while the aortic pressure during diastole determines coronary perfusion. Ideally, central aortic pressures should be measured directly using invasive devices, but there are numerous methods available currently to derive the central pressures by analysing the applanated radial and carotid pulses or carotid distension waves. Higher augmentation index (AI) is linked with coronary artery disease (CAD). Central pressure correlates with cardiovascular risk in apparently healthy subjects as well. Carotid systolic BP is an independent determinant of left-ventricular wall thickness, and late systolic augmentation of the central pressure waveform may denote an increase in left ventricular mass index, independent of age and BP. Study suggests that non-invasively determined central pulse pressure is a better predictor of incident cardiovascular disease than does the corresponding brachial pulse pressure, which may be because of a more accurate representation of the vascular load on the left ventricle. There is growing evidence that central BP may provide incremental value over and above peripheral BP in firmly confirming the cardiovascular risk. The CAFE Study was the first randomized, prospective event-based study which mentioned that central BP and related indices may be a useful guide to treatment [163].Future treatment molecules: Several novel drugs such as peptide- and non-peptide-based therapeutic agents that may function as RAAS inhibitors have been emerging to manage hypertension in diabetic patients. For personalized treatment of hypertension in patients with DM, the use of artificial intelligence technologies such as gene sequencing mechanisms, genomics, transcriptomics, proteomics, and metabolomics is increasing in clinical practice towards understanding the disease pathogenesis for early recognition of possible end-organ damage, detection of the treatment response of the patient, and their monitoring [164, 165]. Currently, among the existing CCBs, cilnidipine is a promising molecule, effective in BP reduction and its multiple pleiotropic benefits, and a good choice for use as a combination therapy for hypertension management in patients with DM [150, 151, 166–168]. As anticipated in the future, the use of other conventional CVD risk reduction drugs such as statins and immunosuppressants such as mycophenolate mofetil may also expand in clinical practice [169]. While new drugs shall continue to emerge, the use of CCBs, ARBs, and ACEi will persist in the future. At the same time, beta-blockers and thiazide agents may need more studies to understand their usage in this sub-set of patients [170]. Summary Key messages: For the management of hypertension in patients with DM (Fig. 9), it is essential to understand the clinical profile of the patient to select the most suitable treatment agents that do not add to any risks.Definition of hypertension. As per the Indian Guideline of Hypertension IV (IGH IV), hypertension is defined as systolic blood pressure (SBP) of ≥ 140 mmHg and/or diastolic blood pressure (DBP) of ≥ 90 mmHg. Type of hypertension. Primary hypertension is mostly asymptomatic, while secondary hypertension is due to various underlying pathologies. Uncontrolled BP, despite the usage of 3 antihypertensive drugs, is referred to as “resistant hypertension”. Epidemiology and risks. Over 1 billion people suffer from hypertension globally, which is expected to rise up to 1.5 billion by 2025. Up to 50% of cases of hypertension are also diagnosed with type 2 diabetes mellitus (T2DM). Hypertension presents as a major risk factor for heart failure, CVD, CKD, PAD, ED, and end-organ damage. Blood pressure measurement. For patients with DM and hypertension, 24-h ambulatory blood pressure monitoring is recommended to maintain BP targets of ~ 120–130 mmHg. The use of an aneroid sphygmomanometer must be preferred over digital devices; however, digital machines may be preferred for home-based measurement. Blood pressure thresholds vary with age and comorbid conditions. Hypertension and diabetes: the relationship. There is a complex cause–effect relationship between hypertension and diabetes, which predisposes the patients to increased risks of cardiovascular complications. Non-pharmacological management of hypertension in diabetic patients. Lifestyle modifications may delay the need for pharmacological interventions or can complement the BP lowering effect of drugs. A low sodium diet, a physical activity, and a healthy diet are recommended to manage hypertension in diabetic patients. Pharmacological management of hypertension in diabetic patients. ARBs are recommended as the choice of therapy preferably in combination with CCBs to manage hypertension and its resulting complications. For combination therapy, newer CCBs (e.g. cilnidipine) along with ARBs are recommended. Cilnidipine is a novel, effective, and safe CCB, which is established for its reno-protective benefits. Combination therapy of ARBs with thiazide-like diuretics also reduces the risk of renal disorders. While telmisartan can be the first-line ARB for treatment of diabetic hypertensives due to its beneficial effects on fasting blood glucose and insulin levels, alternatively, azilsartan, with a similar safety and efficacy profile, is also recommended. Thiazide-like diuretics can be preferred in elderly patients with existing CVDs. ACE inhibitors may be used as an alternative to ARBs for CVD risk reduction in high-risk patients. Beta-blockers may be preferred in patients with a previous history of CVDs and as an alternative to RAS blockers in pregnant women. Hypertension is a strong, modifiable risk factor for the macrovascular and microvascular complications of diabetes. Strong evidence from clinical trials and meta-analyses supports targeting blood pressure reduction to at least140/90 mmHg in most adults with diabetes. Lower blood pressure targets may be beneficial for selected patients with high cardiovascular disease risk if they can be achieved without undue burden, and such lower targets may be considered on an individual basis. In addition to lifestyle modifications, multiple medication classes are often needed to attain blood pressure goals. Fig. 9 Summary of guideline The listed authors have provided the final approval of the recommendations made in this guideline. The authors would like to acknowledge the efforts of Dr. Punit Srivastava and Dr. Nidhi Gupta of Mediception Sciences Pvt. Ltd. (www.mediception.com) for providing writing assistance. Expanded Author Expert Committee Dr. Bikash Bhattacharjee, Dr. Sudhir Bhandari, Dr. Rajeev Chawla, Dr. Rajeev Gupta, Dr. Arvind Gupta, Dr. Sunil Gupta, Dr. Sujoy Ghosh, Dr. Shalini Jaggi, Dr. Pratap Jethwani, Dr. Shashank Joshi, Dr. Anand Moses, Dr. Anuj Maheshwari, Dr. Vijay Panikar, Dr. Sanjay Reddy, Dr. Rakesh Kumar Sahay, Dr. Jugal Kishore Sharma, Dr. L Sreenivasa Murthy Dr. Vijay Viswanathan, Dr. Mangesh Tiwaskar, Dr. S.N.Naringhan, Dr. Narsingh Verma. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Core expert committee. 1.) Dr. Bikash Bhattacharjee. Director and senior consultant diabetologist. Sun Valley Diabetes Care & Research Centre. G. S. Road, Guwahati 781006. Assam. Senior consultant diabetologist. Diabetes & Obesity Centre. Ulubari, Guwahati 781007. 2.) Dr. Sudhir Bhandari. MD, FRCP (London), FRCP (Edinburgh) FACP, FACE. DNB, MNAMS, FICP, AFICA (USA), FISC, FRSSDI. Fellow of diabetes India (FDI). Consultant physician and diabetologist. Sr. professor of medicine. Principal and controller. S.M.S. Medical College & Hospital, Jaipur. Honorary physician to H. E. Governor of Rajasthan. Associate editor of International Journal of Diabetes in Developing Countries. 3.) Dr. Rajeev Chawla. MD, F Diab, FRSSDI, FACP (USA), FRCP U.K. (Edinburgh, London), FACE (USA). Director, North Delhi Diabetes Centre. Honorary prof., Jaipur National University. 4.) Dr. Rajeev Gupta. Preventive Cardiology & Medicine, Eternal Heart Care Centre & Research Institute &. Academic Research Development Unit, Rajasthan University of Health Sciences,. Jaipur, India. 5.) Dr. Arvind Gupta. Senior consultant physician and head,. Department of Diabetes, Obesity and Metabolic Disorders,. Rajasthan Hospital, Jaipur. 6.) Dr. Sunil Gupta. MD, FACE, FRCP (London, Edinburgh, Glasgow),. FACP, FICP, FIAMS, FIACM, FRSSDI. National Treasurer, RSSDI-HQ 2019-22. Managing Director, Sunil’s Diabetes Care n’ Research Centre Pvt. Ltd. 42, Lendra Park, Ramdaspeth,. Nagpur-440010. Maharashtra, India. 7.) Professor Sujoy Ghosh. Dept of Endocrinology. Institute of Post Graduate Medical Education and Research Kolkata. Room 9B. 4th floor. Ronald Ross building. Institute of Post Graduate Medical Education and Research Kolkata. 244 A J C Bose Road, Kolkata, 700020. 8.) Dr. Shalini Jaggi. Dip Diab (UK), Dip Endo (UK), F Diab, FRSSDI, FRCP (London, Glasgow, Edinburgh). Fellow American College of Endocrinology (FACE). Consultant diabetologist and director. Lifecare Diabetes Centre, New Delhi, National EC Member RSSDI, Governing Council Member, DIPSI. 9.) Dr. Pratap Jethwani. Fellow—RSSDI, Fellow—Diabetes India. Consultant Diabetes Specialist, Jethwani Hospital, Rajkot. National EC Member—RSSDI. 10.) Shashank Joshi. Endocrinologist, Lilavati Hospital and Joshi Clinic. Mumbai. 11.) Dr. Anand Moses. Former Professor, Institute of Diabetology, Madras Medical College,. Chennai 34, Casa Major Road, Egmore, Chennai 600008. 12.) Dr. Anuj Maheshwari. MD, FICP, FIACM, FIMSA, FRSSDI, FACP (USA), FACE (USA), FRCP (London, Edinburgh). Vice president, Research Society for Study of Diabetes in India (RSSDI). Professor and head, Department of Medicine, BBD University, Lucknow. Governor, American College of Physicians, India Chapter. 13.) Prof. Vijay Panikar. Dept. of Endocrinology and Diabetes, Lilavati Hospital, Mumbai. 14.) Dr. Sanjay Reddy. MD, consultant diabetologist,. Center For Diabetes & Endocrine Care. Fortis Hospital, Cunningham Road, Bangalore. 15.) Dr. Rakesh Kumar Sahay. Prof. and head, Department of Endocrinology. OSMANIA Medical College, Hyderabad. 16.) Dr. Jugal Kishor Sharma. MD (Med), FICP, FACP, FACE, FRCP (London, Edinburgh, Glasgow, Ireland), FRSSDI, FIACM, FIMSA, FGSI, Fellow Diabetes India, FISH. 17.) Prof. (Dr.) L. Sreenivasa Murthy. M.D., FRCP (Edinburgh), FRCP (Glasgow), FICP, FRSSDI, PDCR,. Senior consultant physician. Life Care Hospital and Research Centre. Professor and head of unit. Dr B R Ambedkar Medical College. Bangalore. 18.) Dr. Vijay Viswanathan. M.D., Ph.D., FRCP (London and Glasgow). Head and chief diabetologist, M.V. Hospital for Diabetes, Royapuram, Chennai. President, Prof. M. Viswanathan Diabetes Research Centre, Royapuram, Chennai. (WHO Collaborating Centre for Research, Education and Training in Diabetes). President, D-Foot International, www.d-foot.org. Vice president—Research Society for the Study of Diabetes—RSSDI. No.4, West Mada Church Street, Royapuram, Chennai - 600 013, Tamil Nadu, India. Website: www.mvdiabetes.com. 19.) Dr. Mangesh Tiwaskar. Consultant physician and diabetologist. 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Harlalka S Roy UK Majumdar G Das K Mandal P An open label prospective study on evaluation of safety and efficacy of cilnidipine over amlodipine in stage 1 hypertensive patients Kathmandu Univ Med J 2020 18 1 42 48 10.3126/kumj.v18i1.33359 168. R R, Om S, Kaladharan A. Evaluation of renoprotective effect of cilnidipine in patients with mild to moderate hypertension and type 2 diabetes mellitus – a prospective study. Asian J Pharm Clin Res. 2021;144–6. 169. Tanase DM Gosav EM Radu S Ouatu A Rezus C Ciocoiu M Costea CF Floria M Arterial hypertension and interleukins: potential therapeutic target or future diagnostic marker Int J Hypertens 2019 2 2019 170. Phillips RA Current and future treatment of hypertension in the SPRINT Era Methodist Debakey Cardiovasc J 2015 11 4 206 213 10.14797/mdcj-11-4-206 27057288

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==== Front Artif Intell Rev Artif Intell Rev Artificial Intelligence Review 0269-2821 1573-7462 Springer Netherlands Dordrecht 10318 10.1007/s10462-022-10318-x Article Evolved distance measures for circular intuitionistic fuzzy sets and their exploitation in the technique for order preference by similarity to ideal solutions http://orcid.org/0000-0002-2171-4139 Chen Ting-Yu tychen@mail.cgu.edu.tw grid.145695.a 0000 0004 1798 0922 Department of Industrial and Business Management, Graduate Institute of Management, Chang Gung University, No. 259, Wenhua 1St Rd., Guishan District, Taoyuan, 33302 Taiwan 15 12 2022 155 © The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Circular intuitionistic fuzzy (C-IF) sets are an up-and-coming tool for enforcing indistinct and imprecise information in variable and convoluted decision-making situations. C-IF sets, as opposed to typical intuitionistic fuzzy sets, are better suited for identifying the evaluation data with uncertainty in intricate realistic decision situations. The architecture of the technique for order preference by similarity to ideal solutions (TOPSIS) provides powerful evaluation tools to aid decision-making in intuitionistic fuzzy conditions. To address appraisal issues associated with decision analysis involving extremely convoluted information, this paper propounds a novel C-IF TOPSIS approach in the context of C-IF uncertainty. This research makes three significant contributions. First, based on the three- and four-term operating rules, this research introduces C-IF Minkowski distance measures, which are new generalized representations of distance metrics applicable to C-IF values and C-IF sets. Such general C-IF distance metrics can alleviate the constraints of established C-IF distance measures, provide usage resiliency through parameter settings, and broaden the applicability of metric analysis. Second, unlike existing C-IF TOPSIS methods, this research fully utilizes C-IF information characteristics and extends the core structure of the classic TOPSIS to C-IF contexts. With the newly developed C-IF Minkowski metrics, this study faithfully demonstrates the trade-off evaluation and compromise decision rules in the TOPSIS framework. Third, this research builds on the core strengths of the pioneered C-IF Minkowski distance measures to create innovative C-IF TOPSIS techniques utilizing four different combinations, including displaced and fixed anchoring frameworks, as well as three- and four-term representations. Such a refined C-IF TOPSIS methodology can assist decision-makers in proactively addressing increasingly sophisticated decision-making problems in practical settings. Finally, this research employs two innovative prioritization algorithms to address a site selection issue of large-scale epidemic hospitals to illustrate the superior capabilities of the C-IF TOPSIS methodology over some current related approaches. Keywords Circular intuitionistic fuzzy (C-IF) set Technique for order preference by similarity to ideal solutions (TOPSIS) C-IF Minkowski distance measure Anchoring framework Site selection National Science and Technology Council, TaiwanNSTC 111-2410-H-182-012-MY3 Chen Ting-Yu http://dx.doi.org/10.13039/501100005795 Chang Gung Memorial Hospital, Linkou BMRP 574 Chen Ting-Yu ==== Body pmcIntroduction Multiple criteria decision analysis (MCDA) is generally delineated as an analytical process for making the most suitable choice with the highest relative dominance out of a group of candidate alternatives characterized by multiple performance criteria (Jaini 2023; Kaya et al. 2022; Shen et al. 2022). To tackle and manage real-world decision issues, numerous MCDA models, approaches, and techniques have been created and applied in a variety of application domains (Garg and Rani 2022; Rani and Garg 2022; Reig-Mullor et al. 2022; Tiwari and Gupta 2022). Many MCDA systems employ a step-by-step evaluation process that entails gathering pertinent information, identifying potential alternatives, and assessing workable solutions to aid decision-makers in making more deliberate and meaningful decisions (Chen 2022a, b; Tsao and Chen 2022). In particular, the technique for order preference by similarity to ideal solutions (TOPSIS), which originated from Hwang and Yoon (1981), is a useful prioritization method in important fields of management analysis and decision theory (Alshammari et al. 2022; Yang et al. 2022). TOPSIS exploits a compensatory aggregation approach that is predicated on the geometric distances between performance ratings associated with candidate alternatives and ideal/anti-ideal alternatives (composed of the best/worst performance ratings in terms of each criterion) to assess the relative merits of candidate alternatives (Guan 2022; Yang et al. 2022; Zhang et al. 2022). The theory of circular intuitionistic fuzzy (C-IF) sets, propounded by Atanassov (2020), is a forward-looking generalization of the intuitionistic fuzzy (IF) theory. In contrast to the IF conformation, an element in the C-IF set is represented by an adjustable circle with a radius parameter, with the center of the circle consisting of membership (i.e., validity) and nonmembership (i.e., non-validity) (Atanassov and Marinov 2021; Çakır et al. 2021). As an illustration in a two-dimensional space, the C-IF conformation is delineated as a high-order uncertain set in which elements in a given finite universe of discourse enjoy the degrees of membership and nonmembership, surrounded by a circle of radius parameter in such a manner that the degrees of membership plus nonmembership do not exceed 1 within this circle (Boltürk and Kahraman 2022; Kahraman and Alkan 2021; Otay and Kahraman 2021). C-IF sets can be efficaciously utilized in MCDA domains because their distinct characteristics can significantly manipulate convolutedly ambiguous information and assist existing MCDA models in obtaining more accurate outcomes, such as a C-IF vlsekriterijumska optimizacija i kompromisno resenje (VIKOR) to treat a waste disposal location selection issue (Kahraman and Otay 2022), an integrated C-IF analytic hierarchy process (AHP) with VIKOR for a multiple expert supplier evaluation problem (Otay and Kahraman 2021), a C-IF decision-making approach through the medium of new defuzzification functions for selecting a health tourism center (Çakır and Taş 2021), a defuzzification and score function-based C-IF decision method for a landfill site selection issue (Çakır et al. 2021), an assessment technique predicated on IF and C-IF sets for evaluating human capital and research indices (Imanov and Aliyev 2021), a present-worth-analysis method grounded in interval-valued IF and C-IF sets for analyzing a water treatment device task (Boltürk and Kahraman 2022), an integrated C-IF AHP approach for assessing remote work adaptation in the midst of the Coronavirus Disease-2019 (COVID-19) pandemic (Çakır and Taş 2022), and an assessment procedure involving C-IF information for selecting industrial symbiotic enterprises (Çakır et al. 2022). The TOPSIS methodology can serve as a powerful prioritization technique to aid decision support for MCDA matters in the context of C-IF sets. With this in mind, Kahraman and Alkan (2021) devised a new C-IF TOPSIS approach based on vague membership functions and utilized it to a supplier selection problem. In the same vein, Alkan and Kahraman (2022b) developed an akin C-IF TOPSIS framework and delivered an implementation procedure to address epidemiological hospital site selection using pessimistic and optimistic decision matrices. Even though Kahraman and Alkan (2021) and Alkan and Kahraman (2022b) proffered the latest C-IF TOPSIS methods, the application of the core TOPSIS framework to C-IF scenarios still has some limitations and research gaps. First, apart from the two studies mentioned above, there is currently little research that extends the classic TOPSIS architecture within the C-IF decision environment for developing a compromising MCDA method involving C-IF uncertainty. Furthermore, the two current studies deviated significantly from the core architecture of the classic TOPSIS because of many modifications. As a result, how to extend the classic TOPSIS into C-IF backgrounds so that the development can faithfully demonstrate the TOPSIS compromise decision-making spirit has become a significant area of study, which constructs the first motivation. Furthermore, in the C-IF TOPSIS methods proffered by Kahraman and Alkan (2021) and Alkan and Kahraman (2022b), the C-IF information (including criterion weights and performance ratings of alternatives judged against the criterion) was converted into IF values for use in the calculations of their developed C-IF TOPSIS procedures. By way of illustration, Kahraman and Alkan (2021) and Alkan and Kahraman (2022b) built individual IF decision matrices and IF criterion weights to generate an aggregated IF decision matrix and aggregated IF weights, respectively. The C-IF decision matrix and C-IF weights were then generated using the maximum radius lengths. However, after putting in a lot of time and effort to create the C-IF decision matrix, it was immediately transformed into two IF decision matrices, pessimistic and optimistic. The C-IF decision matrix was specifically transformed into pessimistic and optimistic decision matrices, with the data in these two decision matrices being ordinary IF values. The relative closeness coefficients based on the pessimistic and optimistic matrices were then calculated to generate composite ratio scores for ranking the alternatives. The C-IF data were constructed in terms of IF linguistic information by Kahraman and Alkan (2021) and Alkan and Kahraman (2022b), but they were in turn converted to IF values. Membership and nonmembership, plus or minus the radius parameter of C-IF values, constitute the IF values embedded in the pessimistic and optimistic decision matrices. The C-IF set containing higher-order fuzzy information is transformed into a general IF set using this simplified pessimistic and optimistic estimation procedure. However, the original goal of using C-IF sets to clarify complex uncertainties is lost in this process. The manipulation process reduces the specificity of C-IF information, reducing flexibility and adaptability when dealing with C-IF uncertainty. Conflicting data processing procedures in the two existing C-IF TOPSIS methods create another research limitation and gap, which serves as the foundation for the second motivation. Aside from that, the distances between target alternatives and ideal/anti-ideal choices are the core concept of TOPSIS, as this is the primary measure of relative closeness coefficients (Alkan and Kahraman 2022a; Han et al. 2022; Sadabadi et al. 2022). Because of this, in C-IF uncertain circumstances, distance measurement is the most important key element in the development of extended TOPSIS. Distance is critical in almost all application problems related to discriminating decision information and comparing performance (Alkan and Kahraman 2022a; Deng and Chen 2022; Szmidt 2014), especially in uncertain circumstances such as the center of gravity distance for fuzzy numbers (Das et al. 2019), the distance and similarity measures for IF sets (Garg and Kumar 2018; Garg and Rani 2021), the exponential distance for interval-valued IF sets (Garg and Kumar 2020), and the distance measures for type 2 IF sets (Garg and Singh 2020; Singh and Garg 2017). Distance metrics, in particular, are not only widely used in decision theory and analysis, but are also crucial in a variety of important domains such as database management, machine learning, knowledge discovery and data mining, information theory, logistics, computer-aided manufacturing, and control theory (Szmidt 2014; Talukdar and Dutta 2021; Tiwari and Gupta 2022). However, the distance measures defined in IF or type-2 IF sets cannot be applied or extended to C-IF environments. The main reason for this is that previous distance measures did not consider intuitionistic ambiguity data for circular structures, nor did they consider the radius of the circular ambiguity range. Accordingly, establishing a metric space is an essential and critical issue in C-IF contexts. Metric space is a fundamental concept in mathematics; its metric is a distance function that can delineate the measure of separation between any two C-IF information within the C-IF environments. As a result, Atanassov and Marinov (2021) propounded four new distance functions for C-IF sets consisting of the three-term based Hamming distance derived from IF Hamming distance, the four-term based Hamming distance stemmed from Szmidt and Kacprzyk’s (2000) form of IF Hamming distance, the three-term based Euclidean distance derived from IF Euclidean metric, and the four-term based Euclidean distance stemmed from Szmidt and Kacprzyk’s (2000) form of IF Euclidean distance. The four new C-IF distance metrics are easy to use, but they have some limitations. To begin with, Atanassov and Marinov’s C-IF distance formulas are only applicable when the radii of the C-IF values in a single C-IF set must be the same length. The advantages of applying the C-IF theory to non-homogeneous uncertainty are diminished by this supposition. Moreover, this supposition restricts the generality and flexibility of C-IF decision information and reduces the effectiveness of applying C-IF theory to real-world issues. The applicability of the C-IF distance formula proposed by Atanassov and Marinov (2021) is therefore severely constrained under such an assumption. Second, the Manhattan metric model and the Euclidean metric model serve as the foundation for the four new distance formulas. However, the Chebyshev metric model, which is commonly used in practical problems, is not covered in the existing literature. Furthermore, generalized forms of C-IF distance measures, such as Minkowski distance (which can be thought of as a generalization of Manhattan distance and Euclidean distance), are not studied in the current C-IF literature. The aforementioned constraints have resulted in research gaps that must be filled as soon as possible, forming the third motivation. Given the research gaps and motivations, the overall goal of this study is to develop advanced C-IF Minkowski distance measures and to deliver an evolved C-IF TOPSIS methodology to manage the MCDA problem in the presence of C-IF uncertainty. Measuring the distance between C-IF values or C-IF sets is critical for quantifying the separation between C-IF uncertain data and distinguishing C-IF information. To manipulate indistinct and imperfect information in the C-IF TOPSIS procedure, decision-makers would have to employ appropriate C-IF distance metrics to clarify the information content and take befitting measurements to process and differentiate the performance information. The C-IF distance formulas proposed by Atanassov and Marinov (2021) do not account for the fact that elements in the C-IF set may have different radii. These assumptions restrict the applicability of their C-IF distance formulations. Further to that, Atanassov and Marinov’s distance formulas only exploited the Manhattan and Euclidean distance models; the Chebyshev distance model, which is commonly used in practical problems, was not discussed. This research establishes two general C-IF distance metrics that cover the existing four C-IF distance metrics, to address the limitations of the existing C-IF distance metrics and increment their flexibility. Based on three- and four-term approaches, this research illustrates generalized representations of two types of C-IF distance measures, dubbed C-IF Minkowski distance measures. The four-term representation takes into account the C-IF set’s radius, membership, nonmembership, and hesitation components; additionally, the three-term representation indicates that the radius, membership, and nonmembership components are considered. Moreover, this study explores certain significant properties of these two evolved C-IF Minkowski distance measures. This study constructs an easy-to-operate C-IF TOPSIS technique based on four basic architectures, including four combinations of displaced and fixed anchoring frameworks and using three- and four-term-based C-IF Minkowski metrics, to advance a C-IF TOPSIS methodology for treating the MCDA issue by incorporating the C-IF Minkowski distance measures. The anchoring mechanism includes displaced (or fixed) ideal and anti-ideal C-IF characteristics that can be employed as anchor points in the C-IF TOPSIS process to formulate subsequent compromise indicators. The displaced (or fixed) anchoring mechanism consists of identifying displaced (or fixed) ideal ratings and displaced (or fixed) anti-ideal ratings, constructing displaced (or fixed) ideal and anti-ideal C-IF characteristics, and determining relative closeness coefficients using C-IF Minkowski distance measures with the three- or four-term representation frame. By comparing the relative closeness coefficients, the best compromise solution to support intelligent decision analysis in complex and uncertain environments can be determined. Finally, this study employs the evolved C-IF TOPSIS methodology to investigate the assessment and selection of appropriate sites for large-scale epidemic hospitals. This research conducts a comparative analysis and explores the applied results in comparison to other approaches to validate the applicability, robustness, and flexibility of the current C-IF TOPSIS technique. The remainder of this paper is structured as follows. Section 2 characterizes some fundamental expressions of C-IF sets. Section 3 presents two evolved C-IF Minkowski distance measures based on three- and four-term approaches to differentiating C-IF information. Section 4 devotes an efficacious C-IF TOPSIS methodology to multiple criteria analysis for decision support. Section 5 explores a realistic application for epidemic hospital siting to illustrate the proposed executive procedure, and comparative research and discussions are conducted to substantiate the strengths of the initiated methodology. Section 6 presents conclusive outcomes as well as promising future research questions. Elementary definitions of C-IF sets The C-IF set concept generalizes the IF set, which uses a circle to express the object’s uncertainty, with the center of the circle consisting of membership and nonmembership degrees. Preliminary definitions of IF sets and C-IFS are presented briefly in this section. Definition 1 (Atanassov 1986) Let Θ be a symbol for a finite universe of discourse. An IF set ϑ is defined in Θ and explained in the following format:1 ϑ=⟨θ,mϑθ,nϑθ⟩θ∈Θ where the degree of membership (i.e., validity) mϑθ:Θ→[0,1], the degree of nonmembership (i.e., non-validity) nϑθ:Θ→[0,1], and mϑθ+nϑθ≤1 for each element θ∈Θ associated with ϑ. The degree of hesitancy (i.e., indeterminacy) corresponding to the IF value (mϑθ,nϑθ) is generated as hϑθ=1-mϑθ-nϑθ. Definition 2 (Atanassov 2020; Atanassov and Marinov 2021) Allow L∗=⟨ζ,ζ′⟩ζ,ζ′∈0,1andζ+ζ′≤1 to be an indication of an L-fuzzy set. A C-IF set C that has the following format in a given finite universe of discourse Θ: 2 C=⟨θ,mCθ,nCθ;rCθ⟩θ∈Θ=⟨θ,OrmCθ,nCθ⟩θ∈Θ where the degree of membership (i.e., validity) mCθ:Θ→[0,1], the degree of nonmembership (i.e., non-validity) nCθ:Θ→[0,1], and mCθ+nCθ≤1 for each θ∈Θ belonging to C. Moreover, the function Or externalizes a circle, whose radius is rCθ:Θ→[0,2] and whose center is (mCθ,nCθ); the expression is as follows: 3 OrmCθ,nCθ=ζ,ζ′ζ,ζ′∈0,1andmCθ-ζ2+nCθ-ζ′2≤rCθ∩L∗=ζ,ζ′ζ,ζ′∈0,1,mCθ-ζ2+nCθ-ζ′2≤rCθ,andζ+ζ′≤1 The degree of hesitancy (i.e., indeterminacy) for the pair (mCθ,nCθ) is produced in this fashion:4 hCθ=1-mCθ-nCθ. Definition 3 (Atanassov 2020; Boltürk and Kahraman 2022) Let ςι=(mCιθ,nCιθ;rCιθ) and ςι′=(mCι′θ,nCι′θ;rCι′θ) signify two C-IF values embedded in the C-IF sets Cι and Cι′, respectively. Fundamental operational laws of intersection, union, addition, and multiplication involving the min and max types, as well as multiplication by and power of a scalar ϖ≥0, are stated in this order: 5 ςι∩minςι′=minmCιθ,mCι′θ,maxnCιθ,nCι′θ;minrCιθ,rCι′θ 6 ςι∩maxςι′=minmCιθ,mCι′θ,maxnCιθ,nCι′θ;maxrCιθ,rCι′θ 7 ςι∪minςι′=maxmCιθ,mCι′θ,minnCιθ,nCι′θ;minrCιθ,rCι′θ 8 ςι∪maxςι′=maxmCιθ,mCι′θ,minnCιθ,nCι′θ;maxrCιθ,rCι′θ 9 ςι⊕minςι′=mCιθ+mCι′θ-mCιθ·mCι′θ,nCιθ·nCι′θ;minrCιθ,rCι′θ 10 ςι⊕maxςι′=mCιθ+mCι′θ-mCιθ·mCι′θ,nCιθ·nCι′θ;maxrCιθ,rCι′θ 11 ςι⊗minςι′=mCιθ·mCι′θ,nCιθ+nCι′θ-nCιθ·nCι′θ;minrCιθ,rCι′θ 12 ςι⊗maxςι′=mCιθ·mCι′θ,nCιθ+nCι′θ-nCιθ·nCι′θ;maxrCιθ,rCι′θ 13 ϖ⊙ςι=1-(1-mCιθ)ϖ,(nCιθ)ϖ;rCιθ 14 (ςι)ϖ=(mCιθ)ϖ,1-(1-nCιθ)ϖ;rCιθ The C-IF set serves as a comprehensive framework for the IF set, the geometric representation of which is sketched in Fig. 1. The graph depicts the distribution space of IF and C-IF values for a triangle in the first quadrant with vertices (0, 0), (1, 0), and (0, 1). The IF value is explained by the point in the triangle with coordinates (mϑθ,nϑθ), while the C-IF value is explained by the circle Or with center (mCθ,nCθ) and radius rCθ. As defined in Eq. (3), Or(mCθ,nCθ) must satisfy the constraints in L∗, so the circle Or can take five different forms, as portrayed in the graph. In the event that rCθ=0 for all θ∈Θ, the C-IF set C composed of C-IF values will degenerate into an IF set; that is, C=⟨θ,O0(mCθ,nCθ)⟩θ∈Θ=⟨θ,mϑθ,nϑθ⟩θ∈Θ=ϑ.Fig. 1 Geometrical representation of a C-IF set Definition 4 (Atanassov and Marinov 2021) Let card(Θ) signify the cardinality of a given finite universe of discourse Θ. Consider two C-IF sets defined in Θ, and assume that rCιθ=rCι and rCι′θ=rCι′ for all θ∈Θ, i.e., Cι=⟨θ,mCιθ,nCιθ;rCι⟩θ∈Θ and Cι′=⟨θ,mCι′θ,nCι′θ;rCι′⟩θ∈Θ. The Manhattan (so-called Hamming) distance measures between two C-IF sets Cι and Cι′ based on the three- and four-term approaches are defined in the following order: 15 D3MCι,Cι′=12rCι-rCι′2+12·cardΘ∑θ∈ΘmCιθ-mCι′θ+nCιθ-nCι′θ 16 D(4)M(Cι,Cι′)=12rCι-rCι′2+12·card(Θ)∑θ∈ΘmCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ Furthermore, the Euclidean distance measures between Cι and Cι′ based on the three- and four-term approaches are described in the following order:17 D3ECι,Cι′=12rCι-rCι′2+12·card(Θ)∑θ∈Θ(mCιθ-mCι′θ)2+(nCιθ-nCι′θ)212 18 D(4)E(Cι,Cι′)=12rCι-rCι′2+12·card(Θ)∑θ∈Θ(mCιθ-mCι′θ)2+(nCιθ-nCι′θ)2+(hCιθ-hCι′θ)212 Evolved C-IF Minkowski distance measures This section will look into new generalized representations of distance metrics that are suitable to the context of C-IF sets. A metric (topological) space is treated as a fundamental space satisfying certain axioms (Das et al. 2019; Garg and Singh 2020; Singh and Garg 2017). Measuring the distance between C-IF uncertain sets is crucial for quantifying the degree of separation between C-IF sets and differentiating C-IF information. Furthermore, the C-IF distance metric can furnish establish more structure than the general topological space. To successfully manage imperfect or uncertain information, decision-makers need to exploit a suitable model to elucidate the information content, and appropriate measures to process and distinguish the information. Among these measures, the notion of distance metric epitomizes a leading role (Garg and Kumar 2018, 2020; Garg and Rani 2021). Atanassov and Marinov (2021) established four fresh distance measures applicable to the C-IF environment; however, they assumed that the radii associated with the two C-IF sets used to calculate the distance are the same. Specifically, Atanassov and Marinov established the special assumption that all elements within a specific C-IF set have the same radius, a narrow assumption that limits the applicability of the four new distance measures. In addition, their distance formulas do not take into account an all-encompassing distance measurement of the general type. This section will propose two general C-IF distance metrics, covering Atanassov and Marinov’s four C-IF distance measures, to loosen the restrictions on the current C-IF distance measures and increase their resilience. This study considers two types of generalized representations of C-IF distance measures (see Fig. 2), based on the three- and four-term approaches, known as C-IF Minkowski distance measures. To be more specific, the four-term representation takes into account the radius, membership, nonmembership, and hesitation components that characterize C-IF sets. The three-term representation takes into account only the radius, membership, and nonmembership components. This study also discusses the key properties of these two new Minkowski metrics.Fig. 2 Proposed generalized representations of C-IF distance measures As previously stated, Atanassov and Marinov (2021) unfolded four new distance metrics for quantifying the degree of separation between C-IF sets. The four new C-IF distance metrics are very useful and easy to operate, but they do have some limitations. For starters, Atanassov and Marinov’s C-IF distance formulas ignore the fact that elements in a C-IF set may have different radii. As shown in the formulas of Definition 4, the radius of all elements in the C-IF set Cι is equal to rCι (i.e., rCιθ=rCι for each θ∈Θ); similarly, the radius of all elements in the C-IF set Cι′ is equal to rCι′ (i.e., rCι′θ=rCι′ for each θ∈Θ). Such assumptions are so strong that the applicability of Definition 4 is severely limited. Second, the four distance formulas are the Manhattan distance measures using the three- and four-term approaches, and the Euclidean distance measures using the three- and four-term approaches. The Chebyshev distance metrics, which are commonly used in practical problems, are, however, not discussed in the existing literature. To relax the constraints of the current C-IF distance measures and extend their resiliency, this study will put forward two general C-IF distance metrics, covering the foregoing four C-IF distance measures in Definition 4, to provide the metric resiliency and broaden the applicability of decision analysis. In the following, this study exploits the three- and four-term representations to present the two C-IF Minkowski metrics for C-IF values, revealed in the first subsection below. Following this, the second subsection delineates the two C-IF Minkowski metrics for C-IF sets based on the three- and four-term representations. C-IF Minkowski metrics for C-IF values Definition 5 Let a positive integer β indicate the metric parameter in C-IF settings, where β∈Z+. Consider any two C-IF values ςι=(mCιθ,nCιθ;rCιθ) and ςι′=(mCι′θ,nCι′θ;rCι′θ). The C-IF Minkowski distance measures separating ςι and ςι′ based on the three- and four-term approaches are elucidated in this order:19 D3βςι,ςι′=1212rCιθ-rCι′θ+12mCιθ-mCι′θβ+nCιθ-nCι′θβ1β 20 D(4)β(ςι,ςι′)=1212rCιθ-rCι′θ+12mCιθ-mCι′θβ+nCιθ-nCι′θβ+hCιθ-hCι′θβ1β Remark 1 In most cases, the C-IF Minkowski distance measures D3β(ςι,ςι′) and D4β(ςι,ςι′) can be utilized with a metric parameter β of 1 or 2, which are equivalent to the C-IF Manhattan and C-IF Euclidean distances between the two C-IF values ςι and ςι′, respectively. Using the three- and four-term representations, the C-IF Manhattan distance measures are portrayed this wise: 21 D31ςι,ςι′=1212rCιθ-rCι′θ+12mCιθ-mCι′θ+nCιθ-nCι′θ 22 D41ςι,ςι′=1212rCιθ-rCι′θ+12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ Moreover, the C-IF Euclidean distance measures are exhibited in this fashion:23 D32ςι,ςι′=1212rCιθ-rCι′θ+12mCιθ-mCι′θ2+nCιθ-nCι′θ2(23) 24 D42ςι,ςι′=1212rCιθ-rCι′θ+12mCιθ-mCι′θ2+nCιθ-nCι′θ2+hCιθ-hCι′θ2 In the limiting situation of β reaching infinity, the C-IF Minkowski distance measures correspond to the C-IF Chebyshev distance measures between ςι and ςι′, as demonstrated: 25 D3∞ςι,ςι′=1212rCιθ-rCι′θ+maxmCιθ-mCι′θ,nCιθ-nCι′θ 26 D4∞ςι,ςι′=1212rCιθ-rCι′θ+maxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ where D3∞ and D4∞ indicate limβ→∞D3β and limβ→∞D4β, respectively.D3β(ςι,ςι′) Example 1 Consider two C-IF values ςι=(0.37, 0.13; 1) and ςι′=(0.51, 0.24; 2). Following the three-term approach, the C-IF Manhattan distance D31(ςι,ςι′), C-IF Euclidean distance D32(ςι,ςι′), and C-IF Chebyshev distance D3∞(ςι,ςι′) can be determined using Eqs. (21), (23), and (25), respectively. Based on the four-term approach, the three C-IF distances D41(ςι,ςι′), D42(ςι,ςι′), and D4∞(ςι,ςι′) are derived using Eqs. (22), (24), and (26), respectively. The relevant calculation process and results are depicted in Table 1. As revealed in the table, the C-IF distances determined by the three- and four-term approaches fulfill the relationships D3∞(ςι,ςι′)>D32(ςι,ςι′)>D31(ςι,ςι′) and D4∞(ςι,ςι′)=D41(ςι,ςι′)>D42(ςι,ςι′), respectively. Regardless of β=1, β=2, or β→∞, the C-IF distances generated by the four-term approach are greater than those yielded by the three-term approach, specifically, D41(ςι,ςι′)>D31(ςι,ςι′), D42(ςι,ςι′)>D32(ςι,ςι′), and D4∞(ςι,ςι′)>D3∞(ςι,ςι′). More exploration of the relationship between these distances will be discussed systematically in the following theorems.Table 1 Computational illustration of the C-IF distances in Example 1 Approach β Demonstration of the calculation process Three-term 1 D31(ςι,ςι′)=(1/2)[(1/2)1-2+(1/2)(0.37-0.51+0.13-0.24)]=0.2089 2 D32(ςι,ςι′)=(1/2){(1/2)1-2+(1/2)[0.37-0.512+0.13-0.242]}=0.2094 ∞ D3∞(ςι,ςι′)=(1/2)[(1/2)1-2+max{0.37-0.51,0.13-0.24}]=0.2164 Four-term 1 D41(ςι,ςι′)=(1/2)[(1/2)1-2+(1/2)(0.37-0.51+0.13-0.24+0.50-0.25)]=0.2714 2 D42ςι,ςι′=12121-2+120.37-0.512+0.13-0.242+0.50-0.252=0.2550 ∞ D4∞(ςι,ςι′)=(1/2)[(1/2)1-2+max{0.37-0.51,0.13-0.24,0.50-0.25}]=0.2714 Theorem 1 Based on the three-term representation, the C-IF Minkowski distance measure D3β for any three C-IF values ςι,ςι′, and ςι" fulfills the following properties: (T1.1) Non-negativity D3β(ςι,ςι′)≥0 for all β∈Z+; (T1.2) Boundedness D3β(ςι,ςι′)≤1 for all β∈Z+; (T1.3) Reflexivity D3β(ςι,ςι)=0 for all β∈Z+; (T1.4) Symmetry D3β(ςι,ςι′)=D3β(ςι′,ςι) for all β∈Z+; (T1.5) Separability D3β(ςι,ςι′)=0 for all β∈Z+ if and only if ςι=ςι′; (T1.6) Triangle inequality D3β(ςι,ςι′)≤D3β(ςι,ςι")+D3β(ςι",ςι′) when β=1 and β→∞. Proof (T1.1) Because of the absolute value properties, the non-negative property can be deduced immediately. (T1.2) As stated in Definition 2, rCθ:Θ→[0,2] and mCθ,nCθ:Θ→[0,1] are known. These axiomatic conditions lead to the conclusion that |rCιθ-rCι′θ|≤2, |mCιθ-mCι′θ|≤1, and |nCιθ-nCι′θ|≤1. It is a direct result of the inequality |mCιθ-mCι′θ|β+|nCιθ-nCι′θ|β≤2. As a result, it concludes that D3β(ςι,ςι′)≤(1/2){(1/2)·2+[(1/2)·2](1/β)}=1 for all β∈Z+. (T1.3) and (T1.4) are trivially correct. (T1.5) If ςι=ςι′, one can obtain mCιθ=mCι′θ,nCιθ=nCι′θ, and rCιθ=rCι′θ, and therefore,D3β(ςι,ςι′)=0 for all β∈Z+. Conversely, if D3β(ςι,ςι′)=0 for all β∈Z+, the three equations |mCιθ-mCι′θ|=0, |nCιθ-nCι′θ|=0, and |rCιθ-rCι′θ|=0 should be satisfied. As a result, one can directly conclude that (mCιθ,nCιθ;rCιθ)=(mCι′θ,nCι′θ;rCι′θ). The sufficiency and necessity for separability are confirmed, confirming the validity of (T1.5). (T1.6) Concerning the three radii rCιθ, rCι′θ, and rCι"θ associated with the C-IF values ςι,ςι′, and ςι", respectively, the following inequality can be generated: rCιθ-rCι′θ=rCιθ-rCι"θ+rCι"θ-rCι′θ≤rCιθ-rCι"θ+rCι"θ-rCι′θ It immediately follows that (1/2)·|rCιθ-rCι′θ|≤(1/2)·|rCιθ-rCι"θ|+(1/2)·|rCι"θ-rCι′θ|. Similarly, the following two inequalities emerge:27 mCιθ-mCι′θ=mCιθ-mCι"θ+mCι"θ-mCι′θ≤mCιθ-mCι"θ+mCι"θ-mCι′θ 28 nCιθ-nCι′θ=nCιθ-nCι"θ+nCι"θ-nCι′θ≤nCιθ-nCι"θ+nCι"θ-nCι′θ The following outcomes can be yielded by fusing both sides of the inequalities in Eqs. (27) and (28):12mCιθ-mCι′θ+nCιθ-nCι′θ≤12mCιθ-mCι″θ+nCιθ-nCι″θ+12mCι″θ-mCι′θ+nCι″θ-nCι′θ Based on the aforementioned outcomes, the validity of the triangle inequality when β=1, i.e., D31(ςι,ςι′)≤D31(ςι,ςι")+D31(ςι",ςι′), can be confirmed. Following that, by taking the maximum operation of both sides of the inequalities in Eqs. (27) and (28), it gives substance to:maxmCιθ-mCι′θ,nCιθ-nCι′θ≤maxmCιθ-mCι″θ,nCιθ-nCι″θ+maxmCι″θ-mCι′θ,nCι″θ-nCι′θ Based on this, the authenticity of the triangle inequality when β→∞, i.e., D3∞(ςι,ςι′)≤D3∞(ςι,ςι")+D3∞(ςι",ςι′), can be confirmed, completing the proof. Theorem 2 Based on the four-term representation, the C-IF Minkowski distance measure D4β for any three C-IF values ςι,ςι′, and ςι" fulfills the following properties: (T2.1) Non-negativity D4β(ςι,ςι′)≥0 for all β∈Z+; (T2.2) Boundedness D4β(ςι,ςι′)≤1 for all β∈Z+; (T2.3) Reflexivity D4β(ςι,ςι)=0 for all β∈Z+; (T2.4) Symmetry D4β(ςι,ςι′)=D4β(ςι′,ςι) for all β∈Z+; (T2.5) Separability D4β(ςι,ςι′)=0 for all β∈Z+ if and only if ςι=ςι′; (T2.6) Triangle inequality D4β(ςι,ςι′)≤D4β(ςι,ςι")+D4β(ςι",ςι′) when β=1 and β→∞. Proof The proofs of (T2.1)−(T2.6) resemble those of (T1.1)−(T1.6), respectively. Following Theorems 1 and 2, the C-IF Minkowski distance measures D3β and D4β are semi-metrics for C-IF values because they fulfill the essential conditions of reflexivity revealed in (T1.3) and (T2.3), symmetry in (T1.4) and (T2.4), and separability in (T1.5) and (T2.5). Furthermore, the C-IF Manhattan distance measures D31 and D41, as well as the C-IF Chebyshev distance measures D3∞ and D4∞, are well-defined metrics for C-IF information because they satisfy the essential conditions of reflexivity exhibited in (T1.3) and (T2.3), symmetry in (T1.4) and (T2.4), separability in (T1.5) and (T2.5), and triangle inequalities in (T1.6) and (T2.6). Theorem 3 The following properties are valid for any two C-IF values ςι and ςι′: (T3.1) D3β(ςι,ςι′)≤D4β(ςι,ςι′) for all β∈Z+; (T3.2) D3βςι,ςι′=D4β(ςι,ςι′) if hCιθ=hCι′θ; (T3.3) D3β(ςι,ςι′)≤D3∞(ςι,ςι′) for all β∈Z+; (T3.4) D4β(ςι,ςι′)≤D4∞(ςι,ςι′) for all β∈Z+. Proof (T3.1) and (T3.2) are trivially correct. (T3.3) First, consider the case where β=1. It is apparent that |mCιθ-mCι′θ|≤max{|mCιθ-mCι′θ|,|nCιθ-nCι′θ|} and |nCιθ-nCι′θ|≤max{|mCιθ-mCι′θ|,|nCιθ-nCι′θ|}. By aggregating both sides of the two inequalities, it can be generated that |mCιθ-mCι′θ|+|nCιθ-nCι′θ|≤2·max{|mCιθ-mCι′θ|,|nCιθ-nCι′θ|}. As a consequence, one can obtain (1/2)·(|mCιθ-mCι′θ|+|nCιθ-nCι′θ|)≤max{|mCιθ-mCι′θ|,|nCιθ-nCι′θ|}. Accordingly, it draws the inference that D31(ςι,ςι′)≤D3∞(ςι,ςι′). Furthermore, as a result of the following outcome:12mCιθ-mCι′θβ+nCιθ-nCι′θβ≤12mCιθ-mCι′θ+12nCιθ-nCι′θβ1β=12mCιθ-mCι′θ+12nCιθ-nCι′θ≤maxmCιθ-mCι′θ,nCιθ-nCι′θ, which leads to the conclusion D3β(ςι,ςι′)≤D3∞(ςι,ςι′). (T3.4) Remember, mCιθ+nCιθ+hCιθ=1, and mCι′θ+nCι′θ+hCι′θ=1. Concerning the comparisons between mCιθ and mCι′θ, nCιθ and nCι′θ, and hCιθ and hCι′θ, the contrast outcomes have six situations, consisting of (i) mCιθ≥mCι′θ,nCιθ≥nCι′θ,hCιθ≤hCι′θ, (ii) mCιθ≥mCι′θ,nCιθ≤nCι′θ,hCιθ≥hCι′θ, (iii) mCιθ≤mCι′θ,nCιθ≥nCι′θ,hCιθ≥hCι′θ, (iv) mCιθ≥mCι′θ,nCιθ≤nCι′θ,hCιθ≤hCι′θ, (v) mCιθ≤mCι′θ,nCιθ≥nCι′θ,hCιθ≤hCι′θ, and (vi) mCιθ≤mCι′θ,nCιθ≤nCι′θ,hCιθ≥hCι′θ. In Case (i), the presuppositions of mCιθ≥mCι′θ, nCιθ≥nCι′θ, and hCιθ≤hCι′θ give substance to the following results:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12mCιθ-mCι′θ+nCιθ-nCι′θ-hCιθ+hCι′θ=12mCιθ-mCι′θ+nCιθ-nCι′θ-1-mCιθ-nCιθ+1-mCι′θ-nCι′θ=122·mCιθ-2·mCι′θ+2·nCιθ-2·nCι′θ=mCιθ-mCι′θ+nCιθ-nCι′θ=-hCιθ+hCι′θ=hCιθ-hCι′θ. In Case (ii), the presuppositions of mCιθ≥mCι′θ, nCιθ≤nCι′θ, and hCιθ≥hCι′θ demonstrate the truth of the following outcomes:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12mCιθ-mCι′θ-nCιθ+nCι′θ+1-mCιθ-nCιθ-1-mCι′θ-nCι′θ=12-2·nCιθ+2·nCι′θ=-nCιθ+nCι′θ=nCιθ-nCι′θ. In Case (iii), the presuppositions of mCιθ≤mCι′θ, nCιθ≥nCι′θ, and hCιθ≥hCι′θ produce the following outcomes:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12-mCιθ+mCι′θ+nCιθ-nCι′θ+1-mCιθ-nCιθ-1-mCι′θ-nCι′θ=12-2·mCιθ+2·mCι′θ=-mCιθ+mCι′θ=mCιθ-mCι′θ. In Case (iv), the presuppositions of mCιθ≥mCι′θ, nCιθ≤nCι′θ, and hCιθ≤hCι′θ generate the following outcomes:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12mCιθ-mCι′θ-nCιθ+nCι′θ-1-mCιθ-nCιθ+1-mCι′θ-nCι′θ=122·mCιθ-2·mCι′θ=mCιθ-mCι′θ=mCιθ-mCι′θ. In Case (v), the presuppositions of mCιθ≤mCι′θ, nCιθ≥nCι′θ, and hCιθ≤hCι′θ yield the following outcomes:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12-mCιθ+mCι′θ+nCιθ-nCι′θ-1-mCιθ-nCιθ+1-mCι′θ-nCι′θ=122·nCιθ-2·nCι′θ=nCιθ-nCι′θ=nCιθ-nCι′θ. In Case (vi), the presuppositions of mCιθ≤mCι′θ, nCιθ≤nCι′θ, and hCιθ≥hCι′θ the produce following outcomes:12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ=12-mCιθ+mCι′θ-nCιθ+nCι′θ+1-mCιθ-nCιθ-1-mCι′θ-nCι′θ=12-2·mCιθ+2·mCι′θ-2·nCιθ+2·nCι′θ=-mCιθ+mCι′θ-nCιθ+nCι′θ=hCιθ-hCι′θ. The following inequality can be deduced by summarizing the results obtained under the above presuppositions in in Cases (i) − (vi):12mCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ≤maxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ As a result, D41(ςι,ςι′)≤D4∞(ςι,ςι′). Furthermore, the following outcome is received:12mCιθ-mCι′θβ+nCιθ-nCι′θβ+hCιθ-hCι′θβ1β≤12mCιθ-mCι′θ+12nCιθ-nCι′θ+12hCιθ-hCι′θβ1β=12mCιθ-mCι′θ+12nCιθ-nCι′θ+12hCιθ-hCι′θ≤maxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ. As a result, it confirms the truth of D4β(ςι,ςι′)≤D4∞(ςι,ςι′). This concludes the proof. C-IF Minkowski metrics for C-IF sets In addition to the C-IF Minkowski distance measures between C-IF values described in the previous subsection, this subsection further introduces new distance metrics for C-IF sets based on the above distance measures. Definition 6 Given a finite universe of discourse Θ (with the cardinality card(Θ)) and a metric parameter β∈Z+, the C-IF Minkowski distance measures separating the C-IF sets Cι=⟨θ,mCιθ,nCιθ;rCιθ⟩θ∈Θ (involving hesitancy hCιθ) and Cι′=⟨θ,mCι′θ,nCι′θ; rCι′θ⟩θ∈Θ (involving hesitancy hCι′θ) based on the three- and four-term approaches are expounded in this order:xx29 D3βCι,Cι′=1212·cardΘ∑θ∈ΘrCιθ-rCι′θ+12·cardΘ∑θ∈ΘmCιθ-mCι′θβ+nCιθ-nCι′θβ1β 30 D(4)β(Cι,Cι′)=1212·card(Θ)∑θ∈ΘrCιθ-rCι′θ+12·card(Θ)∑θ∈ΘmCιθ-mCι′θβ+nCιθ-nCι′θβ+hCιθ-hCι′θβ1β. Remark 2 The C-IF Manhattan distance measures between two C-IF sets Cι and Cι′ are depicted as follows using the three- and four-term representations:31 D(3)1(Cι,Cι′)=1212·card(Θ)∑θ∈ΘrCιθ-rCι′θ+12·card(Θ)∑θ∈ΘmCιθ-mCι′θ+nCιθ-nCι′θ 32 D(4)1(Cι,Cι′)=1212·card(Θ)∑θ∈ΘrCιθ-rCι′θ+12·card(Θ)∑θ∈ΘmCιθ-mCι′θ+nCιθ-nCι′θ+hCιθ-hCι′θ The C-IF Euclidean distance measures between Cι and Cι′ are drawn as follows:33 D(3)2(Cι,Cι′)=1212·card(Θ)∑θ∈ΘrCιθ-rCι′θ+12·card(Θ)∑θ∈Θ(mCιθ-mCι′θ)2+(nCιθ-nCι′θ)212 34 D(4)2(Cι,Cι′)=1212·card(Θ)∑θ∈ΘrCιθ-rCι′θ+12·card(Θ)∑θ∈Θ(mCιθ-mCι′θ)2+(nCιθ-nCι′θ)2+(hCιθ-hCι′θ)212 The C-IF Chebyshev distance measures between Cι and Cι′ are depicted like this:35 D3∞Cι,Cι′=1212·cardΘ∑θ∈ΘrCιθ-rCι′θ+1cardΘ∑θ∈ΘmaxmCιθ-mCι′θ,nCιθ-nCι′θ 36 D4∞Cι,Cι′=1212·cardΘ∑θ∈ΘrCιθ-rCι′θ+1cardΘ∑θ∈ΘmaxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ where D3∞ and D4∞ indicate limβ→∞D3β and limβ→∞D4β, respectively. Example 2 Given a finite universe of discourse Θ={θ1,θ2,θ3}, consider two C-IF sets Cι=⟨θi,mCιθi,nCιθi;rCιθi⟩θi∈Θ (involving the degree of hesitancy hCιθi for θi∈Θ) and Cι′=⟨θi,mCι′θi,nCι′θi;rCι′θi⟩θi∈Θ (involving the degree of hesitancy hCι′θi for θi∈Θ). The detailed data embedded in Cι and Cι′ are shown in the upper part of Table 2. More precisely, the geometrical representation of Cι and Cι′ is portrayed in Fig. 3.Table 2 Data and computation results of the C-IF distances in Example 2 θi Data embedded in the C-IF set Cι Data embedded in the C-IF set Cι′ mCιθi nCιθi rCιθi hCιθi mCι′θi nCι′θi rCι′θi hCι′θi θ1 0.16 0.12 0.07 0.72 0.13 0.23 0.08 0.64 θ2 0.28 0.60 0.06 0.12 0.28 0.48 0.10 0.24 θ3 0.56 0.26 0.09 0.18 0.52 0.13 0.11 0.35 C-IF distance based on the three-term approach C-IF distance based on the four-term approach D(3)1(Cι,Cι′) D(3)2(Cι,Cι′) D(3)∞(Cι,Cι′) D(4)1(Cι,Cι′) D(4)2(Cι,Cι′) D4∞Cι,Cι′ 0.0441 0.0520 0.0682 0.0749 0.0714 0.0749 Fig. 3 Geometrical representation of the C-IF sets Cι and Cι′ The cardinality of Θ is given as cardΘ=3 in this example. The C-IF Manhattan, Euclidean, and Chebyshev distances between Cι and Cι′ are derived using the three-term approach as follows:D31Cι,Cι′=1212·30.07-0.08+0.06-0.10+0.09-0.11+12·30.16-0.13+0.12-0.23+0.28-0.28+0.60-0.48+0.56-0.52+0.26-0.13=0.0441 D32Cι,Cι′=1212·30.07-0.08+0.06-0.10+0.09-0.11+12·30.16-0.132+0.12-0.232+0.28-0.282+0.60-0.482+0.56-0.522+0.26-0.13212=0.0520 D3∞Cι,Cι′=1212·30.07-0.08+0.06-0.10+0.09-0.11+13max{0.16-0.13,0.12-0.23}+max0.28-0.28,0.60-0.48+max{0.56-0.52,0.26-0.13}=0.0682 Similarly, using the four-term approach, the C-IF Manhattan, Euclidean, and Chebyshev distances between Cι and Cι′ are as follows: D(4)1(Cι,Cι′)=0.0749, D(4)2(Cι,Cι′)=0.0714, and D4∞Cι,Cι′=0.0749. The C-IF distances calculated above are listed in the lower part of Table 2. As shown in the table, the C-IF Manhattan, Euclidean, and Chebyshev distances produced by the three-term approach are smaller than those rendered by the four-term approach, i.e., D(3)β(Cι,Cι′)≤D(4)β(Cι,Cι′) for β=1, β=2, and β→∞. Additionally, it can be observed that D31Cι,Cι′<D32Cι,Cι′<D(3)∞(Cι,Cι′) and D42Cι,Cι′<D41Cι,Cι′=D4∞Cι,Cι′ in this example. The following three theorems will systematically investigate the essential properties of these C-IF distances and their relationship. Theorem 4 The C-IF Minkowski distance measure D(3)β for any three C-IF sets Cι, Cι′, and Cι" fulfills the following properties based on the three-term representation: (T4.1) Non-negativity D(3)β(Cι,Cι′)≥0 for all β∈Z+; (T4.2) Boundedness D(3)β(Cι,Cι′)≤1 for all β∈Z+; (T4.3) Reflexivity D(3)β(Cι,Cι)=0 for all β∈Z+; (T4.4) Symmetry D(3)β(Cι,Cι′)=D(3)β(Cι′,Cι) for all β∈Z+; (T4.5) Separability D(3)β(Cι,Cι′)=0 for all β∈Z+ if and only if Cι=Cι′; (T4.6) Triangle inequality D(3)β(Cι,Cι′)≤D(3)β(Cι,Cι")+D(3)β(Cι",Cι′) when β=1 and β→∞. Proof (T4.1) The non-negative property is demonstrated by a non-negative cardinality, i.e., card(Θ)≥0, and the non-negative property in (T1.1). (T4.2) The cardinality card(Θ) is a measure of the number of elements contained in Θ. By reason of |rCιθ-rCι′θ|≤2 and |mCιθ-mCι′θ|β+|nCιθ-nCι′θ|β≤2 (for β∈Z+), it is recognized that ∑θ∈ΘrCιθ-rCι′θ≤2·card(Θ) and ∑θ∈Θ|mCιθ-mCι′θ|β+|nCιθ-nCι′θ|β≤2·card(Θ). Consequently, for all β∈Z+, it is acquired that D3β(Cι,Cι′)≤(1/2){[1/(2·cardΘ)]·(2·cardΘ)+[(1/(2·card(Θ)))·(2·card(Θ))](1/β)}=1. (T4.3) and (T4.4) are trivially correct. (T4.5) In accordance with Definition 2, Cι={⟨θ,mCιθ,nCιθ;rCιθ⟩θ∈Θ} and Cι′={⟨θ,mCι′θ,nCι′θ;rCι′θ⟩θ∈Θ}. The given condition Cι=Cι′ gives substance to mCιθ=mCι′θ,nCιθ=nCι′θ, and rCιθ=rCι′θ for all θ∈Θ, thereby D(3)β(Cι,Cι′)=0 for all β∈Z+. By contrast, the condition D(3)β(Cι,Cι′)=0 for all β∈Z+ establishes evidence of |mCιθ-mCι′θ|=0, |nCιθ-nCι′θ|=0, and |rCιθ-rCι′θ|=0 for each θ∈Θ. As a result, the correctness of {⟨θ,mCιθ,nCιθ;rCιθ⟩θ∈Θ}={⟨θ,mCι′θ,nCι′θ;rCι′θ⟩θ∈Θ} can be supported, corroborating the sufficiency and necessity for the separability property. (T4.6) The following inequalities are fulfilled for each θ∈Θ, as attested by the property in (T1.6): |rCιθ-rCι′θ|≤|rCιθ-rCι"θ|+|rCι"θ-rCι′θ|, |mCιθ-mCι′θ|≤|mCιθ-mCι"θ|+|mCι"θ-mCι′θ|, and |nCιθ-nCι′θ|≤|nCιθ-nCι"θ|+|nCι"θ-nCι′θ|. It is the direct result of the following inequalities:∑θ∈ΘrCιθ-rCι′θ≤∑θ∈ΘrCιθ-rCι"θ+∑θ∈ΘrCι"θ-rCι′θ, ∑θ∈ΘmCιθ-mCι′θ+nCιθ-nCι′θ≤∑θ∈ΘmCιθ-mCι"θ+nCιθ-nCι"θ+∑θ∈ΘmCι"θ-mCι′θ+nCι"θ-nCι′θ, ∑θ∈ΘmaxmCιθ-mCι′θ,nCιθ-nCι′θ≤∑θ∈ΘmaxmCιθ-mCι"θ,nCιθ-nCι"θ+∑θ∈ΘmaxmCι"θ-mCι′θ,nCι"θ-nCι′θ. In light of the previously obtained results and the formulas in Remark 2, the correctness of the triangle inequalities D(3)1(Cι,Cι′)≤D(3)1(Cι,Cι")+D(3)1(Cι",Cι′) and D(3)∞(Cι,Cι′)≤D(3)∞(Cι,Cι")+D(3)∞(Cι",Cι′) when β=1 and β→∞, respectively, can be corroborated, completing the proof. Theorem 5 The C-IF Minkowski distance measure D(4)β for any three C-IF sets Cι, Cι′, and Cι" fulfills the following properties based on the four-term representation: (T5.1) Non-negativity D(4)β(Cι,Cι′)≥0 for all β∈Z+; (T5.2) Boundedness: D(4)β(Cι,Cι′)≤1 for all β∈Z+; (T5.3) Reflexivity D(4)β(Cι,Cι)=0 for all β∈Z+; (T5.4) Symmetry D(4)β(Cι,Cι′)=D(4)β(Cι′,Cι) for all β∈Z+; (T5.5) Separability D(4)β(Cι,Cι′)=0 for all β∈Z+ if and only if Cι=Cι′; (T5.6) Triangle inequality D(4)β(Cι,Cι′)≤D(4)β(Cι,Cι")+D(4)β(Cι",Cι′) when β=1 and β→∞. Proof The proving processes of (T5.1) − (T5.6) are akin to those of (T4.1) − (T4.6), respectively. According to Theorems 4 and 5, the C-IF Minkowski distance measures D(3)β and D(4)β are semi-metrics of the C-IF sets because they satisfy the reflexivity in (T4.3) and (T5.3), symmetry in (T4.4) and (T5.4), and separability in (T4.5) and (T5.5). Furthermore, the C-IF Manhattan distance measures D(3)1 and D(4)1, as well as the C-IF Chebyshev distance measures D(3)∞ and D(4)∞, are well-defined measures of C-IF sets because they satisfy the reflexivity in (T4.3) and (T5.3), symmetry in (T4.4) and (T5.4), separability in (T4.5) and (T5.5), and triangle inequalities in (T4.6) and (T5.6). Theorem 6 The following properties are valid for any two C-IF sets Cι and Cι′: (T6.1) D(3)β(Cι,Cι′)≤D(4)β(Cι,Cι′) for all β∈Z+; (T6.2) D(3)β(Cι,Cι′)=D(4)β(Cι,Cι′) if hCιθ=hCι′θ for all θ∈Θ; (T6.3)D(3)β(Cι,Cι′)≤D(3)∞(Cι,Cι′) for all β∈Z+; (T6.4)D(4)β(Cι,Cι′)≤D(4)∞(Cι,Cι′) for all β∈Z+. Proof (T6.1) and (T6.2) are trivially correct. (T6.3) Based on the proving process in (T3.3), the following inequality holds true for θ∈Θ:12mCιθ-mCι′θβ+nCιθ-nCι′θβ1β≤maxmCιθ-mCι′θ,nCιθ-nCι′θ. When both sides of the inequality are averaged across all θ∈Θ, the following result can be deduced:12·card(Θ)∑θ∈ΘmCιθ-mCι′θβ+nCιθ-nCι′θβ1β ≤1cardΘ∑θ∈ΘmaxmCιθ-mCι′θ,nCιθ-nCι′θ. It directly draws the inference of D(3)β(Cι,Cι′)≤D(3)∞(Cι,Cι′) for all β∈Z+. (T6.4) The following inequality holds true for θ∈Θ, as supported by the proving process in (T3.4):12mCιθ-mCι′θβ+nCιθ-nCι′θβ+hCιθ-hCι′θβ1β ≤maxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ. When both sides of the inequality are averaged across all θ∈Θ, the following result can be deduced:12·card(Θ)∑θ∈ΘmCιθ-mCι′θβ+nCιθ-nCι′θβ+hCιθ-hCι′θβ1β ≤1cardΘ∑θ∈ΘmaxmCιθ-mCι′θ,nCιθ-nCι′θ,hCιθ-hCι′θ. It comes to the conclusion of D(4)β(Cι,Cι′)≤D(4)∞(Cι,Cι′) for all β∈Z+. As previously stated, Atanassov and Marinov (2021) constructed four new C-IF distance metrics. These four new distance measures, however, have significant limitations. Atanassov and Marinov’s C-IF distance formulas, as shown in Definition 4, do not account for the fact that the elements in a C-IF set have different radii. The distance measures advanced by Atanassov and Marinov (2021) are special cases of the evolved C-IF Minkowski metrics, according to the C-IF Minkowski metrics established in this study, if the radius of all elements in each C-IF set Cι is assumed to be equal to rCιθ. Specifically, assume that rCιθ=rCι and rCι′θ=rCι′ for all θ∈Θ. One has:12·card(Θ)∑θ∈ΘrCιθ-rCι′θ=∑θ∈ΘrCι-rCι′2·card(Θ)=card(Θ)·rCι-rCι′2·card(Θ)=rCι-rCι′2. Therefore, D3MCι,Cι′=D(3)1(Cι,Cι′), D4MCι,Cι′=D(4)1(Cι,Cι′), D3ECι,Cι′=D(3)2(Cι,Cι′), and D4ECι,Cι′=D(4)2(Cι,Cι′). The C-IF Manhattan and Euclidean distance measures for C-IF sets revealed in Remark 2 can cover the four C-IF distance metrics in Definition 4. More importantly, two evolved general distance metrics based on three- and four-term representations, namely the C-IF Minkowski metrics for C-IF values in Definition 5 and the C-IF Minkowski metrics for C-IF sets in Definition 6, can improve the limitations of existing C-IF distance metrics and expand their flexibility and applicability. Evolved C-IF TOPSIS methodology This section is dedicated to the development of an evolved C-IF TOPSIS methodology predicated on the C-IF Minkowski metrics to tackle MCDA problems with complex and uncertain decision information as a reference for intelligent decision assistance. As previously stated, Alkan and Kahraman (2022b) and Kahraman and Alkan (2021) developed the C-IF TOPSIS methods. However, they did not fully follow the core architecture of classic TOPSIS but made substantial modifications. Moreover, they converted C-IF information (i.e., criteria weights and performance ratings of alternatives judging by criteria) into IF information for processing in the calculation process of their C-IF TOPSIS procedures. Specifically, the C-IF decision matrix was transformed into pessimistic and optimistic decision matrices, and the data in these two decision matrices are ordinary IF values. This operating procedure may lose the specificity of C-IF information and reduce its flexibility to deal with uncertainty. The question of how to extend the classic TOPSIS architecture to the C-IF environment in such a way that the development can faithfully demonstrate the spirit of TOPSIS’s compromise approach has become critical. As a result, this section is dedicated to creating a new C-IF TOPSIS methodology based on the C-IF Minkowski metric within the TOPSIS core architecture. The C-IF TOPSIS technique proposed in this section is based on four fundamental structures, each of which contains four combinations of the displaced and fixed anchoring frames, as well as the C-IF Minkowski metrics using three- and four-term approaches. Through such a methodological evolution, the theoretical framework of the prestigious TOPSIS can be extended to intricate C-IF environments, thereby expanding the application scope of TOPSIS. Proposed C-IF TOPSIS approaches In this study, the MCDA issue is investigated by evaluating a limited number of candidate alternatives across multiple performance criteria in C-IF uncertain circumstances. Let A=a1,a2,⋯,aA signify a collection of the A(≥2) candidate alternatives; similarly, let P=p1,p2,⋯,pP signify a collection of the P(≥2) performance criteria, wherein A and C are positive integers. Furthermore, the collection P is split into two sub-collections, one for the collection PI of beneficial criteria (to be maximized) and the other for the collection PII of non-beneficial criteria (to be minimized), where PI∩PII=∅ and PI∪PII=P. The C-IF performance rating of a candidate alternative ai (i=1,2,⋯,A) judging by a performance criterion pj (j=1,2,⋯,P) is expressed as ςij=(mij,nij;rij), in which the degree of hesitancy is derived as hij=1-mij-nij. The C-IF characteristic Ci and its embedded function Or are expounded for each candidate alternative ai∈A as follows:37 Ci=⟨pj,mij,nij;rij⟩pj∈P=⟨pj,Ormij,nij⟩pj∈P and Or(mij,nij)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(mij-ζ)2+(nij-ζ′)2≤rij,andζ+ζ′≤1}. The C-IF importance weight of a performance criterion pj (j=1,2,⋯,P) is explicated as wj=(wj,ωj;γj), in which the degree of hesitancy is produced as hij=1-wj-ωj. Remember that the intersection, union, addition, and multiplication operations described in Definition 3 involve the min types (i.e., ∩min, ∪min, ⊕min, and ⊗min) as well as the max types (i.e., ∩max, ∪max, ⊕max, and ⊗max). Herein, these operations using the min and max types are determined by the minimum radius and maximum radius, respectively. In conformity with Kahraman and Alkan (2021), the operations with the min and max types will deliver the outcomes involving minimum and maximum uncertainty levels, respectively. To be more specific, a smaller radius indicates less ambiguity for the operation result of the C-IF paired information, while a larger radius indicates greater ambiguity. This study intends to exploit the multiplication operation with the max type to generate weighted performance ratings in this regard. The weighted performance rating ςijw of ai judging by pj is generated using the multiplication operation ⊗max in Definition 3, i.e., ςijw=wj⊗maxςij, as demonstrated below:38 ςijw=mijw,nijw;rijw=wj·mij,ωj+nij-ωj·nij;maxγj,rij where the degree of hesitancy is derived as hijw=1-mijw-nijw. By collecting the weighted performance rating ςijw over the P criteria, the C-IF characteristic Ciw for each ai is elucidated as:39 Ciw=⟨pj,mijw,nijw;rijw⟩pj∈P=⟨pj,Ormijw,nijw⟩pj∈P in which Or(mijw,nijw)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(mijw-ζ)2+(nijw-ζ′)2≤rijw,andζ+ζ′≤1}. The C-IF TOPSIS methodology, which is scheduled to be developed in this study, is based on the aforementioned C-IF Minkowski metrics using three- and four-term approaches, as well as the displaced and fixed anchoring frameworks. The anchoring mechanism consists of displaced and fixed ideal and anti-ideal C-IF characteristics that can serve as anchoring points in the C-IF TOPSIS procedure to formulate the subsequent compromise indices. The displaced anchoring framework, in particular, can be elicited from the intersection and union operations using the min and max types. To capture the most uncertainty, the operators ∩max and ∪max are utilized to identify the displaced ideal and anti-ideal ratings, as well as C-IF characteristics. The displaced ideal rating ς∗jw can be yielded by performing the union operation ς1jw∪maxς2jw∪max⋯∪maxςAjw and the intersection operation ς1jw∩maxς2jw∩max⋯∩maxςAjw if pj∈PI and pj∈PII, respectively. The displaced anti-ideal rating ς¬jw, on the other hand, can be produced by performing the intersection operation ς1jw∩maxς2jw ∩max⋯∩maxςAjw and the union operation ς1jw∪maxς2jw∪max⋯∪maxςAjw if pj∈PI and pj∈PII, respectively. More specifically, the displaced ideal and anti-ideal ratings are derived as follows:40 ς∗jw=m∗jw,n∗jw;r∗jw=maxi=1Amijw,mini=1Anijw;maxi=1Arijwifpj∈PI,mini=1Amijw,maxi=1Anijw;maxi=1Arijwifpj∈PII; 41 ς¬jw=m¬jw,n¬jw;r¬jw=mini=1Amijw,maxi=1Anijw;maxi=1Arijwifpj∈PI,maxi=1Amijw,mini=1Anijw;maxi=1Arijwifpj∈PII, where h∗jw=1-m∗jw-n∗jw and h¬jw=1-m¬jw-n¬jw are the degrees of hesitancy. Furthermore, the displaced ideal and anti-ideal C-IF characteristics are delineated in this wise:42 C∗w=⟨pj,m∗jw,n∗jw;r∗jw⟩pj∈P=⟨pj,Orm∗jw,n∗jw⟩pj∈P 43 C¬w=⟨pj,m¬jw,n¬jw;r¬jw⟩pj∈P=⟨pj,Orm¬jw,n¬jw⟩pj∈P where Or(m∗jw,n∗jw)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(m∗jw-ζ)2+(n∗jw-ζ′)2≤r∗jw,andζ+ζ′≤1} and Or(m¬jw,n¬jw)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(m¬jw-ζ)2+(n¬jw-ζ′)2≤r¬jw,andζ+ζ′≤1}. The relative closeness of the C-IF characteristic Ciw to the ideal and anti-ideal C-IF characteristics C∗w and C¬w can be delineated in the displaced anchoring framework along these lines: one is derived from the C-IF Minkowski distance measure using the three-term approach, and the other is established using the four-term approach. The relative closeness coefficients R3β∗(ai) and R4β∗(ai) are derived as:44 R3β∗ai=D3βCiw,C¬wD3βCiw,C∗w+D3βCiw,C¬w 45 R4β∗ai=D4βCiw,C¬wD4βCiw,C∗w+D4βCiw,C¬w. Remark 3 The relative closeness coefficients R3β∗(ai) and R4β∗(ai) have the following characteristics: (R3.1) 0≤R3β∗ai≤1 and 0≤R4β∗ai≤1 for all β∈Z+; (R3.2) R3β∗ai=0 and R4β∗ai=0 for all β∈Z+ if and only if Ciw=C¬w; (R3.3) R3β∗ai=1 and R4β∗ai=1 for all β∈Z+ if and only if Ciw=C∗w. Proof (R3.1) For all β∈Z+, it is recognized that 0≤R3β∗ai≤1 and 0≤R4β∗ai≤1 as a consequence of the non-negativity properties in (T4.1) and (T5.1) and the boundedness properties in (T4.2) and (T5.2) (i.e., 0≤D3βCiw,C∗w,D3βCiw,C¬w,D4βCiw,C∗w,D4βCiw,C¬w≤1). (R3.2) The preconditions R3β∗ai=0 and R4β∗ai=0 draw the inferences of zero numerators in Eqs. (44) and (45), respectively; that is, D3βCiw,C¬w=0 and D4βCiw,C¬w=0. As attested by the separability property in (T4.5) and (T5.5), it is received that D3βCiw,C¬w=0 and D4βCiw,C¬w=0, respectively, if and only if Ciw=C¬w. From these explicit discussions, it deduces that R3β∗ai=R4β∗ai=0 for all β∈Z+ if and only if Ciw=C¬w. (R3.3) Concerning all β∈Z+, the given conditions R3β∗ai=1 and R4β∗ai=1 indicate that D3βCiw,C¬w=D3βCiw,C∗w+D3βCiw,C¬w and D4βCiw,C¬w=D4βCiw,C∗w+D4βCiw,C¬w, respectively. Accordingly, the two equalities give rise to D3βCiw,C∗w=0 and D4βCiw,C∗w=0. Based on the separability property in (T4.5) and (T5.5), the sufficient and necessary condition of D3βCiw,C∗w=0 and D4βCiw,C∗w=0, respectively, is Ciw=C∗w. It concludes that R3β∗ai=1 and R4β∗ai=1 for all β∈Z+ if and only if Ciw=C∗w. In the displaced anchoring framework, all of the A candidate alternatives are sorted in diminishing order of their relative closeness coefficients R3β∗(ai) or R4β∗(ai). This method yields the best compromise collections containing the candidates with the highest relative closeness coefficients:46 A3β∗=aimaxi=1AR3β∗(ai),ai∈A, 47 A4β∗=aimaxi=1AR4β∗(ai),ai∈A On the flip side, the fixed anchoring framework can be established on the fixed ideal and anti-ideal ratings as well as C-IF characteristics. Concerning a beneficial criterion pj∈PI, the fixed ideal rating ς+jw is rendered by multiplying the C-IF importance weight wj by the highest performance (1,0;0). Furthermore, the fixed anti-ideal rating ς-jw can be yielded by multiplying wj by the lowest performance (0,1;0). In the case of a non-beneficial criterion pj∈PII, the fixed ideal rating ς+jw is obtained by multiplying wj by the highest performance (0,1;0); additionally, the fixed anti-ideal rating ς-jw is derived by multiplying wj by the lowest performance (1,0;0). To be more specific, the fixed ideal and anti-ideal ratings are identified in this fashion:48 ς+jw=m+jw,n+jw;r+jw=(wj,ωj;γj)⊗max(1,0;0)=wj,ωj;γjifpj∈PI,(wj,ωj;γj)⊗max(0,1;0)=0,1;γjifpj∈PII; 49 ς-jw=m-jw,n-jw;r-jw=(wj,ωj;γj)⊗max(0,1;0)=0,1;γjifpj∈PI,(wj,ωj;γj)⊗max(1,0;0)=wj,ωj;γjifpj∈PII; where h+jw=1-m+jw-n+jw and h-jw=1-m-jw-n-jw are the degrees of hesitancy. The fixed ideal and anti-ideal C-IF characteristics are portrayed in the following manner:50 C+w=⟨pj,m+jw,n+jw;r+jw⟩pj∈P=⟨pj,Orm+jw,n+jw⟩pj∈P 51 C-w=⟨pj,m-jw,n-jw;r-jw⟩pj∈P=⟨pj,Orm-jw,n-jw⟩pj∈P in which Or(m+jw,n+jw)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(m+jw-ζ)2+(n+jw-ζ′)2≤r+jw,andζ+ζ′≤1} and Or(m-jw,n-jw)={⟨ζ,ζ′⟩|ζ,ζ′∈0,1,(m-jw-ζ)2+(n-jw-ζ′)2≤r-jw,andζ+ζ′≤1}. In the fixed anchoring framework, the relative closeness of the C-IF characteristic Ciw to the ideal and anti-ideal C-IF characteristics C+w and C-w can be generated predicated on the C-IF Minkowski distance measures using the three- and four-term approaches. The relative closeness coefficients R3β+(ai) and R4β+(ai) are rendered in this fashion:52 R3β+ai=D3βCiw,C-wD3βCiw,C+w+D3βCiw,C-w 53 R4β+ai=D4βCiw,C-wD4βCiw,C+w+D4βCiw,C-w Remark 4 The relative closeness coefficients R3β+ai and R4β+ai have the following characteristics: (R4.1) 0≤R3β+ai≤1 and 0≤R4β+ai≤1 for all β∈Z+; (R4.2) R3β+ai=0 and R4β+ai=0 for all β∈Z+ if and only if Ciw=C-w; (R4.3) R3β+ai=1 and R4β+ai=1 for all β∈Z+ if and only if Ciw=C+w. Proof The proofs of (R4.1)−(R4.3) are as analogous to those of (R3.1)−(R3.3), respectively. Finally, all of the A candidate alternatives are sorted in decreasing order of their relative closeness coefficients R3β+(ai) or R4β+(ai). The best compromise collections with the highest relative closeness coefficients in the fixed anchoring framework can be generated by54 A3β+=aimaxi=1AR3β+(ai),ai∈A 55 A4β+=aimaxi=1AR4β+(ai),ai∈A Proposed C-IF TOPSIS algorithms The evolved C-IF TOPSIS methodology employs four fundamental architectures to tackle MCDA issues in complex and uncertain situations. As stated in the C-IF TOPSIS technique in the previous subsection, the four basic architectures are: (1) a displaced anchoring frame based on the three-term representation, (2) a displaced anchoring frame based on the four-term representation, (3) a fixed anchoring frame based on the three-term representation, and (4) a fixed anchoring frame based on the four-term representation. The schematic representation of the C-IF TOPSIS methodology is depicted in Fig. 4. The C-IF TOPSIS procedure is divided into two phases: the foundation phase and the critical core technology phase. The foundation phase consists of two tasks: problem statement and data establishment. The problem statement, for example, includes two collections of candidate alternatives and performance criteria (divided into beneficial and non-beneficial criteria). The data establishment includes the ascertainment of C-IF performance ratings and C-IF importance weights in order to calculate weighted C-IF performance ratings and their corresponding C-IF characteristics. Following that, the critical core technology phase involves either a displaced anchoring mechanism or a fixed anchoring mechanism. The displaced anchoring mechanism encompasses the recognition of displaced ideal and displaced anti-ideal ratings, the construction of displaced ideal/anti-ideal C-IF characteristics, and the ascertainment of relative closeness coefficients using the C-IF Minkowski distance measures with a three- or four-term representation frame. Similarly, the fixed anchoring mechanism encompasses the recognition of fixed ideal and anti-ideal ratings, the construction of fixed ideal/anti-ideal C-IF characteristics, and the ascertainment of relative closeness coefficients using a three- or four-term approach. The best compromise collection containing the most suitable solutions can be determined by comparing relative closeness coefficients to support intelligent decision analysis under complicated uncertain scenarios.Fig. 4 Schematic representation of the C-IF TOPSIS methodology The evolved C-IF TOPSIS methodology is implemented using the subsequent algorithmic steps: Step 1 Compile a collection of candidate alternatives A=a1,a2,⋯,aA. Make a collection of performance criteria P=p1,p2,⋯,pP and divide it into two sub-collections: PI, which contains beneficial criteria, and PII, which contains non-beneficial criteria. Step 2 Utilize data collection tools such as semantic assessments to construct the C-IF importance weight wj=(wj,ωj;γj) for all pj∈P and the C-IF performance rating ςij=(mij,nij;rij) of ai∈A judging by each pj. Step 3 Combine ςij with wj to calculate the weighted performance rating ςijw=mijw,nijw;rijw using Eq. (38), which yields the corresponding hesitancy hijw. Employ Eq. (39) to form the C-IF characteristic Ciw for each ai∈A Steps 4−7 Take either a displaced anchoring mechanism or a fixed anchoring mechanism. Prioritization algorithm based on the displaced anchoring mechanism: Step 4 Identify the displaced ideal rating ς∗jw=m∗jw,n∗jw;r∗jw (involving hesitancy h∗jw) using Eq. (40). Establish the displaced ideal C-IF characteristic C∗w using Eq. (42). Step 5 Produce the displaced anti-ideal rating ς¬jw=m¬jw,n¬jw;r¬jw (involving hesitancy h¬jw) using Eq. (41). Build the displaced anti-ideal C-IF characteristic C¬w using Eq. (43). Step 6 Assign a metric parameter β∈Z+. Calculate the C-IF Minkowski distances D3βCiw,C∗w and D3βCiw,C¬w using Eq. (29), or alternately D4βCiw,C∗w and D4βCiw,C¬w using Eq. (30). Step 7 Derive the relative closeness coefficient R3β∗(ai) (or R4β∗(ai)) using Eq. (44) (or Eq. (45)) for each ai∈A. Compose the best compromise collection A3β∗ (or A4β∗) using Eq. (46) (or Eq. (47)) to obtain the most suitable solution(s). Prioritization algorithm based on the fixed anchoring mechanism:Step 4ʹ Identify the fixed ideal rating ς+jw=m+jw,n+jw;r+jw (involving hesitancy h+jw) using Eq. (48). Establish the fixed ideal C-IF characteristic C+w using Eq. (50). Step 5ʹ Produce the fixed anti-ideal rating ς-jw=m-jw,n-jw;r-jw (involving hesitancy h-jw) using Eq. (49). Build the fixed anti-ideal C-IF characteristic C-w using Eq. (51). Step 6ʹ Assign a metric parameter β∈Z+. Calculate the C-IF Minkowski distances D3βCiw,C+w and D3βCiw,C-w using Eq. (29), or alternately D4βCiw,C+w and D4βCiw,C-w using Eq. (30). Step 7ʹ Derive the relative closeness coefficient R3β+ai (or R4β+ai) using Eq. (52) (or Eq. (53)) for each ai∈A. Compose the best compromise collection A3β+ (or A4β+) using Eq. (54) (or Eq. (55)) to obtain the most suitable solution(s). Model application and comparative study This section applies the evolved C-IF TOPSIS methodology to investigate a site selection issue at an epidemic hospital in Istanbul, Turkey. This question was first posed by Alkan and Kahraman (2022b), who examined a real-world MCDA task to assess and select suitable sites for large-scale epidemic hospitals for Istanbul authorities in the post-COVID-19 era. Furthermore, this section will perform sensitivity analyses and comparative studies with other relevant fuzzy TOPSIS methods to confirm the robustness, adaptability, and utility of the current C-IF TOPSIS techniques. Application to epidemic hospital site selection Emerging infectious diseases have spread rapidly in humans in recent years. COVID-19, for example, which appeared in December 2019, is caused by a new type of coronavirus. The COVID-19 outbreak is rapidly spreading worldwide. The majority of infected patients can recover and regain their health. However, a small number of infected patients may develop respiratory distress syndrome, severe pneumonia, shock, multiple organ failure, or even death in severe cases. Various emerging infectious diseases adhere to their transmission pathways and protection principles. However, there are still differences in the characteristics of various pathogens. As a result, in the face of emerging major infectious diseases with unknown causes, health authorities and epidemic prevention experts in various countries must review and revise countermeasures by collecting epidemic development and relevant latest information on a continuous basis. In the post-COVID-19 era, many countries are focusing on establishing a comprehensive medical network for epidemic prevention and control, as well as establishing dedicated epidemic hospitals. The establishment of large-scale epidemic hospitals can improve the grading and treatment of mild and severe cases, patient triage, care subdivision, visitor control, and environmental management. Setting up epidemic hospitals allows infected people to be treated while keeping the health care system running normally. According to Alkan and Kahraman (2022b), the COVID-19 outbreak spread quickly during the pandemic in several cities in Turkey, particularly Istanbul, where large numbers of infected patients accumulated. The Istanbul authorities have decided to establish a large-scale epidemic hospital in seven candidate locations, consisting of Bakırköy (a1), Sancaktepe (a2), Eyüp (a3), Esenyurt (a4), Çatalca (a5), Tuzla (a6), and Ataşehir (a7), to prevent the spread of COVID-19 or other infectious diseases in the future and to allow infected patients to receive proper treatment. Figure 5 depicts a Google map of the seven candidate locations in Istanbul.Fig. 5 Candidate locations for the Istanbul Epidemic Hospital Authorities anticipate that the epidemic hospital will prioritize and treat patients with infectious diseases. Aside from housing COVID-19 patients, the epidemic hospital also prevents other epidemics from spreading to other patients or visitors within the hospital. Furthermore, the epidemic hospital will actively and fully cooperate with the policy of the infectious disease prevention and treatment network, as well as the inspection of facilities, equipment, protective equipment, and work quality in isolation wards, as determined by the competent authority. The Istanbul authorities used seven criteria to evaluate the optimal location of the Istanbul Epidemic Hospital in the problem described by Alkan and Kahraman (2022b), consisting of cost (p1), demographics (p2), environmental factors (p3), transportation opportunities (p4), healthcare and medical practices (p5), infrastructure (p6), and spread of the virus (p7). Only p1 is a non-beneficial criterion among the above, while the other six (i.e., p2−p7) are beneficial. Figure 6 depicts a high-level overview of the site selection problem for the Istanbul Epidemic Hospital under consideration.Fig. 6 Brief description of epidemic hospital location issues This study attempts to employ the C-IF TOPSIS algorithm to deal with the site selection issue of the Istanbul Epidemic Hospital to scrutinize the workableness and suitability of the initiated methodology in realistic problems. In Step 1, the collections of candidate alternatives (i.e., seven locations) and performance criteria are represented as A=a1,a2,⋯,a7 (A=7) and P=p1,p2,⋯,p7 (P=7), respectively, based on Fig. 6. Furthermore, P is divided into two sub-collections: PI=p2,p3,⋯,p7, which contains beneficial criteria, and PII=p1, which contains non-beneficial criteria. In Step 2, as pointed out in the research by Alkan and Kahraman (2022b), the expert group has given semantic assessments of the significance or importance of criteria and the performance of a candidate location judging by each criterion, based on individual professional experience and judgment. After pooling the opinions offered by the expert group, Alkan and Kahraman transformed these semantic assessments into the C-IF values. The data of the C-IF performance rating ςij and the C-IF importance weight wj are revealed in Table 3.Table 3 Data on C-IF performance ratings and C-IF importance weights ai ςi1=(mi1,ni1;ri1) ςi2=(mi2,ni2;ri2) ςi3=(mi3,ni3;ri3) ςi4=(mi4,ni4;ri4) a1 (0.667, 0.283; 0.094) (0.567, 0.383; 0.094) (0.333, 0.617; 0.094) (0.800, 0.167; 0.130) a2 (0.333, 0.617; 0.094) (0.767, 0.183; 0.094) (0.533, 0.417; 0.094) (0.500, 0.450; 0.000) a3 (0.533, 0.417; 0.094) (0.733, 0.217; 0.094) (0.367, 0.583; 0.094) (0.633, 0.317; 0.094) a4 (0.267, 0.683; 0.094) (0.833, 0.133; 0.075) (0.267, 0.683; 0.094) (0.433, 0.517; 0.094) a5 (0.433, 0.517; 0.094) (0.333, 0.617; 0.094) (0.667, 0.283; 0.094) (0.367, 0.583; 0.094) a6 (0.500, 0.450; 0.000) (0.567, 0.383; 0.094) (0.467, 0.483; 0.094) (0.367, 0.583; 0.094) a7 (0.667, 0.283; 0.094) (0.733, 0.217; 0.094) (0.467, 0.483; 0.094) (0.633, 0.317; 0.094) ςi5=(mi5,ni5;ri5) ςi6=(mi6,ni6;ri6) ςi7=(mi7,ni7;ri7) pj wj=(wj,ωj;γj) a1 (0.633, 0.317; 0.094) (0.367, 0.583; 0.094) (0.767, 0.183; 0.094) p1 (0.533, 0.417; 0.094) a2 (0.467, 0.483; 0.094) (0.600, 0.350; 0.141) (0.667, 0.283; 0.094) p2 (0.767, 0.183; 0.094) a3 (0.633, 0.317; 0.094) (0.633, 0.317; 0.094) (0.667, 0.283; 0.094) p3 (0.667, 0.283; 0.094) a4 (0.533, 0.417; 0.094) (0.133, 0.850; 0.120) (0.867, 0.117; 0.075) p4 (0.733, 0.217; 0.094) a5 (0.400, 0.550; 0.141) (0.867, 0.117; 0.075) (0.167, 0.800; 0.120) p5 (0.367, 0.583; 0.094) a6 (0.400, 0.550; 0.141) (0.567, 0.383; 0.094) (0.333, 0.617; 0.094) p6 (0.267, 0.683; 0.094) a7 (0.433, 0.517; 0.094) (0.267, 0.683; 0.094) (0.733, 0.217; 0.094) p7 (0.833, 0.133; 0.075) In Step 3, the weighted performance rating ςijw and its corresponding degree of hesitancy hijw were calculated by combining ςij with wj. Furthermore, the C-IF characteristic Ciw can be constituted by collecting the obtained ςijw across the seven performance criteria. Table 4 displays the results of the related ascertainment. Table 4 Outcomes of weighted performance ratings and their corresponding degrees of hesitancy ai ςi1w=mi1w,ni1w;ri1w hi1w ςi2w=mi2w,ni2w;ri2w hi2w ςi3w=mi3w,ni3w;ri3w hi3w a1 (0.3555, 0.5820; 0.094) 0.0625 (0.4349, 0.4959; 0.094) 0.0692 (0.2221, 0.7254; 0.094) 0.0525 a2 (0.1775, 0.7767; 0.094) 0.0458 (0.5883, 0.3325; 0.094) 0.0792 (0.3555, 0.5820; 0.094) 0.0625 a3 (0.2841, 0.6601; 0.094) 0.0558 (0.5622, 0.3603; 0.094) 0.0775 (0.2448, 0.7010; 0.094) 0.0542 a4 (0.1423, 0.8152; 0.094) 0.0425 (0.6389, 0.2917; 0.094) 0.0694 (0.1781, 0.7727; 0.094) 0.0492 a5 (0.2308, 0.7184; 0.094) 0.0508 (0.2554, 0.6871; 0.094) 0.0575 (0.4449, 0.4859; 0.094) 0.0692 a6 (0.2665, 0.6794; 0.094) 0.0542 (0.4349, 0.4959; 0.094) 0.0692 (0.3115, 0.6293; 0.094) 0.0592 a7 (0.3555, 0.5820; 0.094) 0.0625 (0.5622, 0.3603; 0.094) 0.0775 (0.3115, 0.6293; 0.094) 0.0592 ςi4w=mi4w,ni4w;ri41w hi4w ςi5w=mi5w,ni5w;ri5w hi5w ςi6w=mi6w,ni6w;ri6w hi6w a1 (0.5864, 0.3478; 0.130) 0.0658 (0.2323, 0.7152; 0.094) 0.0525 (0.0980, 0.8678; 0.094) 0.0342 a2 (0.3665, 0.5694; 0.094) 0.0641 (0.1714, 0.7844; 0.094) 0.0442 (0.1602, 0.7940; 0.141) 0.0459 a3 (0.4640, 0.4652; 0.094) 0.0708 (0.2323, 0.7152; 0.094) 0.0525 (0.1690, 0.7835; 0.094) 0.0475 a4 (0.3174, 0.6218; 0.094) 0.0608 (0.1956, 0.7569; 0.094) 0.0475 (0.0355, 0.9525; 0.120) 0.0120 a5 (0.2690, 0.6735; 0.094) 0.0575 (0.1468, 0.8124; 0.141) 0.0408 (0.2315, 0.7201; 0.094) 0.0484 a6 (0.2690, 0.6735; 0.094) 0.0575 (0.1468, 0.8124; 0.141) 0.0408 (0.1514, 0.8044; 0.094) 0.0442 a7 (0.4640, 0.4652; 0.094) 0.0708 (0.1589, 0.7986; 0.094) 0.0425 (0.0713, 0.8995; 0.094) 0.0292 ςi7w=mi7w,ni7w;ri7w hi7w The C-IF characteristic Ciw=⟨pj,mijw,nijw;rijw⟩pj∈P a1 (0.6389, 0.2917; 0.094) 0.0694 C1w=⟨p1,m11w,n11w;r11w⟩,⟨p2,m12w,n12w;r12w⟩,⋯,⟨p7,m17w,n17w;r17w⟩ a2 (0.5556, 0.3784; 0.094) 0.0660 C2w=⟨p1,m21w,n21w;r21w⟩,⟨p2,m22w,n22w;r22w⟩,⋯,⟨p7,m27w,n27w;r27w⟩ a3 (0.5556, 0.3784; 0.094) 0.0660 C3w=⟨p1,m31w,n31w;r31w⟩,⟨p2,m32w,n32w;r32w⟩,⋯,⟨p7,m37w,n37w;r37w⟩ a4 (0.7222, 0.2344; 0.075) 0.0434 C4w=⟨p1,m41w,n41w;r41w⟩,⟨p2,m42w,n42w;r42w⟩,⋯,⟨p7,m47w,n47w;r47w⟩ a5 (0.1391, 0.8266; 0.120) 0.0343 C5w=⟨p1,m51w,n51w;r51w⟩,⟨p2,m52w,n52w;r52w⟩,⋯,⟨p7,m57w,n57w;r57w⟩ a6 (0.2774, 0.6679; 0.094) 0.0547 C6w=⟨p1,m61w,n61w;r61w⟩,⟨p2,m62w,n62w;r62w⟩,⋯,⟨p7,m67w,n67w;r67w⟩ a7 (0.6106, 0.3211; 0.094) 0.0683 C7w=⟨p1,m71w,n71w;r71w⟩,⟨p2,m72w,n72w;r72w⟩,⋯,⟨p7,m77w,n77w;r77w⟩ Following that, the prioritization algorithm of the C-IF TOPSIS methodology is run. Steps 4−7 of the displaced anchoring mechanism or Steps 4ʹ − 7ʹ of the fixed anchoring mechanism can be employed by decision-makers or analysts. This study first demonstrates the implementation process of Steps 4 − 7. In Step 4, this study produced the displaced ideal rating ς∗jw using Eq. (40) and the corresponding degree of hesitancy h∗jw, and the outcomes are listed in the left section of Table 5. Taking p1∈PII and p7∈PI as examples, the ratings ς∗1w and ς∗7w were calculated as follows: ς∗1w=m∗1w,n∗1w;r∗1w=mini=17mi1w,maxi=17ni1w;maxi=17ri1w =min0.3555,0.1775,0.2841,0.1423,0.2308,0.2665,0.3555,max0.5820,0.7767,0.6601, 0.8152,0.7184,0.6794,0.5820;max0.094,0.094,0.094,0.094,0.094,0.094,0.094 =0.1423,0.8152,0.094, ς∗7w=m∗7w,n∗7w;r∗7w=maxi=17mi7w,mini=17ni7w;maxi=17ri7w =max0.6389,0.5556,0.5556,0.7222,0.1391,0.2774,0.6106,min0.2917,0.3784,0.3784, 0.2344,0.8266,0.6679,0.3211;max0.094,0.094,0.094,0.075,0.120,0.094,0.094 =0.7222,0.2344,0.120. Furthermore, their respective hesitancy degrees were calculated as h∗1w=1-0.1423-0.8152=0.0425 and h∗7w=1-0.7222-0.2344=0.0434. In a similar vein, based on Step 5, this study generated the displaced anti-ideal rating ς¬jw using Eq. (41) and its corresponding degree of hesitancy h¬jw; the outcomes are sketched in the right section of Table 5. The displaced ideal C-IF characteristic C∗w and the displaced anti-ideal C-IF characteristic C¬w can be formed by gathering the obtained ς∗jw and ς¬jw, respectively, across all pj∈P. Specifically, C∗w=⟨p1,m∗1w,n∗1w;r∗1w⟩,⟨p2,m∗2w,n∗2w;r∗2w⟩, ⋯,⟨p7,m∗7w,n∗7w;r∗7w⟩ and C¬w={⟨p1,m¬1w,n¬1w;r¬1w⟩,⟨p2,m¬2w,n¬2w;r¬2w⟩,⋯,⟨p7,m¬7w,n¬7w;r¬7w⟩}. The conventional TOPSIS method measures the degrees of separation between candidate alternatives and ideal/anti-ideal solutions using geometric distances in the Euclidean plane. As a result, in the demonstrative case, this study assumes β=2. The C-IF Euclidean distance will be exploited to measure the degree of separation between the C-IF characteristic Ciw and the displaced ideal C-IF characteristic C∗w, as well as the degree of separation between Ciw and the displaced anti-ideal C-IF characteristic C¬w. It is worth noting that the cardinality of the collection P is given as cardP= 7. In Step 6, based on the three-term representation in Eq. (33), the following C-IF Euclidean distances were rendered, including D(3)2C1w,C∗w= 0.0840, D(3)2C2w,C∗w= 0.0636, D(3)2C3w,C∗w= 0.0714, D(3)2C4w,C∗w= 0.0917, D(3)2C5w,C∗w= 0.1527, D(3)2C6w,C∗w= 0.1234, and D(3)2C7w,C∗w= 0.0770 with relevance to the displaced ideal C-IF characteristic C∗w; and D(3)2C1w,C¬w= 0.1288, D(3)2C2w,C¬w= 0.1258, D(3)2C3w,C¬w= 0.1229, D(3)2C4w,C¬w= 0.1480, D(3)2C5w,C¬w= 0.0749, D(3)2C6w,C¬w= 0.0659, and D(3)2C7w,C¬w= 0.1276 in relation to the displaced anti-ideal C-IF characteristic C¬w. Furthermore, based on the four-term representation in Eq. (34), the following C-IF Euclidean distances were generated, including D(4)2C1w,C∗w= 0.0842, D(4)2C2w,C∗w= 0.0637, D(4)2C3w,C∗w= 0.0716, D(4)2C4w,C∗w= 0.0918, D(4)2C5w,C∗w= 0.1527, D(4)2C6w,C∗w= 0.1235, and D(4)2C7w,C∗w= 0.0772 with relevance to C∗w; and D(4)2C1w,C¬w= 0.1289, D(4)2C2w,C¬w= 0.1261, D(4)2C3w,C¬w= 0.1231, D(4)2C4w,C¬w= 0.1480, D(4)2C5w,C¬w= 0.0751, D(4)2C6w,C¬w= 0.0661, and D(4)2C7w,C¬w= 0.1278 in connection with C¬w. Considering the measure D(4)2 between C4w and C¬w, one has:D(4)2C4w,C¬w=1212·70.094-0.094+0.094-0.094+0.094-0.094+0.094-0.130+0.094-0.141+0.120-0.141+0.075-0.120 +12·30.1423-0.35552+0.6389-0.25542+0.1781-0.17812+0.3174-0.26902 +0.1956-0.14682+0.0355-0.03552+0.7222-0.13912+0.8152-0.58202 +0.2917-0.68712+0.7727-0.77272+0.6218-0.67352+0.7569-0.81242 +0.9525-0.95252+0.2344-0.82662+0.0425-0.06252+0.0694-0.05752 +0.0492-0.04922+0.0608-0.05752+0.0475-0.04082+0.0120-0.01202 +0.0434-0.0343212=0.1480. Continue using β=2 as an example to show how the relative closeness coefficients R32∗(ai) and R42∗(ai) are calculated in Step 7. Using the three-term approach, Eq. (44) yields the following: R32∗a1=D32C1w,C¬w/D32C1w,C∗w+D32C1w,C¬w= 0.1288/(0.0840 + 0.1288) = 0.6053, R32∗a2= 0.6642, R32∗a3= 0.6324, R32∗a4= 0.6175, R32∗a5= 0.3291, R32∗a6= 0.3481, and R32∗a7= 0.6236. Since R32∗a2>R32∗a3>R32∗a7>R32∗a4>R32∗a1>R32∗a6>R32∗a5, the priority order of the seven candidate locations is a2≻a3≻a7≻a4≻a1≻a6≻a5, which is consistent with the sorting result solved by Alkan and Kahraman (2022b). Based on Eq. (46), the best compromise collection is A32∗=aimaxi=17R32∗(ai),ai∈A={a2}. Besides this, based on Eq. (45) using the four-term approach, one has R42∗a1= 0.6051, R42∗a2= 0.6642, R42∗a3= 0.6324, R42∗a4= 0.6171, R42∗a5= 0.3298, R42∗a6= 0.3489, and R42∗a7= 0.6232. In view of R42∗a2>R42∗a3>R42∗a7>R42∗a4>R42∗a1>R42∗a6>R42∗a5, the priority order of the candidate locations is a2≻a3≻a7≻a4≻a1≻a6≻a5, which is also concordant with the outcome in Alkan and Kahraman (2022b). The best compromise collection, according to Eq. (47), is A42∗=aimaxi=17R42∗(ai),ai∈A={a2}. Using the three- and four-term approaches in the displaced anchoring mechanism, the C-IF TOPSIS ranking results based on the C-IF Euclidean distance measure, as well as the best compromise collection and the most suitable solution, are the same. In other words, A32∗=A42∗={a2}, and the candidate location Sancaktepe (a2) is the most suitable solution.Table 5 Displaced ideal and anti-ideal ratings and their corresponding degrees of hesitancy pj ς∗jw=m∗jw,n∗jw;r∗jw h∗jw ς¬jw=m¬jw,n¬jw;r¬jw h¬jw p1 (0.1423, 0.8152; 0.0940) 0.0425 (0.3555, 0.5820; 0.0940) 0.0625 p2 (0.6389, 0.2917; 0.0940) 0.0694 (0.2554, 0.6871; 0.0940) 0.0575 p3 (0.4449, 0.4859; 0.0940) 0.0692 (0.1781, 0.7727; 0.0940) 0.0492 p4 (0.5864, 0.3478; 0.1300) 0.0658 (0.2690, 0.6735; 0.1300) 0.0575 p5 (0.2323, 0.7152; 0.1410) 0.0525 (0.1468, 0.8124; 0.1410) 0.0408 p6 (0.2315, 0.7201; 0.1410) 0.0484 (0.0355, 0.9525; 0.1410) 0.0120 p7 (0.7222, 0.2344; 0.1200) 0.0434 (0.1391, 0.8266; 0.1200) 0.0343 Next, this study explicates the calculation process of Steps 4ʹ − 7ʹ using the fixed anchoring mechanism. In Step 4ʹ, this study produced the fixed ideal rating ς+jw using Eq. (48) and the corresponding degree of hesitancy h+jw, and the outcomes are manifested in the left section of Table 6. Using p1 and p7 as an illustration again, the ratings ς+1w and ς+7w were rendered in this fashion: ς+1w=m+1w,n+1w;r+1w=(0.533,0.417;0.094)⊗max(0,1;0)=0,1;0.094, and ς+7w=(m+7w,n+7w; r+7w)=(0.833,0.133;0.075)⊗max(1,0;0)=(0.833,0.133;0.075). Additionally, the corresponding hesitancy degrees were derived as h+1w=1-0-1=0 and h+7w=1-0.833-0.133=0.034. In Step 5ʹ, this study identified the fixed anti-ideal rating ς-jw using Eq. (49) and its corresponding degree of hesitancy h-jw; the outcomes are portrayed in the right section of Table 6. The fixed ideal C-IF characteristic C+w and the fixed anti-ideal C-IF characteristic C-w can be constructed by C+w=⟨p1,m+1w,n+1w;r+1w⟩,⟨p2,m+2w,n+2w;r+2w⟩,⋯,⟨p7,m+7w,n+7w;r+7w⟩ and C-w={⟨p1,m-1w,n-1w;r-1w⟩, ⟨p2,m-2w,n-2w;r-2w⟩,⋯,⟨p7,m-7w,n-7w;r-7w⟩}, respectively. Table 6 Fixed ideal and anti-ideal ratings and their corresponding degrees of hesitancy pj ς+jw=m+jw,n+jw;r+jw h+jw ς-jw=m-jw,n-jw;r-jw h-jw p1 (0.0000, 1.0000; 0.0940) 0.0000 (0.5330, 0.4170; 0.0940) 0.0500 p2 (0.7670, 0.1830; 0.0940) 0.0500 (0.0000, 1.0000; 0.0940) 0.0000 p3 (0.6670, 0.2830; 0.0940) 0.0500 (0.0000, 1.0000; 0.0940) 0.0000 p4 (0.7330, 0.2170; 0.0940) 0.0500 (0.0000, 1.0000; 0.0940) 0.0000 p5 (0.3670, 0.5830; 0.0940) 0.0500 (0.0000, 1.0000; 0.0940) 0.0000 p6 (0.2670, 0.6830; 0.0940) 0.0500 (0.0000, 1.0000; 0.0940) 0.0000 p7 (0.8330, 0.1330; 0.0750) 0.0340 (0.0000, 1.0000; 0.0750) 0.0000 This study still requires β=2 (i.e., C-IF Euclidean distance measure) to provide an example of the execution procedure under the fixed anchoring mechanism. In Step 6ʹ, the following C-IF Euclidean distances were calculated using the three-term representation in Eq. (33): D(3)2C1w,C+w= 0.1431, D(3)2C2w,C+w= 0.1244, D(3)2C3w,C+w= 0.1311, D(3)2C4w,C+w= 0.1419, D(3)2C5w,C+w= 0.2041, D(3)2C6w,C+w= 0.1814, and D(3)2C7w,C+w= 0.1356 relating to the fixed ideal C-IF characteristic C+w; and D(3)2C1w,C-w= 0.2127, D(3)2C2w,C-w= 0.2149, D(3)2C3w,C-w= 0.2081, D(3)2C4w,C-w= 0.2232, D(3)2C5w,C-w= 0.1525, D(3)2C6w,C-w= 0.1558, and D(3)2C7w,C-w= 0.2095 with respect to the fixed anti-ideal C-IF characteristic C-w. On the other hand, using the four-term representation in Eq. (34), the following C-IF Euclidean distances were calculated: D(4)2C1w,C+w= 0.1435, D(4)2C2w,C+w= 0.1247, D(4)2C3w,C+w = 0.1315, D(4)2C4w,C+w= 0.1421, D(4)2C5w,C+w= 0.2043, D(4)2C6w,C+w= 0.1816, and D(4)2C7w,C+w= 0.1360 in relation to C+w; and D(4)2C1w,C-w= 0.2136, D(4)2C2w,C-w= 0.2159, D(4)2C3w,C-w= 0.2091, D(4)2C4w,C-w= 0.2238, D(4)2C5w,C-w= 0.1535, D(4)2C6w,C-w = 0.1569, and D(4)2C7w,C-w= 0.2104 with relevance to C-w. In Step 7ʹ, using the three-term approach and Eq. (52), one can calculate the relative closeness coefficients in this fashion: R32+a1=D32C1w,C-w/(D32C1w,C+w+D32C1w,C-w)= 0.2127/(0.1431 + 0.2127) = 0.5978, R32+a2= 0.6335, R32+a3= 0.6134, R32+a4= 0.6114, R32+a5= 0.4276, R32+a6= 0.4620, and R32+a7= 0.6071. Since R32+a2>R32+a3>R32+a4>R32+a7>R32+a1>R32+a6>R32+a5, the priority order of the candidate locations is a2≻a3≻a4≻a7≻a1≻a6≻a5. In line with Eq. (54), the best compromise collection is A32+=aimaxi=17R32+(ai),ai∈A={a2}. On the flip side, based on Eq. (53) using the four-term approach, the following relative closeness coefficients were derived: R42+a1= 0.5982, R42+a2= 0.6339, R42+a3= 0.6139, R42+a4= 0.6116, R42+a5= 0.4291, R42+a6= 0.4634, and R42+a7= 0.6074, which follows that R42+a2>R42+a3>R42+a4>R42+a7>R42+a1>R42+a6>R42+a5. As a result, the candidate locations are prioritized as a2≻a3≻a4≻a7≻a1≻a6≻a5; additionally, the best compromise collection is identified as A42+=aimaxi=17R42+(ai),ai∈A={a2} using Eq. (55). The C-IF TOPSIS ranking results, as well as the best compromise collection and the most suitable solution, are the same using the three- and four-term approaches in the fixed anchoring mechanism based on the C-IF Euclidean distance model. The priority ranking a2≻a3≻a4≻a7≻a1≻a6≻a5 obtained from the C-IF TOPSIS prioritization procedure in the fixed anchoring mechanism is comparable to the sorting result obtained by Alkan and Kahraman (2022b). The only difference is the outranking relationship between a4 and a7. Even so, a2 is still the most suitable solution because A32+=A42+={a2}. The application of the epidemic hospital site selection case demonstrates that the evolved C-IF TOPSIS methodology propounded in this work is both practicable and effective. The operability and ease of execution of the computational process are also very high, as demonstrated by its operation. Furthermore, by utilizing the C-IF Minkowski distances, the current techniques provide flexible and diverse options, such as a displaced anchoring mechanism based on a three-term approach, a displaced anchoring mechanism based on a four-term approach, a fixed anchoring mechanism based on a three-term approach, and a fixed anchoring mechanism based on a four-term approach. Comparative research and discussions This subsection performs four comparative studies to examine the validity and explore the merits of the evolved C-IF TOPSIS methodology. First, this subsection compares and thoroughly investigates the comparative evaluation of relative closeness coefficients under displaced and fixed anchoring mechanisms. Following that, this subsection discusses and focuses on how the relative closeness coefficient varies at each candidate position level under different anchoring mechanisms and parameter settings. Concerning the Manhattan, Euclidean, and Chebyshev distance models, which are frequently used in practice, this subsection investigates additional comparisons of the applied results yielded by the C-IF Manhattan, Euclidean, and Chebyshev distance measures based on three- and four-term representations. Finally, intending to address the epidemic hospital site selection case within IF or other relevant fuzzy environments, this subsection compares and analyzes the application outcomes of the evolved methodology with other TOPSIS-related methods (such as other C-IF TOPSIS or IF TOPSIS approaches) and has reviewed the strengths of the current C-IF TOPSIS technique in this study. To begin, the C-IF Minkowski distances and relative closeness coefficients were calculated under different metric parameter settings for the first and second comparative studies. The metric parameter was set using β=1,2,⋯,10 and β→∞. The main comparison outcomes of the C-IF Minkowski distances and relative closeness coefficients are documented in the Appendix, including the detailed results based on the displaced and fixed anchoring mechanisms in Tables 10 and 11, respectively, for reference herein. Table 11 reveals the results of D3βCiw,C∗w, D3βCiw,C¬w, and R3β∗(ai) using the three-term approach, as well as D4βCiw,C∗w, D4βCiw,C¬w, and R4β∗(ai) using the four-term approach. Moreover, Table 11 displays the results of D3βCiw,C+w, D3βCiw,C-w, and R3β+ai using the three-term approach, as well as D4βCiw,C+w, D4βCiw,C-w, and R4β+ai using the four-term approach. The first comparative study’s goal is to thoroughly examine the juxtaposition situations of relative closeness coefficients under the displaced and fixed anchoring mechanisms. Figure 7 shows the comparison outcomes based on the three- and four-term representations for the same site selection case of the Istanbul Epidemic Hospital; additionally, these figures sketch the relative closeness coefficients being placed close together to see the contrasting effects in various settings of the metric parameter β. When β=1,2,⋯,10 and β→∞, the comparison and distribution of relative closeness coefficients are exhibited in this figure, which includes the juxtaposition of R3β∗(ai) based on the three-term approach under the displaced anchoring mechanism in Fig. 7a, the juxtaposition of R3β+(ai) based on the three-term approach under the fixed anchoring mechanism in Fig. 7b, the juxtaposition of R4β∗(ai) based on the four-term approach under the displaced anchoring mechanism in Fig. 7c, and the juxtaposition of R4β+(ai) based on the four-term approach under the fixed anchoring mechanism in Fig. 7d.Fig. 7 The juxtaposition of relative closeness coefficients in various scenarios Overall, the relative closeness coefficients of the candidate locations a1, a2, a3, a4, and a7 are greater than those of a5 and a6 in all discussed scenarios. This means that a1, a2, a3, a4, and a7 are far superior to a5 and a6. Furthermore, in Fig. 7a and c, the comparative advantages of the five better candidate locations and the two worst locations are clearly visible, but such gaps are narrowed in Fig. 7b and d. It is recognized from Fig. 7b and d that the relative closeness coefficients R3β+(ai) and R4β+(ai) do not vary much depending on the metric parameter setting values. This demonstrates that, with the fixed anchoring mechanism, the relative closeness coefficients yielded by the C-IF TOPSIS procedure are relatively stable across a range of β values. In contrast, as displayed in Fig. 7a and c, the relative closeness coefficients R3β∗(ai) and R4β∗(ai) vary relatively greatly in different metric parameter settings, particularly in Fig. 7c. This indicates that the relative closeness coefficients generated by the C-IF TOPSIS procedure are moderately affected by different β values under the displaced anchoring mechanism. In a nutshell, the relative closeness coefficients based on the C-IF Minkowski distance measure vary slightly under different β values and the displaced anchoring mechanism but are more stable under the fixed anchoring mechanism. The second comparative study focuses on the variation of relative closeness coefficients for each candidate location level under different anchoring mechanisms based on the C-IF Minkowski distance measures in the epidemic hospital site selection case using three- and four-term approaches. Figure 8 depicts the relative comparison results in different scenarios concerning individual candidate location levels; that is, the outcomes corresponding to the candidate locations a1,a2,⋯,a7 are portrayed in Fig. 8a–g, respectively. The cases of β=1, β=2, and β→∞ represent commonly used distance models, namely the C-IF Manhattan, Euclidean, and Chebyshev metrics, and are highlighted as line graphs in the figure. Group histograms are used to represent other β-value cases.Fig. 8 Variation of relative closeness coefficients for individual candidate location levels The priority ranking outcomes of the seven candidate locations are displayed in Table 7 following the decreasing order of the relative closeness coefficients produced by the two C-IF TOPSIS prioritization algorithms. This table compares the priority ranks of each candidate location sequentially under various metric parameter settings, containing the priority ranks using the three- and four-term approaches with displaced and fixed anchoring mechanisms.Table 7 Summary of the priority ranking orders under various settings The metric parameter β (three-term approach) The metric parameter β (four-term approach) 1 2 3 4 5 6 7 8 9 10 ∞ 1 2 3 4 5 6 7 8 9 10 ∞ Priority ranking order based on R3β∗(ai) Priority ranking order based on R4β∗(ai) a1 4 5 5 4 4 4 3 2 2 2 4 4 5 5 4 4 4 3 2 2 2 4 a2 1 1 1 1 2 3 4 4 4 5 1 1 1 1 1 2 3 4 4 4 5 1 a3 2 2 3 3 3 2 2 3 3 3 2 2 2 3 3 3 2 2 3 3 3 2 a4 3 4 4 5 5 5 5 5 5 4 3 3 4 4 5 5 5 5 5 5 4 3 a5 7 7 7 6 6 6 6 6 6 6 7 7 7 7 6 6 6 6 6 6 6 7 a6 6 6 6 7 7 7 7 7 7 7 6 6 6 6 7 7 7 7 7 7 7 6 a7 5 3 2 2 1 1 1 1 1 1 5 5 3 2 2 1 1 1 1 1 1 5 Priority ranking order based on R3β+ai Priority ranking order based on R4β+ai a1 4 5 5 5 5 5 5 5 5 5 4 4 5 5 5 5 5 5 5 5 5 4 a2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 a3 2 2 3 3 3 3 3 3 4 4 2 2 2 3 3 3 3 3 3 4 4 2 a4 3 3 4 4 4 4 4 4 3 3 3 3 3 4 4 4 4 4 4 3 3 3 a5 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 a6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 a7 5 4 2 2 2 2 2 2 2 2 5 5 4 2 2 2 2 2 2 2 2 5 Remarks about the backdrop color: Aqua blue: a7≻a3≻a2≻a1≻a4≻a5≻a6 Grey: a2≻a3≻a4≻a1≻a7≻a6≻a5 Orange brown: a7≻a3≻a1≻a2≻a4≻a5≻a6 Purple: a2≻a3≻a7≻a4≻a1≻a6≻a5 Light green: a7≻a1≻a3≻a2≻a4≻a5≻a6 Jasmine: a2≻a7≻a3≻a4≻a1≻a6≻a5 Fluorescent yellow: a7≻a1≻a3≻a4≻a2≻a5≻a6 Fluorescent green: a2≻a7≻a3≻a1≻a4≻a5≻a6 Pink: a2≻a3≻a4≻a7≻a1≻a6≻a5 Light red: a7≻a2≻a3≻a1≻a4≻a5≻a6 Dutch blue: a2≻a7≻a4≻a3≻a1≻a6≻a5 Based on the previous juxtaposition and contrasting effects in Fig. 8 and Table 7, it is clear that under the fixed anchoring mechanism, the candidate location a2 enjoys the highest relative closeness coefficients among all the settings of the metric parameter β, implying that a2 is a stable and consistent most suitable solution. In contrast, the candidate locations a2 and a7 have the highest relative closeness coefficients under the displaced anchoring mechanism in the settings of β=1,2,3,4 as well as β→∞ and β=5,6,⋯,10, respectively, so a2 and a7 are tied as the most suitable solutions with relative stability. More specifically, based on the three-term approach under the displaced anchoring mechanism, the following priority rankings of the seven candidate locations were generated from Table 7: a2≻a3≻a4≻a1≻a7≻a6≻a5 when β=1 and β→∞, a2≻a3≻a7≻a4≻a1≻a6≻a5 when β= 2, a2≻a7≻a3≻a4≻a1≻a6≻a5 when β= 3, a2≻a7≻a3≻a1≻a4≻a5≻a6 when β=4,a7≻a2≻a3≻a1≻a4≻a5≻a6 when β=5,a7≻a3≻a2≻a1≻a4≻a5≻a6 when β=6,a7≻a3≻a1≻a2≻a4≻a5≻a6 when β=7,a7≻a1≻a3≻a2≻a4≻a5≻a6 when β=8 and β=9, and a7≻a1≻a3≻a4≻a2≻a5≻a6 when β=10. Except in the case of β→∞, the relative advantage of a2 decreases gradually as the metric parameter β increases. When β=10, the priority of a2 has dropped to fifth. In contrast, the priority of a7 is slightly more pronounced, as it ranks 1st, 2nd, and 3rd when β=5,6,⋯,10, β=3,4, and β=2, respectively. The same observation can be found in the C-IF TOPSIS solution results using the four-term approach with the displaced anchoring mechanism. On the flip side, based on the three-term approach under the fixed anchoring mechanism, the following priority rankings of candidate locations were rendered from Table 7: a2≻a3≻a4≻a1≻a7≻a6≻a5 when β=1 and β→∞, a2≻a3≻a4≻a7≻a1≻a6≻a5 when β= 2, a2≻a7≻a3≻a4≻a1≻a6≻a5 when β=3,4,⋯,8, and a2≻a7≻a4≻a3≻a1≻a6≻a5 when β=9 and β=10. The same ranking outcomes can be found in the C-IF TOPSIS solutions based on the four-term approach with the fixed anchoring mechanism. As a result, the candidate position a7 is the most stable and suitable solution in the fixed anchoring mechanism, with the highest relative closeness coefficients of all β settings. The preceding comparative discussions indicate that when decision-makers require a stable consequence of the most suitable solution, it is best to exploit the fixed anchoring mechanism in the evolved C-IF TOPSIS prioritization algorithm. When decision-makers prefer elastic and changing solution results as references, the displaced anchoring mechanism in the prioritization algorithm is recommended. Given the generality and utility of the Manhattan, Euclidean, and Chebyshev metrics, the third comparative study expands on the application outcomes produced by the C-IF Manhattan, Euclidean, and Chebyshev distance measures (i.e., β=1,2, and β→∞, respectively, in D3β and D4β) using three- and four-term approaches under different anchoring mechanisms. The prioritization results are revealed in Table 8, including the relative closeness coefficients R3β∗(ai), R3β+ai, R4β∗(ai), and R4β+ai, as well as their corresponding priority orders. The outcomes of the relative closeness coefficients calculated using the C-IF Manhattan and Chebyshev distances are similar; additionally, their priority rankings are the same, and both are a2≻a3≻a4≻a1≻a7≻a6≻a5. Based on the C-IF Euclidean distance, the priority rankings judging by the relative closeness coefficients R32∗(ai) (as well as R42∗(ai)) and R32+ai (as well as R42+ai) are a2≻a3≻a7≻a4≻a1≻a6≻a5 and a2≻a3≻a4≻a7≻a1≻a6≻a5, respectively, which are slightly different from the cases of β=1 and β→∞. The priority orders in the three candidate locations a1, a4, and a7 differ from the prioritization results in the displaced anchoring mechanism. When β=1 and β→∞, the priority orders of a1, a4, and a7 are 4th, 3rd, and 5th, respectively. When β=2, however, the priority orders of a1, a4, and a7 are 5th, 4th, and 3rd, respectively. Taking into account the prioritization results in the fixed anchoring mechanism, the priority orders in the two candidate locations a1 and a7 differ. When β=1 and β→∞, the priority orders of a1 and a7 are 4th and 5th, respectively, whereas the priority orders of a1 and a7 are 5th and 4th, respectively, when β=2.Table 8 Prioritization results based on the C-IF Manhattan, Euclidean, and Chebyshev distances ai Displaced anchoring mechanism (three-term approach) Fixed anchoring mechanism (three-term approach) R31∗(ai)(Rank) R32∗(ai)(Rank) R3∞∗(ai)(Rank) R31+(ai)(Rank) R32+(ai)(Rank) R3∞+(ai)(Rank) a1 0.5804 (4th) 0.6053 (5th) 0.5791 (4th) 0.5881 (4th) 0.5978 (5th) 0.5941 (4th) a2 0.6608 (1st) 0.6642 (1st) 0.6622 (1st) 0.6285 (1st) 0.6335 (1st) 0.6334 (1st) a3 0.6227 (2nd) 0.6324 (2nd) 0.6240 (2nd) 0.6126 (2nd) 0.6134 (2nd) 0.6187 (2nd) a4 0.6082 (3rd) 0.6175 (4th) 0.6039 (3rd) 0.6044 (3rd) 0.6114 (3rd) 0.6088 (3rd) a5 0.3062 (7th) 0.3291 (7th) 0.3132 (7th) 0.4497 (7th) 0.4276 (7th) 0.4633 (7th) a6 0.3429 (6th) 0.3481 (6th) 0.3503 (6th) 0.4664 (6th) 0.4620 (6th) 0.4790 (6th) a7 0.5647 (5th) 0.6236 (3rd) 0.5620 (5th) 0.5817 (5th) 0.6071 (4th) 0.5865 (5th) Displaced anchoring mechanism (four-term approach) Fixed anchoring mechanism (four-term approach) R41∗(ai)(Rank) R42∗(ai)(Rank) R4∞∗(ai)(Rank) R41+(ai)(Rank) R42+(ai)(Rank) R4∞+(ai)(Rank) a1 0.5791 (4th) 0.6051 (5th) 0.5791 (4th) 0.5941 (4th) 0.5982 (5th) 0.5941 (4th) a2 0.6622 (1st) 0.6642 (1st) 0.6622 (1st) 0.6334 (1st) 0.6339 (1st) 0.6334 (1st) a3 0.6240 (2nd) 0.6324 (2nd) 0.6240 (2nd) 0.6187 (2nd) 0.6139 (2nd) 0.6187 (2nd) a4 0.6039 (3rd) 0.6171 (4th) 0.6039 (3rd) 0.6088 (3rd) 0.6116 (3rd) 0.6088 (3rd) a5 0.3132 (7th) 0.3298 (7th) 0.3132 (7th) 0.4633 (7th) 0.4291 (7th) 0.4633 (7th) a6 0.3503 (6th) 0.3489 (6th) 0.3503 (6th) 0.4790 (6th) 0.4634 (6th) 0.4790 (6th) a7 0.5620 (5th) 0.6232 (3rd) 0.5620 (5th) 0.5865 (5th) 0.6074 (4th) 0.5865 (5th) For further observation, this study plots the comparison results based on the C-IF Manhattan, Euclidean, and Chebyshev distances, as exhibited in Fig. 9, involving the comparison of line graphs in Fig. 9a, c, e and the comparison of stacked bar charts in Fig. 9b, d, f. As can be confirmed from Fig. 9a, c, e, whether based on the C-IF Manhattan distance, Euclidean distance, or Chebyshev distance, the relative closeness coefficient of a2 performs the best in all four scenarios. On the contrary, the relative closeness coefficients of a5 and a6 are always the worst two in the four scenarios, with significant numerical differences with the other five candidate locations. Figure 9c shows that the relative closeness coefficients enjoyed by a1, a3, a4, and a7 based on the C-IF Euclidean distance metric are very close. The relative benefits of the four candidate locations are fairly close. Although the relative closeness coefficients of a1, a3, a4, and a7 are very close in Fig. 9a and e, there is still a slight difference in their relative advantages. The stacked bar charts in Fig. 9b, d, f, on the other hand, can display part-to-whole relationships. These 100% stacked bar charts, in particular, can display the relative percentages of the relative closeness coefficients of the seven locations a1-a7 in the stacked bar, where the cumulative sum of the stacked bars invariably equals 100%. These stacked bar charts manifest how the proportion changes with different anchoring mechanisms and three- and four-term representations, such as the displaced anchoring mechanism with a three-term representation, the fixed anchoring mechanism with a three-term representation, the displaced anchoring mechanism with a four-term representation, and the fixed anchoring mechanism with a four-term representation.Fig. 9 Contrast results based on the C-IF Manhattan, Euclidean, and Chebyshev distances In the case of the Istanbul Epidemic Hospital site selection, the fourth comparative research examines the rationality, usefulness, and adaptation of the evolved C-IF TOPSIS methodology by performing an overall comparison of the application outcomes generated by the current approach and other TOPSIS-related methods. It should be noted that Alkan and Kahraman (2022b) converted the C-IF performance ratings and C-IF importance weights into IF, picture fuzzy, and Pythagorean fuzzy information for ease of comparison. Furthermore, Alkan and Kahraman (2022b) compared their propounded C-IF TOPSIS method to the IF, picture fuzzy, and Pythagorean fuzzy TOPSIS approaches originally established by Boran et al. (2009), Ashraf et al. (2019), and Akram et al. (2019), respectively. The bases for judging the pros and cons of the candidate locations in this fourth comparative study include the composite ratio scores used in Alkan and Kahraman’s C-IF TOPSIS method, the closeness coefficients used in the IF, picture fuzzy, and Pythagorean fuzzy TOPSIS approaches, and the relative closeness coefficients used in the evolved C-IF TOPSIS methodology. Table 9 reveals the comparison outcomes between the evolved C-IF TOPSIS techniques proposed in this study and the preceding fuzzy TOPSIS-related methods. Table 9 Comparison results with other fuzzy TOPSIS-related methods Source of methods Method Judgment basis Priority rankings of candidate locations TOPSIS-related methods in C-IF, IF, picture fuzzy, and Pythagorean fuzzy settings  Alkan and Kahraman (2022b) C-IF TOPSIS method Composite ratio score a2≻a3≻a7≻a4≻a1≻a6≻a5  Boran et al. (2009) IF TOPSIS approach Closeness coefficient a2≻a3≻a7≻a4≻a1≻a6≻a5  Ashraf et al. (2019) Picture fuzzy TOPSIS approach Closeness coefficient a2≻a3≻a7≻a4≻a1≻a5≻a6  Akram et al. (2019) Pythagorean fuzzy TOPSIS approach Closeness coefficient a2≻a3≻a7≻a4≻a1≻a5≻a6 Judgment basis Anchoring frame Metric parameter Priority rankings of candidate locations Evolved C-IF TOPSIS methodology in the current paper  Relative closeness coefficient (Three- and four-term approaches) Displaced anchoring mechanism β=1, β→∞ β=2 β=3 β=4 β=5 β=6 β=7 β=8,9 β=10 a2≻a3≻a4≻a1≻a7≻a6≻a5 a2≻a3≻a7≻a4≻a1≻a6≻a5 a2≻a7≻a3≻a4≻a1≻a6≻a5 a2≻a7≻a3≻a1≻a4≻a5≻a6 a7≻a2≻a3≻a1≻a4≻a5≻a6 a7≻a3≻a2≻a1≻a4≻a5≻a6 a7≻a3≻a1≻a2≻a4≻a5≻a6 a7≻a1≻a3≻a2≻a4≻a5≻a6 a7≻a1≻a3≻a4≻a2≻a5≻a6  Relative closeness coefficient (Three- and four-term approaches) Fixed anchoring Mechanism β=1, β→∞ β=2 β=3,4,…,8 β=9,10 a2≻a3≻a4≻a1≻a7≻a6≻a5 a2≻a3≻a4≻a7≻a1≻a6≻a5 a2≻a7≻a3≻a4≻a1≻a6≻a5 a2≻a7≻a4≻a3≻a1≻a6≻a5 Based on the comparison outcomes in Table 9, it is concluded that a5 and a6 are the two alternatives with the worst overall performance. Among the prioritization results obtained by the four fuzzy TOPSIS-related methods (i.e., Alkan and Kahraman’s C-IF TOPSIS method, as well as the IF, picture fuzzy, and Pythagorean fuzzy TOPSIS approaches) and the evolved C-IF TOPSIS methodology (under the displaced anchoring mechanism in the situations of β=1,2,3,4 and β→∞, and the fixed anchoring mechanism in the situations of β=1,2,⋯,10 and β→∞), a2 has the best overall performance. In particular, when applying the evolved C-IF TOPSIS methodology to the site selection case of the Istanbul Epidemic Hospital, a7 emerges as the most suitable solution under the displaced anchoring mechanism in the cases of β=5,6,⋯,10. The priority ranking outcomes produced by the four fuzzy TOPSIS-related methods were found to be highly similar. The main distinction occurs only in the outranking relationship between a5 and a6. Using Alkan and Kahraman’s C-IF TOPSIS and the IF TOPSIS approaches, we obtained a6≻a5; however, using the picture fuzzy and Pythagorean fuzzy TOPSIS approaches, we obtained a5≻a6. Aside from that, the outcomes of the four fuzzy TOPSIS-related methods are nearly identical. Furthermore, their execution procedures were incapable of producing tunable or elastic results in response to changing circumstances. It implies that these methods did not provide a simple and straightforward mechanism for obtaining adaptive outcomes in various scenarios for decision-making purposes. On the contrary, the evolved C-IF TOPSIS methodology can easily and effectively adapt to different scenarios, including the setting of the metric parameter and the designation of the anchoring mechanism. The evolved C-IF TOPSIS methodology can generate flexible prioritization results by adjusting the metric parameter and setting the displaced or fixed anchoring mechanism. In conclusion, the current C-IF TOPSIS techniques can produce stable but still resilient results. Conclusion and future scope The circumstances confronting the MCDA problem are becoming increasingly complex, and there is much incomplete, indistinct, and inconsistent information in some unpredictable emergencies or the ever-changing social environment. The evolved C-IF TOPSIS methodology can provide decision-makers with recommendations for making the most appropriate choices within complex realistic environments. Specifically, this study makes the following main contributions to address the limitations of the existing literature and overcome the challenges of research gaps: (1) Based on three- and four-term approaches, this study constructed new C-IF Minkowski distance measures, and such general-purpose metrics can relax the constraints of the current C-IF distance metrics, provide flexibility of use through parameter settings, and broaden the applicability of quantitative analysis. (2) This study applied our newly developed C-IF Minkowski distance measures to the development process of the C-IF TOPSIS methodology, which can better determine the separation of incomplete, uncertain, and inconsistent information and delineate trade-off evaluations and compromise decision rules. (3) This study built displaced and fixed anchoring frameworks with three- and four-term representations in order to create an evolved C-IF TOPSIS methodology for dealing with increasingly complex MCDA problems in real-world settings. (4) This study developed two new effective prioritization algorithms that were practically applied to the site selection issue of large epidemic hospitals, demonstrating the applicability of the new techniques and their superior ability when compared to existing approaches through comparative analysis. However, there may be some limitations to this study. As previously indicated, the C-IF decision matrix was converted into pessimistic and optimistic decision matrices expressed in terms of IF values by Kahraman and Alkan (2021) and Alkan and Kahraman (2022b). They transformed the higher-order fuzzy information included in the C-IF set into a standard IF set with streamlined pessimistic and optimistic estimate processes. While their method may lose sight of the original goal of dealing with complex uncertainties using the C-IF set, the pessimistic and optimistic estimates associated with the C-IF decision setting are indeed issues that are not addressed in the approach presented in this study. If the decision-maker has a particularly pessimistic or optimistic view of the decision-making environment, the results obtained using the suggested C-IF TOPSIS technique must be interpreted with caution. This is the main limitation faced by this study. Other implementation limitations may exist for the proposed C-IF TOPSIS approach. To be specific, possible constraints include the mechanism for setting the metric parameter, and how to specify appropriate parameter values in various MCDA application libraries. Furthermore, a more thorough analysis of case applicability is necessary since the displaced or fixed anchoring frameworks with three- and four-term representations are relevant to various MCDA case bases. This opens up the possibility of conducting a future study in two directions. The relationship between the metric parameter and the optimal solution outcomes should be taken into consideration when building additional C-IF MCDA models using the suggested C-IF Minkowski distance measures. Moreover, an optimal setting mechanism for the metric parameter should be established to enhance the effectiveness and performance of the C-IF MCDA model. Furthermore, how to apply the evolved C-IF TOPSIS methodology to various practical cases, as well as the correctness and validity analysis of the consequences, warrant further investigation. Appendix See Tables 10 and 11Table 10 Main comparison results based on the displaced anchoring mechanism ai DorR β = 1 β = 2 β = 3 β = 4 β = 5 β = 6 β = 7 β = 8 β = 9 β = 10 β = ∞ C-IF Minkowski distances and relative closeness coefficients using the three-term approach a1 D3βC1w,C∗w 0.0682 0.0840 0.0918 0.0967 0.1001 0.1026 0.1046 0.1062 0.1075 0.1086 0.0709 D3βC1w,C¬w 0.0943 0.1288 0.1536 0.1716 0.1851 0.1954 0.2036 0.2103 0.2157 0.2203 0.0976 R3β∗(a1) 0.5804 0.6053 0.6260 0.6397 0.6490 0.6557 0.6606 0.6644 0.6673 0.6697 0.5791 a2 D3βC2w,C∗w 0.0547 0.0636 0.0716 0.0780 0.0831 0.0871 0.0902 0.0928 0.0949 0.0967 0.0567 D3βC2w,C¬w 0.1066 0.1258 0.1408 0.1524 0.1615 0.1686 0.1743 0.1790 0.1829 0.1862 0.1111 R3β∗(a2) 0.6608 0.6642 0.6629 0.6614 0.6603 0.6595 0.6590 0.6586 0.6584 0.6582 0.6622 a3 D3βC3w,C∗w 0.0627 0.0714 0.0769 0.0811 0.0844 0.0871 0.0894 0.0914 0.0932 0.0947 0.0650 D3βC3w,C¬w 0.1034 0.1229 0.1391 0.1515 0.1612 0.1688 0.1749 0.1799 0.1841 0.1877 0.1078 R3β∗(a3) 0.6227 0.6324 0.6438 0.6515 0.6564 0.6595 0.6616 0.6630 0.6640 0.6647 0.6240 a4 D3βC4w,C∗w 0.0648 0.0917 0.1047 0.1124 0.1175 0.1212 0.1240 0.1262 0.1281 0.1296 0.0672 D3βC4w,C¬w 0.1006 0.1480 0.1772 0.1972 0.2118 0.2230 0.2319 0.2390 0.2449 0.2498 0.1024 R3β∗(a4) 0.6082 0.6175 0.6285 0.6369 0.6431 0.6479 0.6515 0.6544 0.6567 0.6585 0.6039 a5 D3βC5w,C∗w 0.1101 0.1527 0.1786 0.1965 0.2099 0.2204 0.2289 0.2359 0.2417 0.2466 0.1119 D3βC5w,C¬w 0.0486 0.0749 0.0885 0.0973 0.1035 0.1083 0.1121 0.1151 0.1177 0.1198 0.0510 R3β∗(a5) 0.3062 0.3291 0.3314 0.3311 0.3303 0.3295 0.3287 0.3280 0.3275 0.3271 0.3132 a6 D3βC6w,C∗w 0.1060 0.1234 0.1388 0.1512 0.1608 0.1684 0.1746 0.1795 0.1837 0.1872 0.1080 D3βC6w,C¬w 0.0553 0.0659 0.0708 0.0740 0.0764 0.0783 0.0800 0.0814 0.0827 0.0838 0.0583 R3β∗(a6) 0.3429 0.3481 0.3377 0.3286 0.3220 0.3174 0.3143 0.3120 0.3104 0.3092 0.3503 a7 D3βC7w,C∗w 0.0723 0.0770 0.0816 0.0857 0.0893 0.0925 0.0952 0.0975 0.0995 0.1013 0.0757 D3βC7w,C¬w 0.0938 0.1276 0.1497 0.1657 0.1778 0.1873 0.1948 0.2009 0.2060 0.2103 0.0972 R3β∗(a7) 0.5647 0.6236 0.6473 0.6591 0.6656 0.6694 0.6718 0.6733 0.6743 0.6750 0.5620 C-IF Minkowski distances and relative closeness coefficients using the four-term approach a1 D4βC1w,C∗w 0.0709 0.0842 0.0918 0.0967 0.1001 0.1026 0.1046 0.1062 0.1075 0.1086 0.0709 D4βC1w,C¬w 0.0976 0.1289 0.1536 0.1716 0.1851 0.1954 0.2036 0.2103 0.2157 0.2203 0.0976 R4β∗(a1) 0.5791 0.6051 0.6260 0.6397 0.6490 0.6557 0.6606 0.6644 0.6673 0.6697 0.5791 a2 D4βC2w,C∗w 0.0567 0.0637 0.0716 0.0780 0.0831 0.0871 0.0902 0.0928 0.0949 0.0967 0.0567 D4βC2w,C¬w 0.1111 0.1261 0.1408 0.1524 0.1615 0.1686 0.1743 0.1790 0.1829 0.1862 0.1111 R4β∗(a2) 0.6622 0.6642 0.6629 0.6614 0.6603 0.6595 0.6590 0.6586 0.6584 0.6582 0.6622 a3 D4βC3w,C∗w 0.0650 0.0716 0.0769 0.0811 0.0844 0.0871 0.0894 0.0914 0.0932 0.0947 0.0650 D4βC3w,C¬w 0.1078 0.1231 0.1391 0.1516 0.1612 0.1688 0.1749 0.1799 0.1841 0.1877 0.1078 R4β∗(a3) 0.6240 0.6324 0.6438 0.6515 0.6564 0.6595 0.6616 0.6630 0.6640 0.6647 0.6240 a4 D4βC4w,C∗w 0.0672 0.0918 0.1047 0.1124 0.1175 0.1212 0.1240 0.1262 0.1281 0.1296 0.0672 D4βC4w,C¬w 0.1024 0.1480 0.1772 0.1972 0.2118 0.2230 0.2319 0.2390 0.2449 0.2498 0.1024 R4β∗(a4) 0.6039 0.6171 0.6285 0.6369 0.6431 0.6479 0.6515 0.6544 0.6567 0.6585 0.6039 a5 D4βC5w,C∗w 0.1119 0.1527 0.1786 0.1965 0.2099 0.2204 0.2289 0.2359 0.2417 0.2466 0.1119 D4βC5w,C¬w 0.0510 0.0751 0.0885 0.0973 0.1035 0.1083 0.1121 0.1151 0.1177 0.1198 0.0510 R4β∗(a5) 0.3132 0.3298 0.3315 0.3311 0.3303 0.3295 0.3287 0.3280 0.3275 0.3271 0.3132 a6 D4βC6w,C∗w 0.1080 0.1235 0.1388 0.1512 0.1608 0.1684 0.1746 0.1795 0.1837 0.1872 0.1080 D4βC6w,C¬w 0.0583 0.0661 0.0708 0.0740 0.0764 0.0783 0.0800 0.0814 0.0827 0.0838 0.0583 R4β∗(a6) 0.3503 0.3489 0.3378 0.3286 0.3220 0.3174 0.3143 0.3120 0.3104 0.3092 0.3503 a7 D4βC7w,C∗w 0.0757 0.0772 0.0816 0.0857 0.0893 0.0925 0.0952 0.0975 0.0995 0.1013 0.0757 D4βC7w,C¬w 0.0972 0.1278 0.1497 0.1657 0.1778 0.1873 0.1948 0.2009 0.2060 0.2103 0.0972 R4β∗(a7) 0.5620 0.6232 0.6473 0.6591 0.6656 0.6694 0.6718 0.6733 0.6743 0.6750 0.5620 Table 11 Main comparison results based on the fixed anchoring mechanism ai DorR β = 1 β = 2 β = 3 β = 4 β = 5 β = 6 β = 7 β = 8 β = 9 β = 10 β = ∞ C-IF Minkowski distances and relative closeness coefficients using the three-term approach a1 D3βC1w,C+w 0.1298 0.1431 0.1547 0.1640 0.1712 0.1770 0.1816 0.1854 0.1886 0.1913 0.1353 D3βC1w,C-w 0.1853 0.2127 0.2341 0.2501 0.2621 0.2714 0.2788 0.2848 0.2898 0.2941 0.1980 R3β+a1 0.5881 0.5978 0.6022 0.6040 0.6048 0.6053 0.6055 0.6057 0.6058 0.6060 0.5941 a2 D3βC2w,C+w 0.1175 0.1244 0.1305 0.1357 0.1402 0.1441 0.1474 0.1502 0.1527 0.1549 0.1226 D3βC2w,C-w 0.1988 0.2149 0.2285 0.2398 0.2491 0.2568 0.2633 0.2688 0.2735 0.2776 0.2118 R3β+a2 0.6285 0.6335 0.6366 0.6386 0.6398 0.6406 0.6411 0.6415 0.6417 0.6418 0.6334 a3 D3βC3w,C+w 0.1207 0.1311 0.1402 0.1479 0.1544 0.1599 0.1647 0.1688 0.1723 0.1754 0.1259 D3βC3w,C-w 0.1908 0.2081 0.2230 0.2350 0.2443 0.2517 0.2576 0.2625 0.2665 0.2700 0.2042 R3β+a3 0.6126 0.6134 0.6140 0.6138 0.6128 0.6115 0.6100 0.6086 0.6073 0.6062 0.6187 a4 D3βC4w,C+w 0.1235 0.1419 0.1579 0.1705 0.1802 0.1878 0.1937 0.1986 0.2026 0.2060 0.1279 D3βC4w,C-w 0.1887 0.2232 0.2484 0.2673 0.2817 0.2928 0.3015 0.3086 0.3144 0.3192 0.1990 R3β+a4 0.6044 0.6114 0.6114 0.6106 0.6098 0.6093 0.6088 0.6084 0.6081 0.6078 0.6088 a5 D3βC5w,C+w 0.1755 0.2041 0.2252 0.2415 0.2543 0.2647 0.2733 0.2805 0.2866 0.2919 0.1789 D3βC5w,C-w 0.1434 0.1525 0.1615 0.1701 0.1782 0.1854 0.1919 0.1975 0.2025 0.2068 0.1544 R3β+a5 0.4497 0.4276 0.4177 0.4134 0.4119 0.4119 0.4124 0.4132 0.4140 0.4147 0.4633 a6 D3βC6w,C+w 0.1687 0.1814 0.1919 0.2007 0.2082 0.2146 0.2200 0.2247 0.2288 0.2323 0.1732 D3βC6w,C-w 0.1475 0.1558 0.1636 0.1709 0.1776 0.1837 0.1892 0.1941 0.1985 0.2023 0.1593 R3β+a6 0.4664 0.4620 0.4602 0.4599 0.4604 0.4613 0.4623 0.4635 0.4645 0.4656 0.4790 a7 D3βC7w,C+w 0.1303 0.1356 0.1410 0.1463 0.1513 0.1557 0.1597 0.1632 0.1662 0.1689 0.1368 D3βC7w,C-w 0.1812 0.2095 0.2295 0.2438 0.2544 0.2625 0.2690 0.2743 0.2788 0.2826 0.1941 R3β+a7 0.5817 0.6071 0.6194 0.6249 0.6271 0.6276 0.6275 0.6270 0.6265 0.6259 0.5865 C-IF Minkowski distances and relative closeness coefficients using the four-term approach a1 D4βC1w,C+w 0.1353 0.1435 0.1547 0.1640 0.1712 0.1770 0.1816 0.1854 0.1886 0.1913 0.1353 D4βC1w,C-w 0.1980 0.2136 0.2342 0.2501 0.2621 0.2714 0.2788 0.2848 0.2898 0.2941 0.1980 R4β+a1 0.5941 0.5982 0.6022 0.6040 0.6048 0.6053 0.6055 0.6057 0.6058 0.6060 0.5941 a2 D4βC2w,C+w 0.1226 0.1247 0.1305 0.1357 0.1402 0.1441 0.1474 0.1502 0.1527 0.1549 0.1226 D4βC2w,C-w 0.2118 0.2159 0.2286 0.2398 0.2491 0.2568 0.2633 0.2688 0.2735 0.2776 0.2118 R4β+a2 0.6334 0.6339 0.6367 0.6386 0.6398 0.6406 0.6411 0.6415 0.6417 0.6418 0.6334 a3 D4βC3w,C+w 0.1259 0.1315 0.1402 0.1479 0.1544 0.1599 0.1647 0.1688 0.1723 0.1754 0.1259 D4βC3w,C-w 0.2042 0.2091 0.2231 0.2350 0.2443 0.2517 0.2576 0.2625 0.2665 0.2700 0.2042 R4β+a3 0.6187 0.6139 0.6140 0.6138 0.6128 0.6115 0.6100 0.6086 0.6073 0.6062 0.6187 a4 D4βC4w,C+w 0.1279 0.1421 0.1579 0.1705 0.1802 0.1878 0.1937 0.1986 0.2026 0.2060 0.1279 D4βC4w,C-w 0.1990 0.2238 0.2485 0.2673 0.2817 0.2928 0.3015 0.3086 0.3144 0.3192 0.1990 R4β+a4 0.6088 0.6116 0.6115 0.6106 0.6098 0.6093 0.6088 0.6084 0.6081 0.6078 0.6088 a5 D4βC5w,C+w 0.1789 0.2043 0.2252 0.2415 0.2543 0.2647 0.2733 0.2805 0.2866 0.2919 0.1789 D4βC5w,C-w 0.1544 0.1535 0.1616 0.1702 0.1782 0.1854 0.1919 0.1975 0.2025 0.2068 0.1544 R4β+a5 0.4633 0.4291 0.4179 0.4134 0.4119 0.4119 0.4124 0.4132 0.4140 0.4147 0.4633 a6 D4βC6w,C+w 0.1732 0.1816 0.1919 0.2007 0.2082 0.2146 0.2200 0.2247 0.2288 0.2323 0.1732 D4βC6w,C-w 0.1593 0.1569 0.1638 0.1710 0.1776 0.1837 0.1892 0.1941 0.1985 0.2023 0.1593 R4β+a6 0.4790 0.4634 0.4604 0.4599 0.4604 0.4613 0.4623 0.4635 0.4645 0.4656 0.4790 a7 D4βC7w,C+w 0.1368 0.1360 0.1411 0.1463 0.1513 0.1557 0.1597 0.1632 0.1662 0.1689 0.1368 D4βC7w,C-w 0.1941 0.2104 0.2296 0.2438 0.2544 0.2625 0.2690 0.2743 0.2788 0.2826 0.1941 R4β+a7 0.5865 0.6074 0.6195 0.6249 0.6271 0.6276 0.6275 0.6270 0.6265 0.6259 0.5865 Acknowledgements The author acknowledges the assistance of the respected editor and the anonymous referees for their insightful and constructive comments, which helped to improve the overall quality of the paper. The author would like to acknowledge the financial support of the National Science and Technology Council, Taiwan (NSTC 111-2410-H-182-012-MY3) and the Fundamental Research Funds from Chang Gung Memorial Hospital, Linkou, Taiwan (BMRP 574) during the completion of this study. Author contributions TYC: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing—original draft, Writing—review & editing, Visualization, Funding acquisition. Funding This work was supported by the National Science and Technology Council, Taiwan [grant numbers: NSTC 111-2410-H-182-012-MY3] and Chang Gung Memorial Hospital, Linkou, Taiwan [Grant Number: BMRP 574]. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Declarations Conflict of interest The author declare that she has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Human and animal rights This article does not contain any studies with human participants or animals that were performed by any of the authors. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Akram M Dudek WA Ilyas F Group decision-making based on Pythagorean fuzzy TOPSIS method Int J Intell Syst 2019 34 7 1455 1475 10.1002/int.22103 Alkan N Kahraman C An intuitionistic fuzzy multi-distance based evaluation for aggregated dynamic decision analysis (IF-DEVADA): Its application to waste disposal location selection Eng Appl Artif Intell 2022 111 6 104809 10.1016/j.engappai.2022a.104809 Alkan N Kahraman C Circular intuitionistic fuzzy TOPSIS method: Pandemic hospital location selection J Intell Fuzzy Syst 2022 42 1 295 316 10.3233/JIFS-219193 Alshammari I Parimala M Ozel C Riaz M Spherical linear Diophantine fuzzy TOPSIS algorithm for green supply chain management system J Funct Spaces 2022 7 12 10.1155/2022/3136462 Ashraf S Mahmood T Abdullah S Khan Q Different approaches to multi-criteria group decision making problems for picture fuzzy environment Bull Braz Math Soc New Ser 2019 50 2 373 397 10.1007/s00574-018-0103-y Atanassov KT Intuitionistic fuzzy sets Fuzzy Sets Syst 1986 20 1 87 96 10.1016/S0165-0114(86)80034-3 Atanassov KT Circular intuitionistic fuzzy sets J Intell Fuzzy Syst 2020 39 5 5981 5986 10.3233/JIFS-189072 Atanassov KT Marinov E Four distances for circular intuitionistic fuzzy sets Mathematics 2021 9 10 1121 10.3390/math9101121 Boltürk E Kahraman C Interval-valued and circular intuitionistic fuzzy present worth analyses Informatica 2022 10.15388/22-INFOR478 Boran FE Genç S Kurt M Akay D A multi-criteria intuitionistic fuzzy group decision making for supplier selection with TOPSIS method Expert Syst Appl 2009 36 8 11363 11368 10.1016/j.eswa.2009.03.039 Çakır E Taş MA Circular intuitionistic fuzzy multi-criteria decision making methodology Eur J Sci Technol 2021 28 900 905 10.31590/ejosat.1011888 Çakır E, Taş MA (2022). Circular intuitionistic fuzzy analytic hierarchy process for remote working assessment in Covid-19. In: C. Kahraman, A. C. Tolga, S. Cevik Onar, S. Cebi, B. Oztaysi, & I. U. Sari, (Eds.) Intelligent and fuzzy systems. INFUS 2022. Lecture Notes in Networks and Systems, vol 504. Springer, Cham. 10.1007/978-3-031-09173-5_68 Çakır E, Taş MA, Ulukan Z (2021) A new circular intuitionistic fuzzy MCDM: A case of Covid-19 medical waste landfill site evaluation. 2021 IEEE 21st international symposium on computational intelligence and informatics (CINTI), pp 143−148. 10.1109/CINTI53070.2021.9668563 Çakır E, Taş MA, Ulukan Z (2022) Circular intuitionistic fuzzy sets in multi criteria decision making. In: R. A. Aliev, J. Kacprzyk, W. Pedrycz, M. Jamshidi, M. Babanli, & F. M. Sadikoglu (Eds.) 11th International Conference on Theory and Application of Soft Computing, Computing with Words and Perceptions and Artificial Intelligence - ICSCCW-2021. ICSCCW 2021. 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Springer, Cham. 10.1007/978-3-030-92127-9_9 Chen T-Y Decision support modeling for multiple criteria assessments using a likelihood-based consensus ranking method under Pythagorean fuzzy uncertainty Artif Intell Rev 2022 55 5 4879 4939 10.1007/s10462-021-10122-z Chen T-Y Likelihood-based agreement measurements with Pythagorean fuzzy paired point operators to enrichment evaluations and priority determination for an uncertain decision-theoretical analysis Eng Appl Artif Intell 2022 113 8 38 10.1016/j.engappai.2022b.104912 Das S Garg A Pal SK Maiti J A weighted similarity measure between Z-numbers and bow-tie quantification IEEE Trans Fuzzy Syst 2019 28 9 2131 2142 10.1109/TFUZZ.2019.2930935 Deng X Chen C Novel linear programming models based on distance measure of IFSs and modified TOPSIS method for portfolio selection Egypt Informs J 2022 10.1016/j.eij.2022.06.002 Garg H Kumar K An advanced study on the similarity measures of intuitionistic fuzzy sets based on the set pair analysis theory and their application in decision making Soft Comput 2018 22 15 4959 4970 10.1007/s00500-018-3202-1 Garg H Kumar K A novel exponential distance and its based TOPSIS method for interval-valued intuitionistic fuzzy sets using connection number of SPA theory Artif Intell Rev 2020 53 1 595 624 10.1007/s10462-018-9668-5 Garg H Rani D Novel similarity measure based on the transformed right-angled triangles between intuitionistic fuzzy sets and its applications Cogn Comput 2021 13 2 447 465 10.1007/s12559-020-09809-2 Garg H Rani D An efficient intuitionistic fuzzy MULTIMOORA approach based on novel aggregation operators for the assessment of solid waste management techniques Appl Intell 2022 52 4 4330 4363 10.1007/s10489-021-02541-w Garg H Singh S Algorithm for solving group decision-making problems based on the similarity measures under type 2 intuitionistic fuzzy sets environment Soft Comput 2020 24 10 7361 7381 10.1007/s00500-019-04359-8 Guan T Green logistics partner selection based on Pythagorean hesitant fuzzy set and multiobjective optimization Math Probl Eng 2022 6 8 10.1155/2022/6993066 Han Q Li W Xu Q Song Y Fan C Zhao M Novel measures for linguistic hesitant Pythagorean fuzzy sets and improved TOPSIS method with application to contributions of system-of-systems Expert Syst Appl 2022 8 19 10.1016/j.eswa.2022.117088 Hwang CL Yoon K Multiple attribute decision making−methods and applications: a state-of-the-art survey 1981 New York Springer Imanov, G., & Aliyev, A. (2021). Circular intuitionistic fuzzy sets in evaluation of human capital. In M. B. F. Romero (Ed.), Revista científica del instituto iberoamericano de desarrollo empresarial (pp. 1−13). Instituto Iberoamericano de Desarrollo Empresarial. No. 04-2018-073111462600–102, ISSN-2683-1562 Jaini NI Application of intuitionistic Z-numbers in supplier selection Intell Automat Soft Comput 2023 35 1 47 61 10.32604/iasc.2023.024660 Kahraman C Alkan N Circular intuitionistic fuzzy TOPSIS method with vague membership functions: supplier selection application context Notes Intuit Fuzzy Sets 2021 27 1 24 52 10.7546/nifs.2021.27.1.24-52 Kahraman C Otay I Kahraman C Cebi S Cevik Onar S Oztaysi B Tolga AC Sari IU Extension of VIKOR method using circular intuitionistic fuzzy sets Intelligent and fuzzy techniques for emerging conditions and digital transformation: INFUS 2021 2022 Cham Springer Kaya İ Karaşan A Özkan B Çolak M An integrated decision-making methodology based on Pythagorean fuzzy sets for social robot evaluation Soft Comput 2022 10.1007/s00500-022-07303-5 Otay İ Kahraman C A novel circular intuitionistic fuzzy AHP&VIKOR methodology: an application to a multi-expert supplier evaluation problem Pamukkale Univ J Eng Sci 2021 28 1 194 207 10.5505/pajes.2021.90023 Rani D Garg H Multiple attributes group decision-making based on trigonometric operators, particle swarm optimization and complex intuitionistic fuzzy values Artif Intell Rev 2022 10.1007/s10462-022-10208-2 Reig-Mullor J Salas-Molina F Vercher-Ferrandiz M Sustainability performance assessment with intuitionistic fuzzy composite metrics and its application to the motor industry Iran J Fuzzy Syst 2022 19 4 57 72 10.22111/IJFS.2022.7087 Sadabadi SA Hadi-Vencheh A Jamshidi A Jalali M An improved fuzzy TOPSIS method with a new ranking index Int J Inf Technol Decis Mak 2022 21 2 615 641 10.1142/S0219622021500620 Shen Q Zhang X Lou J Liu Y Jiang Y Interval-valued intuitionistic fuzzy multi-attribute second-order decision making based on partial connection numbers of set pair analysis Soft Comput 2022 10.1007/s00500-022-07314-2 Singh S Garg H Distance measures between type-2 intuitionistic fuzzy sets and their application to multicriteria decision-making process Appl Intell 2017 46 4 788 799 10.1007/s10489-016-0869-9 Szmidt E Distances and similarities in intuitionistic fuzzy sets 2014 New York Springer International Publishing Szmidt E Kacprzyk J Distances between intuitionistic fuzzy sets Fuzzy Sets Syst 2000 114 3 505 518 10.1016/S0165-0114(98)00244-9 Talukdar P Dutta P Distance measures for cubic Pythagorean fuzzy sets and its applications to multicriteria decision making Granul Comput 2021 6 2 267 284 10.1007/s41066-019-00185-3 Tiwari P Gupta P Novel distance, similarity and entropy measures for interval valued intuitionistic fuzzy soft set J Intell Fuzzy Syst 2022 43 3 3067 3086 10.3233/JIFS-212647 Tsao C-Y Chen T-Y A parametric likelihood measure with beta distributions for Pythagorean fuzzy decision-making Neural Comput Appl 2022 34 16 13757 13806 10.1007/s00521-022-07151-2 Yang S Pan Y Zeng S Decision making framework based Fermatean fuzzy integrated weighted distance and TOPSIS for green low-carbon port evaluation Eng Appl Artif Intell 2022 114 9 8 10.1016/j.engappai.2022.105048 Zhang C Ding J Zhan J Li D Incomplete three-way multi-attribute group decision making based on adjustable multigranulation Pythagorean fuzzy probabilistic rough sets Int J Approx Reason 2022 147 8 40 59 10.1016/j.ijar.2022.05.004

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==== Front STAR Protoc STAR Protoc STAR Protocols 2666-1667 Elsevier S2666-1667(22)00857-7 10.1016/j.xpro.2022.101977 101977 Protocol Protocol for investigating the biogenesis of SARS-CoV2-S pseudoviruses in HEK293T cells transduced to express the virus-specific intrabodies Dahiya Surbhi 21 Singh Sudhakar 21 Sehrawat Sharvan 234∗ 2 Department of Biological Sciences Indian Institute of Science Education and Research Mohali, Sector 81, SAS Nagar Knowledge City PO Manauli, Mohali 140306 Punjab India ∗ Correspondence to: 1 These authors contributed equally to the work. 3 Technical contact 4 Lead contact 15 12 2022 15 12 2022 10197723 9 2022 7 11 2022 12 12 2022 © 2022. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The protocol investigates the influence of anti-cleavage site intrabodies in modulating the output of LV(CoV2-S), a lentivirus based pseudovirus expressing CoV2-S protein using HEK293T cells. We clone the single domain antibody (sdAb) sequence into a lentiviral vector (pLenti-GFP) for intracellular expression and assess not only the viral biogenesis but also the fate of the CoV2-S protein. Graphical abstract Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics. ==== Body pmcThe authors declare no competing interests.

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==== Front J Formos Med Assoc J Formos Med Assoc Journal of the Formosan Medical Association 0929-6646 0929-6646 Formosan Medical Association, Elsevier S0929-6646(22)00441-7 10.1016/j.jfma.2022.12.002 Original Article Correlation of Adverse Effects with Antibody Reponses Following Homologous and Heterologous COVID19 Prime-Boost Vaccinations Cheng Aristine a Hsieh Ming-Ju bc Chang Sui-Yuan de Ieong Si-Man e Cheng Chien-Yu f Sheng Wang-Huei ag∗ Chang Shan-Chwen ag a Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan b Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan c Occupational Safety and Health Office, National Taiwan University Hospital, Taipei, Taiwan d Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan e Department of Laboratory Medicine, National Taiwan University Hospital, Taipei City, Taiwan f Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan g School of Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan ∗ Corresponding author: Department of Internal Medicine, National Taiwan University Hospital, 7, Chung Shan South Road, Taipei City, 10002, Taiwan. Phone number: +886-2-23123456 Ext. 62104 Fax number: +886-2-23971412 15 12 2022 15 12 2022 1 8 2022 23 11 2022 7 12 2022 . 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Studies correlating reactogenicity and immunogenicity of COVID-19 vaccines are limited to BNT162b2, with inconsistent results. We investigated whether adverse reactions after other COVID-19 vaccines reliably predict humoral responses. Methods Adult volunteers were recruited for homologous or heterologous prime-boost vaccinations with adenoviral (ChAdOx1, AstraZeneca) and/or mRNA (mRNA-1273, Moderna) vaccines administered either 4 or 8 weeks apart. Adverse effects were routinely solicited and recorded by subjects in a standard diary card for up to 84 days post booster vaccination. Anti-SARS-CoV-2 IgG titers were measured pre- (visit 1), and post-booster dose at days 14 (visit 2) and 28 (visit 3). Results A total of 399 participants (75% women) with a median age of 41 (interquartile range, 33-48 IQR) years were included. Vaccine-induced antibody titers at days 14 and 28 were significantly higher among subjects who reported local erythema, swelling, pain, as well as systemic fever, chills, headache, myalgia, arthralgia, fatigue compared to those who did not experience local or systemic reactogenicity. Post-vaccination humoral responses did not correlate with the occurrence of skin rash and correlated weakly with gastrointestinal symptoms. A significant correlation between post-vaccination peak body temperature and anti-SARS-CoV-2 spike IgG at Day 14, independent of vaccine type and schedule, was found. Conclusions Specific symptoms of reactogenicity such as post-vaccination injection site pain, swelling, erythema and fever, myalgia and fatigue are significantly predictive of the magnitude of the anti-SARS-CoV-2 antibody response. Article Summary: Whether adverse reactions after vaccination are predictive of immunogenicity is unclear. We show that specific symptoms of reactogenicity such as local pain, swelling, erythema, fever, myalgia, and fatigue correlate significantly with the magnitude of the anti-SARS-CoV-2 antibody response. Keywords reactogenicity immunogenicity adverse effects antibody response anti-SARS-CoV-2 IgG humoral responses COVID19 vaccines ==== Body pmc

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==== Front Gastroenterol Clin North Am Gastroenterol Clin North Am Gastroenterology Clinics of North America 0889-8553 1558-1942 Elsevier Health Science Division S0889-8553(22)00093-0 10.1016/j.gtc.2022.12.003 Article Critical Review of Changes in a Teaching Hospital in Response to the COVID-19 Pandemic: Education in Medical School, Residency, and GI Fellowship and Clinical Practice of GI Attendings and Gastrointestinal Endoscopy Cappell Mitchell S. MD, PhD 1 1 Gastroenterology Service, Department of Medicine, Building 1, Room 3212, Aleda E. Lutz VA Medical Center at Saginaw, 1500 Weiss Street, Saginaw, MI 48602 15 12 2022 15 12 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Aim Critically review approximately two years afterwards the effectiveness of revolutionary changes at an academic gastroenterology division from COVID-19 pandemic surge at metropolitan Detroit epicenter from 0 infected patients on March 9, 2020, to >300 infected patients (one-quarter of) in-hospital census in April 2020 and >200 infected patients in April 2021. Setting GI Division, William Beaumont Hospital which had 36 GI clinical faculty who used to perform >23,000 endoscopies annually with massive plunge in endoscopy volume during the past two years; fully accredited GI fellowship since 1973; employs >400 house staff annually since 1995; predominantly voluntary attendings; and primary teaching hospital, Oakland-University-Medical-School. Methods Expert opinion, based on: Hospital GI chief >14 years until September 2019; GI fellowship program director, at several hospitals at >20 years; author of 320 publications in peer-reviewed GI journals; and committee-member Food-and-Drug-Administration-GI-Advisory Committee for >5 years. Original study exempted by Hospital IRB, April 14, 2020. IRB approval not required for present study because this opinion is based on previously published data. Advantageous changes Division reorganized patient care to add clinical capacity and minimize risks to staff of contracting COVID-19. Affiliated medical school changes included: changing “live” to virtual lectures, meeting, and conferences. Initially virtual meetings usually used telephone conferencing which proved cumbersome until meetings were changed to completely computerized virtual meetings using Microsoft Teams or Google Zoom, which performed superbly. Some clinical electives were cancelled for medical students and residents because of need to prioritize car on COVID-19 infection during the pandemic, and medical students graduated on time despite partly missing electives. Division reorganized by changing “live” GI lectures to virtual lectures; by four GI fellows temporarily reassigned as medical attendings supervising COVID-19-infected patients; postponing elective GI endoscopies; and drastically reducing average number of endoscopies from 100/weekday to a small fraction long-term! GI clinic visits reduced by half by postponing non-urgent visits, and physical visits replaced by virtual visits. Economic pandemic impact included temporary, hospital deficit initially relieved by federal grants and hospital employee terminations. GI program director contacted GI fellows twice weekly to monitor pandemic-induced stress. Applicants for GI fellowship interviewed virtually. Graduate medical education changes included weekly committee meetings to monitor pandemic-induced changes; program managers working from home; canceling annual ACGME fellowship survey, ACGME site visits and national GI conventions changed from physical to virtual. Dubious changes Temporarily mandated intubation of COVID-19-infected patients for EGD; temporarily exempted GI fellows from endoscopy duties during surge; fired highly respected anesthesiology group employed for 20 years during pandemic leading to anesthesiology shortages, and abruptly firing without warning or cause numerous senior respected faculty who greatly contributed to research, academics, and reputation. Conclusion Profound and pervasive GI divisional changes maximized clinical resources devoted to COVID-19-infected patients and minimized risks of transmitting infection. Academic changes degraded by massive cost-cutting while offering institution to about 100 hospital systems and eventually “selling” institution to Spectrum Health, without faculty input. Keywords COVID-19 Coronavirus SARS Pandemic Gastroenterology fellowship Academic gastroenterology Gastroenterology clinical service Clinical schedules ==== Body pmc

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==== Front Cell Rep Med Cell Rep Med Cell Reports Medicine 2666-3791 The Authors. S2666-3791(22)00446-3 10.1016/j.xcrm.2022.100882 100882 Article AZD1222-induced mucosal immune responses are influenced by prior SARS-CoV-2 infection and correlate with virologic outcomes in breakthrough infection Aksyuk Anastasia A. 12 Bansal Himanshu 32 Wilkins Deidre 1 Stanley Ann Marie 1 Sproule Stephanie 3 Maaske Jill 4 Sanikommui Satya 3 Hartman William R. 5 Sobieszczyk Magdalena E. 6 Falsey Ann R. 78∗ Kelly Elizabeth J. 189∗ 1 Translational Medicine, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, MD 20878, USA 3 Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, MD 20878, USA 4 Clinical Development, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, MD 20878, USA 5 Department of Anesthesiology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, WI 53726, USA 6 Division of Infectious Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA 7 University of Rochester School of Medicine and Dentistry, Rochester, New York; NY 14642 USA; Rochester Regional Health, Rochester, New York, NY 14621, USA ∗ Corresponding author (A.R.F); (E.J.K) 2 These authors contributed equally 8 Senior author 9 Lead contact 15 12 2022 15 12 2022 10088213 7 2022 11 11 2022 12 12 2022 © 2022 The Authors. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The nasal mucosa is an important initial site of host defense against SARS-CoV-2 infection. However, intramuscularly administered vaccines typically do not achieve high antibody titers in nasal mucosa. We measure anti-SARS-CoV-2 spike IgG and IgA in nasal epithelial lining fluid (NELF) following intramuscular vaccination of 3,058 participants from the immunogenicity substudy of NCT04516746: A phase 3, double-blind, placebo-controlled study of AZD1222 vaccination. IgG is detected in NELF collected 14 days following first AZD1222 vaccination. IgG levels increase with a second vaccination and exceed pre-existing levels in baseline-SARS-CoV-2-seropositive participants. Nasal IgG responses are durable and display strong correlations with serum IgG, suggesting serum-to-NELF transudation. AZD1222 induces short-lived increases to pre-existing nasal IgA levels in baseline-seropositive vaccinees. Vaccinees display a robust recall IgG response upon breakthrough infection with overall magnitudes unaffected by time between vaccination and illness. Mucosal responses correlate with reduced viral loads and shorter durations of viral shedding in saliva. Graphical abstract The nasal mucosa represents an important initial line of host defense against SARS-CoV-2. Aksyuk et al. describe anti-SARS-CoV-2 spike IgG and IgA responses in the nasal mucosa following intramuscular vaccination and upon breakthrough SARS-CoV-2 infection in participants from NCT04516746: A phase 3, double-blind, placebo-controlled study of AZD1222 (ChAdOx1 nCoV-19) vaccination. Keywords AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine SARS-CoV-2 spike antibodies nasal antibody nasal mucosal immunity mucosal immune response breakthrough infection serology immunoassay Published: January 17, 2023 ==== Body pmc

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Cell Rep Med. 2022 Dec 15;:100882

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==== Front Aten Primaria Aten Primaria Atencion Primaria 0212-6567 1578-1275 The Author(s). Published by Elsevier España, S.L.U. S0212-6567(22)00271-2 10.1016/j.aprim.2022.102551 102551 Article Efecto de Matricaria chamomilla sobre familiares estresados de pacientes de COVID-19 en Comunidades Andinas del Perú Effect of Matricaria chamomilla on stressed relatives of COVID-19 patients in Andean Communities of PeruSaldaña-Chafloque Charles Frank a⁎ Acosta-Román Mercedes a Garcia-Gonzales Christian Yamil b Mostacero-León José c a Universidad Autónoma de Tayacaja Daniel Hernández Morillo, Jr. Bolognesi N° 416 Pampas Tayacaja, Huancavelica, Perú b Universidad Roosevelt, Av. Giráldez N°542, Huancayo, Perú c Universidad Nacional de Trujillo, Av. Juan Pablo II S/N. Urb. San Andrés, Trujillo – La Libertad, Perú ⁎ Autor de correspondencia: Urb. Manuel Arévalo, II etapa, Mz.B30, Lt. 26, La Esperanza, Trujillo, La Libertad, Perú 15 12 2022 15 12 2022 10255111 11 2022 © 2022 The Author(s) 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmc

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Aten Primaria. 2022 Dec 15;:102551

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==== Front Child Abuse Negl Child Abuse Negl Child Abuse & Neglect 0145-2134 1873-7757 Elsevier Ltd. S0145-2134(22)00531-2 10.1016/j.chiabu.2022.105997 105997 Article Prevalence and determinants of sexual abuse among adolescent girls during the COVID-19 lockdown and school closures in Ghana: A mixed method study Owusu-Addo E. a⁎ Owusu-Addo S.B. b Bennor D.M. a Mensah-Odum N. a Deliege A. c Bansal A. c Yoshikawa M. c Odame J. c a Bureau of Integrated Rural Development, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana b Health Promotion Directorate, Ghana Health Service, Ashanti Region, Ghana c UNICEF Ghana Country Office, Accra, Ghana ⁎ Corresponding author. 15 12 2022 1 2023 15 12 2022 135 105997105997 19 4 2022 3 12 2022 9 12 2022 © 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background In the wake of the COVID-19 pandemic, concerns have been raised that the pandemic may derail global efforts against child sexual abuse (CSA). Objectives This study examines the prevalence and associated factors of sexual abuse among adolescent girls in the context of the COVID-19 pandemic in Ghana. Participants and setting The sample comprised 853 adolescent girls aged 13–19 (16.03 ± 2.04 years) in Ghana. Methods The study employed a concurrent mixed-method design. Results Overall, the prevalence of CSA during the COVID-19 lockdown and school closures was 32.5 %. Protective factors for CSA were feeling safe in neighbourhood (AOR = 0.526, 95 % CI = [0.325, 0.850]) and parents often listen to opinions (AOR = 0.446, 95 % CI = [0.241, 0.826]). Risk factors for CSA were physical activity (AOR = 1.649, OR = 1.783, 95 % CIAOR = [1.093, 2.487, 95 % CIOR = [1.241, 2.561]), parents sometimes listen to opinions (AOR = 1.199, OR = 1.924, 95 % CIAOR = [0.504, 2.853], 95 % CIOR = [1.034, 3.582]), living with another relative (AOR = 2.352, OR = 2.484, 95 % CIAOR = [0.270, 20.523], 95 % CIOR = [0.317, 19.475]), Akan ethnicity (AOR = 1.576, OR = 1.437, 95 % CIAOR = [0.307, 8.091], 95 % CIOR = [0.316, 6.534]), having no disability (AOR = 1.099, OR = 1.138, 95 % CIAOR = [0.679, 1.581], 95 % CIOR = [0.786, 1.649]) and having a close relationship with parents (AOR = 1.334, OR = 1.752, 95 % CIAOR = [0.746, 2.385], 95 % CIOR = [1.096, 2.802]). Conclusion Knowledge of the risk and protective factors identified in this study can guide and inform the development of CSA prevention programmes during disruptive occurrences like school closures and lockdown. Keywords Child sexual abuse Concurrent mixed-method design Ghana COVID-19 Lockdown School closures ==== Body pmc1 Introduction Child sexual abuse (CSA) is defined by the World Health Organization (1999) as the “involvement of a child in sexual activity that he or she does not fully comprehend, is unable to give informed consent to, or for which the child is not developmentally prepared and cannot give consent, or that violates the laws or social taboos of society” (p.15). CSA is a violation of human rights and a public health problem with significant consequences for global health and development. While providing an exact figure for the scale of the problem is difficult, the findings from a recent global review shows that CSA is prevalent in all countries of the world and has a significant impact on the health and wellbeing of children (Radford et al., 2020; Singh et al., 2014). A review of 217 studies conducted in 2011, found 1 in 8 of the world's children (12.7 %) had been sexually abused before reaching the age of 18 (Stoltenborgh et al., 2011). Another systematic review and meta-analysis by Barth et al. (2013) which included 55 studies from 24 countries estimated the prevalence of child sexual abuse between 8 and 31 % for girls and 3 to 17 % for boys. A recent review of evidence from UNICEF (2020) estimates that 1 in every 20 girls aged 15 to 19 (around 13 million) will have experienced forced sex at some point in their lifetime. Evidence from the WePROTECT Global Alliance (2019) further shows that the scale, complexity and danger of technology-facilitated child sexual abuse and exploitation is escalating. In terms of absolute numbers, it is estimated that 275 million children worldwide are exposed to domestic violence, including physical, sexual, and emotional abuse (Roca et al., 2020). CSA is gendered with girls more likely to be affected than boys. For instance, it has been estimated that, globally, 30 to 40 % of adolescent girls, experience sexual violence before turning 15 years-old, while approximately 20 % of adolescent boys experience the same before turning 19 years-old (Singh et al., 2014). In Ghana, while official reporting of child sexual abuse cases remains low, the Ghana Demographic Health Survey (DHS) found that 16.5 % of adolescent girls aged 15–19 years old reported having experienced sexual violence (DHS, 2008). Further, one in four women (25 %) reported that their first sexual intercourse was forced and happened when they were <15 years old (DHS, 2008, p. 305). A 2015 study showed that the prevalence of children who had been sexually abused was around 27 % for girls and 11 % for boys (Böhm, 2016). A study by Quarshie (2021) focusing on sexual violence victimization and associated factors among school-going adolescents in urban Ghana found an overall, 17.6 % adolescents (males = 10.4 %; females = 24.3 %) reported sexual violence victimization during the previous 12 months. CSA is associated with a range of psychological and behavioural consequences, including post-traumatic stress disorder, depression, anxiety, self-harm and attempted suicide (Berelowitz et al., 2013; Edinburgh et al., 2015). CSA can occur in all settings in which children spend their time including schools, homes and playgrounds (Bjørnseth and Szabo, 2018; Devries et al., 2015). Ending CSA is a global priority and critical for achieving all the Sustainable Development Goals for children. In September 2015, targets adopted by all United Nations member states in the Sustainable Development Goals (5.2, 16.1 and 16.2) ending all forms of violence against children, including sexual violence, by 2030. In the wake of the COVID-19 pandemic, concerns have been raised that the pandemic may derail global efforts against CSA (Evelyn Aboagye Addae, 2021). According to Sserwanja et al. (2021) COVID-19 lockdown measures have exposed children to more sexual, physical and emotional abuse and neglect. Children, particularly girls, have heightened vulnerability to sexual violence committed by non-stranger perpetrators (e.g., neighbours) at private residences during the daytime, owing to school closures and a lack of alternative safe venues (Heather Flowe et al., 2020). Indeed, a recent paper published in the Lancet Child and Adolescent Health noted that not much is known about the effects of school closures during COVID-19 on sexual violence experienced by adolescents and called for further research in this area to understand the scale of the problem (Burzynska & Contreras, 2020). In Ghana, all schools were closed due to the outbreak of COVID-19 between March 2020 and January 2021 affecting approximately 9.2 million learners from Kindergarten to Senior High School (SHS) (Ministry of Education, 2020). This study aims to examine the prevalence and associated factors of sexual abuse among adolescent girls in the context of the COVID-19 pandemic. We explain the factors accounting for CSA with binary logistic regression and qualitative interviews in a concurrent mixed-method design. The study's findings could help ascertain the magnitude of the burden, which in turn could inform better policy formulation and implementation of intervention strategies. 1.1 Conceptual framework The socio-ecological model (SEM) was used to inform the study. The SEM illustrates multiple dimensions and complex human interactions that influence health behaviours (Lee et al., 2017). The core principles of the model are: (1) there are multiple influences on an individual's behaviours (i.e., adolescent girls' sexual abuse), including factors at the intrapersonal level, interpersonal level, with increasing influence at levels of community, and public policy; (2) influences interaction across these different levels or spheres of influence; and (3) multilevel approaches can be the most effective interventions for preventing adolescent girls' sexual abuse. 2 Methods 2.1 Study design This study employed a concurrent mixed-method design (Schoonenboom and Johnson, 2017). Levitt et al.'s (2018) guidelines on reporting a mixed-method study was used to guide the study. The quantitative component used a cross-sectional survey to ascertain adolescent girls' exposure to sexual violence during the COVID-19 outbreak. As adolescent girls live within a complex environment, specific survey questions were designed along the lines of the SEM to identify factors placing adolescent girls at risk of sexual abuse during the COVID-19 pandemic. The qualitative component was an in-depth exploration of the lived experiences of participants. Qualitative in-depth interviews (IDs) and focus groups discussions (FGDs) explored the lived experiences of adolescent girls during school closures and their effect on sexual violence. Conceptually, the qualitative component draws on psychological and behavioural frameworks, in this case the socio-ecological model (Abbas & Jabeen, 2023) to gain a richer understanding of how adolescent girls were affected by COVID-19 lockdown and school closures. Key Informant Interviews were also held with community leaders, school teachers and service providers including Community Health Nurses, Midwives, and Nurses who provide sexual and reproductive health (SRH) services to adolescent girls. 2.2 Setting To gain a balanced view of the impact of COVID-19 induced school closures on sexual violence among adolescent girls in Ghana, a maximum variation purposeful sampling strategy (Patton, 2014) was used to select two districts: Asokore Mampong Municipal (urban district) and Afigya Kwabre South District (rural district) in Ashanti region. The Ashanti region was chosen for this study as it recorded the highest number of adolescent pregnancies in 2020 in Ghana (Mensah, 2021). Further, the selected districts were part of the COVID-19 lockdown imposed by the Government on the Greater Kumasi Metropolitan Area in the Ashanti region between March 30 and April 20, 2020 as well as the prolonged school closures between March 2020 and January 2021. To maximise variation, in each of the districts, communities exhibiting rural and urban characteristics were selected for the fieldwork. School closures and CSA dynamics may differ between rural and urban settings. It was thus important to ensure that geographical variation among sites was represented in the study to capture any differential effects of the school closures. 2.3 Participants and sampling For the quantitative survey, within the study districts and sites, stratified purposeful sampling (Patton, 2014) was used to include both in and out of school adolescent girls aged 13–19. The survey was conducted on a random sample of 853 adolescent girls (16.03 ± 2.04 years of age). The specific individuals were sampled from adolescent girls who were available on the dates of data collection in each study site. The girls were recruited from both the community and school settings. For girls recruited from school settings, permission was sought from the headmaster of the school to interview the girls during break periods. Assuming a population of approximately 100,000 adolescent girls in both districts, a sample size of 384 is sufficient to obtain a margin of error of 5 % and a 95 % confidence level (Cohen, 1998). For the qualitative component, to capture broader perspectives on the factors accounting for CSA, a maximum variation purposive sampling (Palinkas et al., 2015) was used to select adolescent girls, health care providers, parents and community leaders. 2.4 Data collection procedures The research instruments (questionnaire and interview guides) were developed based on previous studies on the subject matter (Halperin et al., 1996; Mohler-Kuo et al., 2014). The research instruments were peer reviewed by UNICEF experts working in adolescent sexual and reproductive health and rights and child protection. Research assistants and enumerators underwent training on the research background, methodology and ethical considerations including confidentiality, informed consent and data protection. Research instruments were further adjusted after a pilot with 50 adolescent girls. The enumerators were all females, which helped to create a conducive environment for the adolescent girls to talk. The cross-sectional survey was administered between May and August 2021. Each survey lasted approximately 45 to 60 min, and was conducted using a Computer-Assisted Personal Interviewing technique. Before the survey started, the Research Assistants provided a short introduction to the study and informed participants about their rights to choose not to participate in the study and not to answer any question with which they felt uncomfortable. After the survey was completed, participants were referred to institutions that provide protection and counselling services. All in-depth interviews and focus groups took place at designated places and times most convenient for the participants and were audio recorded with consent from the study participants. Focus groups were restricted to a maximum of 5–6 participants to accommodate social distancing protocol. Throughout the fieldwork, field notes were taken to record daily events and experiences. All data were collected face-to-face with strict adherence to COVID-19 safety protocols. 2.5 Measures (quantitative study) The dependent variable was prevalence of CSA (i.e., during the COVID-19 lockdown and school closures). CSA was categorized as follows: “CSA without physical contact”; “CSA with physical contact” (Mohler-Kuo et al., 2014). The questionnaire contained 18 questions to assess various forms of CSA. The “CSA without physical contact,” had yes/no options; the “CSA with physical contact,” had four response options (“Yes”, No”, “Don't know” “Yes”, “Declined”. The SCA with physical contact questions were further categorized into “physical contact with penetration” and “physical contact without penetration.” 2.6 Data analyses The “concurrent” technique was used to analyse the data. This technique allows for quantitative and qualitative findings to be jointly presented and discussed together through comparative analyses, which focus on differences and consistencies in the findings (Creswell, 2014). Statistical analyses were done using SPSS version 26. Chi-square tests were used to assess the differences between CSA prevalence between urban and rural districts. Odds ratios were used to assess the association between sociodemographic characteristics and three categories of CSA (CSA without physical contact, CSA with physical contact without penetration, and CSA with penetration). Sociodemographic characteristics included: age; supervision of parents; relationship with parents; religion; disability; educational level; parents alive; ethnicity; parents, level of education; living arrangements; sense of safety in the neighbourhood; participation in a girl's club; participation in regular physical activity; previous experience of sexual intercourse. Both adjusted and unadjusted odds ratios and 95 % confidence intervals were reported using binary logistic regression models for each CSA type. Significance levels for all associations were set at p < 0.05. The qualitative interviews and focus groups confirmed and extended the information provided by the cross-sectional survey. The qualitative data were analyzed using thematic analysis approach (Braun and Clarke, 2006). The interviews, focus groups, and field note data were transcribed verbatim to aid data analysis. Codes were developed from the combined transcripts and we pulled together core themes running through the entire data set. The analysis did not seek to draw attention to individuals' accounts and their individualised personal experiences, but to map out some of the prevalent issues as reported by the participants. The process was primarily inductive as the findings were dictated by the data. This approach ensured that the findings are dependent on the experiences and views of participants. Nonetheless, the identified themes were connected to the conceptual framework in the presentation and interpretation of the findings. 2.7 Rigour The use of methodological triangulation (questionnaires, interviews and focus groups) and data triangulation (multiple sites for data collection) in this study strengthened the credibility and generalisability of the findings. Similarly, to ensure credibility and transparency in the research process, a memo was kept throughout the research process recording thoughts, feelings, insights, and ideas in relation to the study aims. The memo served as a reflective journal to aid research reflexivity. Additional strategies used to ensure trustworthiness and authenticity include data cleaning, verification of qualitative data through peer and member checking (e.g., seeking clarifications from participants during interviews, and discussion of codes and themes emanating from qualitative data during team meetings). Further, to achieve rigour of the qualitative data, the first and second authors conducted all the interviews and focus groups and thus became familiar with the data through the interview process. Next, after research assistants had transcribed the interviews, we thoroughly read through these and listened to audio recordings on several occasions to check the accuracy of the transcription. The themes were cross-checked with the transcript to ensure that they were coherent and consistent with the data to maximise their reliability. 2.8 Ethical considerations In view of the sensitive nature of this research, we aimed at the highest ethical standards. Ethical review board approval for the study was provided by the Humanities and Social Sciences Research Ethics Committee (HuSSRECC) at the Kwame Nkrumah University of Science and Technology, Ghana. Participants were informed that they had the right to withdraw from the study at any time during the interviews. Introductory scripts were included in the beginning of the survey and at the beginning of each module to inform participants about the personal and sensitive nature of data being collected, and their choice to refuse to answer any question. Confidentiality and anonymity were assured, and factored into selection of the interview site. Participation was voluntary and based on oral informed consent. UNICEF's guideline on ethical research involving children and young people (Graham et al., 2013) guided the conduct of the interviews with children and young people. A response plan was put in place to address any child safety issues that emerged during data collection. All enumerators were required to provide respondents with a Service Information Card containing contact information of social service providers available in the district. Respondents advised on how to store the card safely. All participants were informed that they could opt for referrals to institutions that provide protection, sexual and reproductive health and counselling services in their district. 3 Results A total of 853 adolescent girls aged 13–19 (16.03 ± 2.04 years of age) were surveyed. The predominant ethnic groups of the adolescent girls were Akan (55.8 %) and Northern tribes (39.6 %). In terms of religion practised by the adolescents, 62.3 % were Christians while 37.4 % were Muslims. Regarding disability, a majority of the adolescent girls (70.9 %) did not have any form of disability. However, for those who had, the top four forms of disability were visual (13.2 %), emotional (5.5 %), learning (4.6 %) and hearing (3.6 %). Regarding employment, 52.5 % of the adolescent girls reported working and the nature of work were: learning a trade (29.9 %), domestic work (27.7 %), family business (22.2 %), street hawking (7.3 %) and kayayei1 (0.4 %). Regarding the educational level, 52.4 % had completed Junior High School (JHS), followed by Senior High School (SHS)/Vocational Education (VOC) (29.1 %), primary (12.1 %) and tertiary (0.4 %). About 6.1 % of the adolescent girls had never been to school. Currently, more than half of the adolescent girls (63.3 %) reported being in school. 3.1 Prevalence and forms of CSA The prevalence of sexual abuse was significantly higher in Afigya Kwabre South, the rural district than Asokore Mampong, the urban district (35.8 % vs 28.9 %; χ2 = 4.666, df = 1, p = 0.031). Overall, prevalence of sexual abuse was 32.5 %. That is, 3 in 10 adolescent girls had ever experienced at least one type of child sexual abuse during the COVID-19 lockdown and school closures. As shown in Table 1 , the prevalence of the various forms of CSA during the COVID-19 lockdown and school closures were unwanted sexual touching (20.3 %), pressurised sex (3.5 %), attempted rape (14.5 %), forced sex (1.9 %), and forced exposure to pornography (14.8 %). In all, a total of 19 rape2 cases were reported by the adolescent girls during the COVID-19 lockdown and school closures.Table 1 Prevalence of CSA by type of abuse during the lockdown. Table 1CSA domain Asokore Mampong (Urban) Afigya Kwabre (Rural) Overall sample Chi-Square Test Child sexual abuse with physical contact without penetration Touched in a sexual way 20.0 20.5 20.3 χ2 = 0.040, p < 0.842 Physically forced to have sex against will but did not succeed 12.8 16.0 14.5 χ2 = 1.705, p < 0.192 Child sexual abuse with penetration physically forced to have sex and did succeed 1.9 1.8 1.9 χ2 = 0.011, p < 0.917 Pressurised to have sex and did succeed 3.6 3.4 3.5 χ2 = 0.023, p < 0.880 Child sexual abuse without physical Contact Forced to watch pornographic material 14 15.6 14.8 χ2 = 0.424, p < 0.515 Forced to witness sexual exposure 3.4 3.2 3.3 χ2 = 0.021, p < 0.885 Forced to show naked body 1.9 2.1 2.0 χ2 = 0.016, p < 0.896 Taking pictures against your will 1 0.5 0.7 χ2 = 0.770, p < 0.380 Published nude pictures on the internet or social media platforms 0.5 0.5 0.5 χ2 = 0.003, p < 0.995 Quantitative findings suggest that adolescent girls' perceived vulnerability to CSA increased from 14.2 % before the COVID-19 pandemic to 25.9 % during the pandemic. The qualitative interviews and FGDs support the quantitative findings that adolescent girls were at increased risk of CSA during the school closures and the lockdown. In this area, men treat ladies as something of no value. Sexual abuse was dormant even before the COVID, but the cases became serious when the COVID came. We were on lockdown, and no one was going to school, sometimes parents do not have money, peer influence, you can follow your friend somewhere that your parents will not even know your whereabouts. The school closures contributed a lot to this (IDI, Adolescent girl). Yes, it is increased during the COVID-19. Because of the school closures, you see the boys sitting under a tree and will be calling us. A girl even died from having sex with a guy... I think he added something to a drink and gave it to her to drink. Some guys deceived the girls with materials like phone, laptop and the rest to have sex with them (FGD, Adolescent girls aged 13-19). Watching of pornography too. This increased during the lockdown and school closures. A friend of mine has a lot of them on her phone and she got pregnant because she always wants to practice it with her boy. Some guys will deceive you that they have this and that, but ones you get pregnant, or they sleep with you, they will dump you (FGD, Adolescent girls aged 13-19). Among the victims of CSA with physical contact with or without penetration, the most frequently reported places where incidents took place were another person's house (58.8 %) and the victim's house (17.6 %). The evidence from the in-depth interviews with the adolescent girls revealed that the perpetrators of CSA were mostly adults over 18 years. The older ones because some of them have done it for a long time so they have the experience. Because they are older than you, you don't think bad about them. We were in a room watching TV with a friend. My parents had left after watching the TV so I asked him to also go for me to go and bath. When I came from the bathroom to the room, thinking he had left, I undressed to apply my pomade then he came out from nowhere and saw my nakedness. He used my towel to cover my mouth to have sex with me, but I resisted. (IDI, Adolescent girl) It is the grown-up men, men in their 50's, 60's, 40's who harass us. If the person is a teenager like yourself, you can defend yourself, but the grown-up men are very strong (FGD, Adolescent girls aged 13-19). I attend the same church with a certain man, he was an elder in church, I took him as a brother. He teaches us the word and we used to go for evening service, so one day we were going to do decorations somewhere and we were only two girls and when I got somewhere I felt sleepy, so I went out and he didn't know I was out. We went with a sister, so she was lying in front and the man was in the middle between me and the sister. So, I noticed that whilst we laid down, he was touching the other sister in a sexual way which she did not like. (IDI, Adolescent girl). The narratives above reveal the different circumstances in which adolescent girls were abused sexually in this study. The victims were mostly deceived, lured or pressurised by the perpetrators into the sexual abuse while others could not withstand the power dynamics or physical force exerted by male adults. The quantitative findings showed that the main relationship of the perpetrators of CSA to their victims were acquaintance (31.30 %), romantic partner (25.00 %), neighbour (18.8 %), peers (12.5 %), family member (6.3 %) and other (6.1 %).Maybe he plays with you already so one day he may just take advantage of that to make those advances towards you. Some can send you to bring something to his room and once you enter there, he will just close the door. I have had that experience. He asked me to go to his kitchen to do something for him. (IDI, Adolescent girl). I know of a 15year old girl who was lured, and she has even given birth. I also know of two siblings the older one got pregnant, but the man did not accept the baby and the younger one went somewhere else to give birth. Sometimes bring out the monies they have to lure us, which makes us follow them (IDI, Adolescent girl). I met him during the COVID era. I remember he was visiting our tailoring shop and he expressed his feelings for me and was pestering me for my call contact number. Initially I was hesitant, but he continued putting pressure on me and eventually gave it up and that's where we took it off and had sex (IDI, Adolescent girl). The qualitative findings revealed that the drivers of increased CSA cases were inactivity among adolescent girls due to school closures, poverty, and parental neglect. Most of the adolescent girls noted that their parents' works were negatively affected by the COVID-19 outbreak and preventive measures, especially the lockdown. Others also expressed the view that they were not engaged in learning activities during the school closures, which made them more vulnerable to the advances of the boys/men.Most girls were influenced negatively during the lockdown and school closure because we were not engaged in learning activities. Many girls were taken advantage of by guys especially due to poor economic background, which makes it difficult for them to say no to sex. (IDI, Adolescent girl aged). It was during the school closures that most of the girls became pregnant in this community. When the president lifted the lockdown most of the girls who were in school were not able to go back to school because they were pregnant… Other factors include poor parental care or child neglect, which is common in this community…because some parents in this community are illiterate, they let their children roam, which promotes teenage pregnancies (KII, Parent and community leader). Also, sex education is now more focused on safe sex and prevention of pregnancy rather than abstinence…this makes girls experiment sex and men can take advantage of them (KII, Parent). A few of the parents interviewed expressed a concern that sexuality education seems to have shifted from abstinence to pregnancy prevention and safe sex, which according to them could predispose girls who are adventurous to CSA. The results of the adjusted model as presented in Table 2 indicate that the significant protective factors for CSA are feeling safe in neighbourhood (AOR = 0.526, 95 % CI = [0.325, 0.850]) and parents often listen to opinions (AOR = 0.446, 95 % CI = [0.241, 0.826]). Significant protective factors in the unadjusted model are early adolescence (13–15 years) (OR = 0.592, 95 % CI = [0.398, 0.882]), living with foster parent (OR = 0.399, 95 % CI = [0.198, 0.807]), and feeling safe in neighbourhood (OR = 0.558, 95 % CI = [0.368, 0.847]).Table 2 Determinants of CSA. Table 2Determinants AOR (CI) OR(CI) Age (Early adolescence 13–15 years) 0.766 (0.455, 1.289) 0.592 (0.398, 0.882) ⁎⁎ Supervision of parents (High) 0.934 (0.631, 1.382) 0.769 (0.546, 1.084) Relationship with parents (Close) 1.334 (0.746, 2.385) 1.752 (1.096, 2.802) Disability /None (Yes) 1.036 (0.679, 1.581) 1.138 (0.786, 1.649) Highest level of schooling No formal education 0.478 (0.151, 1.515) 0.532 (0.200, 1.471) Primary 0.498 (0.168, 1.482) 0.549 (0.227, 1.328) JHS 0.615 (0.194, 1.953) 0.457 (0.185, 1.127) SHS/VOC 000 (0.000) 000 (0.000) Currently in school? (Yes) 1.064 (0.654, 1.732) 0.818 (0.581, 1.152) Ethnicity Ethnicity (Akan) 1.576 (0.307, 8.091) 1.437 (0.316, 6.534) Ethnicity (Ewe) 0.970 (0.555, 1.694) 0.875 (0.619, 1.237) Ethnicity (Northern tribes) 0.687 (0.227, 2.082) 0.759 (0.295, 1.953) Are your parents alive? Are your parents alive? (Yes both) 2.034 (0.085, 48.712) 1.183 (0.481, 2.910) Are your parents alive? (Only Father) 0.000 (0.000) 0.840 (0.529, 1.333) Are your parents alive? (Only Mother) 0.000 (0.000) 0.582 (0.249, 1.358) Father's level of education Primary 2.156 (0.895, 5.191) 1.804 (0.816, 3.986) JHS 2.083 (0.800, 5.419) 2.114 (0.895, 4.996) (SHS /VOC 1.898 (0.550, 6.551) 2.460 (0.841, 7.196) Tertiary 3.086 (1.278, 7.454) 2.699 (1.255, 5.807) Mother's level of education Primary 0.676 (0.347, 1.318) 0.802 (0.439, 1.465) JHS 1.367 (0.562, 3.321) 1.630 (0.732, 3.630) SHS/VOC 1.394 (0.232, 8.378) 1.565 (0.321, 7.632) Tertiary 0.796 (0.377, 1.680) 1.195 (0.639, 2.235) What is your living arrangement? With both biological parents 2.267 (0.602, 8.538) 1.587 (0.461, 5.459) With father only 0.775 (0.461, 1.302) 0.762 (0.497, 1.168) With mother only 0.726 (0.430, 1.226) 0.676 (0.442, 1.034) With another relative 2.352 (0.270, 20.523) 2.484 (0.317, 19.475) With foster parent 0.462 (0.196, 1.090) 0.399 (0.198, 0.807) ⁎⁎ My parents or guardians listen when I share my opinion Sometimes 1.199 (0.504, 2.853) 1.924 (1.034, 3.582) Often 0.446 (0.241, 0.826) ⁎⁎ 0.682 (0.449, 1.036) Rarely 0.575 (0.223, 1.481) 0.687 (0.422, 1.120) Neighbourhood environment (Feels safe) 0.526 (0.325, 0.850) ⁎⁎ 0.558 (0.368, 0.847) ⁎⁎ Belong to any girls club (Yes) 0.919 (0.562, 1.504) 0.691 (0.451, 1.059) Practice regular Physical Activity (Yes) 1.649 (1.093, 2.487) 1.783 (1.241, 2.561) Ever talked with anybody about sexual and reproductive health matters(Yes) 0.677 (0.425, 1.080) 0.747 (0.495, 1.127) Have you ever had sexual intercourse? (Yes) 2.207 (1.394, 3.495) 0.747 (0.495, 1.127) ⁎⁎ Significant at p < 0.05. The adjusted model indicates that girls in their early adolescence (13–15 years) had 23.4 % lower risk of CSA during the COVID-19 lockdown and school closures compared to late adolescent girls (16–19 years). The odds of experiencing CSA is 6.6 % lower for respondents with high supervision from parents compared to those with low supervision. Girls with close relationships with parents were 33.4 % more likely to experience CSA compared to those who were not close with their parents. The odds of experiencing CSA for a child living with only father or only mother is 16 % and 41.8 % lower compared to a child living with both parents (which increased the risk by 18.3 %). In relation to educational level, having no formal education had the lowest odds of CSA in the last 12 months (AOR = 0.478). Girls with primary, JHS, SHS/VOC, or tertiary education have higher odds of experiencing CSA compared to respondents with no formal education. Risk factors for CSA in both models include practicing regular physical activity (AOR = 1.649, OR = 1.783, 95 % CIAOR = [1.093, 2.487, 95 % CIOR = [1.241, 2.561]), parents sometimes listen to opinions (AOR = 1.199, OR = 1.924, 95 % CIAOR = [0.504, 2.853], 95 % CIOR = [1.034, 3.582]), living with another relative (AOR = 2.352, OR = 2.484, 95 % CIAOR = [0.270, 20.523], 95 % CIOR = [0.317, 19.475]), living with both parents (AOR = 2.267, OR = 1.587, 95 % CIAOR = [0.602, 8.538], 95 % CIOR = [0.461, 5.459]), Akan ethnicity (AOR = 1.576, OR = 1.437, 95 % CIAOR = [0.307, 8.091], 95 % CIOR = [0.316, 6.534]), having no disability (AOR = 1.099, OR = 1.138, 95 % CIAOR = [0.679, 1.581], 95 % CIOR = [0.786, 1.649]) and having a close relationship with parents (AOR = 1.334, OR = 1.752, 95 % CIAOR = [0.746, 2.385], 95 % CIOR = [1.096, 2.802]). Girls who were currently in school were 6.4 % more likely to have experienced CSA. In relation to living arrangements, living with another relative had the highest odds (AOR = 2.352) of exposure to CSA. In the unadjusted model, girls who were exposed to sexual and reproductive health talk were 25.3 % more likely to experience CSA compared to those who were not exposed. The odds of a girl with both parents alive experiencing CSA is 18.3 % higher compared to a girl whose parents are not alive. All levels of father's education were predictors of CSA while only higher levels of mother's education were predictors of CSA. In the adjusted model, girls with fathers who had obtained tertiary education were 3 times more likely to be sexually abused. 4 Discussion Findings from both the quantitative and qualitative evidence indicate that CSA increased during the COVID-19 lockdown and school closures. The overall CSA prevalence of 32.5 % among adolescent girls during the COVID-19 lockdown and school closures is higher than previous estimates of 27 % (Böhm, 2016), and 16.5 % (DHS, 2008). This is consistent with UNFPA-Ghana's warning that Ghana should expect a spike in gender-based violence, sexual exploitation, rape, incest and other forms of violence during the pandemic (Addae, 2021). In this study, adolescent girls' vulnerability to CSA increased by 11.7 % during the COVID-19. This is lower compared to the South African situation which saw a 61.6 % increase in CSA (Gauteng, 2020), and a 20.1 % increase in CSA in Uganda (Sserwanja et al., 2021), during the COVID-19 lockdown and school closures. Adolescent pregnancy and CSA also increased significantly in Kenya during the COVID-19 pandemic (Stevens et al., 2021). This finding further suggests that CSA generally increases during disruptive occurrences. For instance, school closures during the Ebola epidemic in Sierra Leone in 2014–15 put children at greater risk of rape, and led to 65 % increase in teenage pregnancies (Bandiera et al., 2020; Goulds and Gallinetti, 2020; Onyango et al., 2019). Further, the odds of an adolescent girl in Haiti being sexually abused increased by 41 % during the 2010 earthquake in Haiti (Sloand et al., 2017). The perpetrators of CSA identified in this study were acquaintances (31.30 %), romantic partners (25.00 %) and neighbours (18.8 %). This is in line with other studies, which have shown that children, particularly girls, have heightened vulnerability to sexual violence committed by non-stranger perpetrators (e.g., neighbours) (Flowe et al., 2020; Rockowitz et al., 2021). Among the victims of CSA in this study, the most frequently reported places where incidents happened were another person's house (58.8 %) and the victim's house (17.6 %). This finding corroborates other studies which have shown that CSA largely occurs in another person's house (Bandiera et al., 2020; Flowe et al., 2020; Rockowitz et al., 2021). Results from this study indicate lower odds of prevalence of CSA for early adolescents compared to late adolescents. This is consistent with a self-report survey among adolescents, which revealed high rates of CSA among late adolescents (Finkelhor et al., 2014). Other key determinants of CSA identified in this study were engagement in physical activity, lack of parental supervision, parents not listening to adolescent girls' views, previous experience of sexual abuse and being an orphan. Surprisingly, our findings indicate that having a close relationship with parents is a risk factor for CSA. This contradicts the evidence suggests that having a closer relationship with their children allows parents to have open and honest exchanges about sexual health matters and protect children from CSA (Widman et al., 2016). However, there could be several possible explanations for this finding in our study. For instance, being close to a parent may make a child more trusting of a family acquaintance, who may take advantage of the situation. Further, as shown in this study, lack of parental supervision even when parents are close to their children was a risk factor for CSA. Analysis of CSA perpetrators' modus operandi indicates that they benefit from, and exploit to their advantage, a lack of parental supervision (Leclerc et al., 2011; Leclerc et al., 2015). In examining the preconditions that must be present for CSA to occur, Finkelhor (1984) noted that parental supervision is one of the key external barriers that the perpetrator must be able to overcome in order to commit CSA. This suggests that with strong parental supervision, parents and caregivers are in the best position to maintain strong external barriers that can prevent a perpetrator gaining access to children to commit CSA. Lack of parental supervision has been found to be a risk factor for CSA in other studies (Finkelhor and Baron, 1986; Rudolph and Zimmer-Gembeck, 2018). Evidence from the US context suggests that children of parents who adopt strict supervision, an authoritative and more hands-on parenting style are less likely to engage in risk sexual behaviours (Askelson et al., 2012). A key finding from this study is that children who had experienced sexual abuse were at a higher risk of being abused again. This is known as revictimization (Papalia et al., 2021; Pittenger et al., 2018). This suggests that a child survivor who lacks the support network and tools to cope with the trauma associated with CSA may become more vulnerable to a recurrence of sexual abuse. Also, a child who has been subjected to sexual abuse that has not been dealt with is likely still in an at-risk environment that allows the abuse to continue. This supports the existing evidence on the impact of CSA on sexual relationships in subsequent developmental stages and underline the need to consider CSA as a risk factor of adolescent sexual victimization (Krahé et al., 1999; Miron and Orcutt, 2014). In the present study, some parents noted during the key informant interviews that exposure to sexual and reproductive health talk could put girls at risk of CSA, if the focus of adolescent sexual education moves away from the abstinence message. While this aligns with other studies which found that teaching young children about CSA protective behaviours might not be sufficient for prevention (Rudolph et al., 2018), it also evidences prevailing community perceptions about sexuality education as contributing to early sexual debut or increasing risk-taking sexual behaviours among adolescents. Considered a particularly sensitive topic on cultural and religious grounds in several sub-Saharan African contexts, this perception runs contrary to global evidence which has found that abstinence-only approaches have limited or no positive effect on adolescent sexual behaviours and mitigating risks of CSA (Heels, 2019; Kirby, 2008; UNESCO et al., 2016). The qualitative findings further showed that power dynamics exerted by adult perpetrators and the use of gift items to lure girls contributed to adolescent girls being sexually abused as they could not resist the perpetrators. This aligns with Finkelhor (1984) proposition that for CSA to occur, the perpetrator must be able to overcome the child's resistance. That is, victim resistance is an important CSA preventive measure, and this goes far beyond the child being able to say ‘no’ to a potential abuser, with one major risk factor [being] anything that makes a child feel emotionally insecure, needy or unsupported, and thus being vulnerable and easy to be lured with a gift. Participation in physical activity was also a risk factor for CSA. This may be explained by a variety of reasons. For example, adolescents who practice regular physical activity spend more time outside the family and/or home environment and could be exposed to a wider range of perpetrators in the spaces where they practice physical activity (United Nations Children’s Fund, 2020). Further, adolescents who practice regular PA could be abused by their trainers. During the focus groups, participants reported that adolescent girls who wear revealing dresses often fall prey to sexual violence in the hands of male trainers and peers, reflecting the prevalence of negative social norms that can contribute to gender-based coercion, violence and victim-blaming. Tschan (2013, p. 81) notes that sport is an ideal environment for CSA since it is seen as a ‘sacred’ part of the culture and thus suspends social norms and, therefore, accepts behavior that is normally unacceptable (East, 2012), where the coach is able to touch children as part of their work while enjoying the trust of the parents. In a recent systematic review on sexual violence against children in sports and exercise, both coaches and peer-athletes were identified as perpetrators of CSA (Bjørnseth and Szabo, 2018). Fathers' level of education was found to be a determinant of CSA. A recent study in Nigeria found that fathers who had obtained at least a secondary education were 5 times more likely to have sexually abused children (Chime et al., 2021). 4.1 Limitations The findings of this study need to be interpreted in light of some possible limitations. First, we do not seek to argue for causality as the study is based on cross-sectional data. Further, the sample was drawn from two districts in the Ashanti Region and is not representative of the adolescent girls' population in Ghana. The instruments used in measuring the dependent and independent variables and the qualitative interviews were largely subjective. Therefore, there is a likelihood of social desirability bias, which may have influenced the views of participants instead of sharing their actual experiences. Despite these limitations, the findings align with the extant literature on CSA prevalence and determinants. 4.2 Conclusion and implications This study sought to examine the prevalence and associated determinants of CSA in the context of COVID-19 pandemic among adolescent girls. The findings suggest that CSA increased during the COVID-19 lockdown and school closures. It also indicates that having high supervision from parents, feeling safe in the neighbourhood, and parents/guardians often listening to opinions were protective factors of CSA. The findings indicate that one of the key lessons learned from the COVID-19 induced school closures has been the vital role of schools in safeguarding children – at least for those who attend school. These findings set the foundation for policy, practice and research recommendations relating to public health, child protection and social protection interventions aimed at CSA prevention, mitigation and response. Knowledge of the risk factors identified in this study can guide and inform the development of policies and programs to address CSA. The findings indicate that to protect children from sexual abuse during disruptive occurrences like the COVID-19 induced school closures and lockdown, there is the need for a multi stakeholder approach to CSA prevention and response. While schools are deemed to be one of the most promising institution for the delivery of CSA prevention and response efforts due to their consistent and longitudinal contact with children and their families (Lu et al., 2022), school closures in disruptive occurrences like the COVID-19 pandemic make it necessary to look for alternatives. The findings show that lack of parental supervision and monitoring of adolescent girls were a major risk factor for CSA. This suggests that parents and caregivers play a crucial role in keeping children safe from CSA. There is strong evidence to suggest that parental involvement in CSA prevention is an effective strategy (Walsh et al., 2012). For instance, parents and/or caregivers can play a crucial role as protectors of their children via two pathways: (a) by strengthening external barriers through parent supervision and monitoring; (b) by promoting their child's well-being, and self-esteem, which may make them less likely targets for abuse and better able to protect themselves from abusers who may use gifts to lure them. This means that there is the need to design and implement contextualised and targeted parenting programmes that promote positive parenting practices to reduce CSA risks for vulnerable children. Proactive and involved parenting with appropriate levels of monitoring can create safer environments in which there are fewer opportunities for children to be approached sexually or victimized. One key area, which needs further investigation, but not covered in this paper, is in-depth analysis of adolescent girls' reporting of CSA and help-seeking behaviours during the COVID-19 pandemic and school closures as these have implications for the design of appropriate mitigation and response strategies. Declaration of competing interest This paper is independent research arising from commissioned research funded by UNFPA-UNICEF Global Programme to Accelerate Action to End Child Marriage. The views expressed in this publication are those of the authors and not necessarily those of the funders. The role of the funding body was limited to participating in framing the study aim and questions. They were however, not involved in the design of the study, nor the collection, analysis, and interpretation of data, or in writing the manuscript. 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==== Front Heart Lung Heart Lung Heart & Lung 0147-9563 1527-3288 Published by Elsevier Inc. S0147-9563(22)00283-7 10.1016/j.hrtlng.2022.11.015 Article Invited Editorial for “Physiotherapy practices when treating patients with COVID-19 during a pandemic: A survey study” Bradley Dr. Scott Physiotherapy Alfred Hospital, Australia 15 12 2022 15 12 2022 22 11 2022 28 11 2022 © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcCoronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. In March 2020, the World Health Organization declared the novel coronavirus (COVID-19) a worldwide pandemic.1 This pandemic is the most significant pandemic in over a century, since the 1918–1919 “Spanish” influenza pandemic resulted in approximately 500 million infections and 50 million deaths worldwide.2 The COVID-19 pandemic declaration is still active today, and the emergence of new SARS-CoV-2 variants means that countries, jurisdictions and health services face ongoing demands to manage and treat individuals with COVID-19. This challenge was no greater than during the first wave of COVID-19 that spread globally in 2020. In many circumstances the capacity of health services was overrun by the high number of patients with COVID-19 requiring extensive medical treatment, and the concomitant attrition of hospital based clinicians due to themselves becoming infected with COVID-19. Therefore, in many hospitals, there was a need to mobilize staff to contribute to the care of these patients, particularly to intensive care units (ICU). In many hospitals, and indeed in many ICUs, physiotherapists are key members of the healthcare team. Physiotherapists who work in ICU are typically highly skilled, and often have many years of post-graduate clinical experience. The utilization of these skills was one of the mechanisms used to assist with the surge in COVID-19 patient numbers. These physiotherapists not only continued in their previous roles, but also extended their scope of practice to other tasks that assisted the overall management of COVID-19 patients. In addition, a strategy to help address the workforce needs was to re-deploy physiotherapists from outside of ICU, into the critical care environment. In this edition of Heart and Lung, Trojman et al. (Heart and Lung, 2022) report on the physiotherapy practices with treating patients with COVID-19 during a pandemic.3 This paper reports the survey results from 204 physiotherapists worldwide, who were working with COVID-19 patients in hospital in 2020 during the first wave of the COVID-19 pandemic. Whilst the authors of this paper are based in Australia, the translation of the questionnaire into Spanish, and the distribution of the questionnaire through the Division de Kinesiologia Sociedad Chilena de Medicina Intensiva, saw the largest response rate come from Central and South America (approximately 88%) with over half of these respondents from Chile alone. Therefore, this survey can be seen to reflect physiotherapy experiences in Latin America during the first COVID-19 wave in 2020/early 2021, but may well be representative of practices globally. Not surprisingly, the majority of physiotherapists were working in ICU during this time, however many staff reported that this was not typically their place of work. Many physiotherapists reported that they were re-deployed to ICU during this time of heightened COVID-19 patients being treated in ICU, and indeed, some physiotherapists reported being re-deployed from clinical work that was not as a cardiorespiratory physiotherapist. To help respond to the large COVID-19 clinical caseload in ICU, not only were more physiotherapists working in ICU, but they often reported performing tasks that were new or novel to them. Many of these roles or tasks were considered to be “acting up” beyond the normal physiotherapy service in their ICU service. Approximately half the respondents reported that they acted in a teaching or advisory role for other physiotherapists and staff in ICU, adjusted or suggested changes to ventilation settings, and/or assisted with extubating patients from mechanical ventilation. Furthermore, more than half the respondents reported being part of the team to help position patients in prone in ICU, and over 40% of respondents reported leading these prone positioning teams. In fact, prone positioning for patients with COVID-19,whether intubated or not, became a highly adopted “physical” therapy worldwide, and physiotherapists were often involved with either prone positioning teams for intubated patients or assisting “awake” patients with COVID-19 to position in prone. It is clear that circumstances such as a global infectious disease pandemic impose huge challenges for governments, communities and health services. In order to rapidly upscale the health response under such circumstances requires the mobilisation of significant infrastructure and personnel resources. Physiotherapists, as highly trained health practitioners, often with a significant exposure to acute care, are well placed to respond to such escalation. However, this does not come without significant challenges. Staff need to feel well supported. They need to receive appropriate training, and they need to be guided in the treatments and services they provide. It is important that clinical guidelines are developed4 and disseminated. Just as importantly, the clinical presentation patterns of particular COVID-19 variants and individual patient presentation needs to be considered, so that a physiotherapy reatment strategy can be individually tailored for each patient. With the combination of training, experience and clinical decision making, physiotherapists are well placed to meet this challenge. It is very important to describe the challenges and the opportunities that arise out of such novel circumstances. I thank Trojman et al. for the paper in this edition of Heart and Lung for there efforts in reporting on the global physiotherapy practices in treating patients with COVID-19. I hope that observations from this study and others help us better respond to surges due to COVID-19 variants, or any future pandemics. ==== Refs References 1 World Health Organisation Coronavirus disease 2019 - Situation Report 51 2020 3 World Health Organization Geneva. Switzerland 2 Johnson N.P. Mueller J. Updating the accounts; global mortality of the 1918-1920 “Spanish” influenza pandemic Bull Hist Med 76 2002 105 115 11875246 3 Trojman et al. Physiotherapy practices with treating patients with COVID-19 during a pandemic: a survey study 4 Thomas P. Physiotherapy management for COVID-19 in the acute hospital setting; clinical practice recommendations J Physiotherapy 66 2 2020 73 82

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Heart Lung. 2022 Dec 15; doi: 10.1016/j.hrtlng.2022.11.015

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Heart Lung

10.1016/j.hrtlng.2022.11.015

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==== Front Respir Investig Respir Investig Respiratory Investigation 2212-5345 2212-5353 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society. S2212-5345(22)00156-3 10.1016/j.resinv.2022.11.005 Original Article Antibody responses to second doses of COVID-19 vaccination in lung cancer patients undergoing treatment Narita Daisuke Ebina-Shibuya Risa ∗ Miyauchi Eisaku Tsukita Yoko Saito Ryota Murakami Koji Kimura Nozomu Sugiura Hisatoshi Department of Respiratory Medicine, Tohoku University Graduate School of Medicine 1-1, Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan ∗ Corresponding author. , M.D., Ph.D. Tel.: +81 22-717-8539; fax: +81 22-717-8549 15 12 2022 15 12 2022 22 6 2022 13 11 2022 22 11 2022 © 2022 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Several reports have revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection tends to have more severe outcomes in cancer patients. Although vaccination reduces the risk of severe disease, data on antibody titers achieved by vaccination is scarce in cancer patients. Methods We collected 79 blood samples (69 lung cancer patients and 10 control individuals) and conducted an anti-SARS-CoV-2 antibody assay to compare the antibody titer achieved with current treatment. Sixty-eight patients (86%) received the BNT162 mRNA vaccine and 11 (14%) received the mRNA-1273 vaccine. They were categorized according to the current treatment: control individuals without cancer (cohort A), lung cancer patients who were treated with cytotoxic chemotherapy (cohort B), immunotherapy (cohort C), combination of cytotoxic chemotherapy and immunotherapy (cohort D), tyrosine kinase inhibitors (cohort E), and radiation therapy (cohort F). Results Among 69 lung cancer patients (cohort B–F), 57 (83%) had adenocarcinoma, and 66 (96%) had advanced-stage cancer. In the anti-SARS-CoV-2 antibody assay, the antibody titer was significantly lower in lung cancer patients than in control individuals (p = 0.01). The median antibody titers were 161 AU/ml in control individuals and 59.9 AU/ml in lung cancer patients. Conclusions Antibody titers after the second vaccination were lower in cancer patients than those in healthy individuals. Our findings provide essential information for understanding the benefits and necessity of additional vaccination to prevent SARS-CoV-2 infection in lung cancer patients. Keywords SARS-CoV-2 anti-SARS-CoV-2 antibody assay BNT162 mRNA vaccine mRNA-1273 vaccine lung cancer Abbreviations COVID-19, coronavirus disease 2019 SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 AU, antibody units ==== Body pmcFunding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethical Statement This study was approved on October 26, 2021 by the Institutional Review Board of the Tohoku University (Sendai, Japan; approval number: 2021-1-913). Data Availability Statement Not applicable. 1 Introduction Coronavirus disease 2019 (COVID-19) has spread worldwide with more than 6 million cumulative deaths reported as of April 2022 [1]. The United States Food and Drug Administration and the European Medicines Agency have authorized for emergency use or approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, including BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna Biotech), to prevent the spread of infection. These vaccines have been approved and are available in Japan. In randomized phase III trials, these vaccines exhibited 94–95% effectiveness in preventing COVID-19 [[2], [3], [4], [5], [6]]. Patients with cancer or hematological malignancies who require anticancer treatment, or those who have been diagnosed with cancer, are at risk of becoming severely ill and have high mortality when infected with SARS-CoV-2 [[7], [8], [9], [10]]. Moreover, cancer patients often present with atypical symptoms and severe respiratory failure than those without cancer [11,12]. However, despite having a high risk of contracting COVID-19, cancer patients were excluded from phase III trials of the vaccine [13]. A recent prospective study reported that most patients with solid tumors who received chemotherapy, immunotherapy, or both had an adequate antibody response to two shots of mRNA-1273 vaccine [14]. However, several reports have demonstrated that antibody titers in patients with hematologic or non-hematologic malignancies remain low compared to those of healthy controls [[15], [16], [17], [18], [19], [20], [21], [22]]. A Japanese cross-sectional study prior to large-scale COVID-19 vaccination reported significantly low antibody titers in patients with cancer, despite no difference in the seroprevalence between cancer patients and healthy controls [23]. They also examined SARS-CoV-2 spike protein (S) IgG (S-IgG) and SARS-CoV-2 spike protein (N) IgG (N-IgG) and demonstrated that N-IgG levels were significantly lower in patients who received chemotherapy and both N-IgG and S-IgG levels were significantly higher in patients who received immune checkpoint inhibitors than in those who did not. With the advancement of lung cancer treatment, many personalized treatments, such as chemotherapy, molecular-targeted therapy, immunotherapy, radiotherapy, and combination therapy, are being offered to advanced lung cancer patients. Recent findings raised the concern that lung cancer patients do not acquire sufficient antibody titers even after vaccination, depending on the treatment type they receive. Although several studies have reported on the relationship between vaccines and antibody titers in patients undergoing treatment for lung cancer, few have reported on Japanese patients; therefore, this population needs further research. This study measured antibody titers between patients with and without lung cancer and evaluated the serological response to the BNT162b2 and mRNA-1273 vaccines after the second dose of vaccination. 2 Materials and methods 2.1 Trial design and participants This cross-sectional observational study was approved by the institutional review board on October 26, 2021, and conducted at the Department of Respiratory Medicine, Tohoku University Hospital, Japan, from July 1st to October 31, 2021. We included individuals without lung cancer (controls) and lung cancer patients undergoing anticancer treatment and/or regular follow-up visits at the Tohoku University Hospital. Control individuals included patients who did not have cancer but had underlying diseases, such as chronic obstructive pulmonary disease or sarcoidosis. All participants were aged ≥ 20 years and provided written informed consent. All participants were administered a two-dose regimen of BNT162b2 mRNA or mRNA-1273, and blood samples obtained after the second dose were stored in the Tohoku University Hospital Biobank. The medical records of all lung cancer patients were available and reviewed to obtain clinical information, such as age, sex, TNM stage, vaccination, and current treatment. We enrolled participants into six cohorts: control individuals without cancer (cohort A), lung cancer patients who were treated with cytotoxic chemotherapy (cohort B), immunotherapy (cohort C), a combination of cytotoxic chemotherapy and immunotherapy (cohort D), tyrosine kinase inhibitors (cohort E), and radiation therapy (cohort F). Regarding B, C, D, E and F, those who received treatment within 3 months were included. Combinations of cytotoxic chemotherapy and tyrosine kinase inhibitors were incorporated into cohort B (Supplementary Table 1). Antibody titers were compared among groups undergoing treatment or control individuals. We excluded patients who had a history of COVID-19 infection. The primary endpoint of this study was the antibody titer in lung cancer patients and control individuals after two doses of vaccination. The secondary endpoint was the difference in antibody titers in lung cancer patients, according to the current treatment type. The significance level was set at p = 0.05. 2.2 Anti-SARS-CoV-2 antibody assay Quantitative measurement of anti-S-IgG antibodies was performed using the Lumipulse G SARS-CoV-2 S-IgG assay system, including a set of immunoassay reagents, the SARS-CoV-2 S-IgG Assay Reagent (Fujirebio Inc., Tokyo, Japan). Anti-SARS-CoV-2 spike protein (anti-S) antibody titer in serum samples were measured as binding antibody units (AU)/mL. 2.3 Statistical analyses In examining the effect of treatment on antibody titers, we divided the patients into two groups, individuals whose blood had been collected within 30 days (short period) and those whose blood was collected after ≥ 30 days (long period) after receiving the second vaccination. Patient information and antibody titers were registered with a unique recognition code and analyzed using multiple comparison tests in each cohort. Covariates were compared using the t-test or the Kruskal–Wallis test for continuous variables. Multivariable regression analysis was performed to analyze the association between anti-SARS-CoV-2 antibody levels and variables. The significance level was set at p = 0.05. All analyses were performed using GraphPad Prism version 9.3.1 statistical software with 5% significance level. 3 Results Sixty-nine lung cancer patients and 10 control individuals without cancer were included and assigned to each cohort group (Figure 1 ). Many controls had asthma and sarcoidosis. The median age of the patients was 70 years (44–83 years). Among the 79 evaluable patients who received two doses of the planned vaccination (cohort A-F), 46% were women. Among 69 lung cancer patients (cohort B–F), 57 (83%) had adenocarcinoma, and 36 (52%) had a driver mutation. Most patients had advanced-stage cancer (clinical stage III/IV disease) or recurrence (96%), and the most common current treatment was tyrosine kinase inhibitors (cohort E; Table 1 ). Sixty-eight patients (86%) received the BNT162 mRNA vaccine, and 11 (14%) were administered the mRNA-1273 vaccine.Figure 1 Diagram representing study participants Figure 1 Table 1 Patient characteristics. Table 1 All patients Cohort Aa All cancer patients Cohort Bb Cohort Cc Cohort Dd Cohort Ee Cohort Ff (n=79) (n=10) (n=69) (n=16) (n=13) (n=9) (n=28) (n=3) Age (years)  Median 72 69 70 69.5 72 69 70 72  Range 68–81 62–82 44–83 44–81 48–80 60–77 48–83 68–81 Sex  Female 36 (38%) 6 (60%) 30 (43%) 7 (43%) 3 (23%) 4 (44%) 16 (57%) 0  Male 43 (62%) 4 (40%) 39 (57%) 9 (57%) 10 (77%) 5 (56%) 12 (43%) 3 (100%) Histology  Adenocarcinoma 57 (83%) 57 (83%) 13 (81%) 8 (61%) 7 (78%) 27 (96%) 2 (67%)  Squamous cell carcinoma 8 (12%) 8 (12%) 2 (13%) 3 (23%) 1 (11%) 1 (4%) 1 (33%)  Other 4 (5%) 4 (5%) 1 (6%) 2 (16%) 1 (11%) 0 0 Driver mutation  Wild–type 33 (48%) 33 (48%) 9 (56%) 12 (92%) 9 (100%) 0 3 (100%)  EGFR 28 (41%) 28 (41%) 6 (38%) 0 0 22 (79%) 0  ALK 7 (10%) 7 (10%) 1 (6%) 0 0 6 (21%) 0  Other 1 (1%) 1 (1%) 0 1 (8%) 0 0 0 Tumour stage  I 3 (4%) 3 (4%) 1 (6%) 0 0 1 (4%) 1 (33%)  II 0 0 0 0 0 0 0  III 10 (14%) 10 (14%) 1 (6%) 7 (54%) 2 (22%) 0 0  IV 27 (40%) 27 (40%) 7 (44%) 2 (15%) 4 (44%) 14 (50%) 0  Postoperative recurrence 24 (35%) 24 (35%) 6 (38%) 3 (23%) 1 (12%) 12 (43%) 2 (67%)  Postchemoradiotherapy recurrence 4 (6%) 4 (6%) 1 (6%) 1 (8%) 2 (22%) 0 0  Other 1 (1%) 1 (1%) 0 0 0 1 (4%) 0 Treatment line  1 42 (61%) 42 (61%) 3 (19%) 10 (77%) 7 (78%) 19 (68%) 3 (100%)  2 20 (29%) 20 (29%) 8 (50%) 2 (15%) 2 (22%) 8 (29%) 0  ≥3 7 (10%) 7 (10%) 5 (31%) 1 (8%) 0 1 (4%) 0  None 0 0 SARS–CoV–2 Vaccine  BNT162b2 mRNA vaccine 68 (86%) 7 (70%) 61 (89%) 16 (100%) 10 (77%) 7 (78%) 25 (89%) 3 (100%)  mRNA–1273 vaccine 11 (14%) 3 (30%) 8 (11%) 0 3 (23%) 2 (22%) 3 (11%) 0 Period after the second shot (days)  Median 26 23.5 28 19 33 32 31.5 25  Range 5-115 10–36 5-115 5–37 15–115 10–56 6-90 22–40 a individuals without lung cancer, b patients treated with cytotoxic chemotherapy, c immunotherapy, d combination of cytotoxic chemotherapy and immunotherapy, e tyrosine kinase inhibitors, f radiation therapy To elucidate whether cancer patients responded to vaccination similarly to control individuals, we compared antibody titers between control individuals (cohort A) and lung cancer patients (cohort B–F) after the second vaccination dose. First, we compared the number of days from the second dose of vaccination to blood collection between cohorts A and B–F since it has been reported that antibody titer decreases with time [[24], [25], [26]]. There was no significant difference in the period from the second dose of vaccination to blood collection between the groups (p = 0.280, Table 2 ). Next, we compared the antibody titers between cohorts A and B–F. The results revealed significantly lower antibody titers in cancer patients than in the control group (p = 0.010, Table 2, Figure 2 ). The median antibody titer was 161 AU/mL in the control group (n = 10) and 59.9 AU/ml in lung cancer patients (n = 69). We further analyzed our results using multiple regression analysis to eliminate confounding factors, such as age, sex (male or female), and the period after the second dose (Table 3 ). Lung cancer had a significant effect on antibody titer, whereas age, sex, and the period after the second dose had no significant effect on antibody titer.Table 2 Antibody titer in control individuals (Cohort A) and lung cancer patients (Cohort B–F). Table 2Cohort A B-F P-value Number of Cases 10 69 Days after the second dose 0.280  Median 23.5 28  Range 10-36 5-115 Antibody titer 0.010  Average 207 106.2  Median 161 59.9 Figure 2 Antibody titer of control individuals and cancer patients Figure 2 Table 3 Antibody titer analyzed using multiple regression analysis. Abbreviations: [Y], yes. Table 3Outcome measure Lung cancer [Y] Age (years) Sex [Male] Days after the second dose B P-value B P-value B P-value B P-value R2 Antibody titer -93.99 0.058 -0.22 0.909 3.93 0.903 -0.95 0.256 0.072 Next, we examined whether the lung cancer treatment affected the antibody titer after vaccination. Consistent with previous reports [[24], [25], [26]], the correlation coefficient between the number of days since the second dose of vaccine and antibody titer was -0.16 in this study, indicating a time-associated decrease in antibody. The median number of days of blood collection after the second vaccination dose was 26 (Supplementary Figure 1). Therefore, to eliminate the effects of the time between vaccination and blood sample acquisition, we divided the patients into two groups, those whose blood had been collected in a short period and those whose blood was collected after a long period after the second vaccination. We then compared antibody titers among the treatment cohorts over the short and long period. No significant difference was found among the treatment cohorts (p = 0.195 for short period comparison, and p = 0.326 for long period comparison; Supplementary Table 2, Supplementary Figure 2). 4 Discussion To the best of our knowledge, this is the first study measuring SARS-CoV-2 antibody titers after the second dose of vaccination between lung cancer patients undergoing current treatment. Cancer patients are at a high risk of severe disease due to COVID-19 infection [23,[27], [28], [29], [30], [31]]. Recent studies suggest that cancer patients should be vaccinated as soon as possible according to their vulnerability and high mortality [11,12,[32], [33], [34], [35], [36]]. However, clinical data on the current treatment effects for lung cancer on SARS-CoV-2 antibody titers is insufficient. Our results showed that lung cancer patients undergoing treatment had lower antibody titers than control individuals after vaccination. We further analyzed the effects of the treatment on antibody titer after the second vaccination and found no significant difference in antibody titer among the cohorts. Patients undergoing chemotherapy generally induces myelosuppression, leading to an immunocompromised state, whereas immunotherapy may lead to aberrant activation of immunity. Cytotoxic chemotherapy and immune checkpoint inhibitors do not affect antibody titer after vaccination [13]. However, previous reports did not include patients undergoing molecular-targeted therapy or chemo-immunotherapy. Furthermore, there have been several reports of ethnic differences in response to SARS-CoV-2 infection [[37], [38], [39], [40], [41], [42]]. Therefore, we investigated the effect of vaccination on Japanese patients with lung cancer undergoing treatment. Consistent with previously reported Japanese data [23], in this study, the SARS-CoV-2 antibody titer in cancer patients was significantly lower than that in control individuals, even after the second vaccination dose. The treatment strategy for lung cancer, including molecular-targeted therapy, immune checkpoint inhibitors, and chemotherapy, had no impact on the antibody titer after the second vaccination. However, we could not draw any conclusion from this result because of the small number of patients in each cohort. Therefore, further study is needed to assess the impact of treatment on antibody titers after vaccination. This study showed that lung cancer patients had low antibody titers, suggesting that the immune response against vaccination for SARS-CoV-2 is weak in cancer patients due to cancer-induced immunosuppression, emphasizing the need for a warning for COVID-19 infection in cancer patients even after the second dose of vaccination. Vaccination substantially helps prevent SARS-CoV-2 infection in both cancer and non-cancer patients [[43], [44], [45], [46]]. Moreover, the third dose of vaccination boosts neutralizing antibody responses in cancer patients, including patients who have not acquired antibodies following two doses of vaccination or patients whose antibody titer had decreased [13]. Even in healthy individuals, antibody titers decline over time after the third vaccination [47]; therefore, we argue that the additional third or fourth vaccination should benefit cancer patients whose antibody titers are lower, as shown in our study. The efficacy of a third vaccination has been reported in cancer patients [48]. Furthermore, although antibody titers are lower in cancer patients after the third vaccination than in healthy individuals, antibody titers increase after the fourth vaccination, and an infection-preventive effect is also observed [49]. Based on these reports, third or more dose vaccination will become increasingly important for cancer patients in the future. This study had several limitations. First, it was a single-center study and the follow-up period was relatively short. Furthermore, the overall sample size was small, especially in the control and radiotherapy groups, which might have biased the statistical analyses. Second, the optimal post-immunization antibody titers for establishing the protective effect of COVID-19 vaccines are unclear. Therefore, our results could not determine whether the antibody titer was sufficient to prevent infection in all patients. Third, since we did not collect samples over time, we could not examine the long-term effects of vaccination in cancer patients. Finally, the patients were not identical between the short and long periods. Thus, a longer-term study with a larger number of identical patients should be conducted in the future to draw a satisfying conclusion regarding the effect of vaccination on cancer patients. In conclusion, after the second dose of BNT162b2 or mRNA-1273 vaccination, antibody titers were lower in all cancer patients undergoing treatment than in those without cancer. Lung cancer patients should receive a third or subsequent vaccination to raise the antibody titers, regardless of their treatment. Author Contributions Daisuke Narita contributed to writing the original draft and data analysis. Risa Ebina-Shibuya contributed to data review and interpretation, and editing final daft. Eisaku Miyauchi contributed to the conception and design of the study. All authors participated in interpretation of the results and approved the final version. Conflict of Interest All authors have no conflict of interest to declare. Appendix A Supplementary data The following are the Supplementary data to this article:Supplementary Figure 1 . Relationship between antibody titer and the number of days. Day 26 shows the median number of days after the second vaccination. Supplementary Figure 1 Supplementary Figure 2 . Antibody titer at < 30 days and > 30 days after the second vaccination dose. Abbreviations: Chemo: Chemotherapy, ICI: Immune Checkpoint Inhibitor, TKI: Tyrosine Kinase Inhibitor. Supplementary Figure 2 Supplementary Table 1 . Specific types of pharmacotherapy. Supplementary Table 1 Supplementary Table 2 . Period and antibody titer after the second vaccination in short (<30 days) (A) and long periods (>30 days) (B). Supplementary Table 2 Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.resinv.2022.11.005. ==== Refs References 1 WHO Coronavirus (COVID-19) Dashboard, https://covid19.who.int/; 2022. 2 Thomas S.J. Moreira E.D. Jr. Kitchin N. Absalon J. 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Increased antibody titers and reduced seronegativity following fourth mRNA COVID-19 vaccination in patients with cancer Cancer Cell 40 2022 800 801 35803259

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==== Front Vaccine Vaccine Vaccine 0264-410X 1873-2518 Elsevier Ltd. S0264-410X(22)01539-0 10.1016/j.vaccine.2022.12.024 Article The impact of seasonal influenza vaccination uptake on COVID-19 vaccination attitudes in a rural area in Greece Papazachariou Andria ac1 Tsioutis Constantinos b1 Lytras Theodore b Malikides Onoufrios a Stamatelatou Maria c Vasilaki Nektaria c Milioni Athanasia d Dasenaki Maria c Spernovasilis Nikolaos ef⁎ a Department of Internal Medicine, University Hospital of Heraklion, Heraklion, Greece b School of Medicine, European University Cyprus, Nicosia, Cyprus c Department of Internal Medicine, General Hospital of Sitia, Sitia, Greece d Department of Otorhinolaryngology, “Elpis” General Hospital, Athens, Greece e School of Medicine, University of Crete, Heraklion, Greece f Department of Infectious Diseases, German Oncology Center, Limassol, Cyprus ⁎ Corresponding author at: School of Medicine, University of Crete, P.C.: 71003, Heraklion, Crete, Greece. 1 Equal contribution. 15 12 2022 15 12 2022 9 11 2022 10 12 2022 12 12 2022 © 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Introduction Promoting vaccination for coronavirus disease 2019 (COVID-19), especially for high-risk groups such as the elderly and persons with comorbidities, is important for reducing the incidence of severe disease and death. Methods Retrospective cross-sectional study of factors associated with COVID-19 vaccination, including previous influenza vaccination, among all persons who received medical services in a rural area in Crete, Greece, between October 2020-May 2021. Results Among 3129 participants, receipt of influenza vaccination in 2020–21 was strongly associated with COVID-19 vaccination, as was influenza vaccination in 2019–20, albeit to a lesser extent. In addition, persons older than 59 years (with exception of those 90 + years old) and those who lived closer to the hospital/health center, were more likely to vaccinate for COVID-19. Persons younger than 40 years of age, females, persons with mental illness or neurologic disease, were also less likely to vaccinate for COVID-19 (all p < 0.001). Conclusions COVID-19 vaccination was more likely among those who were vaccinated for influenza before and during the pandemic. Access to healthcare services and specific comorbidities, were important influencers for vaccination, underlying the importance of tailored interventions to enforce vaccination in high-risk groups. Keywords Influenza Vaccination COVID-19 Pandemic Prevention ==== Body pmc1 Introduction Coronavirus disease 2019 (COVID-19) is a highly transmissible respiratory infection caused by the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). The first COVID-19 case in Greece was confirmed in February 2020, with data reporting a total of 5,188,890 cases and 33,750 deaths by 8 November 2022 in the country [1]. Promoting primary prevention through vaccination, especially for high-risk groups such as the elderly and persons with comorbidities, is crucial for reducing the incidence of severe disease and death [2]. In Greece, vaccinations for COVID-19 commenced in late December 2020 and by end of October 2022, a total of 7,910,910 people (74.1 % of the total population) had received at least one vaccine dose [3]. Despite vigorous efforts to achieve high vaccine coverage worldwide through organized vaccination programs and public awareness campaigns, compliance was suboptimal for a significant proportion of the general population [4]. Understanding the barriers to and predictors of COVID-19 vaccination is important to improve coverage and protect public health. Studies have previously sought to juxtapose compliance with and hesitancy about the COVID-19 and influenza vaccines [5]. We therefore hypothesized that acceptance of influenza vaccination might be associated with subsequent COVID-19 vaccination. The aim of our study was to identify individual predictors of COVID-19 vaccination, including past receipt of the seasonal influenza vaccine during the preceding two winter seasons, in a large population sample of a rural area in Greece. 2 Methods 2.1 Study aims The specific aims of this study were to evaluate:a) the rates of influenza vaccination in a large population sample of a rural area in the periods before (influenza vaccination period 2019–2020) and after (influenza vaccination period 2020–2021) the initiation of the COVID-19 vaccination period in Greece. b) the association between influenza vaccination and full COVID-19 vaccination. c) factors associated with COVID-19 vaccination. 2.2 Study design and setting A retrospective cross-sectional study among all adults who visited or were admitted to the General Hospital/Community Health Center and public peripheral medical centers of Sitia, Crete, Greece, from October 2020 through May 2021. This network of public health centers provides health services to a population of more than 18,000 people, with a 75-bed capacity, 15 medical specialties, a 24-hour emergency department and 6 peripheral medical centers. 2.3 Data collection and definitions Demographics, comorbidities, medications, vaccination status for influenza (2019–20 and 2020–21 seasons) and for COVID-19 were retrieved during patient interviews, from clinical records and from the national electronic prescription system. Polypharmacy was defined as concomitant receipt of 5 or more drugs. Immune compromise was defined as a person receiving immunosuppressive agents or corticosteroids > 20 mg/day for more than two weeks, and transplant patients. Malignancy was defined as a person receiving treatment for malignancy or with a current history of malignancy. A person was considered vaccinated for COVID-19 if they had received two vaccine doses by 15 July 2021, which was the last day of data collection. The reason for stopping the collection of data at this specific date was that on that day, the mandatory vaccination of certain professional groups was announced by the Greek government. 2.4 Statistical analysis Individual-level characteristics were compared between participants vaccinated and unvaccinated against COVID-19 using the Mann-Whitney and Pearson chi-squared tests for continuous and categorical variables respectively. Influenza vaccination rates in the 2019–20 and 2020–21 seasons were compared with the McNemar paired test. The association between full COVID-19 vaccination and influenza vaccination during 2019–20 and 2020–21 was examined in a multivariate logistic regression model, adjusted for age, sex, individual comorbidities and distance between the person’s residence and the General Hospital/Health Center. We further attempted to include in the model an indicator for polypharmacy (receipt of five or more drugs regularly), and an interaction term between influenza vaccination during the two seasons (to assess whether regular receipt of the seasonal influenza vaccine during both seasons is a stronger predictor of COVID-19 vaccination); model comparison was performed with a likelihood ratio test. Potential collinearity in all models was examined by calculating Variance Inflation Factors for each covariate. All analyses were performed using the R software environment, version 4.2. 2.5 Ethics Performance of the study and access to patient data was approved by the General Hospital/ Community Health Center of Sitia Scientific Council (decision 5494/20–10-2021). 3 Results During the 8-month study period, a total of 3129 patients visited the General Hospital/Community Health Centers of Sitia and comprise the study population (Table 1 ). Approximately half (1640 persons, 52.4 %) were female, 12.1 % were younger than 60 years old, 45.1 % were 60–79 years old, and 42.8 % were older than 79 years. The most common comorbidities were hypertension (66.0 %), dyslipidemia (60.4 %), diabetes (29.5 %), chronic heart failure (26.4 %) and mental illness (23.5 %).Table 1 Demographic characteristics, comorbidities of study population and univariate comparisons between participants fully vaccinated (with 2 doses as of 15 July 2021) and unvaccinated (or partially vaccinated) for COVID-19. Total (N = 3129) COVID fully vaccinated (N = 2399) COVID unvaccinated / partially vaccinated (1-dose) (N = 730) p-value Females 1640 (52.4) 1213 (50.6) 427 (58.5) <0.001 Age* 76.0 (66.0–84.0) 77.0 (67.0–84.0) 75.0 (63.0–85.8) 0.12 Age < 40 50 (1.6) 24 (1.0) 26 (3.6) <0.001 Age 40–49 91 (2.9) 60 (2.5) 31 (4.2) 0.02 Age 50–59 237 (7.6) 154 (6.4) 83 (11.4) <0.001 Age 60–69 649 (20.7) 516 (21.5) 133 (18.2) 0.06 Age 70–79 763 (24.4) 598 (24.9) 165 (22.6) 0.22 Age 80–89 1075 (34.4) 883 (36.8) 192 (26.3) <0.001 Age 90+ 264 (8.4) 164 (6.8) 100 (13.7) <0.001 Influenza vaccination in 2019 2070 (66.2) 1667 (69.5) 403 (55.2) <0.001 Influenza vaccination in 2020 2665 (85.2) 2135 (89.0) 530 (72.6) <0.001 Distance to center (km)* 9.4 (1.3–23.9) 7.4 (1.3–23.9) 16.8 (1.3–27.3) <0.001 Comorbidities Diabetes mellitus 922 (29.5) 699 (29.1) 223 (30.5) 0.5 Heart failure 826 (26.4) 624 (26.0) 202 (27.7) 0.4 Other cardiovascular disease 706 (22.6) 552 (23.0) 154 (21.1) 0.3 AF or other arrhytmia 723 (23.1) 535 (22.3) 188 (25.8) 0.06 Hypertension 2063 (66.0) 1620 (67.6) 443 (60.7) <0.001 Dyslipidemia 1889 (60.4) 1500 (62.6) 389 (53.3) <0.001 Pulmonary disease 350 (11.2) 256 (10.7) 94 (12.9) 0.11 Gastrointestinal disease 59 (1.9) 43 (1.8) 16 (2.2) 0.59 Mental illness 736 (23.5) 516 (21.5) 220 (30.1) <0.001 Dementia 483 (15.4) 376 (15.7) 107 (14.7) 0.54 Rheumatologic / Connective tissue disease 212 (6.8) 164 (6.8) 48 (6.6) 0.87 Thyroid disease 319 (10.2) 248 (10.3) 71 (9.7) 0.68 Osteoporosis / osteopenia 684 (21.9) 527 (22.0) 157 (21.5) 0.83 Malignancy 147 (4.7) 106 (4.4) 41 (5.6) 0.22 Immunocompromise 264 (8.4) 201 (8.4) 63 (8.6) 0.89 Neurologic disease 210 (6.7) 138 (5.8) 72 (9.9) <0.001 Polypharmacy > 4 drugs 1112 (35.5) 843 (35.2) 269 (36.8) 0.43 * Median (IQR) and Mann-Whitney test. For all other variables: number (percentage) and Fisher’s test. A total of 2070 study participants (66.2 %) were vaccinated for seasonal influenza in the 2019–20 season, rising significantly to 2665 (85.2 %) in 2020–21 (p < 0.001). Among the 1059 participants not vaccinated during 2019–20, 668 (63.1 %) received an influenza vaccine the following season, whereas nearly all influenza vaccine recipients in 2019–20 were vaccinated again in 2020–21 (1997/2070 participants, 96.5 %). A total of 2399 participants (76.7 %) had been vaccinated for COVID-19 with 2 doses until 15 July 2021; the 730 (23.3 %) unvaccinated participants include 86 partially vaccinated with 1 dose (11.8 %) and 644 completely unvaccinated (88.2 %). A comparison of demographic characteristics and comorbidities between COVID-19 fully vaccinated and unvaccinated (or not fully vaccinated) persons is presented in Table 1. The age distribution was similar (p = 0.12) but there were fewer women among the fully vaccinated participants (p < 0.001). Participants fully vaccinated for COVID-19 were more commonly vaccinated for influenza both in 2019–20 and 2020–21, lived closer to the hospital/health center, were more likely to have hypertension and dyslipidemia, but less likely to suffer from mental illness or neurologic disease (all p < 0.001, Table 1). Table 2 presents the results of the multivariable logistic analysis. Receipt of influenza vaccination in 2020–21 was strongly associated with COVID-19 vaccination (Odds Ratio, OR, 2.44, 95 % CI: 1.90–3.13), as was influenza vaccination in 2019–20 albeit to a lesser extent (OR 1.30, 95 % CI: 1.05–1.60). Compared to the 50–59 years age group, people younger than 40 years were less likely to be fully vaccinated against COVID-19, while people older than 59 years more likely to be vaccinated, with the exception of the 90 + years age group (Table 2). Female sex and the presence of diabetes, atrial fibrillation or other arrhythmias, mental illness and neurologic disease, were all independently associated with reduced odds of COVID-19 vaccination, while dyslipidemia was associated with increased odds. Finally, living farther from the hospital/health center decreased the odds of vaccination by about 11 % for every 10 km of distance (Table 2). There was no evidence of collinearity in the model, with all Variance Inflation Factors under 1.6 (data not shown). Adding the variable for polypharmacy in the model did not result in an improved fit (p = 0.18), nor did addition of an interaction term between influenza vaccination during the two seasons (p = 0.7). A sensitivity analysis excluding the 86 persons vaccinated with 1 dose did not meaningfully alter the results (online supplement).Table 2 Multivariate logistic model for predictors of COVID-19 vaccination. Odds Ratio p-value Age < 40 0.49 (0.25–0.94) 0.032 Age 40–49 1.05 (0.61–1.81) 0.86 Age 50–59 Reference Age 60–69 1.56 (1.10–2.21) 0.013 Age 70–79 1.44 (1.02–2.03) 0.039 Age 80–89 1.86 (1.32–2.63) <0.001 Age 90+ 0.66 (0.44–1.01) 0.05 Females 0.70 (0.58–0.85) <0.001 Influenza vaccination in 2019–20 1.30 (1.05–1.60) 0.015 Influenza vaccination in 2020–21 2.44 (1.90–3.13) <0.001 Diabetes mellitus 0.80 (0.65–0.97) 0.027 Heart failure 0.92 (0.76–1.12) 0.42 Other cardiovascular disease 0.93 (0.74–1.16) 0.51 AF or other arrhythmia 0.77 (0.62–0.96) 0.018 Hypertension 1.11 (0.90–1.35) 0.33 Dyslipidemia 1.34 (1.10–1.62) 0.003 Pulmonary disease 0.80 (0.61–1.05) 0.11 Gastrointestinal disease 0.82 (0.44–1.52) 0.52 Mental illness 0.68 (0.55–0.83) <0.001 Dementia 1.28 (0.97–1.71) 0.09 Rheumatologic / Connective tissue disease 1.01 (0.66–1.56) 0.95 Thyroid disease 1.15 (0.85–1.55) 0.36 Osteoporosis / osteopenia 1.06 (0.85–1.33) 0.6 Malignancy 0.65 (0.38–1.11) 0.12 Immunocompromise 1.22 (0.75–1.99) 0.42 Neurologic disease 0.58 (0.41–0.81) 0.001 Distance to center (per 10 km) 0.89 (0.84–0.94) <0.001 4 Discussion Our study population comprises all persons who sought health services in an 8-month period during the first months of the COVID-19 vaccination program in Greece. The study cohort covers a notable proportion of the local population (>17 %) who sought care during the study period. The importance of our study lies in confirming that influenza vaccination (both during seasons 2019–20 and 2020–21) is associated with full COVID-19 vaccination, whereas accessibility is an important driver of vaccination, as longer distance was associated with lower odds of COVID-19 vaccination. The fact that persons older than 89 years were less likely to get vaccinated against COVID-19 compared to persons aged 60–89, can also be considered affirmative of access issues. Previous studies have shown an association between previous influenza vaccination and COVID-19 vaccine willingness and/or acceptance [6], [7]. Our findings add to the literature, by confirming the association between influenza vaccination and vaccination for COVID-19. It is worth noting that a higher proportion of participants were vaccinated for influenza during the 2020–21 season (85.2 %) compared to the 2019–20 season (66.2 %, p < 0.001) and influenza vaccination during the 2020–21 season had a stronger association with COVID-19 vaccination. This could be either due to timing as these persons were closer to their COVID-19 vaccination, thus increasing the odds of vaccine acceptance, or due to more effective health communication provided by healthcare workers [8]. Access, convenience and distance, are important drivers of vaccination, particularly during public health crises [9], [10], [11]. Our findings corroborate those of previous studies that highlighted these factors as important influencers of vaccine acceptance. However, to our knowledge, specific age-stratified determinants of accessibility have not been defined. It is a fact that elderly patients are usually less mobile or rely on their caregivers to reach a health service. From a social perspective, altered risk perception could also be an influencing factor, attributed to social isolation of the elderly during the pandemic, which aimed to minimize contacts and thus decrease their risk of infection. In addition, avoidance of crowded public settings due to fear of contracting COVID-19 might have counterintuitively played a role in avoiding vaccination clinics. Ineffective communication, such as lack of information and misinformation, was also found to be an important contributor in the decision for vaccination among older adults. Hence, in such situations and when specific age groups are considered high risk for severe infection, it is important to address access issues to vaccines with tailored interventions, including improvement of access (e.g., increasing vaccination sites, providing at-home vaccination services) and enhancing communication by providing prompt and accurate information on the usefulness and effectiveness of vaccines. We detected several other factors that lowered the odds of COVID-19 vaccination; specifically, persons younger than 40 years of age, females, persons with mental illness, neurologic disease, diabetes mellitus, and persons with atrial fibrillation or other cardiac arrhythmias. Young adults, probably due to higher confidence and lower risk perception in association with COVID-19, as well as females, are known to have lower rates of COVID-19 vaccination [9], [12], [13], [14]. Mental illness was recorded in a high proportion of our population (23.5 %), which leads us to believe that they represent an heterogenous group of conditions. Therefore, different reasons might have accounted for their lower propensity to vaccinate, such as altered risk perception, altered health beliefs, ineffective communication, and fewer options of access to health services. Given the higher mortality risk due to COVID-19 in persons with severe mental illness compared to the general population, strategies to enhance vaccination acceptance are imperative, including targeted communication and improved access [15]. Similar reasons for lower vaccination might be related to persons with neurologic disease, where another factor could be the general perception that vaccines are associated with neurological adverse events. Persons with dyslipidemia and hypertension typically have frequent visits and contacts with healthcare services and thus, their higher rates of vaccination might reflect effective communication and better access to health centers. In addition, hypertension was found to be associated with severe COVID-19 early during the pandemic, which might have prompted these patients to vaccinate [16]. On the other hand, we were unable to explain the reason why persons with diabetes mellitus and atrial fibrillation/other arrhythmias had lower uptake of COVID-19 vaccination in our study. Certain limitations should be acknowledged in our study. Single country setting and the rural location limit generalizability of our findings. The retrospective manner of the study might have impacted the quality of data, despite the fact that we used various sources to retrieve information. We analyzed partially vaccinated participants together with the unvaccinated, even though their motivations and rates of vaccine acceptance might differ; nevertheless, excluding the partially vaccinated did not meaningfully alter our results and conclusions. We did not have information on past COVID-19 incidence; participants with previous infection might have deferred or avoided vaccination altogether. Finally, although our findings confirm the association between influenza and COVID-19 vaccination and, despite the high influenza vaccination rate among our population, our study was not designed to detect specifically those who were consistently vaccinated every year. In conclusion, the current study provides meaningful information on factors that affected COVID-19 vaccination in a rural area in Greece. The odds of COVID-19 vaccination were higher among those who were vaccinated for influenza before and during the pandemic and those who lived closer to the vaccination center, whereas younger persons and persons with specific underlying conditions such as mental illness and neurologic disease, were less likely to vaccinate. In order to increase vaccine acceptance and vaccination rates, future strategies should be appropriately tailored to the characteristics and needs of different patient groups and geographic situations, whereas ease of access should be taken into account, particularly in rural areas and among populations with accessibility issues. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary material The following are the Supplementary data to this article:Supplementary data 1 Data availability Data will be made available on request. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2022.12.024. ==== Refs References 1 World Health Organization. Greece: WHO Coronavirus Disease (COVID-19) Dashboard With Vaccination Data n.d. https://covid19.who.int (accessed November 8, 2022). 2 Haas E.J. Angulo F.J. McLaughlin J.M. Anis E. Singer S.R. Khan F. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data Lancet 397 10287 2021 1819 1829 33964222 3 European Centre for Disease Prevention and Contro. COVID-19 Vaccine Tracker | European Centre for Disease Prevention and Control. n.d. Available from: https://vaccinetracker.ecdc.europa.eu/public/extensions/COVID-19/vaccine-tracker.html#summary-tab (accessed November 8, 2022). 4 Omer S.B. Benjamin R.M. Brewer N.T. Buttenheim A.M. Callaghan T. Caplan A. Promoting COVID-19 vaccine acceptance: recommendations from the Lancet Commission on Vaccine Refusal, Acceptance, and Demand in the USA Lancet 398 10317 2021 2186 2192 34793741 5 Domnich A. Orsi A. Trombetta C.-S. Guarona G. Panatto D. Icardi G. COVID-19 and seasonal influenza vaccination: cross-protection, co-administration, combination vaccines, and hesitancy Pharmaceuticals (Basel) 15 2022 322 10.3390/ph15030322 35337120 6 Joshi A. Kaur M. Kaur R. Grover A. Nash D. El-Mohandes A. Predictors of COVID-19 vaccine acceptance, intention, and hesitancy: a scoping review Front Public Health 9 2021 698111 10.3389/fpubh.2021.698111 7 Terry E. Cartledge S. Damery S. Greenfield S. Factors associated with COVID-19 vaccine intentions during the COVID-19 pandemic; a systematic review and meta-analysis of cross-sectional studies BMC Public Health 22 2022 1667 10.1186/s12889-022-14029-4 36056325 8 Glenton C, Carlsen B, Lewin S, Wennekes MD, Winje BA, Eilers R, et al. Healthcare workers’ perceptions and experiences of communicating with people over 50 years of age about vaccination: a qualitative evidence synthesis. Cochrane Database Syst Rev 2021;7:CD013706. doi: 10.1002/14651858.CD013706.pub2. 9 Kafadar A.H. Tekeli G.G. Jones K.A. Stephan B. Dening T. Determinants for COVID-19 vaccine hesitancy in the general population: a systematic review of reviews Z Gesundh Wiss 2022 1 17 10.1007/s10389-022-01753-9 10 Batteux E. Mills F. Jones L.F. Symons C. Weston D. The Effectiveness of Interventions for Increasing COVID-19 Vaccine Uptake: A Systematic Review Vaccines (Basel) 10 2022 386 10.3390/vaccines10030386 35335020 11 Crawshaw J, Konnyu K, Castillo G, van Allen Z, Grimshaw J, Presseau J. Factors affecting COVID-19 vaccination acceptance and uptake among the general public: a living behavioural science evidence synthesis (v1.0, Apr 30th, 2021) 2021. 12 Biswas M.R. Alzubaidi M.S. Shah U. Abd-Alrazaq A.A. Shah Z. A scoping review to find out worldwide COVID-19 vaccine hesitancy and its underlying determinants Vaccines (Basel) 9 2021 1243 10.3390/vaccines9111243 34835174 13 Robinson E. Jones A. Lesser I. Daly M. International estimates of intended uptake and refusal of COVID-19 vaccines: a rapid systematic review and meta-analysis of large nationally representative samples Vaccine 39 2021 2024 2034 10.1016/j.vaccine.2021.02.005 33722411 14 Cascini F. Pantovic A. Al-Ajlouni Y. Failla G. Ricciardi W. Attitudes, acceptance and hesitancy among the general population worldwide to receive the COVID-19 vaccines and their contributing factors: a systematic review EClinicalMedicine 40 2021 101113 10.1016/j.eclinm.2021.101113 15 De Hert M. Mazereel V. Stroobants M. De Picker L. Van Assche K. Detraux J. COVID-19-related mortality risk in people with severe mental illness: a systematic and critical review Front Psychiatry 12 2021 798554 10.3389/fpsyt.2021.798554 16 Bellos I. Lourida P. Argyraki A. Korompoki E. Zirou C. Kokkinaki I. Development of a novel risk score for the prediction of critical illness amongst COVID-19 patients Int J Clin Pract 75 4 2021 e13915 10.1111/ijcp.13915 33969593

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==== Front Nano Today Nano Today Nano Today 1748-0132 1878-044X Published by Elsevier Ltd. S1748-0132(22)00357-7 10.1016/j.nantod.2022.101729 101729 Article SARS-CoV-2 multi-variant rapid detector based on graphene transistor functionalized with an engineered dimeric ACE2 receptor Romagnoli Alice abc1 D’Agostino Mattia a1 Pavoni Eleonora d1 Ardiccioni Chiara ac Motta Stefano e Crippa Paolo d Biagetti Giorgio d Notarstefano Valentina a Rexha Jesmina ab Perta Nunzio ab Barocci Simone f Costabile Brianna K. g Colasurdo Gabriele h Caucci Sara i Mencarelli Davide d Turchetti Claudio d Farina Marco d Pierantoni Luca d La Teana Anna abc Hadi Richard Al j Cicconardi Francesco k Chinappi Mauro l Trucchi Emiliano a Mancia Filippo g Menzo Stefano i della Rocca Blasco Morozzo m D’Annessa Ilda n Di Marino Daniele abc⁎ a Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131, Ancona, Italy b National Biodiversity Future Center (NBFC), Palermo, Italy c New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, 60131, Ancona, Italy d Department of Information Engineering, Polytechnic University of Marche, Via Brecce Bianche, 60131, Ancona, Italy e Department of Earth and Environmental Sciences, University of Milano-Bicocca, Milan, Italy f Department of Clinical Pathology, ASUR Marche AV1, Urbino, PU, Italy g Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, 10032, USA h Department of Architecture, Bologna University, Bologna, 40126, Italy i Virology Unit, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Torrette, 60126 Ancona, Italy j Alcatera Inc., 1401 Westwood Blvd Suite 280, Los Angeles, CA 90024, USA k School of Biological Sciences, University of Bristol, Life Sciences Building, 24 Tyndall Ave, Bristol BS8 1TQ, UK l Department of Industrial Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy m Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy n Institute of Chemical Science and Technologies, SCITEC-CNR, Via Mario Bianco 9, 20131, Milan, Italy ⁎ Corresponding author at: Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131, Ancona, Italy. 1 These authors contributed equally to this work 15 12 2022 15 12 2022 10172915 9 2022 14 11 2022 11 12 2022 © 2022 Published by Elsevier Ltd. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Reliable point-of-care (POC) rapid tests are crucial to detect infection and contain the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The emergence of several variants of concern (VOC) can reduce binding affinity to diagnostic antibodies, limiting the efficacy of the currently adopted tests, while showing unaltered or increased affinity for the host receptor, angiotensin converting enzyme 2 (ACE2). We present a graphene field-effect transistor (gFET) biosensor design, which exploits the Spike-ACE2 interaction, the crucial step for SARS-CoV-2 infection. Extensive computational analyses show that a chimeric ACE2-Fragment crystallizable (ACE2-Fc) construct mimics the native receptor dimeric conformation. ACE2-Fc functionalized gFET allows in vitro detection of the trimeric Spike protein, outperforming functionalization with a diagnostic antibody or with the soluble ACE2 portion, resulting in a sensitivity of 20 pg/mL. Our miniaturized POC biosensor successfully detects B.1.610 (pre-VOC), Alpha, Beta, Gamma, Delta, Omicron (i.e., BA.1, BA.2, BA.4, BA.5, BA.2.75 and BQ.1) variants in isolated viruses and patient’s clinical nasopharyngeal swabs. The biosensor reached a Limit Of Detection (LOD) of 65 cps/mL in swab specimens of Omicron BA.5. Our approach paves the way for a new and reusable class of highly sensitive, rapid and variant-robust SARS-CoV-2 detection systems. Graphical abstract We present a graphene field-effect transistor (gFET) biosensor design, which exploits the Spike-ACE2 interaction, essential for infection. Extensive computational analyses show that a chimeric ACE2-Fc construct mimics the native receptor dimer. ACE2-Fc functionalized gFET allows in vitro detection of trimeric Spike, with a limit of detection (LOD) of 20 pg/mL. Our miniaturized POC biosensor successfully detects all prominent virus variants in both isolated viruses and patient’s clinical swabs with a LOD of 65 cps/mL. Keywords SARS-CoV-2 variants biosensor point-of-care gFET molecular dynamics Omicron Centaurus Cerberus ==== Body pmc1 Introduction The pandemic caused by the highly contagious SARS-CoV-2 has greatly impacted human lives and the global economy [1], [2], [3]. To monitor the spread of SARS-CoV-2, several diagnostic tests are being developed [4], with the most widely employed ones being based on viral RNA amplification (i.e., molecular tests) or viral proteins detection via specific antibodies (i.e., antigenic test) [5], [6]. The former represents the gold standard among SARS-CoV-2 tests, but it requires a few hours of turnaround time and specialized machinery. Conversely, most antigen-detecting rapid diagnostic tests (Ag-RDTs) are fast, but show some limitations such as poor sensitivity, time-dependency (accuracy decreases after 3 days of infection), and viral load dependency [7], [8]. Furthermore, the recently emerged SARS-CoV-2 variants bearing mutations in the standard targets of antigenic tests (i.e., viral Spike and Nucleocapsid protein), impact their ability to specifically recognize the virus [9], [10], [11]. Starting from the first recognized variant D614G (i.e., B.1.610) that emerged in March 2020, the virus has rapidly evolved into a series of different variants of concern (VOC) that quickly spread all over the globe. Some of these variants, e.g., the Alpha or the Delta, were shown to be highly transmissible and cause more severe symptomatology [12], [13]. The more recently appeared Omicron, with its sublineages, show many mutations in its genome, seems to be even more contagious than the Delta, inducing a faster circulation of the virus with a higher probability of infection for the population, with an estimated R0 of 3-5 [14], [15], [16], [17]. Virus variants [13], [18] will keep appearing as long as the pandemic is not contained and an incompletely immunized host population exits (i.e., due to slow vaccine roll-out, with delays between the doses, or because of declining protection a few months after the complete vaccination) favouring the selection of antibody-escaping virus variants, as already demonstrated for Omicron [19], [20]. Consequently, Omicron and other variants had an impact on rapid tests, drastically lowering their sensitivity [19], [21]. Thus, alternative variant-robust biosensors, capable of rapidly detecting SARS-CoV-2, have vital importance in monitoring the COVID-19 outbreaks. Thanks to their sensitivity and rapidity, graphene field-effect transistor (gFET) [22], recently proposed also for virus detection [23], [24], [25], [26], [27], [28], [29], represent a promising biosensing approach. In a gFET, a graphene monolayer connects the source and drain electrodes of a transistor and the graphene is functionalized with a bioreceptor able to specifically bind target molecules. The bioreceptor-target interaction alters graphene’s electronic properties resulting in a readily detectable signal [30]. Thus, gFETs are attractive in POC diagnosis due to their miniaturization, the potential for large-scale manufacture, operability by non-specialized personnel and reusability [31], [32], [33]. Here, integrating molecular simulations, nanobiotechnology and electronic engineering we developed a POC device that uses ACE2 as bioreceptor (i.e., the same receptor that SARS-CoV-2 uses to enter in cells), aiming to mimic the viral mechanism of host cell access [34] ( Fig. 1  A). ACE2 is a widely expressed transmembrane-bound carboxypeptidase dimer composed of a collectrin-like domain (CLD) that ends with a single transmembrane (TM) α-helix and by a peptidase domain (PD) [35] (Fig. 1B). In order to use the dimeric membrane receptor (i.e., ACE2) as a functional bioreceptor on the gFET graphene surface, we used a computer-aided protein design approach to generate a stable dimeric structure of ACE2 in the absence of the cellular membrane. To do that, an ACE2-Fragment crystallizable (ACE2-Fc) chimera was generated by linking the extracellular portion of the ACE2 receptor to the immunoglobulins Fc domain. The ACE2-Fc dimer maintains a high capacity to recognize the SARS-CoV-2 Spike protein. The Spike is a trimeric transmembrane protein whose monomers are composed of two subunits, S1 and S2, with S1 containing the receptor-binding domain, RBD (Fig. 1  C) [36]. Contrarily to antibodies (Ab) elicited by a former virus variant, which can be eluded by newly appearing variants (immune escape) [37], the key contact point established by the virus Spike and the host ACE2 conditions the host cell infection, indeed showing increased affinity in some of the most rapidly spreading variants [38], [39], [40], [41].Fig. 1 Probing the interactions of ACE2 and Antibodies with SARS-CoV-2 Spike. A) Schematic representation of ACE2-mediated host cell entry mechanism. B) Cryo-EM structure of dimeric ACE2 receptor (the two monomers are colored differently). The two subunits of a monomer are reported: Peptidase domain (PD) and Collectrin-like domain (CLD) that is composed of neck domain (ND) and transmembrane α-helix (TM α-helix). C) Cryo-EM structure of soluble trimeric Spike protein (the three monomers have different colors). A zoomed-in view of the RBD is shown. D) Peptidase Domain of the ACE2 receptor bound to the RBD of the SARS-CoV-2 Spike protein. E) Antibody Anti-Spike CR3022 (Ab-CR3022), bound to the SARS-CoV-2 Spike protein RBD. F) Force profiles from the Steered Molecular Dynamics (SMD) simulations of RBD unbinding from the ACE2 receptor (orange) and Ab-CR3022 (green). G) Pull-down assay of Spike and ACE2 (upper), and Spike and Ab-CR3022 (lower). Control is represented by the same experiment excluding the Spike protein (bait) from the system. The binding of Spike with ACE2 or Ab-CR3022 were monitored by western blot analysis. Fig. 1 We show that our POC device successfully detects B.1.610 (pre-VOC), Alpha, Beta, Gamma, Delta, Omicron (i.e., BA.1, BA.2, BA.4 and BA.5), Omicron BA.2.75 (i.e., Centaurus) and Omicron BQ.1 (i.e., Cerberus) variants in isolated viruses and patient’s clinical samples (i.e., nasopharyngeal swabs), making this ACE2-Fc/Spike pair a very promising approach to variant-robust SARS-CoV-2 sensing. 2 Materials and Methods 2.1 Structural Clustering of RBD binding modes in experimental complexes The structural comparison among all available complexes of RBD with Antibody or ACE2 (see Supplementary Materials) revealed 3 different binding modes, shown in Figure S1. We chose a representative structure of each group to simulate (PDB ID: 7BEK, 7MF1 and 6YLA) and compared the SMD forces necessary to obtain a complete unbinding. 2.2 Steered Molecular Dynamics simulations Structures were first equilibrated with a multistage equilibration protocol adapted from [42] (details in Supplementary Materials). The SMD simulations were performed by harmonically restraining the x component of the distance between the center of mass of the backbone of the two proteins with a force constant of 10 kJ mol-1 Å-2. Two different simulations for each system were performed with a constant velocity of 0.005 nm ns-1 or 0.002 nm ns-1. See Supplementary Materials for details. 2.3 Simulation of dimeric ACE2 The three systems (ACE2-Membrane, soluble ACE2 and ACE2-Fc) were built starting from the structure 6M17 [33]. Systems were properly equilibrated with a multistage equilibration protocol [43] (see Supplementary Materials) and then simulated in absence of restraints. The first 30 ns of each simulation were discarded as a further equilibration stage, and the subsequent 500 ns were analyzed. Correlation matrices were obtained using a modified version of g_covar, available at the GROMACS [44] user contribution page, which computes the matrix of atomic correlation coefficients. The calculation was performed on Cα atoms of PD and CLD domains of ACE2 for all the three dimeric systems, sampling the frames every 100 ps. 2.4 Non-reducing SDS-PAGE The ACE2-Fc dimerization was assessed through SDS-PAGE [45] and carried out under non-reducing and reducing conditions. Briefly, 2 µg of ACE2-Fc or ACE2 samples were placed 10 minutes at 100°C under denaturing conditions with Laemmli sample buffer reduced by β-mercaptoethanol or under non-reducing condition using a sample buffer without β-mercaptoethanol. 8% gel was used to correctly separate ACE2-Fc or ACE2 monomers from the dimers. 2.5 Purification of Trimeric Spike protein from FreeStyle HEK293-F cells The plasmid for expression of the SARS-CoV-2 prefusion-stabilized Spike ectodomain in HEK293-F cells (Thermo Fisher) was a generous gift from the McLellan laboratory at the University of Texas at Austin [46]. 350 μg and 1.05 mg Polyethylenimine (PEI) (Polysciences Inc.) were used to transfect cells at 1.2 × 106 cells/mL [47]. After five days in suspension culture, the cell supernatant was collected and filtered using a 0.22 μm filter. Protein in the supernatant was bound to Nickel-NTA agarose (Qiagen) while under rotation in buffer composed of 2 mM Tris, 150 mM NaCl and 10 mM imidazole for two hours at 4°C. The resin was then washed in Tris-NaCl buffer, pH 8, with 20 mM imidazole and protein was eluted in 200 mM imidazole. Following overnight dialysis against PBS, the protein was filtered and stored as 0.2 mg/mL aliquots at -80°C. 2.6 Pull-down assay The pull-down assay to validate the interaction between Spike and ACE2 or anti-Spike antibody Ab-CR3022 or ACE2-Fc was performed using a strep-tactin Sepharose resin as previously described [48], with some modifications. Briefly, 80 μL of indicated strep-tactin resin were washed with phosphate-buffered saline (PBS) pH 7.4 (173 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4) and incubated with 5 μg of recombinant trimeric Spike protein with a C-terminus strep-tag (Spike-strep) next to a his-tag at room temperature for 1 hour. After incubation, Spike-bound beads were washed three times with 500 µL of PBST buffer (PBS and 0.05% Tween-20) and then were aliquoted into different tubes. 5 μg of ACE2 in PBS or 5 μg of anti-Spike or 5 μg of ACE2-Fc in PBS were mixed with spike-bound beads in three different 1.5 mL tubes and incubated at room temperature for 1 hour separately. After a 1-hour incubation, beads were washed three times with 500 µL PBST buffer and the bound proteins were eluted using 50 µL of elution buffer (2.5 mM biotin in PBS (Sigma)). The samples were then subjected to SDS–PAGE and analysed by western blotting using an anti-histidine antibody (Thermo Scientific) to detect Spike and ACE2, an anti-rabbit antibody (Santa Cruz Biotechnology) to detect Ab-CR3022 and an anti-ACE2 antibody (EMP Millipore Corp) to detect ACE2-Fc by chemiluminescent revelation [49]. The same protocol, using empty beads (without Spike), was performed as a negative control for each system. 2.7 gFET functionalization protocol Anti-Spike antibody, ACE2, and ACE2-Fc were immobilized over the fabricated gFET chip (Graphenea gFET-S20) through 1-pyrenebutanoic acid succinimidyl ester (PBASE). PBASE is an heterobifunctional linker whose pyrene group is stably immobilized with graphene by π-π stacking, while the N-hydroxysuccinimide (NHS) ester reacts with primary amines located in several biomolecules such as antibodies, thus establishing covalent bond with them [50]. 20 μL of 5 mM PBASE (Thermo Fisher Scientific, Waltham, MA) in dimethylformamide (DMF) was placed on the chip for 2 h at room temperature before being rinsed three times with DMF, deionized water (DI) and dried with N2. Finally, the PBASE-functionalized devices were exposed to 20 μL of 250 μg/mL of anti-Spike (40150-R007; Sino Biological, Inc., China), ACE2 (10108-H08B-100; Sino Biological, Inc., China) or ACE2-Fc (Z03484-1; GenScript Biotech) separately and left overnight in a humidified environment at 4°C. The sensor was then sequentially rinsed ten times with PBS (pH 7.4, 1X), three times with DI water and dried under N2 flow. The chip was subsequently treated with 20 μL of 100 mM glycine in PBS (pH 8.4, 1X) for 30 minutes for the termination of excess PBASE NHS groups at room temperature. After glycine treatment, samples were rinsed ten times with PBS (pH 7.4, 1X), three times with DI water and dried with N2. The reusability of GFETs was performed following manufacturer’s protocol (2021_Measurement Protocols GFET-S2X_v2), with some modifications. Briefly, we washed the chips for 30 min with water, then overnight with 100% acetone. After that, the regenerated chip was properly dried with N2 gun. The same chip was used at least 5 times to avoid the doping-reduction. 2.8 gFET characterization using Raman and AFM Atomic Force Microscopy (AFM) measurements were performed with a SOLVER PRO from NT-MDT, RMS was evaluated by using Nova Px software. A Horiba Jobin-Yvon XploRA Raman microspectrometer, equipped with a 532-nm diode laser (~50 mW laser power at the sample) was used. All measurements were acquired by using a ×100 long working distance objective (LMPLFLN, N.A. 0.8, Olympus). The spectrometer was calibrated to the 520.7 cm-1 line of silicon prior to spectral acquisition. A 2400 lines per mm grating was chosen. The spectra were dispersed onto a 16-bit dynamic range Peltier cooled CCD detector. The spectral range from 1100 to 3000 cm-1 was chosen and spectra were acquired for 3×10 seconds at each measurement spot. Chips were measured before and after PBASE functionalization. For each sample, 10 point/spectra were acquired, and a Raman map was acquired with the same parameters on squared areas (20 µm × 20 µm), with a step size of ~3 µm, for a total number of 36 spectra. On each Raman map, the following values were calculated: intensity of the band centred at 2690 cm-1 (the 2D band), the intensity of the band at 1592 cm-1 (the G band), and the ratio between these two bands (I2D/IG). False colour images were built by using the I2D/IG ratio. 2.9 Electrochemical measurements Sensing performances of gFETs were evaluated by using a Wentworth probe station equipped with a Bausch & Lomb MicroZoom optical microscope and by using an HP4145B semiconductor parameter analyzer (for recombinant proteins) and POC device (for isolated viruses and nasopharyngeal swabs). Current-voltage curves (Ids-Vds) were acquired (i) by applying a Vds between -0.1 V to 0.1 V, (ii) by operating in liquid gating condition with PBS solution pH 7.4, and (iii) by using a Vg of 0 V. Transfer curves (Ids-Vg) were obtained (i) by using Vds 0.050 V, (ii) by operating in liquid gating condition with PBS solution at pH 7.4, (iii) by applying Vg swept from 0 to 1.5 V, (iv) by carrying out a relaxation step to obtain a constant equilibrium of ions on the surface of graphene [23]. During this step, Vds and Vg were both applied on the gFET until no variations on the I-V curves were observed; in this way, the same ions screening effect was maintained during the measurements, and the I-V curves, taken on the same gFET at different times, were completely superimposable. After this brief equilibration stage of the ions on the surface of graphene, the blank was recorded by operating in liquid gating condition with PBS solution at pH 7.4. Then, gFET was incubated for 30 minutes at room temperature with different concentrations of 20 µL of sample (recombinant proteins, viruses or swabs) in PBS pH 7.4 to allow the binding with the attached bioreceptors. To avoid aspecific signals due to adsorption of molecules on the graphene channel, a wash step, using 10 mL of PBS, was performed. Only then, the electrical signal of the sample is recorded, representing the effect of the specific interaction between the bioreceptors and the ligand (Figure S2). mPRO recombinant protein was kindly provided by Prof. Paolo Mariani from Polytechnic University of Marche [51]. Recombinant MERS-CoV Spike protein was purchased from Sino Biological (40069-V08B). 2.10 Statistical analysis Dirac Point values for Blank and sample are compared using paired t-test implemented in Python. Significance was expressed as reported on the relative figures. To plot comparative response the values were normalized for each gFET as follows: Normalized Vd =VdA∑1nVdBn where VdA is the individual value of the Dirac point for (i) Blank or (ii) Sample: after the addition of: SARS-CoV-2 Spike protein, SARS-CoV-2 mPRO, MERS Spike protein, isolated SARS-CoV-2, HVS-1 and nasopharyngeal swabs. VdB are the Dirac point values of the blanks on each gFET with n=6 technical replicates (i.e., number of independent graphene pads on each gFET). The limit of detection (LOD) of ACE2-Fc_gFET was calculated by measuring progressively decreasing concentrations of the Spike protein (i.e., Range of Detection: 2 µg/mL-0.002 ng/mL) and indicates the lowest concentration at which the analyte is detected [22], [52]. All experiments, including the LOD calculation, with recombinant proteins (i.e., SARS-CoV-2 Spike protein, SARS-CoV-2 mPRO, MERS Spike protein) were performed in triplicates (i.e., 3 biological samples). 2.11 SARS-CoV-2 isolation and virus stocks Different lineages of SARS-CoV-2 were isolated from RT-PCR positive nasopharyngeal swabs collected at Ospedali Riuniti, Ancona (Italy) using Vero E6 cells (ATCC n° CRL-1586), as described by Alessandrini et al. 2020 [53]. Vero E6 cells, seeded in 75 cm2 flasks, were subsequently infected with 2 mL of the virus from the isolation to a final volume of 12 mL to obtain a larger stock. Supernatants of the infected cells were harvested after 72 hours, centrifuged at 3000 rpm for 10 minutes, filtered using a 0.2 µm filter, aliquoted and stored at -80°C. Six virus stocks were sequenced and used for the present study: B.1.610 (EPI_ISL_417491), Alpha (EPI_ISL_778869), Gamma (EPI_ISL_1118260), Beta (EPI_ISL_1118258), Delta (EPI_ISL_2975994) and Omicron BA.1 (EPI_ISL_7897869). 2.12 RT-qPCR of patient samples Clinical Samples used in this study were provided by the U.O.C. of Clinical Pathology from the hospital of Urbino (Italy) “Santa Maria della Misericordia” and from Virology Unit from Ospedali Riuniti, Ancona (Italy). Nasopharyngeal swabs from COVID-19 positive patients and COVID-19 negative were stored in PBS 1X and used. The positivity or negativity of these samples were determined by real-time RT-qPCR following manufacturer's specifications (ALLPLEX SARS-CoV-2 ASSAY and MDS methodologies). From the RT-qPCR a Cycle Threshold (Ct) value is obtained. It indicates the viral load, therefore the number of cycles after which the virus can be detected. 2.13 Ethics approval All subjects provided written consent to be used for research purposes. The Ethics Committee of Region Marche (C.E.R.M.) approved the study on 17/12/20. Components of C.E.R.M. are listed here: https://www.ospedaliriuniti.marche.it/portale/index.php?id_sezione=132&id_doc=446&sottosezione=37 2.14 RT-PCR SARS-CoV-2 and Variants Detection Viral RNA was extracted from nasopharyngeal swabs using the Kit QIAsymphony DSP Virus/Pathogen Midi kit on the QIAsymphony automated platform (QIAGEN, Hilden, Germany) according to manufacturer’s instructions. Multiplex real-time RT-PCR assay was performed using qPCRBIO Probe 1-Step Go No-Rox (PCRBIOSYSTEMS, London, UK) on the Applied Biosystems 7500 Fast Dx Real-Time PCR Instrument (Thermo Fisher Scientific). The oligonucleotide primers and probes were designed to detect 69/70 deletion and N501Y mutation from virus Spike gene to discriminate alpha and gamma lineage respectively. Variant lineage was confirmed by sequence analysis of Spike gene using ABI Prism 3100 Genetic Analyzer (Applied Biosystems-HITACHI). Calibration curve was obtained from 10-fold dilutions (105 to 102 cps/rct) of the WHO International Standard for SARS-CoV-2 RNA (cat#20/146), purchased from the National Institute for Biological Standards and Control (NIBSC) to quantify the number of copies of SARS-CoV-2 RNA per milliliter of nasopharyngeal swab ( Table 1, Table 2).Table 1 Table showing samples type, and relative Ct and cps/mL of all the patients tested and reported in Fig. 5 C. Table 1No. Patient Sample type Ct Average cps/mL 1 RV/EV 33,2/31,48 / 2 HPIV 3 31,2 / 3 H3N2 28,7 / 4 Negative / / 5 Negative / / 6 Negative / / 7 Negative / / 8 B.1.610 16.23 7.45E+07 9 Alpha 18.12 9.86E+06 10 Delta 23.4 1.08E+06 11 Delta 14.5 2.17E+08 12 Delta 18.43 6.07E+06 13 Omicron (BA.1) 20.24 4.46E+06 14 Omicron (BA.2) 19.22 9.13E+06 15 Omicron (BA.2) 15.17 1.57E+08 16 Omicron (BA.2) 15.39 1.34E+08 17 Omicron (BA.4) 15.68 1.10E+08 18 Omicron (BA.5) 15.4 1.35E+08 19 Omicron (BA.5) 17.54 2.97E+07 20 Omicron (BA.5) 21.5 1.84E+06 21 Omicron (BA.5) 20 5.28E+06 22 Omicron (BA.5) 19 1.07E+07 23 Omicron (BA.5) 15.26 1.47E+08 24 Omicron (BQ.1) 23.08 6.07E+02 25 Omicron (BQ.1) 14.75 2.11E+05 Table 2 Table showing Ct and cps/mL of all dilutions of the BA.5 swab tested and reported in Fig. 5D. Table 2Ct Average cps/mL 15.38 1.35E+08 21.84 1.45E+06 28.64 1.22E+04 32.65 7.32E+02 36.1 6.5E+01 40.05 4 3 Results 3.1 Soluble ACE2 and Ab binding with SARS-CoV-2 Spike protein As a first step in exploring the possibility of using ACE2 as a bioreceptor, we characterized in silico the force profiles of the ACE2-RBD interaction (Fig. 1D), in comparison to an Antibody-RBD (Ab-RBD) complex (Fig. 1E), by performing a series of constant velocity Steered Molecular Dynamics (SMD) simulations. Since it is the interaction domain [35], RBD was used as a proxy for Spike in our simulations. To account for the various known RBD binding sites (Table S1) we used as initial starting points for SMD three representative structures of clusters obtained by structural comparison of over thirty different complexes (Figure S1). Although they show different patterns of interaction, the force needed to dissociate the RBD from ACE2 or from the most stable Ab-RBD complex (group 3) is comparable (Fig. 1  F) at both velocities tested (Figure S3). A detailed description of the ACE2-RBD unbinding mechanism is shown in Figure S4. The other two structural groups exhibited lower binding forces and were thus less relevant in the comparison. The interaction of ACE2, in its soluble truncated form, with the trimeric Spike protein was also probed with pull-down assays and western blot (Fig. 1  G). Spike-decorated sepharose beads were used to pull down ACE2, and both were recovered in the eluted fractions, confirming its ability in recognizing the Spike protein. Similar pull-down results were obtained for the anti-Spike Antibody (Ab-CR3022). No Spike leakage was observed in the unbound fractions on each pull-down assay (Fig. 1  G, unbound lanes). Taken together, our computational and biochemical results suggest that ACE2 receptor can be used as a bioreceptor for gFETs functionalization. 3.2 SARS-CoV-2 Spike protein detection by ACE2_gFET and Ab-CR3022_gFET Spike detection was performed using a gFET provided by Graphenea (San Sebastian, Spain) consisting of 12 separated single-layer graphene channels connected to source and drain gold electrodes. A non-encapsulated electrode at the center of the chip allows liquid gating through PBS solution ( Fig. 2  A). The bifunctional PBASE was used as a linker between graphene and bioreceptor proteins (i.e., ACE2 and Ab-CR3022) (Fig. 2  A). PBASE pyrene group stacks via π-π interactions on the aromatic graphene lattice, while the succinimide covalently binds amino groups of proteins [54]. To obtain efficient coverage, avoiding the formation of multiple layers of pyrene [55], we treated the gate electrode with a 5 mM PBASE in dimethylformamide (DMF) solution. We then characterized the bare and functionalized gFET by AFM (Figure S5) and Raman spectroscopy (Fig. 2B). Electrical characterization of pristine and activated gFET and Raman maps further confirmed the PBASE attachment to graphene (Figure S6).Fig. 2 gFET setup and Spike recognition. A) gFET (size 10 mm × 10 mm) is composed of two source electrodes each one connected with six graphene channels and the respective drains. A single gate electrode is used for both sides of gFET. A schematic representation of the PBASE-modified gFET is reported in the inset panel. B) Raman Spectra of gFET (black) and gFET-PBASE (red) (diode laser wavelength 523 nm and laser power 50 mW). C) Schematic representation of gFET modified with ACE2. D-E) Detail of Ids-Vg curves obtained for (D) ACE2_gFET (black) and ACE2_gFET + Spike (2 µg/mL) (red). E) ACE2_gFET (black) and ACE2_gFET + mPRO (2 µg/mL) (red). F) Comparative bar charts of ACE2_gFET before (black bars) and after (red bars) the addition of Spike (2 and 0.2 µg/mL) or mPRO (2 µg/mL). G) Schematic representation of gFET modified with Ab (Ab-CR3022). H-I) Detail of Ids-Vg curves for (H) Ab_gFET (black) and Ab_gFET + Spike (2 µg/mL) (red); (I) Ab_gFET (black) and Ab_gFET + mPRO (2 µg/mL) (red); (J) Comparative bar charts of Ab_gFET before (black bars) and after (red bars) the addition of Spike (2, 0.2 and 0.02 µg/mL) or mPRO (2 µg/mL). Details of Vg from 0 to 1.20 V are shown. In (F) and (J): *** p < 0.001, * p < 0.05, error bars represent standard deviation (s.d.). Fig. 2 Next, we investigated the sensing performances of the gFET functionalized with the soluble portion of the ACE2 receptor (residues 1 to 740) (Fig. 2  C and 2 F) and with the antibody Ab-CR3022 (Fig. 2  G and 2 J). Experiments were conducted fixing the drain-source voltage to Vds=50 mV and varying the gate voltage Vg from 0 to 1.5 V. In order to detect the binding between the Spike and bioreceptors, we measured the shift in the charge neutrality point (CNP) value, i.e., the gate voltage associated with the minimum of the transfer curve, also called Dirac point, that represents the most widely used electrical metric in gFET sensing [22]. The Dirac point position is altered when the electronic structure of graphene is perturbed (i.e., by target binding with its associated charges) [30]; in principle the negatively-charged molecules induce p-doping of graphene, resulting to a more positive voltage (i.e., shift to the right); oppositely, positively-charged targets prompt to n-doping and the Dirac point shifts to more negative voltages (i.e., shift to the left). However, this basic scenario is valid for simple systems tested like ions, while in the case of bigger molecules like glucose [31], [56], nucleic acids [57], [58], or proteins [59], [60], this model shows some inconsistencies. Indeed, the direction of the CNP change may be affected by several factors, such as Debye length, pH of the solution, environment, and spatial-dynamical complexity of the bioreceptor-target interaction, which involves several characteristics such as the orientation of the bioreceptor and bioreceptor-target binding mode [22], [61]. Nevertheless, the shift of the CNP, before and after the addition of the analyte, is a reporter of binding [22]. Decreasing concentrations of purified Spike protein were tested. For ACE2_gFET (Fig. 2  C and 2 F), after the addition of the Spike solution at 2 μg/mL we observed a shift of transfer curves (Fig. 2D) while the use of a Spike concentration of 0.2 μg/mL instead resulted in no significant differences (Figure S7). When we tested the Ab_gFET (Fig. 2  G and 2 J), a shift was observed both at 2 (Fig. 2H) and 0.2 μg/mL (Figure S7). Subsequent dilution (0.02 μg/mL) did not elicit a detectable Dirac point shift (Figure S7). The specificity of the bioreceptor-target binding is supported by the absence of significant shifts observed when using mPRO, the main protease of the same virus (Figs. 2E, 2I and S7). 3.3 ACE2-Fc chimera mimics the transmembrane ACE2 dimer Although Ab and ACE2 bind Spike RBD with similar strength their impact on the performance of gFETs is different. To overcome the lower sensitivity of soluble truncated ACE2_gFET as compared to Ab_gFET, we modeled a chimeric version of ACE2 fused with an Fc-tag at its C-terminus (ACE2-Fc). We expected that the disulfide bridges present in the Fc-tag [62] would enforce the formation and stability of dimeric ACE2 complex in solution, mimicking what occurs in physiological conditions on the cell membrane [35]. To test this hypothesis, we computationally characterized via Molecular Dynamics (MD) simulations three systems: i) a complete ACE2 system with transmembrane helices embedded in a POPC:CHOL (90:10) bilayer ( Fig. 3  A and 3B); ii) the soluble truncated form of ACE2 (Fig. 3  C); and iii) a chimeric system composed of the soluble portion (PD, CLD, ND) of ACE2 linked to Fc (Fig. 3D, ACE2-Fc). In the ACE2-Fc chimeric system, after a transient period of about 100 ns, we observed that the Fc domain, that has been connected to the soluble portion of the ACE2 receptor through two small unstructured regions (Fig. 3D), bends significantly (Fig. 3E), thus stabilizing the region of the receptor that is directly involved in the recognition of the Spike protein. This fast conformational change causes a more generalized structure stabilization, forcing the ACE2-Fc to maintain a stable dimeric conformation for the rest of the 500 ns sampled (Fig. 3  G). This dimeric conformation is very similar to the membrane-embedded one, as shown by the distance between the PD domains center of mass, used to monitor the intra-monomer distance (Figs. 3E, 3  F). In both membrane-embedded ACE2 and chimeric ACE2-Fc systems, the distance fluctuates around a value of 7 nm, rarely sampling more open conformations (up to 8 nm). On the contrary, in soluble ACE2 the monomers tend to separate more from each other (Fig. 3H, grey curve). The rearrangement of monomers is also evident from the time evolution of the number of contacts between them involving the PD and CLD regions, with the soluble ACE2 system losing more contacts over time (Fig. 3  G, grey curve), and from the comparison of the RMSD of the two PD domains (Figure S8A). Furthermore, the presence of the Fc domain, despite its significant size (~26 KDa), allows to considerably increase the compactness of the ACE2-Fc construct, decreasing its length. This is clearly underlined by the analysis of the gyration radius showing how the soluble ACE2, despite being smaller than the ACE2-Fc, tends to reach a more extended shape (Figs. S8C, 3E). The acquisition of a globular conformation does not influence the stabilization of the dimeric conformation, indeed an even more comprehensive reporter on the dimer dynamics is the cross-correlation of the motion of individual residues during the simulation. The corresponding maps (Fig. 3I full length vs. truncated and 3 L full length vs. ACE2-Fc) clearly highlight how the internal dynamics of ACE2-Fc resembles much more the membrane-embedded ACE2, especially in the PD domain involved in the Spike recognition. On the contrary, the soluble truncated ACE2 presents more marked differences both in the profile and intensities of the correlated motions. Overall, these results indicate that the chimeric ACE2-Fc system better preserves the dynamical properties of ACE2 in the membrane (Movie S1). This can be ascribed to an overstabilization of the CLD domains due to the close distance of the CLD-Fc connecting linker (Figure S8B) that are held together by the disulfide bridges in the Fc region (Figure S9).Fig. 3 MD simulations of full length, soluble and Fc tagged ACE2 dimers. A) Representative structure of the full-length ACE2 dimer embedded in a membrane. B) Same as (A) but the membrane is omitted to show the TM helices. C) Soluble truncated ACE2 conformation. D) Starting configuration of the ACE2-Fc chimera. For B-D two orthogonal views are shown. E) Representative snapshots of ACE2-Fc structures sampled during the MD trajectory, side view. The PD centers of mass distance is shown by a dashed red line. F) Top view of soluble ACE2, the PD centers of mass distance is shown by a dashed black line. G) Number of contacts between the two PD-CLD regions of monomers for membrane embedded full length ACE2 (in black), ACE2-Fc (red) and soluble ACE2 (grey). H) Time evolution of the intermonomer distance measured between the PD domains, color code as in (G). Comparative Dynamics as reported by the cross-correlation matrices of concerted motions of the residues of our three dimeric systems during the MD simulations. In (I) correlations in the full length ACE2 embedded in the membrane (upper triangle) and soluble truncated ACE2 (lower triangle). L) Same comparison as (I) between full length ACE2 embedded in the membrane (upper triangle) and ACE2-Fc (lower triangle). Fig. 3 Supplementary material related to this article can be found online at doi:10.1016/j.nantod.2022.101729. The following is the Supplementary material related to this article Video S1 Video S1 The dimerization propensity of the ACE2-Fc chimera inferred from the computational investigation was confirmed by performing SDS-PAGE electrophoresis with (Wβ) and without (W/o β) β-mercaptoethanol. When ACE2-Fc is in reducing conditions ( Fig. 4  A, Wβ), the disulfide bonds in the Fc region are reduced, and the protein migrates as a monomer. On the other hand, ACE2-Fc in non-reducing conditions runs as a dimer (Fig. 4  A, W/o β), consistently with the computational results. Soluble ACE2 is not affected by reducing conditions, as expected by the absence of disulfide bonds. In addition, the interaction of ACE2-Fc with the trimeric Spike protein was also confirmed with pull-down assays and western blot (Fig. 4B).Fig. 4 ACE2-Fc as bioreceptor and LOD calculation. A) SDS-PAGE under reducing (w β lanes) and non-reducing (w/o β lanes) conditions of soluble ACE2 and ACE2-Fc; B) Pull-down assay of Spike and ACE2-Fc. The binding of Spike with ACE2-Fc was monitored by western blot. C) Schematic representation of gFET modified with ACE2-Fc. D) Comparative bar chart showing the ACE2-Fc_gFET response to different concentrations of SARS-CoV-2 Spike. E) Comparative bar chart showing the ACE2-Fc_gFET response to MERS-CoV Spike protein (2 µg/mL) and SARS-CoV-2 mPRO (2 µg/mL). In (D) and (E): *** p < 0.001, ** p < 0.01 and * p < 0.05, error bars represent s.d. Fig. 4 3.4 SARS-CoV-2 Spike protein detection by ACE2-Fc_gFET: sensitivity and specificity evaluation gFETs were functionalized with ACE2-Fc (Fig. 4  C) and the sensitivity of the system was tested using different concentrations of trimeric Spike protein (Fig. 4D and Figure S10). ACE2-Fc_gFET is able to detect the Spike protein at lower concentrations, achieving a LOD of 0,02 ng/mL (20 pg/mL), in a range of detection that spans from 2 μg/mL to 2 pg/mL of Spike (Fig. 4D and Figure S10). No significant differences are observed for mPRO (Fig. 4E). Thus, the dimeric ACE2-Fc bioreceptor is specific for Spike and provides the highest sensitivity, far outperforming both the soluble truncated ACE2 (no signal for 0.2 μg/mL, Fig. 2  F) and the Ab-based system (no signal for 0.02 μg/mL, Fig. 2  J). Notably, our sensitivity is comparable to that of lateral-flow based devices [63] and to other SARS-CoV-2 biosensors (Table S4). Since ACE2 is the receptor for only three coronaviruses, one of which is contained and the other, HcoV-NL63, has low binding affinity, specificity is reasonably assured [64]. To further confirm the specificity of the interaction, we also tested the closely related MERS-CoV Spike protein. We did not observe any significant signal using the MERS-CoV Spike protein in solution at 2 μg/mL (Fig. 4E and Figure S10). 3.5 Detection of SARS-CoV-2 variants from both cultured viruses and nasopharyngeal swabs by POC device Mutations along the genome characterizing SARS-CoV-2 variants have impacted virus transmissibility and antigenicity, while influencing the sensitivity of rapid diagnostic tests [10], [11], [65]. All Spike residues of B.1.610, Alpha, Delta and Omicron subvariants for which substitutions affected recognition by antibodies are summarized in Fig. 5  A. On the other hand, ACE2 is still recognized by all SARS-CoV-2 variants. Therefore, the development of a portable POC device that exploits ACE2-Fc as bioreceptor can allow to detect all circulating variants of the virus.Fig. 5 POC device detects SARS-CoV-2 variants in clinical samples up to low viral concentrations. A) Detailed amino acid mutations of SARS-CoV-2 Spike proteins in B.1.610, Alpha, Delta, Omicron (BA.1, BA.2, BA.4, BA.5 and BQ.1) variants, compared to the wild-type Whuan-Hu1 of SARS-CoV-2. Positions of mutations are shown both on a schematic domain representation of the protein and on the 3D model (PDB ID: 7DWZ). B) Photograph of the gFET Cartridge Unit and the Signal acquisition modules connected to form the entire POC. A reference dimension bar is reported. Also, a schematic representation of gFET modified with ACE2-Fc tested with different SARS-CoV-2 samples is shown. C) Bar graph reporting ACE2-Fc_gFET signal before (black) and after the addition of nasopharyngeal swab samples from patients (red). D) Comparative bar chart showing the ACE2-Fc_gFET response to different dilutions of Omicron BA.5 swab. Ct and cps/mL of each patient or dilution are shown in Table 1 or Table 2, respectively. In (C) and (D): *** p < 0.001, ** p < 0.01 and * p < 0.05, error bars represent s.d. Fig. 5 To improve portability, we designed and tested a miniaturized, reusable POC device accommodating the gFET chip (Fig. 5B and Figure S11), that yields the same readouts of the lab-scale probe station used during sensor implementation and testing (Figure S12). The manufacturing process is described in the Supplementary Materials, as well as the solutions adopted to realize an energy-efficient, battery-powered, Bluetooth device able to reliably detect currents around 10 μA and Dirac voltage shifts of a few millivolts. The ability of the prototype to detect different SARS-CoV-2 variants was assessed with ACE2-Fc_gFET loaded on our POC device, testing both isolated viruses and clinical nasopharyngeal swabs. To assess the performance of the device, different isolated SARS-CoV-2 variants were tested (Figures S13 and S14). From the analysis of pre-VOC B.1.610 and four VOC, including the recently emerged Omicron BA.1, a shift of the Dirac point is always observed (Figures S13 and S14). We report also that, for a limited number of gFETs, the direction of the CNP shift is toward lower voltages. This is not so surprising since the sensing response of a gFET is influenced by different parameters, such as the total number of adsorbed bioreceptors, their orientation on the graphene surface [22], [61], [66], the net charges and subsequent surrounding presence of anions and/or cations [22], [67] and the Debye Length [22], [68]. All these factors could lead in some cases to have the CNP shift in a different direction than expected (Figure S15A, B and C). In particular, through an accurate analysis of the MD trajectory, we observe for the ACE2-Fc construct that despite the protein remains in a stable dimeric conformation in solution increasing the degree of compactness (Figs. S8C, 3E and 3 F), it continues to sample various conformational sub-states thanks to its intrinsic structural plasticity (Figure S15D). The conformational sub-states are characterized by the fluctuation in the length of the protein and mainly by the changing of the PD domains orientation with respect to the Fc domain (Figure S15D, E and S16). These conformational sub-states can be essentially divided in two subgroups in which one conformational sub-state is sampled more often than the other by shifting the conformational balance (Figure S15D). In this scenario, it is therefore conceivable that these few differences in the direction of the Dirac point shift could be explained by the presence of different conformations of ACE2-Fc, as seen in the MD simulations, which can reorient the bioreceptor charge closer to or farther away from the FET channel, changing the surface potential thus altering the doping state of graphene in its initial value (Figure S15A, B and C). There are several examples in which the bioreceptor structural plasticity and therefore conformational changes play a crucial role in the detection of biomolecules and signals analysis in biosensing experiments [61], [69], [70], [71], [72], [73], however, this mechanism will need to be further investigated. Nevertheless, the specificity of the target-receptor interaction allowed us to always have a significant signal in presence of the sample, while yielding no changes with our various controls (see Fig. 2, Fig. 4, Fig. 5 and Figures S7, S10, S13, S17). Specificity was also probed using isolated Herpes Simplex virus 1 (HSV-1) that recognizes a different receptor. Even with such more complex systems, the negative samples do not show any change in the Dirac point, confirming that the specificity of the interaction and the thorough washing steps in our protocol (see Materials and Methods and Figure S2) yield significant differences only in presence of the correct viral target. Furthermore, we tested the detection performance of the ACE2-Fc_gFET using clinical samples (Fig. 5  C, S17 and Table 1). Nasopharyngeal swabs with minimal processing, only resuspended in PBS, were used. The shift of the Dirac point (Fig. 5  C and S17) demonstrates that our POC device clearly discriminates between SARS-CoV-2 positive and negative samples. RT-qPCR results indicate that eighteen patients were positive for SARS-CoV-2, carrying one B.1.610, one Alpha, three Delta, thirteen Omicron (one BA.1, three BA.2, one BA.4, six BA.5 and two of the recently appeared BQ.1), whereas the other seven tested negative (Fig. 5  C and Table 1). Among negatives, one resulted positive to RhinoVirus (RV)/EnteroVirus (EV), one to Human Parainfluenza Virus Type 3 (HPIV3) and one to Influenza A Virus (H3N2). These results confirm once again the specificity of our biosensor toward SARS-CoV-2, showing no cross-reaction with other common human viruses (Fig. 5  C, S17 and Table 1). The average Ct values for both isolated viruses and patient swabs are reported in Figure S14 and Table 1 respectively, together with the corresponding cps/mL. In addition, we have evaluated the detection limit of the real samples measuring a nasopharyngeal swab specimen (Omicron BA.5 variant) at different dilutions (Fig. 5D and Table 2). The ACE2-Fc_gFET sensor responded to patient samples diluted as much as Ct 36 (determined by RT-qPCR), which corresponds to 65 cps/mL, that we consider as our empirical LOD. This result indicates that ACE2-Fc_gFET biosensor has the potential to be used for COVID-19 diagnosis for all known variants. For the sake of completeness, we also tested samples in Universal Transport Medium (UTM) but due to the complexity of this medium (i.e., amino acids, salts and BSA), we did not achieve clear results (data not shown). Finally, to ensure that different ACE2-Fc_gFET performed similarly, we carried out reproducibility assays using three different POC devices and three functionalized gFET (Figure S18). The tests were run on different days and yielded reproducible results. Taken together, our findings show that our ACE2-Fc_gFET biosensor successfully detected SARS-CoV-2 from isolated virus and clinical samples without any pre-processing steps. 4 Discussion Rapid, sensitive and variant-robust detection systems have been immediately acknowledged as crucial in the COVID-19 global containment strategy. Since generalized social restrictions (i.e., lockdowns) are not applicable anymore for their high social and economic costs, and vaccines are unevenly rolling out in the world, with efficacies that seem to be temporary, the virus is far from being contained. Thus, accurate detection tests able to provide quick response are even more necessary. Highly sensitive PCR-based molecular tests still require a few hours for the result, lab scale facilities and specialized personnel, whereas antigen-detecting rapid diagnostic tests (Ag-RDTs) are characterized by lower accuracy [74], which is further affected by newly emerging virus variants [21], [75]. Most Ag-RDTs were evaluated for their performance (i.e., specificity and sensitivity) far before the emergence and spread in the world population of SARS-CoV-2 VOC [75]. For example, Omicron, and its subvariants Centaurus and Cerberus, accumulated several mutations in both Spike and Nucleocapsid protein and this results in a lowered reliability of Ag-RDTs [9], [10], [11], [21], [76], [77], [78], [79]. Moreover, both testing approaches (i.e., PCR-based and Ag-RDTs) employ disposable plastic supplies in their procedures raising concerns about the environmental impacts associated with the global scale testing campaigns [80]. Here, we present a gFET sensor that exploits as bioreceptor a chimeric version of the human receptor ACE2 which outperforms an anti-Spike antibody in detecting specifically the SARS-CoV-2 Spike protein. Recently, other ACE2-based sensors have been developed [81] (Table S4), but none of them are optimized to resemble its physiological counterpart and none of them tested all the known variants. We believe that using a chimeric version of ACE2 composed of the soluble part of the protein and the Fc region of the antibodies is a better bioreceptor choice to detect SARS-CoV-2. In fact, the fusion of the Fc-tag on ACE2's C-terminus promotes stable protein dimerization, making it more similar to its native state on the cell membrane [62], as shown by our computational and in vitro biochemical analyses (Fig. 3, Fig. 4). By mimicking the actual virus-host interaction for cell infection, whose affinity has been shown to have improved in some of the late variants [38], [39], [82], our sensor is robust to current and future virus mutations. The LOD achieved by our ACE2-Fc_gFET were 20 pg/mL and 65 cps/mL for recombinant Spike and swab specimens respectively. Notably, electrochemical measurements using nasopharyngeal swab specimens did not show an optimal linear concentration-dependent response (Fig. 5  C and 5D), therefore reliable virus quantification cannot be acquired. Thus, qualitative (yes/no) response can be obtained from our gFET biosensor. Anyhow, the empirical LOD achieved using both recombinant Spike and swabs from patients confirms the high sensitivity of our gFET device, especially the one obtained with nasopharyngeal swabs which is comparable with most of the existing tests (some of them are reported for comparison in Table S4), including the gold standard RT-qPCR [83]. Nevertheless, we believe that RT-qPCR remains the most solid method to confirm a COVID-19 diagnosis. Considering this, our intent is not to substitute this test but to provide a faster screening approach. Our biosensor, aptly miniaturized into a reusable, low-waste user-friendly POC device, was successfully tested on complex samples, such as isolated viruses and clinical samples from patients infected by the most prominent virus variants: B.1.610, Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.2, BA.4, BA.5, BA.2.75 and BQ.1. The number of different types of assays also proves the robustness of the ACE2-Fc_gFET (Table S5). Our approach can detect all the circulating variants within ~40 minutes using 20 µL of the sample without any pre-processing steps. The ready-to-use gFET needs only a few preparation phases, widely described in the literature and well-characterized for other gFET technologies, therefore this procedure can be easily applicable in any laboratory (Figure S2). Anyhow, drawbacks are also present, such as the cost and the commercial availability of manufactured bare-gFET chips (See Supplementary Materials text). This is the first study to reliably detect almost all SARS-CoV-2 variants, among others the latest appeared Omicron in all its sub-lineages and the currently circulating Centaurus and Cerberus variants in different specimens (Fig. 5, S14 and S15), dissimilarly from others comparable biosensor developed (Table S4). We strongly believe that our technology could be considered as a new tool for COVID-19 management, especially for future variants, taking into account that growing evidence demonstrated that antigen tests are less sensitive for Omicron detection [77]. Furthermore, using our graphene-based POC device, with its digitized electrical recordings, ensures higher performance in the collection, handling and screening of the data as compared to most rapid tests. 5 Conclusions Through a multidisciplinary effort we developed a novel point-of-care graphene-based device able to detect all known SARS-CoV-2 variants. Driven by computational and biochemical approaches that were useful to characterize the structural and dynamical properties of the chimeric ACE2-Fc construct, which mimics the functional dimeric conformation of the receptor, we attained an optimal sensitivity and specificity for the detection of SARS-CoV-2 in nasopharyngeal swabs. Our technology can complement the gold standard PCR methods and can be considered as an additional instrument in the fight against the COVID-19 pandemic, leveraging on its robustness to the virus variants, a possible pitfall of Ag-RDTs. In addition, modifications of the ACE2 amino acid sequence, which are expected to increase binding affinity with the viral Spike [62], [84], could also further improve the sensitivity of our ACE2-Fc gFET-based biosensor. In general, our novel biosensor sets the basis for a class of highly sensitive, fast, reusable and variant-robust SARS-CoV-2 detection systems that, in a close future can be extended for the detection of other diagnostic relevant biomarkers, i.e., other viruses or extracellular vesicles. CRediT authorship contribution statement A.R., M.DA and E.P. contributed equally to this work. D.DM. conceived and designed the study. M.DA, E.P., A.R. and A.LT. designed the protocols and performed experiments on gFET. C.A., D.M. and P.C. contributed to electrical measurements. G.B. and C.T. designed the electronics of the device. V.N. performed Raman experiments. S.M., D.DM. and I.DA. performed and analyzed the MD simulations. E.P. performed AFM experiments. S.B. and S.C. contributed to patient samples collection and analysis. J.R. and S.Me. carried out virus isolation and culture. B.K.C. and F.M. expressed the Spike protein. D.DM., M.F., L.P., F.C., M.C., N.P., B.MDR., and E.T. contributed to data interpretation. G.C. designed the case and carrier units of POC. R.AH. contributed to the design of the POC. S.M., D.DM., M.C., E.P., M.DA. and B.MDR. prepared the figures. D.DM., E.T., F.C., F.M., I.DA., M.C., M.DA., A.R., S.M. and B.MDR. wrote the original draft. All authors reviewed the manuscript. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The ACE2-Fc functionalization of gFET and the design of the POC device are under patent pending, applied by Polytechnic University of Marche. D.DM., M.DA., C.A., A.R., I.DA., D.M., E.P., P.C., G.B., L.P., M.F. are the inventors of the patent application N. 102021000000533 filed in 01/13/2021. All other authors declare they have no competing interests Appendix A Supplementary material Supplementary material Data availability Data will be made available on request. Acknowledgements DDM acknowledges funding from the Italian Ministry of Research, Project N. FISR2020IP_03475. We acknowledge the CINECA as part of the agreement with the University of Milano-Bicocca for the availability of high-performance computing resources. Conflict of interest The ACE2-Fc functionalization of gFET and the design of the POC device are under patent pending, applied by Polytechnic University of Marche. D.DM., M.DA., C.A., A.R., I.DA., D.M., E.P., P.C., G.B., L.P., M.F. are the inventors of the patent application N. 102021000000533 filed in 01/13/2021. All other authors declare they have no competing interests. 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10.1016/j.nantod.2022.101729

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==== Front J Surg Educ J Surg Educ Journal of Surgical Education 1931-7204 1878-7452 Association of Program Directors in Surgery. Published by Elsevier Inc. S1931-7204(22)00310-5 10.1016/j.jsurg.2022.11.007 Original Reports “Sip & Share”: Building Resilience in Surgery Residency Through Moral Distress Rounds Teo Richard *† Grosser Rachel *† Thuppal Hayavadhan *† Statter Mindy B. *†1 ⁎ Department of Surgery, Montefiore Medical Center, Bronx, New York † Division of Pediatric Surgery, Department of Surgery, Children's Hospital at Montefiore, Bronx, New York 1 Correspondence: Inquiries to Mindy B. Statter MD MBE, Division of Pediatric Surgery, The Children's Hospital at Montefiore, 111 E 210th St, Bronx NY 10467 15 12 2022 15 12 2022 © 2022 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved. 2022 Association of Program Directors in Surgery Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. OBJECTIVE Resident moral distress rounds were instituted during the COVID-19 pandemic to provide a safe zone for discussion, reflection, and the identification of the ethical challenges contributing to moral distress. The sessions, entitled “Sip & Share,” also served to foster connectedness and build resilience. DESIGN A baseline needs assessment was performed and only 36% of general surgery residents in the program were satisfied with the current non-technical skills curriculum. Only 62% were comfortable with navigating ethical issues in surgery. About 72% were comfortable with leading a goals-of-care discussion, and 63% of residents were comfortable with offering surgical palliative care options. Case-based discussions over video conferencing were organized monthly. Each session was structured based on the eight-step methodology described by Morley and Shashidhara. Participation was voluntary. The sessions explored moral distress, and the ethical tensions between patient autonomy and beneficence, and beneficence and non-maleficence. SETTING Large general surgery residency in an urban tertiary medical center. PARTICIPANTS General surgery residents. RESULTS A post-intervention survey was performed with improvement in the satisfaction with the non-technical skills curriculum (70% from 36%). The proportion of residents feeling comfortable with navigating ethical issues in surgery increased from 62% to 72%. A survey was performed to assess the efficacy of the moral distress rounds after eight Sip & Share sessions over ten months. All thirteen respondents agreed that the discussions provided them with the vocabulary to discuss ethical dilemmas and define the ethical principles contributing to their moral distress. 93% were able to apply the templates learned to their practice, 77% felt that the discussions helped mitigate stress. All respondents recommended attending the sessions to other residents. CONCLUSIONS Moral distress rounds provide a structured safe zone for residents to share and process morally distressing experiences. These gatherings mitigate isolation, promote a sense of community, and provide a support network within the residency. In addition, residents are equipped with the vocabulary to identify the ethical principles being challenged and are provided practical take-aways to avoid similar conflicts in the future. KEY WORDS Moral distress Moral resilience Ethics Surgery residency Abbreviations PGY, post graduate year ICU, intensive care unit Competencies Systems-Based Practice Professionalism Interpersonal and Communication Skills ==== Body pmcINTRODUCTION The concept of moral distress was first introduced in the nursing literature by Andrew Jameton in 1984, and was described as the psychological distress of being in a situation in which one is constrained from acting on what one knows to be right.1 This insight was based on his observations of nursing students during classroom discussions of bioethical dilemmas, where they described scenarios such as performing painful procedures on patients they that believed to be futile. This concept has since expanded beyond Jameton's original definition to include any psychological distress causally related to a moral event.2 Causes of moral distress can be further subcategorized into five types:• Moral-constraint distress • Moral-uncertainty distress • Moral-conflict distress • Moral-dilemma distress • Moral-tension distress3 Moral distress is certainly apropos to the field of surgery as surgery has been described as an “intense form of applied ethics”,4 where practitioners constantly make decisions and provide treatments with moral implications. Residents are the patient-facing constituent of the surgical service, are tasked with delivering bad news, guiding patients and their families, managing end-of-life care, and are vulnerable to moral distress. Accordingly, the prevalence of burnout among general surgery residents is high, and has been estimated to be between 20% to 69% on multiple large national surveys.5, 6, 7, 8 Unmitigated moral distress in residents can contribute to moral injury and burnout, with deleterious effects on mental and physical well-being, as well as on patient care and outcomes.6 , 9 , 10 This distress was exacerbated during the COVID-19 pandemic, when surgical residents were deployed to care for COVID-19 patients.11 , 12 Residents of all training backgrounds faced moral dilemmas relating to diagnostic and therapeutic uncertainty, allocation of resources, and medical futility with the unprecedented surge in critically ill COVID patients. As surgery residents were grappling with the practical and moral implications of caring for this new group of patients, and experiencing an unprecedented amount of death, our program launched virtual moral distress rounds to address how the pandemic was affecting them as an individual, as a surgical trainee, and as a member of the surgical workforce. These trainee-centric sessions focused on the resident's perspective, emotional reactions, and feelings, to ultimately equip participants with the vocabulary to deconstruct the dilemma, identify the ethical principles and values being challenged or violated, share coping strategies, and identify practical take-aways to diffuse conflicts in the future. This safe zone gave residents a revived sense of community in which they could share and validate feelings, reinforce a common humanity, allow for vulnerability and tolerance for expressing uncertainty, re-invigorate a sense of purpose, and confirm their surgical identity. This capacity of an individual to preserve or restore integrity in response to moral adversity or distress is described as moral resilience.13 After receiving positive feedback from residents on the utility of virtual moral distress rounds in decompressing the cumulative stress of COVID-19 patient care, we decided to expand moral distress rounds to address ethically challenging cases encountered by surgery residents. These moral distress rounds were named “Sip & Share”. MATERIALS AND METHODS Needs Assessment Prior to the intervention, an internal program survey was performed to assess the residents’ satisfaction with the current education curriculum, including resident satisfaction with the non-technical skills curriculum as well as resident comfort with ethically challenging scenarios. The survey was completed by 67 general surgery residents out of 77 total residents in the program with a response rate of 87%. Senior residents (PGY4 and 5) comprised 20% of respondents. Only 36% of residents (24/67 residents) were satisfied or very satisfied with the current non-technical skills curriculum. Only 63% (42/67 residents) were comfortable with navigating ethical issues in surgery. About 72% (48/67 residents) were comfortable or very comfortable with leading a goals-of-care discussion with a patient and their family members, and 63% of residents (42/67 residents) were comfortable or very comfortable with offering surgical palliative care options to a patient and their family members. Senior residents (PGY4 and 5) were more comfortable than junior residents (PGY 1, 2 and 3) with navigating ethical issues (93% vs 55%), leading a goals-of-care discussion (100% vs 64%), and offering surgical palliative care options (93% vs 55%). Prior to the intervention, the non-technical skills curriculum consisted mainly of ethics case discussions and debates. Goals & Objectives The goals of the moral distress discussions were to: (1) provide a safe space for residents to share their feelings that lead to moral distress without being mired down in the clinical details, (2) equip residents with the vocabulary to deconstruct the case, identify the ethical principles and values being challenged, and discuss ethical dilemmas, (3) mitigate the isolation that can accompany moral distress through camaraderie reinforcing that they are a group with a shared common goal – the well-being of our patients, (4) to share coping strategies, and (5) provide practical take-aways. Educational Strategies One-hour “Sip & Share” discussions over video conferencing were organized monthly. General surgery residents were invited to submit their cases to the faculty facilitator, a surgeon-ethicist (M.B.S.) who serves as the residency program director of wellness. Before the session, the facilitator would send out an introductory email to the session often including a reading for background or to illustrate the teaching points of the case. The eight-step methodology described by Morley and Shashidhara (Figure 1 ) was utilized as a framework for these sessions.14 The sessions were optional to all residents and were attended by about 20 residents each time. At the beginning of the session the ‘rules’ are established: the faculty facilitator defines the goals and expectations, explains that the purpose of the gathering is to allow those in attendance to safely express their feelings, and discuss strategies to address future cases with similar challenges. Participants must be allowed to speak uninterrupted; all voices must be heard. It is imperative on a virtual platform that all participants are present – video is ‘on’ for participants to see each other – no ‘in and out’. The presenting resident provides a brief case summary, without getting mired down in the clinical details, labeling the emotions they experienced during and after this clinical encounter. The resident reflects on the experience and deconstructs the case identifying the ethical principles or core values that were being challenged that caused the moral distress. Participants are then invited to share their reactions to the case and their experience with similar cases again labeling their feelings. The facilitator then focuses on practical takeaways, including communication templates and tools that can be used to mitigate conflicts in future cases. The gathering is concluded by the facilitator thanking participants for their courage to speak openly and share with the group. The faculty facilitator sends out an email to the entire residency program the next day summarizing the case presented, lessons learned, and the practical take-aways, and pertinent references as a resource.Figure 1 Summary of eight-step process for moral distress rounds. Figure 1: Implementation Cases reviewed from previous sessions with practical take-aways: Moral Injury A common source of frustration for the mid-level surgical consult resident was when consulting services did not appreciate the patient's level of acuity and when urgent recommendations made by the surgical service were not executed in a timely fashion. The case presented involved a consultation for abdominal distention and obstipation in an elderly patient that was admitted to the medical service for altered mental status. Suspecting a small bowel obstruction, the consult resident recommended placement of a sump decompression tube and abdominal imaging. The tube was not placed in a timely fashion and the patient suffered a terminal aspiration event. The surgical resident expressed regret that he did not simply place the tube himself, but also raised the question regarding the responsibility of the consulting physician to the patient and the necessary communication required to fulfill that obligation; specifically engaging the consulting team and emphasizing the level of acuity and the need for this intervention. This dilemma resonated with many of the residents; through the subsequent active discussion, residents appreciated that they are not alone in these experiences and parsed out what factors contribute to their moral distress in this interaction. In the surgeon-patient relationship the surgeon's action is intimately linked to the response and the outcome of the patient which differs in other areas of medicine. The inability to ‘do the right thing’ – in this case deferring to the consulting team to execute the recommendations, challenges the surgeon's sense of accountability, responsibility, and personal culpability. A surgeon's professional integrity stems from these attributes and violation of these core values results in moral distress. The feelings of frustration, guilt, and compromised integrity can linger if not acknowledged and shared, they can accumulate and intensify contributing to moral injury. Tension Between Patient Autonomy vs. Beneficence A resident described an encounter with a patient diagnosed with a superior mesenteric artery pseudoaneurysm where a recommendation was made for surgical repair to eliminate the risk of rupture. Despite a prolonged conversation regarding the natural history of pseudoaneurysms and the potentially devastating sequelae of foregoing repair, the patient declined surgery. This case illustrates the ethical tension between beneficence and patient autonomy; the surgeon wanting to act in the best interest of their patient while respecting patient autonomy and choice. The presenting resident expressed frustration about the time he devoted to counseling the patient, and his frustration was validated by the other resident participants. When the resident was asked by his peers why the patient refused operative intervention, he admitted that he never asked the patient this question. This led to a robust discussion about the imperative of being curious and keeping our discussions patient centric instead of surgeon centric. The concept of humble inquiry, based on the book by Edgar Schein of the same name, is the art of drawing someone out by asking questions derived from genuine curiosity.15 By exploring the patient's reasons for refusal we can attempt to address their concerns and fears, dispelling misinformation. Learning to be inquisitive and simply asking why can help us to identify the patient's true preferences and values which are integral to the shared decision-making process. This in turn can help us as practitioners cope with our frustrations regarding the choices that patients make that may not be in line with our own values. Tension Between Beneficence vs. Non-maleficence Transitioning from patient care ethics to public health ethics contributed to moral distress for all types of health care providers. At the height of the COVID pandemic, consultations requesting tracheostomies and feeding access contributed to moral confusion and moral distress in many surgical residents. Performing these procedures conflicted with the surgeon's personal values when the surgeon viewed them non-beneficial interventions. There was limited experience with the disease course of COVID and the outcomes after tracheostomy. Importantly, at the peak of the pandemic it was necessary to place tracheostomies and feeding tubes on patients in the intensive care unit (ICU) to allow for their transfer out of the ICU, making beds available for other COVID patients. Many of these patients died soon after transferring out of the ICU. Many residents experienced moral distress due to the tension between beneficence and maleficence; the intention of acting in the patient's best interest with the subsequent realization that the procedure may have caused more harm than benefit. Furthermore, with cessation of all non-emergent surgery at the peak of the pandemic, these procedures were the few operative opportunities available to surgical residents, which contributed to the cognitive dissonance of surgical training versus patient care. Moral Uncertainty Distress A middle-aged patient with significant comorbidities underwent emergent major abdominal surgery and subsequently experienced a complication requiring multiple invasive interventions and a prolonged ICU stay. The resident involved expressed frustration with the nature of a prolonged ICU course – “felt stuck in a holding pattern” and “it's not the pace of surgery”. The resident expressed further frustration in being caught up in the “therapeutic momentum” of proposing additional invasive solutions to each of the patient's maladies even when the patient failed to show any meaningful clinical improvement. This case illustrates the recurrent ethical tension experienced by surgeons between beneficence, patient autonomy, and the concern for maleficence. We discussed how these cases create moral uncertainty distress in that there remains an element of uncertainty as to outcome; at every moment, it is unclear whether the patient will derive any long-term benefit from a string of invasive procedures. There is also moral dilemma distress and an ongoing ethical concern for respecting patient autonomy. While the patient may have agreed to the initial life-saving intervention, every subsequent procedure requires representative consent. Families themselves get caught up in the therapeutic momentum and seek guidance in deciding what is truly in the best interest of their loved one. For the surgeon, ‘wanting to do the right thing’ is challenged by the element of uncertainty as to the outcome and in providing potentially inappropriate treatment with the potential for inflicting harm. As a practical take-away, the option of a time-limited trial was discussed. This approach was described as a patient-centered approach to decrease the utilization of non-beneficial ICU care.16 RESULTS A post-intervention programmatic survey was performed. The proportion of residents satisfied or very satisfied with this non-technical skills curriculum increased from 36% to 70%. The proportion of residents feeling comfortable or very comfortable with navigating ethical issues in surgery increased from 62% to 72%. Approximately 89% were comfortable or very comfortable with leading a goals of care discussion with a patient and their family members, an increase from 72%. In terms of comfort of offering surgical palliative care options, the proportion of residents feeling comfortable or very comfortable increased from 63% to 82%. Other additions to the non-technical skills curriculum included a Residents as Teachers and Leaders series and a Transition to Practice series. Residents were then surveyed to assess the efficacy of these moral distress rounds after eight Sip & Share sessions over ten months. Of the thirteen respondents, all strongly agreed (61%) or agreed (39%) that the discussions provided them with the vocabulary to discuss ethical dilemmas. All respondents strongly agreed (54%) or agreed (46%) that the discussions helped them define the ethical principles that are challenged and contributing to their moral distress. Most respondents strongly agreed (54%) or agreed (39%) that they have been able to apply the lessons and templates learned to their daily interactions with patients. When asked if the discussions helped them mitigate stress, 15% of respondents strongly agreed and 62% agreed with the statement. These questions were used as a surrogate indicator for moral resilience. All respondents strongly recommended (69%) or recommended (31%) attending Sip & Share discussions to other residents. Residents were also allowed to share their perceptions and experience of attending Sip & Share in the survey. This was used as a qualitative assessment of the efficacy of the program. Representative comments included:“I was able to apply the vocabulary I previously learned to real clinical scenarios and thus gain a better understanding of the language used to discuss ethics. The session also reinforced the sense of community among residents where we were able to speak openly in a safe and private setting about our individual experiences and find shared lessons through discussion of our experiences. The session was inclusive and welcoming, and I look forward to participating throughout residency.” “Sip & Share has helped me appreciate the universality of many of my experiences as a surgery resident and has also enabled me to learn from the moral distress of others. I think having it in a more relaxed setting than a formal M&M has enabled it to become a sort of emotional M&M space. It also enables us to share things that aren't appropriate for a setting that includes many attendings but having moderation by an attending helps us put things in context.” “It is a safe space to discuss times where I have felt distressed, upset, or conflicted about a patient's care that I've participated in. These discussions with my peers help me better articulate what exactly I am feeling, and then I am better able to process those feelings and move forward.” “One idea could be to have a session where multiple members from the same care team offer their various perspectives on certain clinical scenarios in order to display and create an opportunity for safe discussion of how different members of a care team experience a situation, whether similarly or differently.” “I grapple with the appropriateness of having the entire residency participate in one discussion. On the one hand I love learning from the more senior residents, and I think that emotional intelligence can vary across years and doesn't necessarily correlate with years of training. There is also something meaningful about putting everyone on the same level. However, I do think there is a higher level of stress and moral responsibility that you feel as you progress through training, and I wonder if it would be good for more senior residents to have a unique forum for that.” DISCUSSION Our study demonstrates the efficacy of moral distress rounds in building resilience among surgery residents. Initially the ethics curriculum in the program included ethics case discussions and debates that were patient-centric where the focus was on identifying patient-centered ethical dilemmas. It became apparent that residents were experiencing moral distress from these cases, the discussions were then adapted to become surgeon-centric, focusing on clinical cases where there were personal or core ethical values that were violated. Residents who participated in the program expressed appreciation for the new set of vocabulary that they now had at their disposal and felt better equipped to define and address ethical challenges. In recent years, the psychological well-being of healthcare providers, and surgery residents in particular, has become a topic of tremendous exploration and debate.7 This issue was exacerbated by the COVID-19 pandemic, where caregiver burnout due to both emotional and moral distress continues to be a threat to the healthcare workforce up to this day.17 Moral distress rounds during the pandemic were therapeutic to most residents. It was the only time we could in some way and be together in a time we had been forced apart. We grieved the losses of patients and even of colleagues. We shared the few success stories with hope to keep the rest motivated. We found it helpful to reframe moral dilemmas from the perspective of others. We channeled negative feelings into opportunities for learning and growth. Moral distress rounds fostered reflection, connectedness, and bolstered resilience. We demonstrate that by creating a safe space for residents to explore the experiences that effect their professional integrity and career identity, we have demonstrated that residents can be empowered with tools to mitigate the moral distress that they will certainly experience throughout their careers in surgery. It is important to make the distinction between emotional distress and moral distress. While emotional distress describes the emotional reaction, sadness, or grief, moral distress is the perceived violation of one's core values with the feeling of being limited from taking an ethically appropriate action. The important distinction is that moral distress is more powerful because it includes the perception that one's professional, personal, or core values are infringed upon.18 , 19 The feelings described by those experiencing moral distress are anger, frustration, anxiety, guilt, powerlessness, and psychological disequilibrium. Moral distress is disruptive to professional and moral integrity. While each episode of moral distress may seem manageable, the cumulative effect of unaddressed moral distress can generate portentous psychological outcomes –depression, suicide, and burnout- and can also be directly dangerous to patient care. Moral distress has the potential to negatively impact work performance, retention, recruitment, and job satisfaction. The post intervention survey that we performed indicates that moral distress rounds were successful in equipping the residents with the vocabulary to define the ethical tension, mitigating moral distress and isolation, and providing practical take-aways to use in similar future encounters. Barriers to education and intervention addressing moral distress and moral injury include the hierarchy inveterate to surgical culture and the stigma against admitting moral distress. Senior surgeons may seem impervious to moral injury and impede or intimidate a trainee from seeking help. Trainees who feel vulnerable within the power hierarchy may be reluctant to express feelings associated with moral distress because of fear of being perceived as weak, lacking confidence, or self-perceived inadequacy, or shame.20 During and after an adverse event our emotions can escalate from ‘this is bad’ to ‘I am bad’. Shame is defined as an intensely painful feeling of believing we are flawed, inadequate and unworthy. Shame is different from guilt. In guilt, we judge our behavior as wrong. Guilt is “I did something bad”; shame is “I am bad”.21 Perfectionism can trigger shame in individuals who experience failure. As surgeons we tend to be perfectionists and therefore are exceptionally vulnerable to shame.22 Moral distress rounds created a forum to discuss this distinction so that residents can appropriately label their own thoughts and emotions in the throes of crisis without feeling shame in doing so. One of the most important aspects of these gatherings was the creation of a non-judgmental safe zone. By expressing and labeling emotions amongst their peers, residents create a moral community that can both mitigate feelings of isolation and foster resilience. A survey comment suggested having separate sessions for each post-graduate year to address the perspectives unique to the level of training as intern, consult resident, and chief resident, which could be one iteration of moral distress rounds. In our experience, the purpose of these gatherings is to promote connection and the reassurance to all residents that residents at all levels of training make mistakes, face uncertainty, fail, and experience both emotional and moral distress. As trainees navigate the challenges of residency, the relationships within this communal support system allow for vulnerability, for questioning, and tolerance for expressing uncertainty.23 One limitation to implementing this framework is the need for a clinical ethicist to serve as the facilitator. An option is utilizing regional or national clinical ethical expertise on the virtual platform. While the intention of these sessions was to add to ethics curriculum which also included case discussions and debates, the voluntary nature of the sessions meant that not all residents experienced these sessions. Inherently there is also a selection bias in that the sessions are voluntarily attended by residents interested in bioethics. Anecdotally the virtual format did allow for more frequent sessions at a time where social interaction in the residency was limited due to the pandemic, but participants did seem to experience Zoom fatigue with the return of in person social/education events. At this time more formal moral distress rounds were also organized during the residency's protected education time to allow all residents to attend. Surgeons experience moral distress throughout their training and careers. We believe there is significant utility to the provision of these safe space gatherings within surgical programs for the resident in training, the surgeon transitioning into the attending role, and even for the seasoned surgeons to mitigate moral distress. CONCLUSIONS Moral distress rounds provide a structured discussion format within a safe zone for residents to share and process clinical experiences that challenge their professional and moral integrity. Addressing moral distress is integral to psychological, emotional, and physical well-being and fosters resilience. Self-care and the maintenance of well-being is constitutive to professionalism and necessary in the provision of quality patient care. Conflict of interest None. ==== Refs References 1 Jameton A. Nursing Practice : The Ethical Issues 1984 Prentice-Hall Englewood Cliffs, N.J. 2 Lamiani G Borghi L Argentero P. When healthcare professionals cannot do the right thing: a systematic review of moral distress and its correlates J Health Psychol 22 2017 51 67 26220460 3 Morley G Bradbury-Jones C Ives J. What is 'moral distress' in nursing? A feminist empirical bioethics study Nurs Ethics. 27 2020 1297 1314 31566094 4 Kodner IJ. Surgeons and clinical ethics Surgery 143 2008 460 462 18374040 5 Dyrbye LN West CP Satele D Burnout among U.S. medical students, residents, and early career physicians relative to the general U.S. population Acad Med 89 2014 443 451 24448053 6 Elmore LC Jeffe DB Jin L Awad MM Turnbull IR National survey of burnout among US general surgery residents J Am Coll Surg 223 2016 440 451 27238875 7 Lebares CC Guvva EV Ascher NL O'Sullivan PS Harris HW Epel ES. Burnout and stress among US surgery residents: psychological distress and resilience J Am Coll Surg 226 2018 80 90 29107117 8 Hu YY Ellis RJ Hewitt DB Discrimination, abuse, harassment, and burnout in surgical residency training N Engl J Med 381 2019 1741 1752 31657887 9 Dewa CS Loong D Bonato S Trojanowski L Rea M. The relationship between resident burnout and safety-related and acceptability-related quality of healthcare: a systematic literature review BMC Med Educ 17 2017 195 10 Hewitt DB Ellis RJ Chung JW Association of surgical resident wellness with medical errors and patient outcomes Ann Surg 274 2021 396 402 32282379 11 Abdelsattar JM Coleman JR Nagler A Lived experiences of surgical residents during the COVID-19 pandemic: a qualitative assessment J Surg Educ 2021 12 Aziz H James T Remulla D Effect of COVID-19 on surgical training across the United States: a national survey of general surgery residents J Surg Educ 78 2021 431 439 32798154 13 Rushton CH. Moral resilience: a capacity for navigating moral distress in critical care AACN Adv Crit Care 27 2016 111 119 26909461 14 Morley G Shashidhara S. Debriefing as a response to moral distress J Clin Ethics 31 2020 283 289 32960811 15 Schein EH. Humble Inquiry: The Gentle Art of Asking Instead of Telling 2021 Berrett-Koehler [S.l.] 16 Chang DW Neville TH Parrish J Evaluation of time-limited trials among critically Ill patients with advanced medical illnesses and reduction of nonbeneficial ICU treatments JAMA Intern Med 181 2021 786 794 33843946 17 Romanelli J Gee D Mellinger JD The COVID-19 reset: lessons from the pandemic on burnout and the practice of surgery Surg Endosc 34 2020 5201 5207 33051763 18 Hamric AB. Empirical research on moral distress: issues, challenges, and opportunities HEC Forum 24 2012 39 49 22476738 19 Epstein EG Hamric AB. Moral distress, moral residue, and the crescendo effect J Clin Ethics 20 2009 330 342 20120853 20 Lillemoe HA Geevarghese SK. Stopping the progression of moral injury: a priority during surgical training Ann Surg 274 2021 e643 e645 34387198 21 Brown B. Dare to Lead: Brave Work. Tough Conversations. Whole Hearts 2018 Vermilion London, England 22 Cameron L. The Power of Self-Compassion. In: Audible; 2020. 23 Traudt T Liaschenko J Peden-McAlpine C. Moral agency, moral imagination, and moral community: antidotes to moral distress J Clin Ethics 27 2016 201 213 27658275

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==== Front Farm Hosp Farm Hosp Farmacia Hospitalaria 1130-6343 2171-8695 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Published by Elsevier España, S.L.U. S1130-6343(22)00012-5 10.1016/j.farma.2022.12.003 Original Resultados en la práctica asistencial y coste marginal del tratamiento con tocilizumab en pacientes COVID-19. Efficacy and marginal cost of treatment with tocilizumab in covid-19 patientsGarcia-Molina A. 12⁎ Alos-Almiñana M. 123 1 Hospital Clínico Universitario de Valencia. Av. De Blasco Ibáñez, 17, 46010, Valencia, (Valencia) 2 Fundación INCLIVA. Av. Menéndez y Pelayo 4, acc, 46010, Valencia (Valencia) 3 Universidad de Valencia. Av. Blásco Ibañez, 13, 46010, Valencia (Valencia) ⁎ Autor para correspondencia: Dirección postal (permanente): Paseo de la estación, 29, 5°A, 02630, La Roda, (Albacete). 15 12 2022 15 12 2022 12 4 2022 26 8 2022 © 2022 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Published by Elsevier España, S.L.U. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objetivo: Describir el coste marginal y la supervivencia de los pacientes tratados con tocilizumab en un hospital universitario en condiciones de vida real. Y evaluar los factores que podrían influir los costes y los resultados en salud. Metodología: Estudio observacional, retrospectivo y unicéntrico de una cohorte de pacientes adultos infectados con SARS-COV2 tratados con tocilizumab. Se analizó, en años de vida ganados (AVG), la media de supervivencia restringida a 1 año. Se evaluó la influencia del sexo, la edad y la gravedad en la supervivencia de los pacientes. Se calcularon el ratio coste marginal/AVG y coste marginal/superviviente. Resultados: Se incluyeron 508 pacientes (66 ± 13 años; 32% mujeres). Un 17% ingresó en UCI. La supervivencia global fue del 77%. Se identificaron como factores de riesgo la edad mayor de 71,5 años (HR = 1,08; IC95% 1,07–1,10; p < 0,001), y el ingreso en UCI al iniciar el tratamiento (HR = 2,01; IC95% 1,30–3,09; p = 0,002). El impacto presupuestario total de tocilizumab en el periodo analizado ascendió a 206.466€. Los pacientes con mayor coste por unidad de resultado en salud son los pacientes ingresados en UCI y mayores de 71,5 años, que presentan un coste marginal/AVG de 966 € y un coste marginal/superviviente de 1.136€. Conclusión: La eficiencia del tratamiento con tocilizumab se asocia a la edad y a la gravedad de los pacientes. Las cifras son inferiores en todos los subgrupos a los umbrales habitualmente utilizados en las evaluaciones coste-efectividad. Los resultados del presente estudio sugieren que el inicio precoz de tocilizumab es una estrategia eficiente. Objective: To describe the marginal cost and survival of patients treated with tocilizumab in a university hospital under real-life conditions and to evaluate factors that could influence costs and health outcomes will be evaluated. Methods: Observational, single-center, retrospective study of a cohort of adult patients infected with SARS-COV2 treated with tocilizumab. The 1 year restricted mean survival time was analyzed in life-years gained (LYG). The influence of sex, age and severity on patient survival was evaluated. The marginal cost/LYG and marginal cost/survivor ratios were calculated. Results: 508 patients (66 ± 13 years; 32% women) were included. Seventeen percent were admitted to the ICU. Overall survival was 77%. Age older than 71.5 years (HR = 1.08; 95%CI 1.07–1.10; p < 0.001) and ICU admission at initiation of treatment (HR = 2.01; 95%CI 1.30–3.09; p = 0.002) were identified as risk factors. The total budgetary impact of tocilizumab in the period analyzed was 206,466 euros. The patients with the highest cost per unit of health outcome were those admitted to the ICU and those over 71.5 years, with a marginal cost/LYG of €966 and a marginal cost/survivor of €1136. Conclusion: The efficiency of treatment with tocilizumab is associated with the age and severity of the patients. The figures are lower in all subgroups than the thresholds usually used in cost-effectiveness evaluations. The results of the present study suggest that early first dose of tocilizumab is an efficient strategy. Palabras clave SARS-COV2 tocilizumab farmacoeconomía asistencia sanitaria farmacología Keywords SARS-COV2 tocilizumab pharmacoeconomics delivery of health care pharmacology ==== Body pmcAportación a la literatura científica. La pandemia producida por el SARS-COV2 ha tenido un gran impacto tanto en los sistemas de salud, como en los sistemas socioeconómicos y políticos de todo el mundo, por ello, es relevante la evaluación de los factores, tanto demográficos/clínicos, como económicos para tener una visión crítica de lo sucedido durante los meses de mayor incidencia de infectados y fallecidos por COVID-19. Es importante tener datos de la efectividad de los tratamientos que utilizamos en las condiciones de uso en la práctica asistencial. Además, es interesante identificar los subgrupos de población que potencialmente van a tener mejores resultados. Los resultados del estudio cuantifican la eficiencia del tratamiento con tocilizumab en los pacientes con COVID-19 y sugieren que el inicio precoz de tocilizumab puede ser una opción terapéutica eficiente con respecto a su uso en pacientes graves. Estos resultados deben tenerse en cuenta a la hora de plantear el abordaje terapéutico de los pacientes con riesgo de padecer complicación por la infección del virus. INTRODUCCIÓN. La enfermedad causada por el SARS-COV2 cursa con diversas manifestaciones y fases clínicas (fase viral, pulmonar e inmunológica)1, El tratamiento farmacológico se basa en el uso de fármacos antivirales, inmunomoduladores y otros para combatir las complicaciones asociadas. Durante la fase viral el objetivo terapéutico se centra en disminuir la carga vírica. El fármaco con propiedades antivirales más utilizado es remdesivir. No obstante, la evidencia en cuanto su utilización es modesta, mostrando una reducción en el tiempo de recuperación de pacientes hospitalizados limitada2. Tras la fase viral se observa un estado de hiperinflamación sistémica que puede acompañarse de un síndrome de liberación de citoquinas en los pacientes más graves, con elevación de numerosas citoquinas como IL-6, IP10, MCP1, TNF-α, IL-2R y la IL-103 , 4. Durante este estado inflamatorio se produce la desregulación de monocitos, macrófagos y células dendríticas que provoca la acumulación de infiltrados de macrófagos a nivel pulmonar y provoca un síndrome hemofagocítico5. La utilización de corticoides sistémicos como la dexametasona han demostrado disminuir la mortalidad en pacientes críticos6. La IL-6 parece tener un papel importante en la regulación de la respuesta inmune en los pacientes con COVID. La elevada concentración de IL-6 observada en pacientes graves convierte sus antagonistas farmacológicos en potenciales candidatos a tratamiento de esta fase de la enfermedad. No obstante, la respuesta inflamatoria es compleja y multifactorial. Intervienen otras vías de señalización como la vía JAK1/2-STAT que participa en el proceso de activación macrofágica hacia el perfil M2 tras la activación del IL-4R7. Esto genera otra nueva diana terapéutica para inhibidores JAK1/2 como el baricitinib en la fase inflamatoria de los pacientes COVID. Otros fármacos inmunomoduladores han sido utilizados durante el transcurso de la pandemia como el ruxolitinib, anakinra y colchicina8 , 9. Tocilizumab es un anticuerpo monoclonal humanizado que se une al receptor de IL-6 (IL6-R), tanto receptor soluble como unido a membranas, con indicación en artritis reumatoide y artritis juvenil idiopática. Las dosis habituales utilizadas en artritis reumatoide son 4 mg/kg u 8 mg/kg vía intravenosa cada cuatro semanas. También existe presentación subcutánea de 162 mg que se administra semanalmente10. Dado el carácter pleiotrópico de IL-6R y su rol central en el control de la inflamación se utiliza como tratamiento en el síndrome de liberación de citoquinas que se produce tras la administración de la terapia CAR-T. Las similitudes entre este cuadro clínico y el causado por el SARS-COV2 han propuesto a tocilizumab como potencial agente terapéutico11. No obstante, los estudios publicados son inconsistentes y generan dudas sobre la efectividad de tocilizumab. La supervivencia en pacientes con enfermedad moderada no mejoró con la administración de tocilizumab12 , 13. Sin embargo, en pacientes críticos el bloqueo de IL-6R con tocilizumab (o sarilumab) mejoró la supervivencia, demostrando un claro beneficio clínico en estos pacientes14. La pandemia del COVID-19 tiene gran repercusión en los sistemas sanitarios y es necesaria la evaluación del impacto económico de las estrategias terapéuticas15. Los principales costes de la hospitalización son los gastos en pruebas diagnósticas, tanto de laboratorio como de imagen y el gasto en medicamentos16. Por este motivo es importante realizar un análisis económico del coste de las opciones terapéuticas que se utilizan en la práctica clínica habitual. El objetivo principal de este trabajo es describir los costes marginales y la supervivencia de los pacientes tratados con tocilizumab en un hospital universitario en condiciones de vida real y evaluar los factores que podrían influir los costes y los resultados en salud. MATERIAL Y MÉTODOS. Estudio observacional retrospectivo y unicéntrico en una cohorte de pacientes hospitalizados con COVID-19 que recibieron al menos una dosis de tocilizumab durante el periodo de estudio comprendido desde febrero de 2020 hasta febrero de 2021. El estudio fue aprobado por el CEIm del Hospital. Los criterios de inclusión fueron: pacientes mayores de 18 años con diagnóstico confirmado de infección por SARS-CoV2 por PCR o test de antígenos o evidencia clínica de neumonía COVID-19 e ingreso en unidades de hospitalización. Los pacientes se estratificaron en función de la gravedad en: pacientes críticos (UCI: hospitalización en unidad de pacientes críticos) y pacientes no críticos (hospitalización convencional en unidades médicas) (UH). La clasificación se realizó en el momento de la primera administración de tocilizumab. Se excluyeron los pacientes que recibieron tocilizumab en este periodo para indicaciones reumatológicas o hematológicas. Las dosis utilizadas de tocilizumab fueron 400 mg para pacientes con peso menor de 75 kg y 600 mg en pacientes con peso mayor de 75 mg en dosis única, aunque se permitió la administración de dosis sucesivas si la situación clínica lo requería. No se estableció un número máximo de dosis de tocilizumab. Se realizó una dispensación y registro individualizado de tocilizumab. Se evaluó la supervivencia desde la administración de la primera dosis de tocilizumab hasta el final del seguimiento o el exitus por COVID-19. El paciente fallecido por una causa no vinculada al evento de interés se consideró como censurado. Cuando los tiempos de supervivencia no se conocían con exactitud o no se ha producido el evento, los datos se consideraron también como censurados. La supervivencia se analizó mediante el método de Kaplan–Meier y la media de supervivencia restringida (RMST) a 1 año. Se realizó un análisis de regresión de COX para identificar posibles factores de riesgo asociados a la supervivencia: edad, sexo y área de hospitalización (UCI/UH). Para la categorización de la variable edad se construyó previamente una curva ROC que permitió identificar el punto de corte con mayor sensibilidad y especificidad mediante la aplicación del índice de Youden. Para el análisis estadístico se utilizó el software SPSS ®. El análisis de costes se ha llevado a cabo desde la perspectiva del financiador, considerando exclusivamente como coste marginal el coste de adquisición de tocilizumab, en euros. Dependiendo de la disponibilidad de las diferentes presentaciones, los viales de tocilizumab que se emplearon fueron de 80, 200 y 400 mg con un coste de 114€, 285€ y 573€ respectivamente. No se aplicó tasa de descuento, por tratarse de un horizonte temporal restringido. Los años de vida ganados (AVG) se calcularon como producto de la media de supervivencia restringida (RMST) multiplicado por el número de pacientes en cada subgrupo analizado. El número de supervivientes se calculó como producto de la probabilidad de supervivencia al final del estudio multiplicado por el número de pacientes en cada subgrupo analizado. Como aproximación a la evaluación de la eficiencia se calcularon el ratio coste marginal/AVG y el ratio coste marginal/superviviente. El proyecto de investigación con número de expediente 85/21 fue aprobado el 31/05/2021 por el CEIm del Hospital Clínico Universitario de Valencia. RESULTADOS Se identificaron 508 pacientes que cumplían criterios de inclusión del estudio. La media de edad fue de 66 ± 13 años; un 32% eran mujeres. Se clasificaron como pacientes críticos en el momento de la primera administración de tocilizumab 87 pacientes (17%). La supervivencia global registrada en el conjunto de los pacientes incluidos en el estudio fue del 77%. A lo largo de las sucesivas “olas” el Hospital se ha visto afectado de modo variable en el periodo que abarca el estudio (Figura 1). El número de pacientes tratados con tocilizumab fue claramente mayor en el periodo comprendido entre noviembre y enero del 2021, coincidiendo con los peores datos de evolución de la pandemia. Además, la proporción de pacientes de pacientes ingresados en UCI fue muy superior en la primera “ola” (marzo 2020 – mayo 2020) que en la segunda (agosto 2020 – febrero 2021). Sin embargo, no existen diferencias estadísticamente significativas (p = 0,97) en la supervivencia entre ambos periodos que fueron, respectivamente, del 74% y del 77%. En el análisis de regresión de COX (Figura 2) se identificaron como factores de riesgo de muerte la severidad médica del proceso y la edad del paciente. La variable sexo no mostró influencia en la mortalidad en la población analizada. En el horizonte analizado (1 año), en ninguno de los grupos se alcanza la mediana de supervivencia. En cuanto a la severidad clínica del proceso, se utilizó como variable subrogada el ingreso en UCI o en UH; esta variable mostró un HR = 2,01 (IC95% 1,30 – 3,09; p = 0,002). Con relación a la edad de los pacientes, como se indicó más arriba el análisis de la curva ROC, indicó que el punto de corte óptimo, con una sensibilidad y especificidad de 0,701, se situaba en 71,5 años. En el análisis de regresión de COX, la edad mayor de 71,5 años mostró un HR = 1,08 (IC95% 1,07 – 1,10; p < 0,001). Cuando se evalúa la edad mayor de 71,5 años (figura 2), grupo que incluye 309 (70%) pacientes, la supervivencia al final del estudio (59%) resulta estadísticamente muy inferior (p < 0,001) a la observada (89%) en los pacientes de menor edad. En el análisis de supervivencia estratificado según la severidad del cuadro (UCI/UH), los pacientes ingresados en las UCI presentaron una supervivencia estadísticamente (p = 0,037) inferior (68%) a la de los pacientes hospitalizados en unidades médicas (79%). La mortalidad al día 90 tras la administración de tocilizumab fue del 33% en los pacientes ingresados en las UCI y del 21% en los pacientes ingresados en unidades médicas de hospitalización convencional (UH). En este estudio, la mortalidad fue 41% en los mayores de 71,5 años frente a 11% en los menores de esta edad. El coste de adquisición de tocilizumab es prácticamente el mismo en todo el periodo analizado. El impacto presupuestario total de tocilizumab en el periodo analizado ascendió a 206.466€. Sin embargo, el coste marginal por AVG o por superviviente es diferente en los distintos subgrupos de la población (Tabla 1 ). Las mayores diferencias en eficiencia se encuentran entre los subgrupos de población mayores de 71,5 años (701 €/AVG y 726 €/superviviente) y menores de esta edad (467€/AVG y 478 €/superviviente). (See Figura 1, Figura 2 .)Tabla 1 Se presentan, como información de la supervivencia, el valor de la media de supervivencia restringida a 1 año (RMST) para el conjunto de los pacientes (n = 508) y en cada subgrupo analizado en función de la gravedad del paciente y la edad.Asimismo, se muestran, el coste marginal por AVG o por superviviente, en euros para los distintos subgrupos de la población. Tabla 1Subgrupo n RMST (años) Coste marginal / AVG (€) Coste marginal /superviviente (€) Global 508 0,761 530 € 552 € Severidad UCI 87 0,676 666 € 675 € UH 421 0,764 579 € 551 € Edad Mayores 71,5 199 0,581 701 € 726 € Menores 71,5 309 0,872 467 € 477 € Figura 1 El periodo de tiempo incluido en el presente estudio abarca desde febrero de 2020 a febrero de 2021. Se recoge en la figura la evolución mensual de los ingresos por COVID durante ese periodo. En los datos se han incluido el número total de pacientes ingresados cada mes (Pacientes); el número de pacientes ingresados en unidades de pacientes críticos (Pacientes uci) o en unidades convencionales de hospitalización (Pacientes planta); y, también, el número de tratamientos de tocilizumab (N° Dosis) administrado mensualmente en el periodo estudiado. Figura 1 Figura 2 En el análisis de supervivencia se muestran por separado la influencia de la edad mayor de 71,5 años (figura 2a) y de la gravedad de la situación del paciente (figura 2b), subrrogada al ingreso en las unidades de pacientes críticos (UCI) o en las unidades de hospitalización convencional (UH). En el horizonte analizado (1 año), en ninguno de los grupos se alcanza la mediana de supervivencia. En cuanto a la severidad clínica del proceso (UCI/UH) el hazard ratio mostró un valor de HR = 2,01 (IC95% 1,30 – 3,09; p = 0,002). Con relación a la edad por encima de los 71,5 años el HR = 1,08 (IC95% 1,07 – 1,10; p < 0,001). El eje de abcisas presenta el tiempo en días. Figura 2 Por otra parte, en un análisis estratificado se observó que los pacientes con mayor coste por unidad de resultado en salud son los pacientes ingresados en UCI y mayores de 71,5 años, que presentan un coste marginal/AVG de 966 € y un coste marginal/superviviente de 1.136€ (Tabla 2 ).Tabla 2 Como aproximación a la eficiencia del tratamiento con tocilizumab, se presenta un análisis estrtificado, en base a la edad y la gravedad de los pacientes, de los valores Coste margina/AVG (€) y Coste marginal/superviviente(€). Los pacientes con mayor riego de mortalidad, mayores de 71,5 años ingresados en UCI, presentan los valores más altos de Coste marginal/AVG (966 €) y Coste marginal/superviviente(1.136 €). Tabla 2 Mayores 71,5 años Menores 71,5 años UCI Coste marginal/AVG (€) 966 € 576 € Coste marginal/superviviente(€) 1.136 € 589 € UH Coste marginal/AVG (€) 679 € 451 € Coste marginal/superviviente(€) 680 € 468 € DISCUSIÓN. En la población en estudio se han identificado como factores pronósticos negativos de supervivencia la edad mayor de 71 años y la gravedad de la situación clínica del paciente al inicio del tratamiento con tocilizumab. La evaluación de estos factores es importante dada la disparidad de resultados de eficacia que muestran los ensayos clínicos realizados, que reportan tasas de mortalidad similares del tratamiento con tocilizumab en comparación con placebo o el mejor tratamiento estándar12 , 13 , 17., 18., 19.. Además, otros parámetros de eficacia como la disminución del riesgo de ingreso en UCI o el riesgo de ventilación de mecánica también muestran resultados controvertidos. No obstante, los investigadores del REMAP-CAP han reportado resultados favorables a tocilizumab con una disminución significativa en la reducción de la mortalidad en pacientes críticos con necesidades de soporte respiratorio o cardiovascular14. La mortalidad de nuestros pacientes críticos es ligeramente más alta que la reportada en REMAP-CAP. Esto puede explicarse por la elevada presión asistencial sobre las UCI y por la gravedad de los pacientes en el periodo analizado. En un análisis post-hoc se reporta una mortalidad del 11% en el día 90 en pacientes sin requerimientos de ventilación mecánica tratados con tocilizumab20, concluyendo que el tocilizumab podría ser una buena opción para este tipo de pacientes cuándo además presenten valores de proteína C reactiva (PCR) menores de 150 mg/L. Teniendo en cuenta el porcentaje de mortalidad obtenido en nuestro estudio en pacientes menores de 71,5 años cabe esperar que esta población sea la que mejores resultados de supervivencia obtenga. La disparidad en estos resultados radica en la variabilidad de criterios de inclusión en los estudios, del tiempo de inicio de tratamiento con tocilizumab y de otros factores como los tratamientos asociados que reciben los pacientes21. Por ello, es importante reflejar la realidad del pronóstico de los pacientes en la práctica clínica habitual. Uno de los puntos clave fue la inclusión del tratamiento con corticoides sistémicos tras la evidencia en la mejora de la supervivencia en julio de 20206. Además, otro factor que distingue las diferentes “olas” de la fue el diferente manejo clínico; más incierto durante la primera ola, cuando se utilizaron estrategias terapéuticas como la hidroxicloroquina, el interferón-beta o la combinación lopinavir/ritonavir, finalmente en desuso tras haber demostrado la falta de eficacia22 , 23. Por su peor pronóstico, la población con mayor coste por año de vida ganado (AVG) son los pacientes críticos mayores de 71,5 años. No obstante, los beneficios potenciales del tratamiento en cuanto a la reducción de la estancia en UCI y disminución del tiempo total de ingreso hospitalario podrían superar potencialmente el mayor coste marginal observado. La media de edad reportada en el estudio REMAP-CAP14 fue similar a la de nuestra cohorte. Estos datos están en consonancia con los reportados recientemente en un meta-análisis que incluye un total de más de 10.000 pacientes. En este estudio, se observó un menor riesgo de muerte en el grupo de tocilizumab frente al placebo o el mejor cuidado estándar de los pacientes. En el análisis por edades de este meta-análisis se reporta beneficio del tratamiento con tocilizumab en pacientes mayores de 70 años, edad similar a la encontrada en nuestro estudio como punto de corte. Asimismo, el estudio informa de una mortalidad del 40% en el día 28 en este grupo de pacientes, en concordancia con la mortalidad reportada en nuestra cohorte. Aunque la diferencia de costes pueda parecer poco significativa en términos absolutos, en términos relativos el coste/superviviente supone un 140% más en pacientes UCI mayores de 71,5 años con respecto a pacientes UH menores de 71,5 años. En términos de impacto presupuestario, en un contexto global de pandemia, pueden cobrar mayor importancia. Especialmente, en circunstancias severas de desabastecimiento de tocilizumab que podrían plantearse en un futuro. Por otra parte, además de los gastos directos asociados a la adquisición del medicamento, es factible analizar o modelizar otros costes sanitarios directos, en particular los derivados de una reducción del riesgo de ingreso en las UCI y de la disminución de la estancia hospitalaria24. Pero, esta posibilidad supera los objetivos del presente estudio. Los datos presentados se centran en una aproximación a la eficiencia del uso de tocilizumab en la práctica clínica real, cuantificando el coste marginal/AVG y el coste marginal/superviviente en la práctica clínica real y deberían tenerse en cuenta a la hora de seleccionar los tratamientos óptimos en cada momento y para cada paciente, incluyendo otras alternativas como baricitinib que también han demostrado mejorar el pronóstico de pacientes COVID-19 25. En resumen, el tratamiento con tocilizumab en pacientes COVID-19 continúa generando incertidumbre en cuanto a su eficacia, tanto en la disminución de la gravedad de la enfermedad como en la mejora de la supervivencia26. En nuestro análisis se han detectado diferencias en la supervivencia, en función de la gravedad clínica al inicio del tratamiento, entre pacientes que reciben tocilizumab en las UCI y en las UH. Asimismo, se ha evidenciado el mejor pronóstico de supervivencia para los pacientes menores de 71,5 años. En el presente estudio, la eficiencia del tratamiento con tocilizumab se asocia a la edad y a la gravedad de los pacientes. Pero, en cualquier caso, las cifras se sitúan en todos los subgrupos evaluados muy por debajo de los umbrales habitualmente utilizados en las evaluaciones coste-efectividad. En consecuencia, los resultados del presente estudio sugieren que el inicio precoz de tocilizumab es una estrategia eficiente. Declaración de autoría. Como autor principal del trabajo declaro que mi participación en el estudio ha sido la de participar en el diseño del mismo, la recogida y análisis de datos, así como, la redacción, elaboración de las tablas y figuras y preparación del documento para el envío. 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Med. 383 2020 2333 2344 10.1056/NEJMoa2028836 33085857 13. Hermine O. Mariette X. Tharaux P.L. Resche-Rigon M. Porche R. Ravaud P. CORIMUNO-19 Collaborative Group Effect of Tocilizumab vs Usual Care in Adults Hospitalized with COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial JAMA Intern. Med. 181 2021 32 40 10.1001/jamainternmed.2020.6820 33080017 14. Investigators R.E.M.A.P.-C.A.P. Gordon A.C. Mouncey P.R. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 N Engl J Med. 384 16 2021 1491 1502 10.1056/NEJMoa210043315 33631065 15. Sutherland J. The Mounting Opportunity Cost of Pivoting to COVID-19-Related Health Systems and Services Research Healthc. Policy | Polit. Santé 16 2021 6 15 16. Zhao J. Yao Y. Lai S. Zhou X. Clinical immunity and medical cost of COVID-19 patients under gray relational mathematical model Results Phys. 22 2021 103829 10.1016/j.rinp.2021.103829 17. Rosas I.O. Bräu N. Waters M. Go R.C. Hunter B.D. Bhagani S. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia N Engl J Med. 384 16 2021 1503 1516 10.1056/NEJMoa2028700 33631066 18. Salama C. Han J. Yau L. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia N Engl J Med. 384 1 2021 20 30 10.1056/NEJMoa2030340 33332779 19. Salvarani C. Dolci G. Massari M. Merlo D.F. Cavuto S. Savoldi L. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized with COVID-19 Pneumonia: A Randomized Clinical Trial JAMA Intern. Med. 181 2021 24 31 10.1001/jamainternmed.2020.6615 33080005 20. Mariette X. Hermine O. Tharaux P.L. Resche-Rigon M. Steg P.G. Porcher R. Effectiveness of Tocilizumab in Patients Hospitalized With COVID-19: A Follow-up of the CORIMUNO-TOCI-1 Randomized Clinical Trial JAMA Intern. Med. 2021 10.1001/JAMAINTERNMED.2021.2209 21. Rubin E.J. Longo D.L. Baden L.R. Interleukin-6 Receptor Inhibition in Covid-19 — Cooling the Inflammatory Soup N. Engl. J. Med. NEJMe2103108 2021 10.1056/nejme2103108 22. RECOVERY Collaborative Group Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19 N Engl J Med. 383 21 2020 2030 2040 10.1056/NEJMoa2022926 33031652 23. RECOVERY Collaborative Group Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial Lancet. 396 10259 2020 1345 1352 10.1016/S0140-6736(20)32013-4 33031764 24. RECOVERY Collaborative Group Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial Lancet. 397 10285 2021 May 1 1637 1645 10.1016/S0140-6736(21)00676-0 33933206 25. Goletti D. Cantini F. Baricitinib Therapy in Covid-19 Pneumonia — An Unmet Need Fulfilled N. Engl. J. Med. 384 2021 867 869 33657299 26. Sinha P. Linas B.P. Combination Therapy With Tocilizumab and Dexamethasone Cost-Effectively Reduces Coronavirus Disease 2019 Mortality Clin. Infect. Dis. 2021 10.1093/CID/CIAB409

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==== Front Egypt Rheumatol Egypt Rheumatol The Egyptian Rheumatologist 1110-1164 2090-2433 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. S1110-1164(21)00047-8 10.1016/j.ejr.2021.06.001 Article Systemic flare and cutaneous ulceration following cytomegalovirus infection in a patient with anti-melanoma differentiation-associated protein 5 (MDA5) associated myositis: Diagnostic challenge during the time of coronavirus disease (COVID-19) pandemic Gupta Prakash a Kharbanda Rajat b Lawrence Able b Gupta Latika b⁎ a Saint Louis University Hospital of the Sacred Heart-Baguio City, Virgen Milagrosa University Foundation-College of Medicine, San Carlos City, Pangasinan, Philippines b Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India ⁎ Corresponding author. 9 6 2021 10 2021 9 6 2021 43 4 271274 26 3 2021 5 6 2021 © 2021 THE AUTHORS 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Anti-melanoma differentiation-associated protein 5 (MDA5) associated idiopathic inflammatory myopathy (IIM) often manifests with minimal muscle weakness and rapidly progressive interstitial lung disease (RP-ILD) with a poor prognosis. The clinical presentation may be varied in different ethnic groups. The ongoing coronavirus disease (COVID-19) pandemic has made management even more challenging as certain manifestations may be difficult to diagnose remotely. Aim of the work To throw light on the rare association of CMV infection in established anti-MDA5 myositis with severe consequences. Similar cases were presented and compared. Case report A 42-year-old lady presented with heliotrope rash, periorbital edema, ulcerated Gottron’s papules, proximal muscle weakness and intermittent fever of six-month duration. Anti-MDA5 antibodies were positive. Active disease, including myocarditis and RP-ILD, were challenging to diagnose on teleconsultation. Upon initiating tofacitinib, cytomegalovirus (CMV) polymerized chain reaction (PCR) came positive. Ganciclovir was started with the possibility of viral activation being the potential driving force for interferon pathway activation and dermatomyositis (DM) flare, but the patient succumbed to the illness. Conclusion Viral triggers are known to induce autoimmune disease in the genetically predisposed. However, CMV infection in established anti-MDA5 myositis is uncommon and further association with myocarditis is a rare occurrence. Ulcerated Gottron’s and periorbital oedema may carry a sinister connotation in Indians with anti-MDA5 DM, with worse manifestations such as myocarditis– which albeit rare, can be fatal. Keywords Myositis Dermatomyositis Cytomegalovirus Teleconsultation Immunodeficiency ==== Body pmc1 Introduction: Dermatomyositis (DM) presents with florid muscle weakness and varied cutaneous manifestations and comprises skin features as heliotrope rash, gottron’s papules, macular erythema, and occasionally palmar papules and skin ulceration [1], [2]. In contrast, anti-melanoma differentiation-associated protein 5 (MDA5) positive DM is a rare subset which oftentimes manifest with minimal muscle weakness and rapidly progressive interstitial lung disease (RP-ILD) with a poor prognosis unless diagnosed by testing for specific Myositis-specific antibodies (MSAs) [3], [4]. Classic cutaneous manifestations vary in different ethnic groups and may be important pointers towards diagnosis [5], [6]. Cutaneous ulceration is reported in 50% of anti-MDA5 associated idiopathic inflammatory myopathies (IIM), most frequently over the elbows, knuckles, knees, lateral nail folds and also seen over sun exposed areas as chest or back [1], [3]. Interstitial lung disease (ILD) among Asians is generally rapidly progressive compared to Westerners and frequently culminates in fatal outcomes with up to 70% mortality in patients with anti-MDA5 IIM [4], [5]. It is crucial to initiate prompt intensive treatment for RP-ILD with anti-MDA5 antibody due to its poor prognosis. The measurement of titer of anti-MDA5 antibodies takes several days and this can delay the necessary intervention. Consequently, identifying key clinical signs in suspects can offer important guidance for initiating early aggressive therapy. The ongoing coronavirus disease (COVID-19) pandemic has made management challenging as certain manifestations may be difficult to diagnose remotely. As we are in the midst of an unprecedented pandemic, we can only speculate the long-term effects and implications of COVID-19 [6]. A negative impact of the pandemic on the QoL of RA patients has been described [7]. Among persons with COVID-19, the development of fibromyalgia syndrome was anticipated as a consequence to pandemic-associated stressors [6]. A causal relationship between vasculitis and viral infections has been postulated. Vasculitis is potentially one of COVID-19′s presenting symptoms and prompt diagnosis and treatment is crucial in improving outcome of patients [8]. Viral triggers are known to induce autoimmune disease in the genetically predisposed. However, the hypothesis that viral infections can drive autoimmunity in established anti-MDA5 myositis is proposed but poorly studied. Myocarditis is another cause of mortality in IIM though not typically described in anti MDA5 IIM. A case is presented with anti MDA5 positive IIM with CMV infection associated flare of dermatomyositis (DM), who succumbed to RP-ILD and myocarditis. Albeit rare, myocarditis should be actively looked out for in patient with MDA5 positive IIM. 2 Methods A search was conducted using the terms (“Cytomegalovirus and myositis”) published on MEDLINE any time. Of fifty-eight articles obtained, 38 case reports were identified. After excluding articles in languages other than English and those without available full-text, six reports were used for further analysis. Written consent was obtained from the patient described (Fig. 1 ).Fig. 1 Flow chart for the search strategy of the terms (“Cytomegalovirus and myositis”) published on MEDLINE any time. 3 Case presentation A 42-year-old lady presented with heliotrope rash and periorbital edema, ulcerated Gottron’s papules, proximal muscle weakness, and intermittent fever of six-month duration. Computerized Tomography (CT) of the chest suggested early ILD. Myositis specific autoantibodies were sent, and azathioprine (AZA) initiated for DM. The patient developed cytopenia with AZA which improved on discontinuing the drug though the patient’s condition rapidly deteriorated during the imposed lockdown period. She returned with symptoms of easy fatiguability, dyspnea, and vasculitis ulcers over the Gottron’s rashes, elbow, and feet (Fig. 2 a–d) requiring in-patient admission nine months after initial presentation and 15 months into the illness. Anti- MDA5 antibodies tested positive. 2D-Echocardiography confirmed systolic dysfunction and CT revealed rapid progression of interstitial lung disease (RP-ILD), both of which were missed on teleconsultations (Fig. 2e, f).Fig. 2 A: Heliotrope rash with periorbital puffiness; B: Vasculitis ulcer over knuckles; C: Vasculitis ulcer involving elbow; D: Vasculitis ulcer involving feet; E: Both the lung fields having patchy consolidations with ground glass opacities suggestive of an organizing pneumonia pattern; F: Timeline of the patient's clinical manifestations along with treatment. As she continued to worsen despite pulse methylprednisolone and cyclophosphamide, tofacitinib was initiated. However, it had to be discontinued after CMV polymerized chain reaction (PCR) turned positive. She was treated with ganciclovir with the possibility of viral activation being the potential driving force for interferon pathway activation and flare of DM. Despite continuing high dose glucocorticoids and antivirals, CRP (18 mg/dl) and high ferritin (>1500 ng/ml) remained high, and patient succumbed to her illness over a fortnight of in-patient management. 4 Discussion Ulcerated Gottron’s and periorbital edema can be important clues to underlying anti-MDA5 DM and viral activation could be the underlying driver of autoimmunity [9]. Six other cases were identified in literature reporting the intersection of CMV with IIM (Table 1 ). A few cases were successfully managed with ganciclovir though many succumbed despite treatment. High mortality of anti-MDA5 positive DM and association with CMV infections and seasonality of the former opens the case to explore underlying inborn immune pathway defects which may predispose these individuals to viral infections [10]. Recently identified similarity between COVID-19 and anti-MDA5 positive IIM further highlights an important role of viruses in triggering and sustaining autoimmunity. MDA5 being the cytoplasmic sensor for viral RNA could potentially predispose to infections when defective or lead to autoimmunity from hyperfunctioning gain-of-function mutations. Autoimmunity and primary immunodeficiency are now known to be along a continuum, with the recent recognition of heritable digenic and polygenic defects in several autoimmune disorders with widespread availability of whole exome sequencing [11].Therefore, it seems plausible that greater insight into the area may potentially classify anti-MDA5 DM as an adult-onset primary immunodeficiency with autoimmunity with important therapeutic implications [12]. Milder disease course in another subset of anti-MDA5 IIM suggests the disease may be bi-phenotypic with two distinct variants in the Indian population [9].Table 1 Association of cytomegalovirus (CMV) infection with myositis case reports. Case Report Country/year Caseage/sex Risk factors With CMV MSA Other organs involved Treatment Outcome Gupta et al India/2021 42/F DM Yes MDA5 Myocarditis, ILD AZA, MP, CYC, tofacitinib, GCV Death Sakthivadivel et al [14] India/2020 29/M GBS Yes None Oral ulcer, Myonecrosis P, valganciclovir, plasmapheresis Improved with plasmapheresis. Zhang et al [15] China/2020 61/M DM Yes None Pneumonia, Bronchitis MP, moxifloxacin, TZP, oseltamivir, voriconazole, GCV. Resolved after 4 days Lange et al [16] USA/2018 Middle aged/F MAS Yes anti-RNP anti-Ro Endocarditis, DPI, GNB, UTI Valganciclovir, DX, anakinra etoposide Death Hozumi et al [17] Japan/2012 62/F PM Yes None Ulcerating bronchitis IV GCV Improved after 3 wks Hashimoto et al [18] Japan/2006 67/F DM Yes None ILD CYC, P, GCV Death 72/F DM Yes None P, GCV Improved after 3 mo Naylor et al [19] UK/1987 65/F – Yes None ARF Peritoneal dialysis Ms. strength recovery 4 mo after discharge 69/F – No None subclinical HT Corticosteroids DM: Dermatomyositis, GBS: Guillain-Barre syndrome, MAS: macrophage activation syndrome, CMV: cytomegalovirus, MSA: myositis-specific autoantibodies, PM: Polymyositis, MTX: methotrexate, anti-RNP: anti-ribonucleoprotein, UTI: urinary tract infection, ILD: Interstitial Lung disease, DPI: Diffuse pulmonary infiltrates, GNB: gram-ve bacteremia, ARF: acute renal failure, HT: Hashimoto's thyroiditis, AZA: azathioprine, MP: methylprednisolone, TZP: Piperacillin/Tazobactam, GCV: Ganciclovir, DX: dexamethasone, CYC: cyclophosphamide, P: Prednisolone, TMP-SMX: Trimethoprim-sulfamethoxazole, Ms: muscle. Teleconsultation has assumed the center stage in management of chronic diseases during the COVID-19 pandemic [13]. Although the preferred means of communication in these unusual times, there is felt need to develop means of better clinical examination and identify key aspects of poor health like cardiac or muscle disease through audiovisual consultations [11]. The rare occurrence of myocarditis in anti-MDA5 DM may be fatal as in this case, and greater attention to cardiac function may be considered in management. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments We are thankful to the Connecting Researchers and Dr Malke Asaad for their help with this work. Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ==== Refs References: 1 Narang N.S. Casciola-Rosen L. Li S. Chung L. Fiorentino D.F. Cutaneous ulceration in dermatomyositis: Association with anti–melanoma differentiation–associated gene 5 antibodies and interstitial lung disease Arthritis Care Res 67 5 2015 667 672 2 Li L. Wang Q. Yang F. Wu C. Chen S. Wen X. Anti-MDA5 antibody as a potential diagnostic and prognostic biomarker in patients with dermatomyositis Oncotarget 8 16 2017 26552 26564 28460448 3 Tansley S.L. Betteridge Z.E. Gunawardena H. Jacques T.S. Owens C.M. Pilkington C. Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study Arthritis Res Ther 16 4 2014 R138 24989778 4 Kawasumi H. Gono T. Kawaguchi Y. Yamanaka H. Recent treatment of interstitial lung disease with idiopathic inflammatory myopathies Clin Med Insights Circ Respir Pulm Med 9 2015 9 17 26279636 5 Chino H. Sekine A. Baba T. Kitamura H. Iwasawa T. Okudela K. Interstitial lung disease with anti-melanoma differentiation-associated protein 5 antibody: rapidly progressive perilobular opacity Intern Med 58 18 2019 2605 2613 31178482 6 Gheita T.A. Fathi H.M. ElAdle S.S. Eesa N.N. Hammam N.H. Coronavirus disease 2019 (COVID-19) an emerging trigger for primary fibromyalgia syndrome: A tale of three cases post-COVID-19 Int J Clin Rheumatol 16 4 2021 129 135 7 Zomalheto Z. Assogba C. Dossou-yovo H. Impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and disease-2019 (COVID-19) on the quality of life of rheumatoid arthritis patients in Benin Egyptan Rheumatol 43 1 2021 23 27 8 Assar S. Pournazari M. Soufivand P. Mohamadzadeh D. Sanaee S. Microscopic polyangiitis associated with coronavirus disease-2019 (COVID-19) infection in an elderly male Egypt Rheumatol 43 3 2021 225 228 9 Gupta L. Naveen R. Gaur P. Agarwal V. Aggarwal R. Myositis-specific and myositis-associated autoantibodies in a large Indian cohort of inflammatory myositis Semin Arthritis Rheum 51 1 2021 113 120 33360322 10 Mehta P. Agarwal V. Gupta L. High early mortality in idiopathic inflammatory myopathies: Results from the inception cohort at a tertiary care center in northern India Rheumatology (Oxford) 2021 keab001 11 Gupta L. Chinoy H. Monitoring disease activity and damage in adult and juvenile idiopathic inflammatory myopathy Curr Opin Rheumatol 32 6 2020 553 561 32890032 12 Rathore U. Haldule S. Gupta L. Psoriasiform rashes as the first manifestation of anti-MDA5 associated myositis Rheumatology (Oxford) 2020 keaa821 13 Gupta L. Lilleker J.B. Agarwal V. Chinoy H. Aggarwal R. COVID-19 and myositis - unique challenges for patients Rheumatology (Oxford) 60 2 2021 907 910 33175137 14 Sakthivadivel V. Naveenraj P. Kachhwaha A. Kumar D. Anne P.B. Elhence P. Concurrent acute myositis and Guillain-Barre syndrome in cytomegalovirus infection – a rare case report BMC Infect Dis 20 1 2020 10.1186/s12879-020-05506-5 15 Zhang K. Yu C. Li Y. Wang Y. Next-generation sequencing technology for detecting pulmonary fungal infection in bronchoalveolar lavage fluid of a patient with dermatomyositis: a case report and literature review BMC Infect Dis 20 2020 16 Lange AV, Kazi S, Chen W, Barnes A. Fatal case of macrophage activation syndrome (MAS) in a patient with dermatomyositis and cytomegalovirus viraemia. BMJ Case Rep.2018. 2018:bcr2018225231. 17 Hozumi H. Fujisawa T. Kuroishi S. Inui N. Nakamura Y. Suda T. Ulcerating bronchitis caused by cytomegalovirus in a patient with polymyositis Intern Med 51 20 2012 2933 2936 23064571 18 Hashimoto A. Okuyama R. Watanabe H. Tagami H. Aiba S. Cytomegalovirus infection complicating immunosuppressive therapy for dermatomyositis Acta Derm Venereol 86 6 2006 535 537 17106602 19 Naylor C.D. Jevnikar A.M. Witt N.J. Sporadic viral myositis in two adults CMAJ 137 1987 819 821 2832046

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Egypt Rheumatol. 2021 Oct 9; 43(4):271-274

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==== Front Am J Prev Med Am J Prev Med American Journal of Preventive Medicine 0749-3797 1873-2607 American Journal of Preventive Medicine. Published by Elsevier Inc. S0749-3797(22)00526-8 10.1016/j.amepre.2022.10.007 Research Article Associations of Physical Inactivity and COVID-19 Outcomes Among Subgroups Young Deborah Rohm PhD 1⁎ Sallis James F. PhD 23 Baecker Aileen PhD 1 Cohen Deborah A. MD, MPH 1 Nau Claudia L. PhD 1 Smith Gary N. PhD 4 Sallis Robert E. MD 5 1 Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, California 2 University of California San Diego, San Diego, California 3 Australian Catholic University, Melbourne, Australia 4 Economics Department, Pomona College, Claremont, California 5 Department of Family and Sports Medicine, Kaiser Permanente Medical Center, Fontana, California ⁎ Address correspondence to: Deborah Rohm Young, PhD, Department of Research & Evaluation, Kaiser Permanente Southern California, 100 South Los Robles, 6th Floor, Pasadena CA 91101. 15 12 2022 15 12 2022 © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. 2022 American Journal of Preventive Medicine Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Introduction Physical activity before COVID-19 infection is associated with less severe outcomes. The study determined whether a dose‒response association was observed and whether the associations were consistent across demographic subgroups and chronic conditions. Methods A retrospective cohort study of Kaiser Permanente Southern California adult patients who had a positive COVID-19 diagnosis between January 1, 2020 and May 31, 2021 was created. The exposure was the median of at least 3 physical activity self-reports before diagnosis. Patients were categorized as follows: always inactive, all assessments at 10 minutes/week or less; mostly inactive, median of 0–60 minutes per week; some activity, median of 60–150 minutes per week; consistently active, median>150 minutes per week; and always active, all assessments>150 minutes per week. Outcomes were hospitalization, deterioration event, or death 90 days after a COVID-19 diagnosis. Data were analyzed in 2022. Results Of 194,191 adults with COVID-19 infection, 6.3% were hospitalized, 3.1% experienced a deterioration event, and 2.8% died within 90 days. Dose‒response effects were strong; for example, patients in the some activity category had higher odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), deterioration (OR=1.83; 95% CI=1.49, 2.25), and death (OR=1.92; 95% CI=1.48, 2.49) than those in the always active category. Results were generally consistent across sex, race and ethnicity, age, and BMI categories and for patients with cardiovascular disease or hypertension. Conclusions There were protective associations of physical activity for adverse COVID-19 outcomes across demographic and clinical characteristics. Public health leaders should add physical activity to pandemic control strategies. ==== Body pmcINTRODUCTION The coronavirus disease 2019 (COVID-19) pandemic represents one of the largest threats to population health in more than a century. As of September 2022, >6.4 million deaths globally were attributed to COVID-19.1 As new mutations evolve, it is apparent that the virus will not be eliminated in the near future and that strategies for managing life with COVID-19 are needed.2 By winter 2022, it became clear that recommendations for vaccinations, boosters, frequent handwashing, wearing protective face coverings, and social distancing were not sufficient to avoid infection.3 Although most fully vaccinated people (i.e., those who received the full dose [2 injections for 2 of the 3 vaccines available at the time] but not necessarily booster vaccinations) who become infected with COVID-19 had mild symptoms, there remains a proportion who experienced adverse outcomes, including hospitalization and death.4 Additional behaviors should be considered to reduce the odds of severe outcomes among those infected. There are now >25 studies5 and a meta-analysis6 reporting on the association of physical activity or fitness with adverse outcomes for those infected with COVID-19. For instance, a previous report from Kaiser Permanente Southern California (KPSC) categorized patients as consistently meeting physical activity guidelines7 (≥3 assessments of at least 150 minutes per week of physical activity), consistently inactive (≥3assessments <10 minutes per week of physical activity), or some activity (3 or more assessments in between these requirements). Patients who were consistently inactive had greater odds of hospitalization, admission to intensive care, and death than patients who were consistently active or engaged in some activity.8 Regular physical activity can reduce the risk of cardiometabolic diseases and premature mortality,9 improve immune function,10, 11, 12 and reduce inflammatory responses,13 all of which may explain the consistent associations of physical activity with less severe COVID-19 outcomes.5 Although evidence is building on the benefits of physical activity and less severe COVID-19 outcomes, knowledge gaps remain. The amount of physical activity associated with less severe COVID-19 outcomes is not clear. Those who were more physically active before infection may have a lower prevalence of underlying chronic conditions that predispose to adverse outcomes. However, studies have yet to identify whether physical activity is associated with less severe outcomes for those who do have chronic conditions. Furthermore, sociodemographic inequities in COVID-19 case rates and outcomes are central concerns in pandemic control. Older age may be the strongest risk factor,14 and males are more likely to have severe outcomes than females.15 Racial and ethnic disparities in infection rates and severe COVID-19 outcomes have been apparent since the beginning of the pandemic in the U.S., and disparities persist.14 , 16 , 17 It is important to determine whether the obvious benefits of physical activity for COVID-19 outcomes apply similarly across age, sex, race, and ethnic population subgroups.18 Knowledge about subgroup effects could help to inform the development of targeted physical activity recommendations as a component of COVID-19 guidelines. The goal of this study was to assess the association of physical activity with severe COVID-19 outcomes in a dose/response fashion. The study also assessed the strength of associations across major demographic subgroups and for those with and without chronic conditions. Results provide initial information regarding the minimal amount of physical activity that may be associated with less severe COVID-19 outcomes and determine whether potential benefits may be experienced across demographics and chronic conditions. METHODS The study was conducted in KPSC, an integrated health system that serves over 4.7 million members. The region is diverse in racial and ethnic makeup, education, and rurality/urbanicity. KPSC patients comprise about 20% of the Southern California population and reflect the area population, with marginal underrepresentation of those with extremely low income and with high education.19 Study data were taken from electronic health records (EHRs), a data system that captures all aspects of patient care, including diagnoses, inpatient and outpatient encounters, pharmacy encounters, and laboratory tests. The study was approved by the KPSC IRB. Study Participants Cohort participants were those who tested positive or were diagnosed with COVID-19 infection between January 1, 2020 and May 31, 2021. Additional eligibility criteria included age ≥18 years at the time of infection, continuous enrollment in KPSC for at least 6 months before diagnosis, and 3 or more assessments of physical activity in the 2 years before infection. Pregnant patients with COVID-19 who were hospitalized to give birth during the study period were excluded. Measures Physical activity was assessed using the Exercise Vital Sign (EVS).20 This brief self-report has been administered at KPSC outpatient visits since 2009. Trained medical assistants asked patients 2 questions: On average, how many days per week do you engage in moderate to strenuous exercise (like a brisk walk)? and On average, how many minutes do you engage in exercise at this level? Response choices for days were 0–7, and choices for minutes were recorded as 0, 10, 20, 30, 40, 50, 60, 90, 120, and ≥150 minutes. Responses were recorded in each patient's EHR, and minutes per week of moderate‒vigorous physical activity were calculated. The EVS has a good face, discriminant validity20 , 21 and validity with accelerometry-based physical activity.22 , 23 The median EVS for all measures completed on patients in the 2 years before their COVID-19 test or diagnosis was calculated, and patients were categorized as always inactive, 3+ EVS assessments at 10 minutes/week or less; mostly inactive, at least 1 EVS >10 minutes/week (median EVS of 0–60 minutes/week); some activity, median EVS of 60–150 minutes/week; consistently active, at least 1 EVS <150 minutes/week (median EVS greater 150 minutes/week) (meeting national guidelines)7; and always active, 3+ EVS assessments >150 minutes/week. COVID-19 diagnosis was determined by a positive test or a diagnosis in a patient's EHR. COVID-19 severity was assessed by (1) requiring hospitalization, (2) experiencing deterioration while hospitalized, and (3) death. COVID-19 hospitalizations were those occurring within 21 days of a diagnosis. A deterioration event was requiring intensive respiratory care, intensive-level care, or intensive-care-unit admission. Only cases of hospitalizations occurring at KPSC hospitals were included because data derived from non‒Kaiser Permanente facilities do not include the same level of detail. Age was categorized into <40 years, 40–49 years, 50–59 years, 60–69 years, and ≥70 years. Sex, race, and ethnicity were obtained from the EHR on the basis of self-report and categorized as male, female, other and Asian or Pacific Islander, Black or African American, Hispanic, non-Hispanic White, or other (e.g., American Indian, >1 race or ethnicity). Medicaid status (enrolled versus not) was determined from enrollment files. Smoking status (never versus ever) was queried during outpatient visits and recorded in the EHR. Height was typically measured once in adults. Weight was assessed at all outpatient visits, and the most recent value before diagnosis was used to calculate BMI (kg/m2). BMI was categorized as normal or underweight (<25 kg/m2), overweight (25–29 kg/m2), Class 1 obesity (30–34 kg/m2), or Class 2 obesity (≥35 kg/m2). Clinical conditions included underlying medical conditions identified by the Centers for Disease Control and Prevention (CDC) as associated with adverse COVID-19 outcomes,24 present before COVID-19 infection. Previous organ transplantation was documented in the EHR. The ICD-10 codes of I10.XX, I11.XX, I12.XX, I13.XX, and I15.XX identified hypertension. The Charlson Comorbidity Index25 disease categories were used to identify cardiovascular disease (i.e., myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease), chronic obstructive pulmonary disease, and cancer and metastatic cancer. The most recent value of HbA1c in the EHR was categorized as <7%, 7% to <8%, ≥8%, or missing (HbA1c is routinely measured for patients at risk for or diagnosed with prediabetes or diabetes). Given that patients with other underlying conditions may have increased susceptibility to adverse COVID-19 outcomes, the authors controlled for the number of emergency department visits and hospitalizations in the 6 months before diagnosis. Statistical Analysis Patient demographics, utilization, clinical characteristics, and comorbidities across physical activity groups were compared using chi-square tests. Logistic regression was used to estimate the odds of hospitalization or death after a COVID-19 diagnosis. Covariates included age category, sex, race, ethnicity, BMI, ever smoker, hospital utilization, HbA1c, comorbidities, Medicaid status, and vaccination status before COVID-19 diagnosis. Patients with a missing BMI were excluded from the analysis. To account for multiple comparisons, a conservative Bonferroni correction α=0.05/21=0.00238 was used for the p-values for interaction, and the 95% CIs were Bonferroni adjusted. All analyses and figures were produced using SAS 9.4 (Cary, NC). Analyses were completed in 2022. RESULTS Between January 1, 2020 and May 31, 2021, 481,061 KPSC patients with a COVID-19‒positive test or diagnosis were identified. After applying inclusion and exclusion criteria, the analytic cohort included 194,191 adults (Appendix Figure 1 , available online) with a mean of 6.4±4.6 EVS assessments. Those excluded were more likely to be aged <40 years (51.6% vs 32.4%) or over 60 years (11.2% vs 29.2%), more likely to be male (55.1% vs 37.5%), more likely to be categorized as other race/ethnicity (9.0% vs 3.0%), and less likely to have any comorbidities than patients in the cohort. As displayed in Table 1 , most were of Hispanic ethnicity (61.3%), with 21.4% identified as White patients, 7.3% identified as Black patients, and 6.8% identified as Asian or Pacific Islander patients. Over half had BMI ≥30 kg/m2. There were 21.8% with a diagnosis of hypertension and 9.2% with a cardiovascular disease diagnosis.Figure 1 ORs of the association between physical activity categories and (A) hospitalization and (B) death, adjusted for age category, sex, race, ethnicity, BMI, ever smoker, hospital utilization, HbA1c, comorbidities, Medicaid status, and vaccination status before COVID-19 diagnosis. Figure 1 Table 1 Characteristics of Patients Diagnosed or Tested Positive by Physical Activity Category and Total Table 1 Physical activity category Characteristics Always inactive (All EVS ≤10 min/week; median=0) Mostly inactive(EVS median 0–60 min/week; median=0) Some activity (EVS median 61–150 min/week; median=90) Consistently active (EVS median >150 min/week; median=210) Always active (All EVS >150 min/week; median=300) Total p-Valuea (n=29,099; 15.0%) (n=83,452; 43.0%) (n=42,490; 21.9%) (n=27,871; 14.3%) (n=11,279; 5.8%) (N=194,191) Age category, n (%) <0.01  <40 years 8,109 (27.9) 24,798 (29.7) 13,941 (32.8) 10,868 (39.0) 5,193 (46.0) 62,909 (32.4)  40–49 years 5,698 (19.6) 14,629 (17.5) 7,805 (18.4) 4,839 (17.4) 1,953 (17.3) 34,924 (18.0)  50–59 years 6,357 (21.8) 17,142 (20.5) 8,875 (20.9) 5,130 (18.4) 1,992 (17.7) 39,496 (20.3)  60–69 years 4,546 (15.6) 13,948 (16.7) 6,975 (16.4) 4,109 (14.7) 1,381 (12.2) 30,959 (15.9)  ≥70 years 4,389 (15.1) 12,935 (15.5) 4,894 (11.5) 2,925 (10.5) 760 (6.7) 25,903 (13.3) Sex, n (%) <0.01  Female 18,218 (62.6) 54,383 (65.2) 27,499 (64.7) 15,667 (56.2) 5,660 (50.2) 121,427 (62.5)  Male 10,881 (37.4) 29,067 (34.8) 14,991 (35.3) 12,202 (43.8) 5,619 (49.8) 72,760 (37.5)  Other 0 (0.0) 2 (0.0) 0 (0.0) 2 (0.0) 0 (0.0) 4 (0.0) Race and ethnicity, n (%) <0.01  Asian or Pacific Islander 1,617 (5.6) 5,437 (6.5) 3,420 (8.0) 1,957 (7.0) 857 (7.6) 13,288 (6.8)  Black 2,097 (7.2) 6,791 (8.1) 3,009 (7.1) 1,961 (7.0) 586 (5.2) 14,444 (7.4)  Hispanic 18,707 (64.3) 52,178 (62.5) 25,939 (61.0) 16,142 (57.9) 6,000 (53.2) 118,966 (61.3)  Other 842 (2.9) 2,220 (2.7) 1,255 (3.0) 988 (3.5) 553 (4.9) 5,858 (3.0)  White 5,836 (20.1) 16,826 (20.2) 8,867 (20.9) 6,823 (24.5) 3,283 (29.1) 41,635 (21.4) Smoking status <0.01  Ever smoker, n (%) 8,315 (28.6) 22,649 (27.1) 9,945 (23.4) 6,522 (23.4) 2,232 (19.8) 49,663 (25.6) BMI category, n (%) <0.001  <25 4,153 (14.3) 12,758 (15.3) 7,682 (18.1) 6,295 (22.6) 3,345 (29.7) 34,233 (17.6)  25–29 7,903 (27.2) 24,519 (29.4) 14,171 (33.4) 9,938 (35.7) 4,322 (38.3) 60,853 (31.3)  30–34 7,980 (27.4) 22,472 (26.9) 11,014 (25.9) 6,823 (24.5) 2,368 (21.0) 50,657 (26.1)  ≥35 9,054 (31.1) 23,678 (28.4) 9,607 (22.6) 4,811 (17.3) 1,238 (11.0) 48,388 (24.9)  Missing 9 (0.0) 25 (0.0) 16 (0.0) 4 (0.0) 6 (0.1) 60 (0.0) Emergency encounters before infection <0.01 Yes, n (%) 4,279 (14.7) 13,210 (15.8) 4,976 (11.7) 3,193 (11.5) 886 (7.9) 26,544 (13.7) Inpatient encounters before infection <0.01  Yes, n (%) 2,715 (9.3) 9,376 (11.2) 3,807 (9.0) 2,179 (7.8) 519 (4.6) 18,596 (9.6) HbA1c, n (%) <0.01  <7% 7,255 (24.9) 23,556 (28.2) 12,071 (28.4) 7,427 (26.6) 2,632 (23.3) 52,941 (27.3)  7–<8% 1,310 (4.5) 4,220 (5.1) 1,844 (4.3) 923 (3.3) 209 (1.9) 8,506 (4.4)  ≥8% 1,880 (6.5) 5,544 (6.6) 2,167 (5.1) 1,072 (3.8) 218 (1.9) 10,881 (5.6)  Missing 18,654 (64.1) 50,132 (60.1) 26,408 (62.2) 18,449 (66.2) 8,220 (72.9) 121,863 (62.8) Ever had organ transplantation <0.01  Yes, n (%) 66 (0.2) 338 (0.4) 171 (0.4) 91 (0.3) 13 (0.1) 679 (0.3) <0.01 Hypertension diagnosis <0.01  Yes, n (%) 6,772 (23.3) 21,556 (25.8) 8,362 (19.7) 4,604 (16.5) 1,082 (9.6) 42,376 (21.8) Cardiovascular disease diagnosis <0.01  Yes, n (%) 3,066 (10.5) 9,593 (11.5) 3,101 (7.3) 1,817 (6.5) 380 (3.4) 17,957 (9.2) Chronic pulmonary disease diagnosis <0.01  Yes, n (%) 2,591 (8.9) 8,234 (9.9) 3,189 (7.5) 2,072 (7.4) 550 (4.9) 16,636 (8.6) Renal disease diagnosis <0.01  Yes, n (%) 2,080 (7.1) 6,320 (7.6) 1,846 (4.3) 977 (3.5) 185 (1.6) 11,408 (5.9) <0.01 Cancer or metastatic cancer diagnosis  Yes, n (%) 794 (2.7) 3,119 (3.7) 1,200 (2.8) 614 (2.2) 136 (1.2) 5,863 (3.0) <0.01 COVID-19 vaccination status <0.01  Yes, n (%) 584 (2.0) 1,754 (2.1) 1,014 (2.4) 600 (2.2) 252 (2.2) 4,204 (2.2) <0.01 Note: Boldface indicates statistical significance (p<0.01). EVS, Exercise Vital Sign; min, minute. a Chi-square p-value. Table 1 shows the categorization of physical activity by median EVS. There were 15.0% categorized as always inactive, 43.0% categorized as mostly inactive, 21.9% categorized as some activity, 14.3% categorized as consistently active, and 5.8% categorized as always active. At higher physical activity categories (i.e., consistently active, always active), patients were more likely to be younger, male, never smokers, and in the lower BMI categories. Patients classified in the lower physical activity categories (e.g., always inactive, mostly inactive) were more likely to be of Hispanic ethnicity or Black race, have a diagnosis of cardiovascular disease or hypertension, or have a BMI ≥30 kg/m2. About 2% of patients were vaccinated before a COVID-19 infection, which did not differ by physical activity category (during the study period, vaccinations were not readily available). Over the study period, 12,530 (6.3%) patients were hospitalized, 5,943 (3.1%) experienced a deterioration event, and 5,427 (2.8%) patients died within 90 days of a COVID-19 diagnosis. There was a higher prevalence of adverse COVID-19 outcomes across lower physical activity categories; patients classified as always inactive had the highest prevalence of hospitalization, deterioration event, or death (Figure 1). Appendix Figure 1 (available online) displays the odds of hospitalization and death across physical activity categories, controlling for demographics and comorbidities. Results for deterioration events are provided in Appendix Figure 2 (available online). Patients in the some activity category (median EVS of 60–150 minutes/week) had 43% greater odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), 83% higher odds of a deterioration event (Appendix Figure 2, available online) (OR=1.83; 95% CI=1.49, 2.25), and 92% greater odds of death (OR=1.92; 95% CI=1.48, 2.49) than patients in the always active category (median EVS of 300 minutes/week). There was a consistent dose‒response association across lower physical activity categories, with the strongest association comparing the always active with the always inactive category. Patients in the always inactive category (median EVS≤10 minutes/week) had 91% higher odds of hospitalization (OR=1.91; 95% CI=1.68, 2.17), 139% higher odds of a deterioration event (Appendix Figure 2, available online) (OR=2.39; 95% CI=1.94, 2.94), and 291% higher odds of death (OR=3.91; 95% CI=3.01, 5.07) than patients in the always active category.Figure 2 AORs of the association between physical activity categories and hospitalization by (A) sex, (B) race and ethnicity, (C) age group, (D) BMI category, (E) with and without a diagnosis of cardiovascular disease, and (F) with and without a diagnosis of hypertension. ORs were adjusted for age, sex, race, ethnicity, BMI, ever smoker, emergency department visits, inpatient visits, comorbidities, cardiovascular disease, hypertension, Medicaid status, and vaccination before COVID-19 diagnosis. CVD, cardiovascular disease; PI, Pacific Islander. Figure 2 Figure 2 displays the adjusted odds of hospitalization across physical activity categories by demographic and chronic condition categories. Deterioration events are presented in Appendix Figure 3 (available online). The odds of hospitalization for patients in the some activity category were 31% greater for males (OR=1.31; 95% CI=1.05, 1.62) and 84% greater for females (OR=1.84: 95% CI=1.30, 260) than for those in the always active category, with an interaction indicating greater odds for females than for males across physical activity categories (p<0.001). Results were consistent across racial and ethnic and age categories, although not always reaching statistical significance. Patients in the higher BMI categories had higher odds of hospitalization than patients in lower BMI categories (p<0.001), but dose‒response associations with physical activity were apparent for all BMI categories. Dose‒response effects were strong for patients with cardiovascular disease or hypertension diagnosis for odds of hospitalization. Appendix Table 1 (available online) presents the ORs and corresponding 95% CIs for all comparisons.Figure 3 AORs of the association between physical activity categories and death by (A) sex, (B) race and ethnicity, (C) age group, (D) BMI category, (E) with and without a diagnosis of cardiovascular disease, and (F) with and without a diagnosis of hypertension. ORs were adjusted for age, sex, race, ethnicity, BMI, ever smoker, emergency department visits, inpatient visits, comorbidities, cardiovascular disease, hypertension, Medicaid status, and vaccination before COVID-19 diagnosis. CVD, cardiovascular disease; PI, Pacific Islander. Figure 3 Figure 3 displays the adjusted odds of death across physical activity categories by demographic and chronic conditions categories. Dose‒response effects were strong across all categories except for patients aged <40 years. For patients with hypertension, even the some activity category had higher odds of death than the always active category (OR=1.89, 95% CI=1.05, 3.40). Significant ORs were noted for patients with cardiovascular disease comparing the mostly inactive with the always active category (OR=2.39, 95% CI=1.21, 4.75). Odds were similar in magnitude for patients with or without a diagnosis of either condition (Figure 3 and Appendix Table 1, available online). DISCUSSION The results of this study document substantially higher odds of hospitalization, deterioration events, and death, with lower amounts of self-reported physical activity in a stepwise fashion for adults infected with COVID-19. The ORs are striking. In the full sample, those who were consistently inactive were 191% more likely to be hospitalized and 391% more likely to die than those who were consistently active. Dose‒response effects were mostly present across sex, race/ethnicity, age category, BMI category, and history of cardiovascular disease and hypertension, although the CIs sometimes included one. Although the odds were highest for patients in the always inactive category, every lower category of physical inactivity increased the odds of adverse COVID-19 outcomes. Higher odds of adverse COVID-19 outcomes among physically inactive patients were documented in all racial and ethnic categories, in most age categories, in all BMI categories, and for patients with and without diagnoses of cardiovascular disease or hypertension. However, there were some variations across categories, with trends for lesser effect sizes in the older ages and higher BMI categories. Regardless of demographic factors and common chronic health conditions, results suggest that reducing physical inactivity may be one pathway to lowering the odds of adverse COVID-19 outcomes. The benefits of reducing physical inactivity should lead to its recommendation as an additional pandemic control strategy for all, regardless of demographics or chronic disease status. Black, Hispanic, and Asian patients who contracted COVID-19 have a greater risk of adverse outcomes than their White counterparts.16 , 17 Reasons for these disparities are complex and likely stem from social inequities rooted in historical disenfranchisement and discrimination. Although physical activity has similar benefits for all racial and ethnic groups,7 it is more difficult to be physically active for people of low SES (who are disproportionately non-White), who have fewer financial resources, who are more likely to live in unsafe neighborhoods, and who may have limited time for physical activity owing to multiple jobs.26 Public health leaders should take the results as further impetus to develop and implement equitable promotional strategies and opportunities for physical activity for all people. Pre-existing chronic conditions, such as obesity, CVD, diabetes, and hypertension, are strongly associated with COVID-19‒related deaths.27 People with these conditions are cautioned to take all safeguards to avoid contracting COVID-19. These data indicate that if a person with chronic disease was infected, the odds of hospitalization, inpatient deterioration event, and death were lowered among those who were engaged in some physical activity before COVID-19 diagnosis, compared with those in the always inactive category. Limitations One important limitation was that physical activity was determined from a brief self-report instrument. Nonetheless, the instrument has been validated,20 ‒ 22 and at least 3 assessments improved measurement quality. A study from South Africa assessed physical activity from smart devices on over 60,000 adults who tested positive for COVID-19, with results similar to those of this study.28 Evidence from both these large studies is consistent with those from other studies included in CDC's systematic review5 and a meta-analysis,6 providing strong and consistent evidence of the benefits of physical activity and fitness for adverse COVID-19 outcomes. The actual cause of hospitalization or death was not able to be ascertained. The study used previously used protocols to identify COVID-19‒related hospitalizations and death.29, 30, 31 The cohort consisted of adults living in Southern California, and results may not be generalizable to other regions. Some of the CIs were large in the subgroup analyses; nonetheless, the trends were consistent. The cohort consisted of patients with a COVID-19 diagnosis or positive test available in their EHR, which may have resulted in selection bias. Vaccines were just becoming available, so the study could not detect whether physical activity improved outcomes among the vaccinated. Patients were not randomized to physical activity category, so there may be underlying unaccounted confounders. Thus, causality cannot be established. The definitions used for categorizing physical activity undoubtedly led to some misclassification. All patients were insured, and whereas Medicaid patients were included, uninsured patients were excluded. CONCLUSIONS In CDC review of the protective effects of physical activity or fitness on severe COVID-19 outcomes, consistent and conclusive evidence of benefits was found.5 This study showed stepwise higher odds of adverse COVID-19 outcomes with each increment in physical inactivity. It examined the critical question of the amount of physical inactivity among patients with COVID-19 with the highest risk for severe outcomes; those with common chronic diseases; older individuals; and Asian or Pacific Islander, Black, and Hispanic persons. Across virtually all subgroups, substantial deleterious effects of higher amounts of physical inactivity were found. The cumulative evidence of less physical inactivity's benefits for people with COVID-19, even those in the highest risk categories, has public health significance. Adults, regardless of demographic category or chronic disease status, should be encouraged to reduce their physical inactivity as another COVID-19 mitigation strategy. Appendix SUPPLEMENTAL MATERIAL Image, application 1 ACKNOWLEDGMENTS The authors thank the patients of Kaiser Permanente for helping to improve care through the use of information collected through our electronic health record systems. This study was supported in part by funding from the Kaiser Permanente Community Health Funds. No financial disclosures were reported by the authors of this paper. CREDIT AUTHOR STATEMENT Deborah R. Young: Conceptualization, Methodology, Supervision, Writing – original draft. James F. Sallis: Conceptualization, Writing – original draft, Writing – review & editing. Aileen Baecker: Data curation, Formal analysis, Methodology, Writing – review & editing. Deborah A. Cohen: Conceptualization, Writing – review & editing. Claudia L. NMethodology, Writing – review & editing. Gary N. Smith: Conceptualization, Methodology. Robert Sallis: Conceptualization, Methodology, Writing – review & editing. Supplemental materials associated with this article can be found in the online version at https://doi.org/10.1016/j.amepre.2022.10.007. ==== Refs REFERENCES 1 Coronavirus disease (COVID-19) pandemic. World Health Organization.https://www.who.int/emergencies/diseases/novel-coronavirus-2019?adgroupsurvey={adgroupsurvey}&gclid=EAIaIQobChMIp7r9staI-gIVqxXUAR27qQwdEAAYAiAAEgKSJfD_BwE. Updated November 29, 2022. Accessed November 29, 2022. 2 Emanuel EJ Osterholm M Gounder CR. A national strategy for the “new normal” of life with COVID JAMA 327 3 2022 211 212 10.1001/jama.2021.24282 34989789 3 Centers for Disease Control and Prevention. COVID-19 after vaccination: possible breakthrough infection.https://www.cdc.gov/coronavirus/2019-ncov/vaccines/effectiveness/why-measure-effectiveness/breakthrough-cases.html. Updated June 23, 2022. Accessed November 29, 2022. 4 Johnson AG Amin AB Ali AR COVID-19 incidence and death rates among unvaccinated and fully vaccinated adults with and without booster doses during periods of delta and omicron variant emergence - 25 U.S. Jurisdictions, April 4–December 25, 2021 MMWR Morb Mortal Wkly Rep 71 4 2022 132 138 10.15585/mmwr.mm7104e2 35085223 5 Hill AL, Whitfield G, Morford M, et al. Brief summary of findings on the association between physical inactivity and severe COVID-19 outcomes. https://www.cdc.gov/coronavirus/2019-ncov/downloads/clinical-care/E-Physical-Inactivity-Review.pdf. Accessed April 12, 2022. 6 Ezzatvar Y Ramírez-Vélez R Izquierdo M Garcia-Hermoso A. Physical activity and risk of infection, severity and mortality of COVID-19: a systematic review and non-linear dose-response meta-analysis of data from 1 853 610 adults Br J Sports Med 2022 10.1136/bjsports-2022-105733 In press. Online August 23 7 Piercy KL Troiano RP Ballard RM The physical activity guidelines for Americans JAMA 320 19 2018 2020 2028 10.1001/jama.2018.14854 30418471 8 Sallis R Young DR Tartof SY Physical inactivity is associated with a higher risk for severe COVID-19 outcomes: a study in 48 440 adult patients Br J Sports Med 55 19 2021 1099 1105 10.1136/bjsports-2021-104080 33849909 9 Powell KE King AC Buchner DM The scientific foundation for the physical activity guidelines for Americans J Phys Act Health 16 1 2018 1 11 10.1123/jpah.2018-0618 10 Chastin SFM Abaraogu U Bourgois JG Effects of regular physical activity on the immune system, vaccination and risk of community-acquired infectious disease in the general population: systematic review and meta-analysis Sports Med 51 8 2021 1673 1686 10.1007/s40279-021-01466-1 33877614 11 Laddu DR Lavie CJ Phillips SA Arena R. Physical activity for immunity protection: inoculating populations with healthy living medicine in preparation for the next pandemic Prog Cardiovasc Dis 64 2021 102 104 10.1016/j.pcad.2020.04.006 32278694 12 Simpson RJ Katsanis E. The immunological case for staying active during the COVID-19 pandemic Brain Behav Immun 87 2020 6 7 10.1016/j.bbi.2020.04.041 32311497 13 Zheng G Qiu P Xia R Effect of aerobic exercise on inflammatory markers in healthy middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials Front Aging Neurosci 11 2019 98 10.3389/fnagi.2019.00098 31080412 14 Rossen LM Ahmad FB Anderson RN Disparities in excess mortality associated with COVID-19 - United States, 2020 MMWR Morb Mortal Wkly Rep 70 33 2021 1114 1119 10.15585/mmwr.mm7033a2 34411075 15 Ahmad FB Cisewski JA Miniño A Anderson RN. Provisional mortality data - United States, 2020 MMWR Morb Mortal Wkly Rep 70 14 2021 519 522 10.15585/mmwr.mm7014e1 33830988 16 Mackey K Ayers CK Kondo KK Racial and ethnic disparities in COVID-19-related infections, hospitalizations, and deaths: a systematic review Ann Intern Med 174 3 2021 362 373 10.7326/M20-6306 33253040 17 Magesh S John D Li WT Disparities in COVID-19 outcomes by race, ethnicity, and socioeconomic status: a systematic-review and meta-analysis JAMA Netw Open 4 11 2021 e2134147 10.1001/jamanetworkopen.2021.34147 18 Hasson R Sallis JF Coleman N Kaushal N Nocera VG Keith N. COVID-19: Implications for physical activity, health disparities, and health equity Am J Lifestyle Med 16 4 2022 420 433 10.1177/15598276211029222 35855783 19 Koebnick C Langer-Gould AM Gould MK Sociodemographic characteristics of members of a large, integrated health care system: comparison with U.S. Census Bureau data Perm J 16 3 2012 37 41 10.7812/TPP/12-031 20 Coleman KJ Ngor E Reynolds K Initial validation of an exercise “vital sign” in electronic medical records Med Sci Sports Exerc 44 11 2012 2071 2076 10.1249/MSS.0b013e3182630ec1 22688832 21 Young DR Coleman KJ Ngor E Reynolds K Sidell M Sallis RE. Associations between physical activity and cardiometabolic risk factors assessed in a Southern California health care system, 2010–2012 Prev Chronic Dis 11 2014 E219 10.5888/pcd11.140196 25523350 22 Kuntz JL Young DR Saelens BE Validity of the exercise vital sign tool to assess physical activity Am J Prev Med 60 6 2021 866 872 10.1016/j.amepre.2021.01.012 33781618 23 Joseph RP, Keller C, Adams MA, Ainsworth BE. Validity of two brief physical activity questionnaires with accelerometers among African-American women. Prim Health Care Res Dev. 2016;17(3):265–276. https://doi.org/10.1017/S1463423615000390. 24 People with certain medical conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Updated November 22, 2022. Accessed November 29, 2022. 25 Charlson ME Pompei P Ales KL MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 40 5 1987 373 383 10.1016/0021-9681(87)90171-8 3558716 26 Williams DR Sternthal M. Understanding racial-ethnic disparities in health: sociological contributions J Health Soc Behav 51 suppl 2010 S15 S27 10.1177/0022146510383838 20943580 27 Williamson EJ Walker AJ Bhaskaran K Factors associated with COVID-19-related death using OpenSAFELY Nature 584 7821 2020 430 436 10.1038/s41586-020-2521-4 32640463 28 Steenkamp L Saggers RT Bandini R Small steps, strong shield: directly measured, moderate physical activity in 65 361 adults is associated with significant protective effects from severe COVID-19 outcomes Br J Sports Med 56 10 2022 568 576 10.1136/bjsports-2021-105159 35140062 29 Nau C Bruxvoort K Navarro RA COVID-19 inequities across multiple racial and ethnic groups: results from an integrated health care organization Ann Intern Med 174 8 2021 1183 1186 10.7326/M20-8283 33872046 30 Sharp AL Huang BZ Broder B Identifying patients with symptoms suspicious for COVID-19 at elevated risk of adverse events: the COVAS score Am J Emerg Med 46 2021 489 494 10.1016/j.ajem.2020.10.068 33189516 31 Tartof SY Qian L Hong V Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization Ann Intern Med 173 10 2020 773 781 10.7326/M20-3742 32783686

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==== Front Transfus Apher Sci Transfus Apher Sci Transfusion and Apheresis Science 1473-0502 1473-0502 Elsevier Ltd. S1473-0502(22)00333-0 10.1016/j.transci.2022.103626 103626 Article Spotlight on SARS CoV-2 infection inducing autoimmunity, through the formation of autoantibody to self hemostatic components or to host cells, often leading to severe thrombotic or bleeding events Seghatchian Jerard International Consultancy in Innovative Manufacturing and Quality/Safety of Blood-Derived Bioproducts. London, England, UK 15 12 2022 15 12 2022 103626© 2022 Elsevier Ltd. All rights reserved. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcWHAT’S ’HAPPNING? [TRASCI 62.1 NOV ISSUE] Spotlight on SARS CoV-2 infection inducing autoimmunity, through the formation of autoantibody to self hemostatic components or to host cells, often leading to severe thrombotic or bleeding events, in some individual: Seeking expert insights on the latest predictive diagnostic and treatment options of the ongoing subvariant alone or the expected mix “tripledemic” viral infections, with influenza and flu, expected in colder season The main objective of this What’s Happening is to encourage international teams on working strategies for risk assessment, predictive diagnosis, and patient management, so as to collectively bring, today, what will be tomorrow’s news. With the recent appearance of a third respiratory respiratory syncytial virus, or R.S.V., in the mix with cases of influenza and flu, that were already begun to increase earlier than the usual than in the colder season, a better understanding of mixed respiratory pathogens inducing autoimmunity becomes an unmet high priority challenges to be explored. This is of particular relevance right now as these _______ respiratory pathogens which have similar respiratory symptoms, has soared in children infected with R.S.V. rhinoviruses and enterovirus and have already created some straining in many pediatric hospitals in several countries. It is now fully confirmed that Coronavirus infections cause severe inflammation, hypercoagulability and autoimmunity in some predisposed individuals leading to severe thrombotic or bleeding manifestations, depending upon the functionality of the targeted hemostatic components involved. While the true mechanism and etiology of these events remain to be fully established but, in clinical practice, similar to most diagnosed autoimmune diseases, a prothrombotic state involving some important haemostatic proteins or their intermediate phospholipid complexes occurs, similar to the well documented severe lupus anticoagulant, anti -phospholipid, heparin or PF4 inducing thrombotic and other hemostatic complications. These include the very rare cases of autoimmunity to vWF that leads to severe bleeding because of the ongoing infection- induced microvascular endothelial dysfunction and cellular injury. In fact, the elevated VWBF: Ag ratio to ADAMTS13, of greater than to 1.5 is currently used as a predictive diagnostic of infection-induced vascular abnormality. The key question, in the context of CoV-2 infection- induced autoimmunity, that remains to be answered, is why, in a similar situations, only some patients and not everyone develops an asymptomatic pathogenic antibodies provoking the host hemostasis proteins to deviate from their normal functions, and become harmful to the host. In this context I have invited Jean AMIRAL, Scientific consultant and the company’s founder of HYPHEN BioMed, and an international expert in the field of innovative tools for diagnosis and monitoring hemostatic abnormalities and autoimmunity -induced thrombotic or bleeding and vascular abnormalities events, to lead a systematic synthesis of the latest opinions on the coronavirus induced autoimmunity and consequential treatments of choice, a topic of interest to both contributors and readers alike. Currently, numerous innovative large-scale diagnostic tools exist to mange novel therapies of autoimmunity and the follow up strategies for managing the challenges of using novel therapeutic interventions in autoimmunity induced hemostatic abnormalities, including the associated treatment-emergent adverse events. In most cases various ELISA-based assays are used for the rapid analysis of the autoimmune status but with the recent innovative technological advances some newer innovative capture assays using PF4 coated solid surfaces become the most preferred option. More recently, a more specific ELISA assay developed and applied in coronavirus infection- induced autoimmunity, in Jean AMIRAL’s laboratory. This is a basic example of the single or multiple mix infections by CoV-2 subvariants alone or combined with influenza and other infections. This will open the gate for many others experts to provide their own personal views and experiences on the topic of autoimmunity, that remain the focus of this section of Trasci in 2022. In context to the effectiveness of COVID-19 mRNA vaccines against COVID-19–associated hospitalizations it is worthwhile to highlight that the two consecutive doses of any vaccine, or if mixed matched, are less effective than two doses of the recent booster vaccines. Moreover, among Immunocompromised adults during CoV-2 Omicron predominance, vaccines in the general adult population have been found to be 70-90% effective, but, for the immunocompromised, a much lower range — 34-71% of effectiveness is documented in the Indian public health institute. Therefore, those with healthy immune systems should keep in mind their responsibility to fellow community members who are immunocompromised or have other conditions that place them at higher risk for Covid, or mixed disease, even after vaccination. Clearly, additional precautions are still needed especially when the transmission rates remains high, even in heavily booster vaccinated countries. Looking at the future perspectives in exploring current thinking on technological innovations in any pandemic that affect our future we need to vigorously pursue international team working strategies, because we don’t know what the future will bring all over the world. Looking at the trends today and thinking about what the future of multiple infections would look like, we must remain prepared and keep the issue of autoimmunity in the ranks of high priority unmet challenges. Clearly, only through international team working strategies we will be able to close the gap between the perception and reality. I wish to take this opportunity to express my most sincere thanks to Jean for sharing his insights and personal hands on experiences on the topic of autoimmunity with the readers of this section and for his continual help and support, for many decades, as an essential part of our team working regularly to deliver some high quality joint ventures for this section of Trasci. Clearly I could not do without his inputs.

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==== Front Explor Res Clin Soc Pharm Explor Res Clin Soc Pharm Exploratory Research in Clinical and Social Pharmacy 2667-2766 Published by Elsevier Inc. S2667-2766(22)00113-5 10.1016/j.rcsop.2022.100214 100214 Article Effectiveness and cost analysis of methods used to recruit older adult sedative users to a deprescribing randomized controlled trial during the COVID-19 pandemic Murphy Andrea L. a⁎ Turner Justin P. bf1 Rajda Malgorzata c Allen Kathleen G. d Pinter Kamilla d1 Gardner David M. e a College of Pharmacy and Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada b Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Science, Monash University, Melbourne, Victoria, Australia c Sleep Disorders Clinic and Laboratory, QEII Health Sciences Centre, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada d Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada e Department of Psychiatry and College of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada f Centre de recherche, Institut universitaire de gériatrie de Montréal, Montréal, Québec, Canada ⁎ Corresponding author. 1 At the time of research. 15 12 2022 15 12 2022 10021413 9 2022 16 11 2022 13 12 2022 © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Recruitment to clinical trials is a challenge for researchers that became more pronounced because of COVID-19 public health protective measures, especially with respect to studies enrolling older adults. We completed an effectiveness and cost analysis of the recruitment methods used in The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study, a randomized controlled trial of a deprescribing intervention that recruited older adults with chronic use of sedatives during the pandemic. Methods Study recruitment began during the COVID-19 pandemic. Strategies included random digit dialing (RDD), a targeted mail campaign and advertising through newspapers, online platforms (Google and Facebook), and television. Other awareness raising and recruitment strategies involved seniors' organizations, pharmacies, television news stories, and referrals. Recruitment effectiveness and cost analysis involved enrollment rate (ER), cost per randomized participant (CPRP), fractional cost (FC), fractional enrollment (FE), fractional enrollment-cost ratio (FEC), and efficacy index (EI) calculations. Results There were 1295 interested older adults with 594 randomized into the study for an enrollment rate of 46%. The efficacy index (EI) was highest for Facebook ads (EI = 0.681) followed by television (EI = 0.426), and newsprint ads (EI = 0.295). The cost of RDD was highest per randomized participant at $1117.90 and produced the lowest EI (0.013). Conclusion Facebook ads had the best efficacy index (EI = 0.681) for recruiting older adults to the YAWNS NB study during the COVID-19 pandemic and television ads produced the most enrollments. RDD was expensive and yielded few recruits. Recruitment costs can be significant for recruiting community-dwelling older adults. This experience can inform recruitment strategy and budget development for future community studies enrolling older adults, especially in the context of the COVID-19 pandemic. Keywords Patient selection Randomized controlled trials Cost and cost analysis Aged Sedative-hypnotics Deprescribing Pandemic ==== Body pmcIntroduction Efficient recruitment of the targeted sample size of study participants within the planned timeline of a randomized controlled trial is the exception rather than the rule.1 The identification of specific factors necessary for recruitment success remain elusive, however best practices indicate that successful recruitment requires the development and implementation of a recruitment strategy inclusive of what is often a substantial portion of the project's budget.2 Much depends on the success of the study's recruitment efforts, as a study that falls well below its planned recruitment is at risk of failing to answer its research questions and in so doing squander its funding.3 The complexity and intensity of the recruitment strategy and its apportioned budget vary depending on numerous factors including access to potential participants, trust of the researcher by study candidates, participant interest in the project's objectives, and effort required by participants to complete the study.4 Even a well-planned and sufficiently funded recruitment plan may be disrupted by one or more unforeseen challenges to recruitment, for example pandemic-related public health measures limiting direct access to potential study candidates. A combination of traditional recruitment methods (i.e., print/flyers, word-of-mouth) with online free and paid promotion advertising (i.e., social media) are recommended as potentially cost-effective and often necessary ways of spreading awareness to potential participants including hard to reach populations.5., 6., 7. Older adults can be particularly difficult to recruit to randomized controlled trials due to health status impairments, comorbidities, restricted enrollment criteria, and a diversity of health beliefs.8., 9., 10., 11. The COVID-19 pandemic has created additional challenges with reaching, engaging with, and recruiting older adults to clinical research, leading researchers to increasingly rely on online methods of recruitment.12 The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) was a randomized controlled trial that investigated the impact of sending a direct-to-patient educational intervention package to older adults.13 YAWNS NB study recruitment launched approximately 6 months after the COVID-19 pandemic was declared. This necessitated a shift in the original recruitment strategy and budget by suspending plans for direct engagement at in-person events run by seniors' organizations and requiring a reappraisal of the effectiveness of various non-face-to-face recruitment methods. This analysis reports the comparative effectiveness and cost analysis of several traditional and online recruitment methods of older adults used for recruiting participants to the YAWNS NB study during the height of COVID-19 pandemic public health protections across the province of New Brunswick, Canada. Methods Participants New Brunswick is a Canadian province of over 71,000 km2 and 794,000 people. It has the second highest proportion of people 65 and older in Canada (22.7%), a large proportion of the population living rurally (50%) or in small population centres (19%), and has the highest rate of chronic use of BZRAs among older adults (25%) living in Canada.13., 14., 15. The YAWNS NB study (registration NCT04406103) was a randomized, parallel assignment, three-arm, open-label trial.13 Participants were English-speaking residents of New Brunswick, community-dwelling, aged ≥65 years, responsible for their healthcare decisions, and long-term users of benzodiazepine receptor agonists (BZRAs), the most commonly prescribed sedative-hypnotics for insomnia. All study participants were invited to complete a 60-min telephone interview at baseline and a 6-month follow-up telephone interview of similar duration. The study did not require participant travel or any in-person assessments. The target number of completers per group was 188 for a total of 564 completers across three groups. To account for a dropout rate of up to 25%, the planned recruitment sample size was 705 randomized participants. Ethics approval was received by the Ethics Board of Dalhousie University. All participants consented prior to enrollment. Recruitment approaches The YAWNS NB study used several recruitment strategies over 13 months. Random digit dialing (RDD) involved direct, unsolicited telephone calls by a contracted vendor using an undifferentiated list of active New Brunswick telephone numbers and a preliminary screening tool. All other methods used various mechanisms to raise awareness of the study and invited potentially interested individuals to contact the researchers for more information and initial screening. Strategies included traditional advertising and announcements in newspapers, television (TV), and targeted mailing using postcards and pamphlets. Online Google and Facebook paid advertising were also used. Mailings were sent via Canada Post routes selected based on their high proportion of older adults. Other strategies included reaching out to NB seniors' organizations by email requesting sharing of notifications, using NB pharmacies to distribute YAWNS NB study postcards to people taking BZRAs, news media reports about BZRA use in older adults and the YAWNS NB study, and referrals from healthcare professionals and others. Strategies were staggered, beginning with RDD and newspaper ads, and subsequently transitioning to mail campaigns, social media, TV ads, and other methods. Analysis As per the methods of Chin Feman and colleagues (2008), we used several metrics to determine the most effective recruitment strategies used for the YAWNS NB study.16 They included: Enrollment rate (ER): The proportion of participants who enrolled in the study compared to all who expressed initial interest. ER was calculated by dividing the number of participants randomized by the total number interested.ER=nrandomizedpermethodninterested Cost per randomized participant: total cost of the recruitment strategy divided by number randomized attributed to that recruitment strategy.CPRP=recruitmentmethodcostnrandomized Fractional enrollment (FE): Fractional enrollment is the ratio of the number of enrollments for an individual recruitment method over the total number of enrollments.16 FE measures the contribution that a recruitment type brought to the overall effort. FE was calculated by dividing the number randomized per recruitment method by the total randomized.FE=nrandomizedpermethodtotalnrandomized Fractional cost (FC): The fractional cost is the ratio of the cost of each recruitment strategy over the total cost of recruitment. FC measures the proportion of the overall budget consumed by each individual recruitment strategy. FC was calculated by dividing the cost of each individual recruitment strategy by the total cost of recruitment.FC=recruitmentmethod$totalrecruitment$ Fractional enrollment-cost (FEC) ratio: The ratio of the fractional enrollment (FE) over the fractional cost (FC) for each recruitment type indicates its relative performance in terms of benefit versus cost. Ratios >1 indicate better than average performance and < 1 indicate less than average performance. FEC = FEFC. Efficacy index (EI): EI is a dynamic measure that combines the relative cost effectiveness of each recruitment method with its fractional contribution to the recruitment strategy. It adjusts the fractional enrollment-cost ratio based on overall fraction of enrollments per recruitment method. EI calculations yield a precise comparison of recruitment method effectiveness. When two methods have similar FEC ratios, the recruitment method that yielded a higher number of enrollments would have a higher efficacy index. Likewise, when two methods lead to a similar number of enrollments, the preferred method is the one that is less costly. As such, the higher the EI values, the more cost effective the method. The EI is calculated by multiplying each method's fractional enrollment-cost ratio by its fractional enrollment. EI = FEFC ⦁ FE Results A total of 1295 people were screened for eligibility (244 referred from RDD, 583 study website contacts, 438 study telephone calls received, and n = 29 other methods (e.g., referrals)). Of the 1295 screened, 350 were ineligible, 263 declined to participate, and 650 agreed to receive a consent form by mail. Of those 650 individuals, 594 consented to participate and were randomized, yielding an enrollment rate of 46%. The total cost of recruitment for the YAWNS NB trial was $132,344 ($224/participant) representing 33% of the total budget. RDD consumed the largest portion of the budget ($44,716) followed by TV ads ($39,965) and the targeted mail campaign ($31,251). The remaining recruitment strategies were used less intensively and were significantly less costly (e.g., newspaper print ads, pharmacy outreach, online ads), and several methods were free of charge (e.g., referrals). The CPRP, FC, FE, FE/FC, and EI are presented in Table 1 . Facebook, TV, and newspaper ads had the most favourable EIs and RDD the least.Table 1 Recruitment metrics based on recruitment strategies in the YAWNS NB study. Table 1Recruitment source Study months Enrolled Total cost Cost per randomized participant (CPRP) Fractional enrollment (FE) Fractional cost (FC) Fractional enrollment-cost ratio (FEC) Efficacy index (EI) Random digit dialing † 1–4 40 $44,716 $1117.90 0.067 0.338 0.199 0.013 TV Ads ‡ 4–13 213 $39,965 $187.63 0.359 0.302 1.187 0.426 Targeted mail ^ 2,3,6–11 58 $31,251 $538.81 0.098 0.236 0.414 0.040 Newsprint ads 1,4,6 81 $8280 $102.22 0.136 0.063 2.165 0.295 Pharmacies 3–7 19 $5851 $307.95 0.032 0.044 0.727 0.023 Facebook Ads 5–7,9–13 62 $2113 $34.08 0.104 0.016 6.524 0.681 Google Ads 2 0 $303 – 0.000 0.002 – – News report (any medium) 2–4 66 0 – 0.111 0.000 – – Friend/family Any 30 0 – 0.051 0.000 – – Seniors' organizations Any 13 0 – 0.022 0.000 – – Healthcare provider referral Any 7 0 – 0.012 0.000 – – Other⁎ Any 5 0 – 0.008 0.000 – – TOTAL 594 $132,344 Mean $223.80 † 32,224 calls were attempted. 244 of 4751 potentially eligible contacts agreed to having their contact information shared with the YAWNS NB researchers. ‡ TV advertisements included paid (n = 451) and bonus (n = 817) advertising slots. ^ The mail campaign averaged 13,640 recruitment items mailed per month over 8 months. Cost of mailing included a 43.1% volume discount. ⁎ Other recruitment methods including community posters, referrals from religious and community leaders, etc. All costs are Canadian dollars. Discussion Overall recruitment cost per participant (CA$224) was less than half the median recruitment cost from 30 clinical trials (US$409 is ~CA$540) reported by Speich and colleagues.2 The efficacy index was highest for Facebook ads (0.681) followed by TV ads (0.426) and newspaper ads (0.295) for recruiting older adults to the YAWNS NB study during the COVID-19 pandemic. The EI for these strategies were greater than their respective FE values, demonstrating their superiority at recruiting participants over other strategies.16 Recognizing social media's potential value in recruitment, the National Institute on Aging Recruiting Older Adults in Research (ROAR) toolkit includes sample messaging for platforms such as Facebook.17 Generally, evidence for recruiting older adults via social media remains limited, especially during the pandemic, but promising research from other hard to reach groups shows successes with recruitment at reasonable costs.18 Additionally, Facebook advertising click-through rates may be higher with older adults compared to younger age groups.19 TV ads may be well suited for recruiting older adults as research participants. >80% of those ≥65 years old watch approximately 4 h of TV daily, thus creating opportunities for recruitment ads that target this age group.20 The RDD method failed to provide an acceptable recruitment yield (EI = 0.013). It was both costly and had a low FE. The RDD process uses the completes per hour (CPH) metric, which is the number of individuals willing to provide contact details to researchers called per hour. The estimated CPH before recruitment was 0.7 to 1.3, but the actual CPH was 0.23. Research has shown that older adults may be vulnerable to telephone scams21 and, more recently, scam awareness campaigns may have improved vigilance against information sharing between older adults and unknown callers.22 Anecdotally, telephone scams may have become more prevalent during the pandemic. Facebook ads, in contrast, which are passive versus RDD, may provide opportunities to consider and check the credibility of the invitation. More research regarding whether social media, TV ads, and RDD are trusted and appropriate for older adults in the context of the pandemic should be conducted and deposited in the Online Resource for Research in Clinical trials (ORRCA).23 Research within ORRCA would provide investigators with evidence regarding the challenges and opportunities with recruitment and retention strategies of older adults in trials during pandemic times.23 The YAWNS NB trial followed the best practices outlined by Pitkala and Strandberg (2022) during participant recruitment and retention practices. This included using several recruitment strategies to reach potential participants and using various sensitive practices to increase participant retention.24 A limitation of this analysis is that research staff time (i.e., salary) was not factored into cost recruitment calculations. Conclusion Recruiting older adults to a deprescribing study during the COVID-19 pandemic was supported most with Facebook, TV, and newspaper ads. Random digit dialing was costly without producing the desired results. The recruitment results corroborated other findings demonstrating recruitment costs can be significant. More research regarding recruiting older adults during the pandemic would support investigators' recruitment strategies. Funding statement The YAWNS NB sleep study was funded by the Healthy Seniors Pilot Projects grant competition. The funding for the grant program comes from the Public Health Agency of Canada and the Government of New Brunswick. This study was approved by the Institutional Review Board for Dalhousie University (research ethics board number 2020-5184; clinical trial registry NCT4406103) and all participants reviewed a physical or electronic version of the consent form before providing verbal consent. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements Sandra Magalhaes, PhD of the NB-Institute for Research, Data, and Training and Department of Sociology, University of New Brunswick, Fredericton, New Brunswick, Canada is a team member of the study and primarily responsible for statistical analysis of administrative data. ==== Refs References 1. McDonald A.M. Knight R.C. Campbell M.K. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies Trials 7 2006 9 16603070 2. Speich B. von Niederhäusern B. Schur N. Systematic review on costs and resource use of randomized clinical trials shows a lack of transparent and comprehensive data J Clin Epidemiol 96 2018 1 11 29288136 3. Bower P. Brueton V. Gamble C. Interventions to improve recruitment and retention in clinical trials: a survey and workshop to assess current practice and future priorities Trials 15 2014 399 25322807 4. Campbell M. Snowdon C. Francis D. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study Health Technol Assess 11 48 2007 iii, ix-105 5. Frandsen M. Thow M. Ferguson S.G. The effectiveness of social media (Facebook) compared with more traditional advertising methods for recruiting eligible participants to health research studies: a randomized, controlled clinical trial JMIR Res Protoc 5 3 2016 e161 6. Frandsen M. Walters J. Ferguson S.G. Exploring the viability of using online social media advertising as a recruitment method for smoking cessation clinical trials 16 2 2014 247 251 7. Kayrouz R. Dear B.F. Karin E. Facebook as an effective recruitment strategy for mental health research of hard to reach populations Internet Interv 4 2016 1 10 30135786 8. Ridda I. MacIntyre C.R. Lindley R.I. Difficulties in recruiting older people in clinical trials: an examination of barriers and solutions Vaccine 28 4 2010 901 906 19944149 9. Forsat N.D. Palmowski A. Palmowski Y. Recruitment and retention of older people in clinical research: a systematic literature review J Am Geriatr Soc 68 12 2020 2955 2963 33075140 10. Denson A.C. Mahipal A. Participation of the elderly population in clinical trials: barriers and solutions Cancer Control 21 3 2014 209 214 24955704 11. Buttgereit T. Palmowski A. Forsat N. Barriers and potential solutions in the recruitment and retention of older patients in clinical trials-lessons learned from six large multicentre randomized controlled trials Age Ageing 50 6 2021 1988 1996 34324628 12. Sharma R.K. Teng A. Asirot M.G. Challenges and opportunities in conducting research with older adults with dementia during COVID-19 and beyond J Am Geriatr Soc 70 5 2022 1306 1313 35285942 13. Murphy A.L. Turner J.P. Rajda M. A protocol for a randomized controlled trial comparing Sleepwell, EMPOWER, and treatment-as-usual for benzodiazepine receptor agonist discontinuation in older adults: the Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study Explor Res Clin Soc Pharm 7 2022 e100164 14. Government of Canada SC Demographic estimates by age and sex, provinces and territories: Interactive dashboard https://www150.statcan.gc.ca/n1/pub/71-607-x/71-607-x2020018-eng.htm (2020, accessed 15 November 2022) 15. Government of Canada SC Annual demographic estimates, rural and urban areas: Interactive dashboard https://www150.statcan.gc.ca/n1/pub/71-607-x/71-607-x2021030-eng.htm (2022, accessed 15 November 2022) 16. Chin Feman S.P. Nguyen L.T. Quilty M.T. Effectiveness of recruitment in clinical trials: an analysis of methods used in a trial for irritable bowel syndrome patients Contemp Clin Trials 29 2 2008 241 251 17919993 17. National Institute of Health Recruiting Older Adults into Research (ROAR) Toolkit 2022 National Institute on Aging https://www.nia.nih.gov/health/recruiting-older-adults-research-roar-toolkit (accessed 5 July 2022) 18. Wozney L. Turner K. Rose-Davis B. Facebook ads to the rescue? Recruiting a hard to reach population into an internet-based behavioral health intervention trial Internet Interv 17 2019 100246 19. Cowie J.M. Gurney M.E. The use of Facebook advertising to recruit healthy elderly people for a clinical trial: baseline metrics JMIR Res Protoc 7 1 2018 e7918 20. Government of Canada SC A day in the life: how do older Canadians spend their time? https://www150.statcan.gc.ca/n1/pub/75-006-x/2018001/article/54947-eng.htm (2018, accessed 11 July 2022) 21. James B.D. Boyle P.A. Bennett D.A. Correlates of susceptibility to scams in older adults without dementia J Elder Abuse Negl 26 2 2014 107 122 24499279 22. Government of Canada What every older Canadian should know about: fraud and scams https://www.canada.ca/en/employment-social-development/corporate/seniors/forum/fraud-scams.html (2016, accessed 11 July 2022) 23. Kearney A. Ashford P.-A. Butlin L. Developing an online, searchable database to systematically map and organise current literature on retention research (ORRCA2) Clin Trials 19 1 2022 71 80 34693794 24. Pitkala K.H. Strandberg T.E. Clinical trials in older people Age Ageing 51 5 2022 afab282 35526845

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==== Front J Microbiol Immunol Infect J Microbiol Immunol Infect Journal of Microbiology, Immunology, and Infection 1684-1182 1995-9133 Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. S1684-1182(22)00285-7 10.1016/j.jmii.2022.12.004 Review Article COVID-19 associated Mold Infections: Review of COVID-19 associated pulmonary aspergillosis and mucormycosis Huang Shiang-Fen aba Ying-Jung Wu Alice ca Shin-Jung Lee Susan bd Huang Yu-Shan e Lee Chun-Yuan fghi Yang Te-Liang jk Wang Hsiao-Wei l Chen Hung Jui m Chen Yi Ching n Ho Tzong-Shiann op Kuo Chien-Feng cq∗∗ Lin Yi-Tsung ar∗ the GREAT working group a Division of Infectious Disease, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan b School of Internal Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan c Division of Infectious Diseases, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan d Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Taiwan e Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan f Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan g Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan h School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan i M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan j Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch k Department of Pediatrics, National Taiwan University Children’s Hospital l Division of Infectious Diseases, Department of Internal Medicine, Shin Kong Wu Ho- Su Memorial Hospital, Taipei, Taiwan m Department of Infectious Diseases, Chi-Mei Medical Center, Tainan, Taiwan n Department of pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan o Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan p Department of Pediatrics, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan q MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan r Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan ∗ Yi-Tsung Lin . ∗∗ Chien-Feng Kuo. a Shiang-Fen Huang and Alice Ying-Jung Wu contributed equally as first authors. 15 12 2022 15 12 2022 12 5 2022 3 12 2022 6 12 2022 © 2022 Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. COVID-19-associated mold infections (CAMI) is defined as development of mold infections in COVID-19 patients. Co-pathogenesis of viral and fungal infections include the disruption of tissue barrier following SARS CoV-2 infection with the damage in the alveolar space, respiratory epithelium and endothelium injury and overwhelming inflammation and immune dysregulation during severe COVID-19. Other predisposing risk factors permissive to fungal infections during COVID-19 includes the administration of immune modulators such as corticosteroids and IL-6 antagonist. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) is increasingly reported during the COVID-19 pandemic. CAPA usually developed within the first month of COVID infection, and CAM frequently arose 10-15 days post diagnosis of COVID-19. Diagnosis is challenging and often indistinguishable during the cytokine storm in COVID-19, and several diagnostic criteria has been proposed. Development of CAPA and CAM is associated with a high mortality despite of appropriate anti-mold therapy. Both isavuconazole and amphotericin B can be used for treatment of CAPA and CAM; voriconazole is the primary agent for CAPA and posaconazole is an alternative for CAM. Aggressive surgery is recommended for CAM to improve patient survival. A high index of suspicion and timely and appropriate treatment is crucial to improve patient outcome. Keywords aspergillosis mucormycosis COVID-19 CAPA CAM ==== Body pmc

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==== Front J Infect J Infect The Journal of Infection 0163-4453 1532-2742 The British Infection Association. Published by Elsevier Ltd. S0163-4453(22)00702-2 10.1016/j.jinf.2022.12.011 Letter to the Editor Letter to the Editor Changes of respiratory syncytial virus infection in children before and after the COVID-19 pandemic in Henan, China Zhang Mengxin 1 Gao Jing 1 Guo Qingfeng 2 Zhang Xianwei 1⁎⁎ Zhang Wancun 1⁎ 1 Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China 2 Huanghe Science and Technology College, Zhengzhou, 450018, China ⁎ Corresponding author: Dr. Wancun Zhang, Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou 450018, China ⁎⁎ Corresponding author: (Xianwei Zhang) 15 12 2022 15 12 2022 10 12 2022 © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved. 2022 The British Infection Association Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcDear Editor, We read with interest the publication by Li et al. and Zhou et al. reporting a decreasing trend of the infection in children with Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) before and after the coronavirus disease 2019 (COVID-19) pandemic in Henan, China1 , 2. However, respiratory syncytial virus (RSV), which is one of the leading causes of lower respiratory tract infection in children as well as the bacteria mentioned in this journal, has not been reported on the epidemiology dynamics resulting from the COVID-19 pandemic. Therefore, we demonstrated the changes of RSV infection in children before and after the COVID-19 pandemic in Henan, China. RSV is a non-segmented single negative strand RNA enveloped virus belonging to the Paramyxoviridae family, and is related to clinical pictures such as bronchiolitis, pneumonia, ashmatic bronchitis3. RSV is the most important virus responsible for hospitalization and even death in children under 5 years of age with acute lower respiratory tract infection (ALRI), especially in infants4 , 5. A global report published recently noted that there were 33 million infections of RSV in children and 101,400 deaths under 5 years old in 20196. Otherwise, multiple studies have shown that RSV not only causes reinfections throughout the life, but also increases the risk of asthma attacks and language learning disabilities in pre-school children7 , 8. Unfortunately, attempts to date have failed to develop safe and effective vaccines for clinical prevention in RSV infection in children, though developing vaccines for RSV has been a global priority. Nevertheless, RSV causes annual epidemic outbreaks between September and May in the Northern Hemisphere, posing a serious threat to the health of children in low-income and middle-income countries3. Therefore, monitoring the changes of RSV infection in children is necessary to explore control strategies and improve the survival of children. Henan Children's Hospital is a 3A pediatric hospital with more than 2 million visits per year, accounting for approximately 10% of total number of children in Henan, which has been approved as the National Children's Regional Medical Center, Henan Children's Medical Center, and Henan Pediatric Disease Clinical Medical Research Center. In this study, laboratory-based surveillance of RSV infection in children under 11 years old were conducted from January 2017 to October 2022 at Henan Children's Hospital. We compared the number of RSV infections as well as the permillage of positive in six years before and after the COVID-19 pandemic to explore the impact of the outbreak on the prevalence trend of RSV infection in children. As shown in Fig. 1 , RSV infections and positive rate demonstrated seasonal fluctuations annually between September and May from 2017 to 2019, whereas there were two sharp drops in RSV infections in January 2020 and July 2021, reflecting the two outbreaks of the COVID-19 pandemic in Henan. Although there was a modestly increase in RSV infection and positive rate in children during the recovery period of the COVID-19 pandemic from September 2020 to March 2021, it was still lower than the same period before the COVID-19 pandemic. Notably, the reduction of RSV infections and positive rates persisted for several months after the end of the second COVID-19 pandemic, which may have suppressed the seasonal rise trend in RSV infection. Therefore, epidemiological trend of the infection of RSV in children had indeed changed before and after the COVID-19 pandemic in Henan.Fig. 1 The number of positive and positive rates of RSV infection among children aged 0 - 11 years during January 2017 to October 2022. Fig 1 Furthermore, RSV infections and positive rates were evaluated in different age groups (0 - 1 month, 1 month - 2 years, 2 - 5 years, and 5 - 11 years) before and after the COVID-19 pandemic. The number of positive decreased after the COVID-19 pandemic in the third and fourth age groups, while those in the first and second age groups (children at home) remained unchanged or even rose ( Fig. 2 A), which indicated that the COVID-19 pandemic may have hindered community transmission of RSV, rather than household transmission. In addition, there were obvious decrease in positive rates of RSV in all age groups, especially in children over 5 years old, suggesting that the COVID-19 pandemic had reduced the prevalence of RSV infection in school- age children. Remarkably, after the outbreak of the COVID-19 pandemic, 2y - 5y replaced over 5 years old as the main age of RSV infection and the infection risk of pre-school children was increasing relatively, proving that the susceptible age of RSV was decreasing ( Fig. 2 B). Hence, the epidemiological characteristics of RSV were changed before and after the COVID-19 pandemic in children of different ages, which may be caused by a combination of many factors, such as class suspension, increased awareness of wearing masks, reducing contact between children, maintaining ventilation, and paying attention to hand hygiene.Fig. 2 (A) The number of positive of RSV infection by month in every age group from January 2017 to October 2022. (B) The permillage of positive of RSV infection in children during January 2017 to October 2022. Note: the data of 2022 only covers the period from January to October. Fig 2 The COVID-19 pandemic has ravaged the world, reminding us once again that our fate is closely linked to the natural world. Although countries around the world have taken a series of measures to temporarily slow the spread of the virus, scientific analysis is necessary to prevent similar incidents from happening again, as the outbreak of the COVID-19 pandemic will affect more than just the epidemic trend of the respiratory pathogens. Thus, it is urgent to establish a new balanced relationship between human and nature, as well as call for a global community with a shared future for mankind. The future should be a post-pandemic era where ecology, economy and safety are integrated into how we learn, travel and work. In conclusion, the COVID-19 pandemic had a certain impact on the transmission of RSV in children, specifically referring to the reduction of RSV infection in school-age children and the relative increase in the risk of RSV infection in pre-school children. Close monitoring of epidemiology changes is of great significance for the prevent of RSV infection in children, especially in children aged from 1 month to 5 years. Declaration of Competing Interest None. Acknowledgment This work was funded by the National Natural Science Foundation of China (32201237), China Postdoctoral Science Foundation (2020M672301), Scientific and technological projects of Henan province (222102310270, 222102310109). ==== Refs References 1 Zhou J Zhao P Nie M Gao K Yang J Sun J. Changes of Haemophilus influenzae infection in children before and after the COVID-19 pandemic, Henan China. J Infect. 2022 10.1016/j.jinf.2022.10.019 2 Li Y Guo Y Duan Y. Changes in Streptococcus pneumoniae infection in children before and after the COVID-19 pandemic in Zhengzhou China. J Infect. 85 2022 e80 e81 10.1016/j.jinf.2022.05.040 35659542 3 Bermudez Barrezueta L Matias Del Pozo V Lopez-Casillas P Brezmes Raposo M Gutierrez Zamorano M Pino Vazquez MA. Variation in the seasonality of the respiratory syncytial virus during the COVID-19 pandemic Infection 50 2022 1001 1005 10.1007/s15010-022-01794-y 35316529 4 Wong-Chew RM Garcia-Leon ML Noyola DE Respiratory viruses detected in Mexican children younger than 5 years old with community-acquired pneumonia: a national multicenter study Int J Infect Dis 62 2017 32 38 10.1016/j.ijid.2017.06.020 28673837 5 Nair H Nokes DJ Gessner BD Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis The Lancet 375 2010 1545 1555 10.1016/s0140-6736(10)60206-1 6 Li Y Wang X Blau DM Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis Lancet 399 2022 2047 2064 10.1016/S0140-6736(22)00478-0 35598608 7 Pena M Jara C Flores JC Severe respiratory disease caused by human respiratory syncytial virus impairs language learning during early infancy Sci Rep 10 2020 22356 10.1038/s41598-020-79140-1 33349647 8 Kuhdari P Brosio F Malaventura C Human respiratory syncytial virus and hospitalization in young children in Italy Ital J Pediatr 44 2018 50 10.1186/s13052-018-0492-y 29728106

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==== Front J Affect Disord J Affect Disord Journal of Affective Disorders 0165-0327 1573-2517 Elsevier B.V. S0165-0327(22)01409-4 10.1016/j.jad.2022.12.049 Article Olfactory-related quality of life impacts psychological distress in people with COVID-19: The affective implications of olfactory dysfunctions Bochicchio Vincenzo a⁎ Mezzalira Selene a Maldonato Nelson Mauro b Cantone Elena b Scandurra Cristiano b a Department of Humanities, University of Calabria, Rende, CS, Italy b Department of Neurosciences, Reproductive Sciences, and Dentistry, University of Naples Federico II, Napoli, Italy ⁎ Corresponding author at: Department of Humanities, University of Calabria, Via Pietro Bucci Cubo 18/C, Rende 87036, Italy. 15 12 2022 15 12 2022 25 11 2021 10 5 2022 12 12 2022 © 2022 Elsevier B.V. All rights reserved. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Coronavirus disease 2019 (COVID-19) often causes chemosensory impairment, and olfactory dysfunctions may have negative consequences on psychological distress. This study aimed at assessing which dimension of perceived olfactory disfunctions (i.e., subjective olfactory capability, smell-related problems, or olfactory-related quality of life [QoL]) was most associated with psychological distress in people diagnosed with COVID-19. Methods 364 participants (65 men and 299 women) diagnosed with COVID-19 on average 7 months prior to the beginning of the study were recruited between June 5 and 21, 2021, to take part in an online cross-sectional survey. Participants answered questions on demographics, clinical factors, perceived olfactory functioning, and psychological distress. Hierarchical multiple linear regression analysis was conducted, assessing the role of demographics, clinical factors, and perceived olfactory functioning dimensions on psychological distress. Results More than half of the participants met the cut-off for all perceived olfactory dysfunctions scales and psychological distress. Being women, smoker, with comorbidities, and greater severity of COVID-19 symptoms were associated with higher scores on psychological distress. Among perceived olfactory functioning scales, only impairment in olfaction QoL was associated with psychological distress. Limitations Limitations concerned the cross-sectional nature of the study and the unbalanced sample in terms of gender. Conclusions The study confirmed the core intertwining between mood, perceived QoL, and olfactory functioning, showing how impairments in olfactory processing are strongly correlated with psychological distress through the impact they have on the perceived QoL. Keywords COVID-19 Olfactory functioning Psychological distress Quality of life Anosmia Hyposmia ==== Body pmc1 Introduction Coronavirus disease 2019 (COVID-19), which is caused by the Sars-Cov-2 virus, has spread across the world very quickly, representing a global health emergency due to the impressive rates of deaths and hospitalizations (Cantone and Gamerra, 2020; Cecchetto et al., 2021). COVID-19 is mainly characterized by symptoms of fever, cough, and shortness of breath, as well as by the onset of chemesthesis, smell and taste dysfunctions, particularly anosmia and hyposmia. In addition to being iatrogenic as to the overall individual's mental health (Xiong et al., 2020; Salari et al., 2020), COVID-19 is indeed associated with loss or impairment of the sense of smell (Cameron et al., 2021). Therefore, the outbreak of the COVID-19 witnessed a renewed interest in the research on olfactory dysfunctions and the effects they have on the individuals affected by the disease. Even before the outbreak of the COVID-19 pandemic, it was well-known that olfactory dysfunctions have negative consequences on the quality of life (QoL; Frasnelli and Hummel, 2005; Shu et al., 2011), which can be defined as the individuals' conscious perception of their well-being. Food and eating habits, feelings of vulnerability, mood changes, and social life all appear to worsen in the face of smell loss or impairment (Hummel and Nordin, 2005). More specifically, olfactory dysfunctions are associated with decreased QoL and mental health problems (e.g., anxiety and depression) (Erskine and Philpott, 2020). Olfactory deficits have been also reported as markers for several neuro-psychiatric disorders such as neurodegenerative pathologies (e.g., Parkinson's or Alzheimer's disease; Wilson et al., 2009) and mental illnesses (e.g., schizophrenia; Turetsky et al., 2009). The four processes in which olfaction is typically articulated, namely, perception, discrimination, identification, and valence, have been less studied in individuals suffering from bipolar disorder (Henry et al., 2020). However, identification of pleasant odors seems also to be altered in this population (Kazour et al., 2020). The volume of the olfactory bulb is significantly reduced in patients with acute major depression disorder (Negoias et al., 2010), and appears to be closely related to symptom severity (Wang et al., 2020). Depression has also been associated to olfactory dysfunctions (Siopi et al., 2016). Furthermore, by virtue of their power to elicit emotions, odors have been suggested to be useful in treating this condition (Kadohisa, 2013). In fact, patients suffering from depression have reduced olfactory ability compared to healthy controls; conversely, patients with olfactory dysfunction tend to suffer from depression that worsens with severity of smell loss (Kohli et al., 2016). The association between olfactory dysfunctions and mood disorders can be better understood if we focus on the neurobiological processes entailed in the decorrelation of the olfactory stimulus. Primary olfactory areas, indeed, are directly linked with many brain regions involved in emotion and mood, even though these can be differently influenced by olfaction (Kontaris et al., 2020). Whether consciously perceived or not, odors can modulate mood and emotion, and are also associated with emotional memory (Kadohisa, 2013). Odors elicit dichotomic affective responses, which can be pleasant or unpleasant. In fact, olfactory processing is associated with brain regions that subserve emotional processing, namely, the orbitofrontal cortex, the amygdala, and the hippocampus (Gottfried, 2006). Olfactory impairments can indeed cause reduced emotional processing, which relies on several distributed networks in the brain, also depending on whether emotions are perceived as positive or negative (Han et al., 2019). Even though it is the phylogenetically oldest sensory mode, human beings and many other animals possess to appraise the world, olfaction has long been considered of minor importance in human action and perception (Bochicchio and Winsler, 2020; Calvi et al., 2020). The development of the neocortex in humans and some other primates determined the predominance of the visual sensory modality over olfaction. However, evidence exists as to the influence that chemosensory signals associated with body odors have on human and animal behavior (Hofer et al., 2020). As opposed to sight, where the intertwining between context and background is essential to determine visual perception, olfaction refers to a sensory mode that produces unified, one-dimensional, and all-saturating perceptions (Bochicchio et al., 2018, Bochicchio et al., 2019; Bochicchio and Winsler, 2020). Considering the role of olfactory disfunctions in COVID-19, Sedaghat et al. (2020) pointed out the relevance of hyposmia and anosmia as a tool for identifying infected patients, in particular, those that are asymptomatic carriers and therefore unaware of their disease. Dubé et al. (2018) had already shown that coronaviruses attack the central nervous system through the neuroepithelium and propagate from the olfactory bulb. Coronaviruses-related olfactory dysfunctions are caused by the destruction of the olfactory epithelium, whereby odors are impaired from binding to the corresponding receptors (Murphy et al., 2003). Besides the intensification or precipitation of negative mental health outcomes – namely, post-traumatic stress disorder, alcohol abuse, obsessive-compulsive behaviors, anxiety, depression, panic, and paranoia (Pedrosa et al., 2020) – COVID-19-related olfactory dysfunctions are also significantly correlated with psychological distress and affective disorders (Nettore et al., 2021). In addition, smell loss caused by COVID-19 has been shown to negatively impact the individual's QoL, significantly influencing the person's daily activities associated with olfactory functions (Elkholi et al., 2021). In this regard, Speth et al. (2020) found that decreased sense of smell due to COVID-19 is associated with depressed mood and anxiety, which in turn are not associated with other COVID-19 symptoms such as fever, cough, or shortness of breath. In other words, the severity of core, typical COVID-19 symptoms (i.e., fever, cough, and shortness of breath) is not associated with emotional problems, whereas olfactory dysfunctions are. Therefore, Speth et al. (2020) raised the hypothesis that emotional disturbances, psychological distress, and olfactory dysfunctions might be possible manifestations of a central nervous system mechanism related to COVID-19. However, no previous studies clarified which dimension of perceived olfactory disfunctions – that, according to Pusswald et al. (2012) are the subjective olfactory capability, the smell-related problems, and the olfactory-related QoL – is most associated with psychological distress and affective disorders in people diagnosed with COVID-19. Thus, the current study had the objective to assess which domain of perceived olfactory disfunctions is stronger associated with psychological distress. Several confounding variables were considered, as follows: age, gender, educational level, smoking history, duration of the COVID-19 related symptoms, hospitalization, comorbidities (e.g., anxiety, depression, cancer, diabetes), drug consumption to treat the COVID-19 (yes vs. no), and severity of COVID-19 symptoms. Indeed, previous research has shown that certain socio-demographic and clinical factors can affect the olfactory functioning more than others; therefore, it is plausible to hypothesize that they may exacerbate the impact of olfactory dysfunctions on psychological distress. Specifically, Hasan et al. (2021) found that younger patients and smokers are more likely to experience olfactory dysfunctions than their counterparts. Meini et al. (2020) found that olfactory dysfunctions in women are less frequent than men, but longer lasting. Castillo-López et al. (2020) found that low educational level and medical comorbidities were associated with greater olfactory dysfunctions. Findings concerning the association between severity of the COVID-19 and olfactory dysfunctions are mixed (Lechien et al., 2021; Vaira et al., 2020), while the longer the duration of the disease, the stronger the olfactory dysfunctions (Vaira et al., 2020). 2 Methods 2.1 Procedures A cross-sectional web-based Italian survey was administered via Qualtrics software between 5 and 21 June 2021. The participants were reached through advertisements published on Italian online social groups sharing their experiences about being infected by Sars-Cov-2. Additionally, participants were also involved through a snowball recruitment procedure, by asking people interested in the survey to share the study to other potential interested participants they personally knew. All participants took part in our survey on a voluntary basis and were not granted any economic incentive for their participation. By clicking on the link provided, participants were directed to the first page of the survey, where informed consent of the study was uploaded. Thus, participants were informed about objectives, benefits, risks, information about researchers, and anonymity of the survey. After reading the informed consent, participants had to give their consent to participate in the study by clicking “I accept to participate in the study.” To avoid missing data, all questions were mandatory, but participants were informed about their right to stop the survey in any moment they wanted. The study was approved by the ethical committee of the University of Blinded for Review (protocol number Blinded for Review), developed in accordance with the EU General Data Protection Regulation, and designed in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. 2.2 Participants Participants could take part in the survey if they satisfied the following inclusion criteria: (1) being at least 18 years old (the Italian age of consent); (2) being or having been positive for COVID-19 not >1 year ago; and (3) having received a certified diagnosis (e.g., by swab or serological test). A total of 383 participants took part in the survey. Among these, 19 did not satisfy one of the inclusion criteria. Thus, the final sample was composed of 364 Italian participants. 2.3 Measures 2.3.1 Demographics and clinical information Sociodemographic and clinic variables included age, gender (men, women, and other with specification), smoking history (never smoker, past smoker, and current smoker), time of the diagnosis for COVID-19 (from “less than one month ago” to “1 year ago”), duration of the COVID-19 related symptoms, hospitalization (yes vs. no), comorbidities (e.g., anxiety, depression, cancer, diabetes; yes vs. no), drug consumption to treat the COVID-19 (yes vs. no), and severity of COVID-19 symptoms. This latter dimension was measured by asking participants to rate the typical COVID-19 related symptoms (i.e., fever, myalgia, cough, shortness of breath, chest pain, hearth palpitations, gastrointestinal disturbances, conjunctivitis, sore throat-rhinorrhea, and headache; olfactory and taste disorders were excluded as assessed through a specific scale) reported by Adorni et al. (2020) on a 10-Likert scale, from 1 (“absent”) to 10 (“maximum”). A composite scale of “severity of COVID-19 symptoms” was created by summing the scores obtained at each symptom. 2.3.2 Perceived olfactory functioning Subjective perceptions of one's own olfactory functioning were measured through the 12-item questionnaire for the Assessment of Self-Reported Olfactory Functioning and Olfaction-Related Quality of Life (ASOF; Pusswald et al., 2012). ASOF consisted of three domains, as follows: (1) Subjective Olfactory Capability scale (SOC), that assesses perceived olfactory performance through 1 item (i.e., “How would you rate your sense of smell over the past four weeks?”) on a Likert scale ranging from 0 (“unable to smell”) to 10 (“best possible smell”); (2) Smell-Related Problems scale (SRP), that measures subjective capability of perceiving specific odors scale (e.g., “During the past four weeks, how often have you had problems smelling the odor of spoiled food?”) through 5 items on a Likert scale ranging from 1 (“very often”) to 5 (“never”); and (3) Olfactory-Related Quality of Life scale (ORQ), that assesses perceived QoL concerning olfactory functioning in different domains (i.e., cooking, sexual life, eating food, drinking beverages, using perfumes, and perceiving the scent of flowers) through 6 items on a Likert scale ranging from 1 (“Very much impaired”) to 5 (“not at all impaired”). SOC ≤ 3, SRP ≤ 2.9, and ORQ ≤ 3.7 have been individuated as cut-off scores indicating, respectively, abnormal olfactory capabilities, problems in smelling odors, and smell-related problems in QoL. Thus, lower scores on all ASOF subscales indicate greater perceived impairment in olfactory functioning. The α coefficient for the current sample was 0.97 for SRP scale and 0.92 for ORQ. 2.3.3 Psychological distress Psychological distress was assessed through the Kessler Psychological Distress Scale (K10; Kessler et al., 2002), a 10-item questionnaire detecting psychological distress based on questions about anxiety and depressive symptoms experienced during the last 30 days. The response options ranged from 1 (“none of the time”) to 5 (“all of the time”). An example item is “During the last 30 days, about how often did you feel tired out for no good reason?”. Higher scores indicate greater psychological distress. Consistently with Andrews and Slade (2001), the cut-off score of 24 was adopted to detect the likelihood of presence of moderate-to-severe psychological distress. The α coefficient for the current sample was 0.93. 2.4 Preliminary and statistical analyses Preliminary analyses concerned the translation and reliability assessment of the ASOF, a scale that was not previously validated in Italy. For this reason, ASOF has been translated into Italian following all the phases of the back-translation method suggested by Behling and Law (2000). Then, a Confirmatory Factor Analysis (CFA) with the Maximum Likelihood estimation with Robust Standard Errors was performed to assess the goodness of fit of the ASOF using R-Studio, and the following indices were used (Kline, 2011): Chi-Square/degrees of freedom (χ 2/df), Root Mean Square Error of Approximation (RMSEA), Standardized Root Mean Square Residual (SRMR), Comparative Fit Index (CFI), and Tucker–Lewis Index (TLI). The fit indices of the ASOF were: χ 2/df = 1.92, p = 0.058; RMSEA = 0.050; SRMR = 0.021; CFI = 0.992; TLI = 0.988. Based on the suggestions by Hooper et al. (2009), the goodness of fit indices of the Italian version of the ASOF can be considered more than acceptable. In addition, although K-10 is a scale widely used in Italy both before (e.g., Barbero et al., 2015; Bartoli et al., 2018; Carrà et al., 2011) and during the Covid-19 outbreak (e.g., De Micco et al., 2020; Janiri et al., 2021; Moccia et al., 2020), there is no specific Italian study on its validation. Therefore, we performed another CFA with the same method used for ASOF. The CFA showed very good fit indices for the Italian version of K10, as follows: χ 2/df = 1.89, p = 0.061; RMSEA = 0.049; SRMR = 0.022; CFI = 0.992; TLI = 0.984. All other statistical analyses were performed with SPSS version 27, setting the level of significance at 0.05. First, participants characteristics, descriptive statistics (means, standard deviation, and cut-off scores of the scales), and bivariate correlations between the main study's variables (perceived olfactory functioning and psychological distress) were calculated. Then, the associations between perceived olfactory functioning and psychological distress were assessed through a hierarchical multiple linear regression analysis, with psychological distress as the outcome variable and perceived olfactory functioning dimensions as independent variables. This analysis was controlled for age, gender (1 = male; 2 = female), smoking history (0 = smoker; 1 = no-smoker), duration of the COVID-19 related symptoms, hospitalization (0 = no; 1 = yes), comorbidities (0 = no; 1 = yes), drug consumption to treat the COVID-19 (0 = no; 1 = yes), and severity of COVID-19 symptoms. As an indicator of the effect size, Cohen's f 2 method was used, according to which f 2 ≥ 0.02, f 2 ≥ 0.15, and f 2 ≥ 0.35 represent small, medium, and large effect sizes (Cohen, 1988). To ascertain the absence of multicollinearity, we assessed the variance inflation factor (VIF). Conventionally, VIFs near or above 5 may be considered acceptable values (Akinwande et al., 2015). 3 Results 3.1 Socio-demographic and clinical characteristics of participants Sixty-five (17.9 %) participants were males and 299 (82.1 %) females. Participants ranged in age from 18 to 79 years old (M = 42.46, SD = 13.53). Most of the sample had an educational level ≤ high school (n = 231; 63.5 %). Participants were diagnosed with COVID-19 on average 7 months prior to the start of the study (SD = 3.10), only 8 (2.2 %) were asymptomatic, 32 (8.8 %) were hospitalized, and 180 (49.5 %) took drugs to treat the Sars-Cov-2. About a quarter of the participants (n = 94; 25.8 %) declared to have some type of comorbidities, as follows: anxiety (n = 39; 10.7 %), depression (n = 12; 3.3 %), cancer (n = 1; 0.3 %), or diabetes (n = 3; 0.8 %). Finally, 61 participants (16.8 %) were smokers. 3.2 Descriptive statistics and bivariate correlations Means, standard deviations, and bivariate correlations between the main variables analyzed (perceived olfactory functioning and psychological distress) are reported in Table 1 . Percentages of participants who were above the cut-off of dimensions analyzed are also reported.Table 1 Descriptive statistics and bivariate correlations between perceived olfactory functioning and psychological distress. Table 1 1 2 3 4 M ± SD > cut-off n (%) SOC − 3.65 ± 3.59 238 (65.4) SRP 0.50*** − 2.25 ± 1.37 226 (62.1) ORQ 0.54*** 0.70*** − 2.78 ± 1.36 238 (65.4) K10 −0.12* −0.20*** −0.33*** − 29.39 ± 10.09 247 (67.9) Notes. SOC = Subjective Olfactory Capability; SRP = Smell-Related Problems; ORQ = Olfactory-Related Quality of Life; K10 = Kessler Psychological Distress Scale; M = Mean; SD = Standard Deviation. *p < 0.05; ***p < 0.001. Results of the Pearson correlation indicated that all healthy olfactory functioning variables correlated positively with each other and negatively with psychological distress. Furthermore, more than half of the sample met the cut-off for all the perceived olfactory dysfunctions scales and psychological distress. 3.3 Associations between perceived olfactory functioning and psychological distress Results for hierarchical multiple linear regression analysis are reported in Table 2 . All VIFs were acceptable, ranging from 1.03 to 2.34.Table 2 Hierarchical multiple linear regression of psychological distress on perceived olfactory functioning dimensions. Table 2 Psychological distress B (SE) β 95 % CI Step 1 – Control variables Age −0.05 (0.04) −0.07 −0.12, 0.22 Gender (male) 5.74 (1.26) 0.22*** 3.25, 8.23 Smoker (no) 2.63 (1.28) 0.10* 0.12, 5.14 Duration of symptoms 0.27 (0.21) 0.06 −0.14, 0.67 Hospitalization (no) −0.56 (1.76) −0.02 −4.01, 2.90 Drugs for COVID-19 (no) −0.56 (0.96) −0.03 −2.44, 1.32 Comorbidities (no) 3.42 (1.10) 0.15** 1.25, 5.59 Severity of symptoms 1.80 (0.27) 0.33*** 1.27, 2.33 R2 = 0.239; F = 13.97*** Step 2 – Olfactory functioning Age −0.05 (0.04) −0.07 −0.12, 0.02 Gender (male) 5.28 (1.23) 0.20*** 2.85, 7.70 Smoker (no) 2.77 (1.24) 0.10* 0.32, 5.22 Duration of symptoms 0.29 (0.20) 0.07 −0.10, 0.68 Hospitalization (no) 0.29 (1.72) 0.01 −3.09, 3.67 Drugs for COVID-19 (no) −0.08 (0.93) −0.01 −1.92, 1.75 Comorbidities (no) 3.79 (1.07) 0.16*** 1.67, 5.90 Severity of symptoms 1.36 (0.28) 0.25*** 0.81, 1.91 SOC 0.09 (0.15) 0.03 −0.22, 0.39 SRP 0.16 (0.48) 0.02 −0.78, 1.10 ORQ −2.02 (0.51) −0.27*** −3.02, −1.02 R2 = 0.291; ΔR2 = 0.051***; F = 13.11*** Notes. B = Unstandardized regression coefficient; SE = Standard error; CI = Confidence interval; β = Unstandardized regression coefficient; R2 = R-square; ΔR2 = Change in R2; SOC = Subjective Olfactory Capability; SRP = Smell-Related Problems; ORQ = Olfactory-Related Quality of Life. ***p < 0.001; **p < 0.01; *p < 0.05. Demographics and clinical characteristics in step 1 explained 23.9 % of variation in psychological distress, with a medium effect size (f 2 = 0.31). Specifically, being women, smoker, with comorbidities, and greater severity of COVID-19 symptoms were associated with higher scores on psychological distress. Adding perceived olfactory functioning scales in step 2 of the regression model explained a significant additional 5.1 % of the variation in psychological distress. Specifically, among perceived olfactory functioning scales, only impairment in olfaction QoL was associated with higher levels of psychological distress. The final statistical model for all dimensions accounted for 29.1 % of the variance in psychological distress, with a large effect size (f 2 = 0.41). Finally, to assess the weight of specific ORQ dimensions on psychological distress we run another hierarchical multiple linear regression, with psychological distress as the outcome variable and the six items of the ORQ as independent variables. This analysis was controlled for covariates resulted significant in the previous regression model (i.e., gender, smoker status, comorbidities, and severity of symptoms). Among all items, only item 8 (i.e., sexual life) and item 11 (i.e., using perfumes) resulted statistically significant (F (10, 353) = 15.59, p < 0.001), explaining 28.7 % of the variance in psychological distress, with a large effect size (f 2 = 0.40). Specifically, impairment in sexual life (b = −0.17, p = 0.003) and in using perfumes (b = −0.20, p = 0.023) were associated with higher scores on psychological distress. 4 Discussion The current study was aimed at assessing the association between domains and effects of olfactory dysfunctions and psychological distress. Results mainly indicated that, among the domains of perceived olfactory functioning, the impairment in olfaction QoL was the only domain associated with psychological distress. First, it is noteworthy that more than half of the participants of our study met the cut-off for all perceived olfactory dysfunctions scales and psychological distress. This result confirmed a finding already present in the literature, namely, the fact that olfactory dysfunctions are strongly correlated with psychological distress. Houghton et al. (2019), for instance, found that individuals who consider themselves “odor sensitive” show increased symptoms of anxiety, depression, and psychological distress. In fact, reduced olfactory sensitivity tends to accompany depressive symptoms, and this correlation has been suggested to be mediated by modifications in brain regions that subserve primary olfactory processing, such as the amygdala and piriform cortex (Pollatos et al., 2007). Conversely, depressive symptomatology negatively impacts olfactory functioning (Pabel et al., 2018), which might thus be taken as a marker for depression (Croy et al., 2014). Also, the severity of major depressive disorders has been shown to be associated with impairments in odor identification (Khil et al., 2016). Lower thresholds in odor detection, greater olfactory awareness, and enhanced reactivity to odors have been found in individuals with panic disorder as well (Burón et al., 2015). When compared to non-infected persons, COVID-19 patients can maintain a similar capacity to recognize odors, but the intensity of the perceived odors appears as significantly diminished (Nettore et al., 2021). That is, COVID-19 seems to be associated with impairment of the quantitative features of odor recognition, but not with its qualitative aspects. Impairment in the sense of olfaction, which is the phylogenetically oldest sensory mode human beings are endowed with, significantly impacts mental health and psychological well-being. Therefore, mental health seems to be strongly influenced by how functional our senses are in determining the features of our surroundings. Ultimately, COVID-19-related anosmia can have serious consequences for the person's sense of mental health and well-being (Gerkin et al., 2021). As to the significance of covariate variables, we found that being women, being a smoker, having comorbidities, and manifesting greater severity of COVID-19 symptoms was associated with higher scores on psychological distress. It is well-known that, even when they present similar physical or psychiatric problems, women tend to seek medical care more than men (Koopmans and Lamers, 2007). Barsky et al. (2001) also found that gender differences exist as to the referred psychosomatic problems by men and women, whereby the latter report more intense, frequent, and numerous symptoms than the former. Smoking habits seem also to be intrinsically related to psychological distress. There is indeed a significant relationship between tobacco smoking and mental conditions such as depression (Wiesbeck et al., 2008) and anxiety (Morissette et al., 2007). In this regard, Fischer et al. (2012) demonstrated the interconnectedness between the use of tobacco and psychopathology. Instead, results concerning the associations of comorbidities and greater severity of COVID-19 symptoms with psychological distress confirmed previous studies reporting that, among others, these variables are significant predictors of negative mental health outcomes in people diagnosed with COVID-19 (e.g., Liu et al., 2020). However, the main result of our study consists in the fact that, among the measures obtained through the ASOF (Pusswald et al., 2012), only impairment in olfactory-related QoL was associated with higher levels of psychological distress. This finding may be explained by taking into account that the impact of olfaction on QoL seems to be mediated by the immediacy that characterizes the pathway of the sense of olfaction when the odor is processed in the olfactory areas of the brain, and by the subsequent recording of the smell as a pre-reflective perception, as it can be registered also by non-concept-using individuals (Roberts, 2015). Conscious awareness is often bypassed by the unconscious triggering of memories upon odor perception, which can be influenced by stimulus-related emotions, and by the individual's actual emotional state as well (Chen and Dalton, 2005). Yet olfaction first and foremost impacts the “here and now,” as it is associated with the degree to which we can sense the external world immediately and pre-reflectively, in a way that points to the relevance of our core bodily self-awareness (Colombetti, 2011). Olfaction appears to shed light on the realm of pre-reflective experience because smell is often not (yet) explicitly thematized as an “object” for one's self-awareness (Picolas and Soueltzis, 2019). Therefore, olfactory perception may strongly impact the QoL as a pre-reflective appraisal of the external world and may be associated with the immediacy of our perception of the surroundings and our modalities of non-verbal communication as well (Andersen and Andersen, 2005). Ultimately, the results of our study point to the fact that it is not the olfactory dysfunction per se that causes the person's psychological distress, but rather the impact that olfactory dysfunctions have on the perceived QoL. Therefore, it seems that is the relationship between olfactory dysfunctions and the impact they have on the QoL that determines the severity of the person's perceived psychological distress. Finally, among the ASOF measures, the ORQ assessed the perceived QoL associated with olfactory functioning in different domains (i.e., cooking, sexual life, eating, drinking, using perfumes, and perceiving the scent of flowers). The results of our study showed that only impairments in sexual life and in using perfumes were associated with higher levels of psychological distress. As opposed to the other activities (cooking, eating, drinking, and perceiving the scent of flowers), which, although being also interactive actions, do not necessarily involve significant relationships with others, sexual life and the perception of a person's scent imply our core interconnectedness with other persons. From a speculative point of view, this seems a very relevant finding, which would point to the significance of olfaction of relevant relationships in human life. Our existence, indeed, takes shape according to the value that interpersonal interchanges have in the very constitution of our Self. From the beginning of life, we are embedded in our caring environment, whose features massively influence our (more or less successful) growth trajectories. Every developmental stage of human existence is shaped through relational figures, which in turn significantly contribute to determine one's well-being. The results of our study can therefore be interpreted within the relational framework that encompasses the individual's physical and psychological health and well-being. The interpersonal dimension of human existence is grounded in all the features that characterize the significant others. Not only we become able to grasp the others' thoughts through the meaning we bestow on their intentional life (as described in the theories of mind), but we are also able to “sense” them through our sensory modes of perception (e.g., when we smell their scent). Sexual life is essentially intertwined with the capacity to understand the other person's intentions, whereas the person's perfume deeply influences the emotional value of the interpersonal situation. In fact, among the ORQ domains, these appear to be the only activities that are directly related to the intersubjectively constituted world, which confirms that the possibility to find a common framework of perception and interaction is rooted in the very nature of us as human beings. Although this study was intended to fill a gap in the explanation of the impact that COVID-19-related olfactory dysfunctions have on psychological distress, its limitations should be considered when interpreting the results. First, the study was cross-sectional in nature, and allowed for a picture of the sample only, taken as representative of a larger population. Future research should pay attention to this aspect, by expanding the sample size and exploring hypothesized relationships between variables in a longitudinal manner (e.g., by assessing the impairment of the perceived olfactory functioning domains throughout the course of the disease). Second, there is a clear gender disparity in the sample, as 299 participants (82.1 %) were female, and only 65 (17.9 %) were male. Future research should consider whether including a more gender-balanced sample might offer the opportunity to improve these results. Third, this study was conducted online, which prevented us from recruiting participants who do not have access to the Internet. Contemporary society is widely provided with access to the Internet, however, especially the elderly might not have the same chances that younger individuals have to be reached by the researchers. Lastly, the study utilized self-report measures as opposed, for instance, to olfactory sniffin’ sticks, which would have been more accurate as to the measurement of the individual's olfactory functioning. Therefore, future studies could use this type of measure instead of basing the interpretation of the results on self-reported information, thus improving the accuracy levels of the measurement. Despite limitations, the findings of the current study may inform clinical practice related to emotional disorders. Indeed, it is important to stress that clinicians (psychologists and/or psychiatrists) must be aware that anosmia – and olfactory impairment in general – can be a triggering factor for psychic distress such as depression and anxiety, which must be taken seriously into account. Anosmia involves a worsening of the individual's psychic condition, and has significant affective implications. Therefore, the presence of anosmia and olfactory impairment, along with other possible Covid-19-related symptoms, seem crucial in their potential to impact the patient's mood. This is the reason why it is important that clinicians take into account the possibility of psychological support for individuals exhibiting signs of olfactory dysfunctions. 5 Conclusions Sensory modes of perception, such as olfaction (the phylogenetically oldest sensory mode human beings are endowed with) strongly influence how the world and the surroundings are perceived in relation to others. In particular, olfactory impairments can significantly impact the person's feeling of psychological well-being. Our study showed that COVID-19 olfactory dysfunctions strongly impact the person's reported psychological distress, and that COVID-19-related anosmia can have serious consequences as to the person's perception of his or her QoL. More specifically, among the perceived olfactory functioning scales, only impairment in olfactory-related QoL was associated with higher levels of psychological distress. This result points to the fact that it is the impact that olfactory dysfunctions have on the perceived QoL that mediate the perceived psychological distress, rather than olfactory dysfunctions being per se the causes of such distress. In other words, it is the very relationship between olfactory functioning and the impact it has on the perceived QoL that appears to correlate with the person's feeling of being psychologically distressed. Ultimately, this study confirmed the core intertwining between mood, perceived QoL, and olfactory functioning, showing how impairments in olfactory processing are strongly correlated with psychological distress through the impact they have on the perceived QoL. CRediT authorship contribution statement Vincenzo Bochicchio (VB), Selene Mezzalira (SM), and Cristiano Scandurra (CS) designed the study. VB, SM, Nelson Mauro Maldonato (NMM), Elena Cantone (EC), and CS contributed to the acquisition of data. VB and CS analyzed the data. VB, SM, NMM, EC, and CS interpreted the data. VB, and SM, drafted the manuscript. EC, NMM, and CS critically revised the manuscript. VB and CS had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. All authors have read the manuscript and have agreed with its submission. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Consent to participate and for publication By clicking on the link provided, participants were directed to the first page of the survey containing the informed consent of the study, its objectives, benefits, and risks, information about researchers, and their emails and telephone numbers. Furthermore, in the informed consent was clearly reported that the data would have been published in scientific journals and that the data would have been analyzed in aggregate ways. After reading all information, participants gave their consent to participate in the survey by clicking “I accept to take part in the survey.” Uncited references Herz, 2002 Pabel et al., 2020 Sartorius, 2007 Declaration of competing interest The authors declare that they have no conflict of interest. Data availability The data and materials that support the findings of this study are available from the corresponding author upon reasonable request. Acknowledgment None. ==== Refs References Adorni F. Prinelli F. Bianchi F. Giacomelli A. Pagani G. Bernacchia D. Rusconi S. Maggi S. Trevisan C. Noale M. Molinaro S. Bastiani L. Fortunato L. Jesuthasan N. Sojic A. Pettenati C. Tavio M. Andreoni M. Mastroianni C. Antonelli Incalzi R. Galli M. Self-reported symptoms of SARS-CoV-2 infection in a nonhospitalized population in Italy: cross-sectional study of the EPICOVID19 web-based survey JMIR Public Health Surveill. 6 2020 e21866 10.2196/21866 Akinwande M. Dikko H. Samson A. 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Scents and nonsense: olfactory dysfunction in schizophrenia Schizophr. Bull. 35 2009 1117 1131 10.1093/schbul/sbp111 19793796 Vaira L.A. Hopkins C. Salzano G. Petrocelli M. Melis A. Cucurullo M. Ferrari M. Gagliardini L. Pipolo C. Deiana G. Fiore V. De Vito A. Turra N. Canu S. Maglio A. Serra A. Bussu F. Madeddu G. Babudieri S. Giuseppe Fois A. Pirina P. Salzano F.A. De Riu P. Biglioli F. De Riu G. Olfactory and gustatory function impairment in COVID-19 patients: italian objective multicenter-study Head Neck. 42 2020 1560 1569 10.1002/hed.26269 32437022 Wang F. Wu X. Gao J. Li Y. Zhu Y. Fang Y. The relationship of olfactory function and clinical traits in major depressive disorder Behav. Brain Res. 386 2020 112594 10.1016/j.bbr.2020.112594 Wiesbeck G.A. Kuhl H.-C. Yaldizli Ö. Wurst F.M. Tobacco smoking and depression – results from the WHO/ISBRA study Neuropsychobiology 57 2008 26 31 10.1159/000123119 18424908 Wilson R.S. Arnold S.E. Schneider J.A. Boyle P.A. Buchman A.S. Bennett D.A. Olfactory impairment in presymptomatic Alzheimer’s disease Ann. N. Y. Acad. Sci. 1170 2009 730 735 10.1111/j.1749-6632.2009.04013 19686220 Xiong J. Lipsitz O. Nasri F. Lui L. Gill H. Phan L. Chen-Li D. Iacobucci M. Ho R. Majeed A. McIntyre R.S. Impact of COVID-19 pandemic on mental health in the general population: a systematic review J. Affect. Disord. 277 2020 55 64 10.1016/j.jad.2020.08.001 32799105

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==== Front Public Health Pract (Oxf) Public Health Pract (Oxf) Public Health in Practice 2666-5352 Published by Elsevier Ltd on behalf of The Royal Society for Public Health. S2666-5352(22)00123-9 10.1016/j.puhip.2022.100347 100347 Article Comparison of capillary blood and plasma samples for the evaluation of seroprevalence to SARS-CoV-2 antibodies by lateral flow immunoassay in a university population in Medellín, Colombia, 2020 Navarro Miguel Octavio Pérez a∗ Gaviria Núñez Angela María ab Cuervo Araque Claudia María b Figueroa Mónica María b Mejía Muñoz Alejandro a Segura Caro Juan Aicardo a a Research Laboratory, Faculty of Health Sciences, Institución Universitaria Colegio Mayor de Antioquia, Colombia b Group of Respiratory Diseases, Research Laboratory, Faculty of Health Sciences, Institución Universitaria Colegio Mayor de Antioquia, Colombia ∗ Corresponding author. Institución Universitaria Colmayor, Carrera 78 # 65, 46 Bloque Patrimonial, Piso 1, Medellín, Antioquia, Colombia. 15 12 2022 15 12 2022 10034717 8 2022 24 11 2022 © 2022 Published by Elsevier Ltd on behalf of The Royal Society for Public Health. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objectives The aim of this study was to estimate the seroprevalence of anti-SARS-CoV-2 antibodies using the SARS-CoV-2 antibody test in a university population. Capillary blood and plasma samples were compared and correlated with symptomatology to establish rapid treatment processes and develop a public health strategy within the community. Study design Descriptive study of seroprevalence of anti-SARS-CoV-2 antibodies in a university population. Methods Standardised and validated laboratory serological tests were used to assess the immune response detected in capillary blood and plasma samples. In this study, 280 participants from the University Colegio Mayor de Antioquia in the Municipality of Medellín, Colombia, were tested for SARS-CoV-2 antibodies in capillary blood and plasma samples between November 2020 and January 2021. Results In total, 29 (11.2%) individuals had positive results for anti-SARS-CoV-2 antibodies (IgG/IgM); 28 (96.6%) had positive results in plasma samples and 11 (37.9%) in capillary blood samples. The two tests were compared, and the overall sensitivity and specificity of capillary vs plasma samples was 36.7% and 99.6%, respectively. Conclusions Anti-SARS-CoV-2 antibodies (IgG/IgM) can be used to estimate the seroprevalence in populations, including immunity by vaccination; however, capillary blood samples should not be used to detect previous infection as they provide low sensitivity compared to plasma samples. Keywords COVID-19 Predictive values Youden statistic Sensitivity and specificity ==== Body pmc1 Introduction COVID-19 is the infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has spread rapidly throughout the world resulting in a global pandemic. Colombia confirmed its first case of COVID-19 in the capital, Bogotá, on 6 March 2020 in a man who had recently visited Milan, Italy. Seroprevalence studies provide an important role in the evaluation of immune response against a virus. For the timely management of the COVID-19 pandemic, accurate, standardised and validated laboratory serological tests were required to assess the seroprevalence and immunisation status of the population [1,2]. Sensitivity, specificity and precision of the technique in relation to the type of sample are important factors in providing accurate results in epidemiological studies. Laboratory tests can directly or indirectly identify infection caused by SARS-CoV-2 in different sample types. Immunoassay techniques are designed to detect antibodies in blood samples by identifying specific anti-SARS-CoV-2 antibodies that are present approximately 10 days after the first clinical manifestation of infection [3]. A positive result confirms contact with the virus and is of great value from an epidemiological perspective because it enables detection of asymptomatic individuals. Asymptomatic individuals can be a source of infection; thus, identification of these individuals allows a more accurate calculation of the seroprevalence of COVID-19 infection in the population. The sensitivity and specificity of the COVID-19 seroprevalence assays quickly led to the recognition that robust internal validation and regulatory control was required. In addition, research was required to link specific serological variables with immunity against SARS-CoV-2 [4], including vaccination; thus, seroprevalence studies provided information about the duration of vaccine immunity and the induced herd immunity. Globally, the COVID-19 pandemic required the expansion of commercial rapid serological tests for use on different sample types to enable mass screening and testing of the entire population. In Colombia, the approved tests by the INVIMA (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) jurisdiction, must be validated and verified before their use in clinical assays. The SARS-CoV-2 Antibody Test (Lateral Flow Method) (Guangzhou, Wondfo Biotech Co., Ltd.) has been used to detect antibodies in serum, plasma and capillary blood; however, one study suggested that this test showed a low sensitivity when performed with capillary blood and therefore not be performed using capillary blood samples [5]. The current study aimed to estimate the seroprevalence of anti-SARS-CoV-2 antibodies using the SARS-CoV-2 Antibody Test in a university population. Capillary blood and plasma samples were compared and correlated with symptomatology to establish rapid treatment processes and develop a public health strategy within the community. 2 Methods 2.1 Study population A descriptive study was conducted in a population of men and women from the Institución Universitaria Colegio Mayor de Antioquia in the Municipality of Medellín, Colombia, between November 2020 to January 2021. Eligible participants (N = 280) were aged ≥18 years, and were able to read and sign informed consent documents. All participants voluntarily agreed to take part in the study. A survey collected data from participants, including the dates of any previous COVID-19-related symptoms, such as headache, fatigue, fever or respiratory signs. To calculate sensitivity, individuals who had previously tested positive for COVID-19 by RT-PCR (n = 10) were included. To calculate specificity, both individuals who had previously tested negative for COVID-19 by RT-PCR (n = 10) and plasma samples collected before the SARS-CoV-2 outbreak and stored at −80 °C (n = 10) were included. This low-risk study was conducted during the COVID-19 pandemic and under a declaration of a state of emergency. An ethical approval certificate was obtained from the research committee of the Hospital General de Medellín and the study was conducted in accordance with the ethical principles of the Declaration of Helsinki. 2.2 Specimen collection and procedures The SARS-CoV-2 Antibody Test (Lateral Flow Method) (Guangzhou, Wondfo Biotech Co., Ltd.) Cat N° W195 is based on the principle of capture immunoassay for determination of SARS-CoV-2 IgG/IgM antibodies in humans. When the SARS-CoV-2 antibody levels in the specimen are at or above the cut-off value (the detection limit of the test), the antibodies bound to the antigen-dye conjugate are captured by anti-human IgG antibody and anti-human μ chain antibody immobilised in the Test Region (T) of the device; this interaction produces a coloured test band that indicates a positive result. When the SARS-CoV-2 antibody levels in the specimen are zero or below the cut-off value, the coloured band is not visible in the Test Region (T) of the device. The test cassette was used at the site according to manufacturer's instructions for plasma and capillary whole blood. To collect capillary blood samples, a lancet was used to prick the side of the fingertip resulting in the formation of a large drop of suspended blood. This blood sample was collected with a dropper (10 μl approximately, included in the kit) and deposited on the appropriate well of the test cassette. In addition, following the standard venous blood collection procedure, a whole blood specimen was collected in a tube containing EDTA. Immediately, the plasma was separated from blood by centrifugation at 3500 rpm for 5 min at 25 °C. This plasma sample was collected with a 10 μl micropipette that filled automatically and was deposited in the appropriate well of the test cassette. 2.3 Data analyses All data were entered into an Excel file and analysed by Software SPSSv25. The validity of the capillary blood sample was evaluated by determining the sensitivity and specificity of the test, and the Youden statistic was also calculated. The safety of the capillary blood sample was evaluated by means of the positive (PPV) and negative (NPV) predictive values. The recommended sample (plasma) was considered as the reference standard. 3 Results The SARS-CoV-2 Antibody Test (Lateral Flow Method) for detecting anti-SARS-CoV-2 IgM/IgG antibodies was evaluated using plasma and capillary blood samples. The serology was performed on 260 participants. In total, 29 (11.2%) individuals were positive for anti-SARS-CoV-2 antibodies (IgG/IgM); 28 (96.6%) had positive results in plasma samples and 11 (37.9%) in capillary blood samples. Thus, 10 (34.4%) participants had positive results in both plasma and capillary blood samples. The sensitivity and specificity for detecting IgM/IgG in capillary blood was 36.7% and 99.6%, respectively. The PPV was 91% and the NPV was 93%. The Youden statistic was 36.3%. In participants who had previously been diagnosed with COVID-19 (positive control) from July to November 2020 (2–20 weeks before the test), the sensitivity for detecting IgM/IgG in plasma and capillary blood samples was 100% (10/10) and 90% (9/10), respectively. Thus, the sensitivity was not affected over time and IgM/IgG antibodies were detected in plasma. Of the 10 negative controls, all 10 tested negative for IgM/IgG antibodies (100%) in both plasma and capillary blood samples. Of 10 plasma samples collected before the SARS-CoV-2 outbreak, no samples tested positive. The overall specificity of the Wondfo test was 100%. 4 Discussion According to the COVID-19 Testing Project, the Wondfo test has an overall sensitivity of 86.4% 20 days after onset of symptoms and a specificity of 99% in serum samples [6]. In the current study, capillary blood samples (obtained by finger prick) were shown to exhibit comparable sensitivity to plasma samples for detecting anti-SARS-CoV-2 IgM/IgG antibodies in patients with severe COVID-19 symptoms and who had previously been diagnosed with COVID-19 by RT-PCR. However, when the results for capillary blood and plasma samples were compared in the whole study population, they did not show consistency. Similar findings were previously reported for the same serological test, showing a low sensitivity with capillary blood samples (55%) [5]. Several factors impact the performance and quality of the tests, including the stage of disease, the handling of the test procedures, the type of sample used, as well as the understanding of the strengths and limitations of such tests [7]. Of the 29 IgG/IgM positive participants in this study, 25 (86.2%) reported not having had severe COVID-19 symptoms; from these 25 individuals, 16 (64%) had negative test results with capillary blood samples. This observation might be explained by lower antibody levels in asymptomatic individuals compared with symptomatic patients, thus leading to poor detection in capillary blood samples. Other studies have reported a higher detectable SARS-CoV-2 viral load was associated with increased symptoms [8]. These results highlight the need for regular testing of asymptomatic individuals to reduce the possibility of transmission and to help combat the COVID-19 pandemic [9]. 5 Conclusion Serological testing is essential to verify the immune status. The SARS-CoV-2 Antibody Test (Lateral Flow Method) (Guangzhou, Wondfo Biotech Co., Ltd.) for detecting anti-SARS-CoV-2 IgM/IgG antibodies can be used to estimate the seroprevalence in a population, including immunity by vaccination, to help guide public health policies. However, we recommend that the Wondfo SARS-CoV-2 Antibody Test (Lateral Flow Method) should not be used with capillary blood samples as this type of specimen showed low sensitivity in asymptomatic COVID-19 individuals and is not suitable for detecting previous infection when compared with plasma samples. Additional longitudinal serological studies in asymptomatic COVID-19 populations are required to determine the duration of antibody-mediated immunity. Ethical approval This low-risk study was conducted during the pandemic and under a declaration of a state of emergency. An approval certificate (004_03072018) was obtained from the research committee of the Hospital General de Medellín and the study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Funding None declared. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The authors wish to express thanks to Saúl Colorado, Santiago Franco and Santiago Cardona. ==== Refs References 1 Huang A.T. Garcia-Carreras B. Hitchings M.D.T. Yang B. Katzelnick L.C. Rattigan S.M. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity Nat Commun [Internet 11 1 2020 Dec 17 4704 Available from: https://www.nature.com/articles/s41467-020-18450-4 32943637 2 Serrano M.M. Rodríguez D.N. Palop N.T. Arenas R.O. Córdoba M.M. Mochón M.D.O. Comparison of commercial lateral flow immunoassays and ELISA for SARS-CoV-2 antibody detection J Clin Virol [Internet] 129 2020 Aug 104529 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1386653220302717 3 Cheng M.P. Yansouni C.P. Basta N.E. Desjardins M. Kanjilal S. Paquette K. Serodiagnostics for severe Acute respiratory syndrome–related Coronavirus 2 Ann Intern Med [Internet 173 6 2020 Sep 15 450 460 Available from: https://www.acpjournals.org/doi/10.7326/M20-2854 32496919 4 Zhao J. Yuan Q. Wang H. Liu W. Liao X. Su Y. Antibody responses to SARS-CoV-2 in patients with novel Coronavirus disease 2019 Clin Infect Dis an Off Publ Infect Dis Soc Am 71 16 2020 Nov 2027 2034 5 Santos VA dos Rafael M.M. Sabino E.C. Duarte AJ. da S. Sensitivity of the Wondfo One Step COVID-19 test using serum samples Clinics [Internet] 75 2020 e2013 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1807593222003957 6 Whitman J.D. Hiatt J. Mowery C.T. Shy B.R. Yu R. Yamamoto T.N. Test performance evaluation of SARS-CoV-2 serological assays medRxiv [Internet] 2020 Jan 1 2020.04.25.20074856. Available from: http://medrxiv.org/content/early/2020/05/17/2020.04.25.20074856.abstract 7 Zitek T. The appropriate use of testing for COVID-19 West J Emerg Med [Internet] 21 3 2020 Apr 13 Available from: https://escholarship.org/uc/item/1gh0z5t0 8 Scohy A. Anantharajah A. Bodéus M. Kabamba-Mukadi B. Verroken A. Rodriguez-Villalobos H. Low performance of rapid antigen detection test as frontline testing for COVID-19 diagnosis J Clin Virol [Internet] 129 2020 Aug 104455 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1386653220301979 9 Mina M.J. Andersen K.G. COVID-19 testing: one size does not fit all Science (80) [Internet] 371 6525 2021 Jan 8 126–7. Available from: https://www.science.org/doi/10.1126/science.abe9187

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==== Front Diagn Microbiol Infect Dis Diagn Microbiol Infect Dis Diagnostic Microbiology and Infectious Disease 0732-8893 1879-0070 Elsevier Inc. S0732-8893(22)00244-9 10.1016/j.diagmicrobio.2022.115880 115880 Original Article Authorized SARS-CoV-2 molecular methods show wide variability in the limit of detection. Blommel Joseph H ab Jenkinson Garrett a Binnicker Matthew J a Karon Brad S a Boccuto Luigi b Ivankovic Diana S b Sarasua Sara M b Kipp Benjamin R a⁎ a Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA b Department of Biological Sciences, School of Nursing, Clemson University, Clemson, SC 29634, United States ⁎ Corresponding author: 15 12 2022 15 12 2022 1158804 8 2022 25 11 2022 9 12 2022 © 2022 Elsevier Inc. All rights reserved. 2022 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. On February 29th, 2020, the U.S. Food and Drug Administration issued the first Emergency Use Authorization (EUA) for a SARS-CoV-2 assay outside of the U.S. Centers for Disease Control and Prevention. As of May 3rd, 2021, 289 total EUAs have been granted. Like influenza, there is no standard for defining limit of detection (LoD), but rather guidance that analytical sensitivity/LoD be established as the level that gives a 95% detection rate in at least 20 replicates. Here we compare the performance characteristics of SARS-CoV-2 tests receiving EUA by standardizing sensitivity to a common unit of measure and assess the variability in LoD between tests. Additionally, we looked at factors that may impact sensitivities due to lack of standardization of the test development process and compare results for a standardized reference panel for comparative analysis within a subset of EUA tests offered by the U.S. Food and Drug Administration. Keywords SARS-CoV-2 Nucleic Acid Amplification Tests PCR Limit of Detection ==== Body pmc1 Introduction Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 500 million cases and 6 million deaths as of May 2022. [1] From the beginning of the pandemic, significant efforts have been directed toward diagnostic testing for SARS-CoV-2 to help prevent, mitigate, and respond to this deadly virus. On February 4th, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Centers for Disease Control and Prevention (CDC) COVID RT-PCR diagnostic panel. In the absence of a public health emergency, Clinical Laboratory Improvement Amendments (CLIA) typically govern Laboratory Developed Tests (LDTs). However, the declaration of a public health emergency meant no SARS-CoV-2 tests could be offered without FDA EUA. [2] While full FDA approval of LDTs has been seen as a hindrance to test development due to time and expense, the process for FDA EUA is in place to provide resources for expedited release of tests under FDA guidance. [3] [4] It is important to note that EUA is not a full FDA approval and authorization of these tests is discontinued when there is no longer a public health emergency. Despite differences between full FDA approval, EUA and CLIA regulated LDTs, the latter of which is regulated by the Centers for Medicare and Medicaid Services rather than the FDA, both require documentation of sensitivity/Limit of Detection (LoD) [5] [6] [7]. Though LoD documentation for these tests is required, there is no benchmark set for a minimum detectable level. Despite these challenges, SARS-CoV-2 test development ensued at a rapid pace with the CDC offering RT-PCR-based test kits on Feb. 5th, 2020. On Feb. 29th, 2020, the FDA opened the EUA process due to issues with control material in kits provided by the CDC, which at the time had the only EUA, and the first diagnostic test EUA was granted by the FDA that same day. [8] As of May 3rd, 2021, the total number of tests having received FDA EUA for SARS-CoV-2 molecular diagnostic testing reached 290. [9, 10] As the number of available diagnostic tests for the SARS-CoV-2 virus grew, their performance relative to one another became increasingly important for those seeking to use an existing EUA test. With so many differences in how LoD is established, it is difficult to accurately compare between tests. The FDA therefore created a reference panel to provide a comparative analysis between tests using a common material and unit of measure. [11] As part of the study, participants are asked to perform an LoD study with the supplied sample material. Unfortunately, the reference panel was designed for nucleic acid tests and did not include antigen-based testing. While it is widely held that antigen testing has lower sensitivity than nucleic acid tests due to the lack of target amplification, the EUA documentation provides a robust dataset for comparison of antigen as well as nucleic acid tests. Furthermore, the FDA reference panel data provide an opportunity to compare LoD not only between tests but also serve as a comparator within tests. The objectives of this study were to create a comprehensive list of EUA reported LoD, convert their results to a common unit of measurement, investigate factors that may impact those results such as sample type, and finally to investigate discrepancies between the LoD reported in EUA documentation and that reported for the FDA reference panel. 2 Materials and Methods 2.1 Study design The FDA requires all manufacturers to report test development documentation to their publicly available website (https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2) and this site was utilized on May 3, 2021, to obtain data for this investigation. At that time, 290 assays were reported as having received EUA, and Supplemental Table S1 documents this study's data provenance for these assays. Limit of detection data were retrieved from these documents accessed between 5/3/2021 and 8/1/2021. In our subsequent analyses, 247 of the 290 EUA tests were considered. Exclusion criteria were: non-nucleic acid target Antigen test (n=11), reference to or license from an existing EUA (n=2), validation of a direct-to-consumer or home collection device on an existing EUA with (n=25), sample pooling for an existing EUA (n=3), duplicate study data reported or reference to a LoD that could not be converted to Genome Copy Equivalents per milliliter (GCE/mL)(n=2). Other information collected for this study included date of issue, LoD, material used for determination of LoD (i.e., live virus, inactivated virus, extracted RNA, synthetic transcript(s) or synthetic whole viral genome), test method (e.g., antigen, RT-PCR hydrolysis probe, RT-PCR with other detection methods such as CYBR Green, or other amplification method such as Loop-mediated isothermal amplification), sample type (swab/saliva), target gene/protein, and control type (human, internal control non-human origin or both). Additionally, LoD data from the FDA reference panel were downloaded from the FDA website and compared against LoD data provided in EUA documents. 2.2 LoD value conversion To enable comparison between values listed as plaque forming units (PFU), tissue culture infective dose 50 (TCID50), nucleic acid amplification test-detectable units (NDU) and GCE, all units of measure were converted to GCE/mL using the following conversions: 1 NDU/mL = 1 GCE/mL -with one target copy (NDU) the equivalent of 1 full genome copy, 1 TCID50/mL = 103.8 GCE/mL based upon the mean log10 ratio of RNA copies/infectious units in humans and 1 PFU/mL = 9.01 × 103 GCE/mL. -with PFU converted to TCID50/mL through multiplication by 0.57 × 104.2 with 104.2 representing copy number across all cell types tested by Sendet et al. [12, 13] In instances where LoD was reported as TCID50/mL and material lot information was given, the corresponding certificate of analysis was downloaded, and, if present, GCE/mL was taken from that document. 2.3 Analysis Analysis of variance (ANOVA) was used to compare LoD values between test parameters (e.g. type, number of targets, etc.) Tukey's Honest Significant Difference (HSD) test was then used to evaluate the difference in means between EUA listed LoD and that reported in the FDA reference panel testing. Lastly, for reference to the average and the +/- 1 standard deviation of viral load as reported by Jones et al, GCE/mL was estimated by taking the 1st test mean viral load per swab (106.39) and dividing by either 2mL (106.09) or 4.3mL (105.76) and then taking the average of the two values to arrive at 105.95 GCE/mL. The same steps were repeated with values for the +/- 1 standard deviation values. [14] 3 Results 3.1 Emergency Use Authorization February 1st, 2020, through September 30th saw an average of 26 EUAs per month while October 1st, 2020, through May 1st, 2021, saw an average of 10.25 EUAs per month. (Figure 1 ) Of the 247 SARS-CoV-2 EUAs included in this study, 230 (93%) were swab-based while 17 (7%) were saliva-based. (Table 1 A) There were 197 (80%) RT-PCR tests using hydrolysis probes (e.g., TaqMan®) with the remaining 50 (20%) EUAs for nucleic acid testing split between those using RT-PCR but other signal detection methodologies (e.g., sequencing, target capture, mass spectrometry) or alternate amplification methods at 30 (12%) and 20 (8%) EUAs, respectively. The reported LoD values for all nucleic acid tests had a mean of 8840 copies per milliliter with a minimum LoD of 6.31 copies per milliliter and a maximum LOD of 630957 copies per milliliter. (Table 1B) For reference, the LoD of the major commercial SARS-CoV-2 molecular methods as reported by Campbell and Binnicker, are shown in Table 1C. [15] The LoD of these tests were then compared with summary statistics and while there is high variability amongst tests (standard deviation: 43397 GCE/mL) this variability is not statistically significantly dependent on test type. Namely comparing the means of Nucleic Acid - RT PCR TaqMan®, Nucleic Acid - RT PCR Other, and Nucleic Acid – Other, showed no significant difference between the mean LoD for each group (ANOVA p-value: 0.55).Figure 1. Plot showing new cases/10,000, total cases/1,000,000, tests receiving EUA and total EUA's issued/10 from 2/4/2020 to 5/3/2021 Figure 1: Table 1. A-Characteristics of 247 SARS-CoV-2 tests receiving EUA (Feb 2020 through May 2021). B- Limit of Detection by test type. C- LoD values of major commercial molecular assays. Table 1:A Parameter Variables N (%) Sample collection type Swab 230 (93%) Saliva 17 (7%) Analysis method RT-PCR – Hydrolysis probes 197 (80%) RT-PCR – Other 30 (12%) Nucleic Acid - Other 20 (8%) Control type Human Control 137 (55%) Internal Control (non-human origin) 101 (41%) Both 9 (4%) LoD sample material Inactivated virus 70 (28%) Extracted RNA 62 (25%) Live virus 35 (14%) Synthetic transcripts 74 (30%) Synthetic whole viral genome 6 (2%) B LoD (GCE/mL) All Nucleic Acid Tests Nucleic Acid – Other Nucleic Acid - RT PCR Other Nucleic Acid - RT PCR TaqMan® Antigen* (n=247) (n=20) (n=30) (n=197) (n=11) Min 6 6 109 9 189287 Max 630957 77143 6310 901368 47763471 Average 8840 10180 1323 10834 9319512 Standard Dev. 43397 22879 1623 66148 17234960 Median 1000 1150 720 1000 887126 Mode 1000 125 1000 1000 N/A C Assay LoD GCE/mL Assay Type Reference ID NOW COVID-19 125 Nucleic Acid - Other https://www.fda.gov/media/136525/download Abbott RealTime SARS-CoV-2 assay 100 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136258/download BD SARS-CoV-2 Reagents for BD MAX System 640 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136816/download BioGX SARS-CoV-2 Reagents for BD MAX System 40 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136653/download BioFire COVID-19 Test 330 Nucleic Acid - RT PCR Other https://www.fda.gov/media/136353/download Xpert Omni SARS-CoV-2 400 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/144033/download Xpert Xpress SARS-CoV-2 test 126 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136314/download Simplexa COVID-19 Direct assay 500 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136286/download ePlex SARS-CoV-2 Test 1000 Nucleic Acid - RT PCR Other https://www.fda.gov/media/136282/download Aptima SARS-CoV-2 assay 83 Nucleic Acid - Other https://www.fda.gov/media/138096/download Panther Fusion SARS-CoV-2 Assay 74 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136156/download ARIES SARS-CoV-2 Assay 333 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136693/download Cobas SARS-CoV-2 66 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136049/download Amplitude Solution with the TaqPath COVID-19 High-Throughput Combo Kit 250 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/147548/download TaqPath COVID-19 Combo Kit 2000 Nucleic Acid - RT PCR TaqMan® https://www.fda.gov/media/136112/download 3.2 Variables in test development Next, the number of targets (i.e., number of viral genomic regions evaluated), control type, and LoD sample type were evaluated. Interestingly, there is no requirement to disclose the exact viral genomic location of the target, though some EUA submissions chose to do so. Due to the lack of exact target location, we were unable to assess if the genetic target location plays a role in test sensitivity though we evaluated whether the number of targets impacted sensitivity. None of the parameters evaluated including number of targets, material used for LoD (live virus, inactivated virus, extracted RNA, synthetic transcript(s) or synthetic whole viral genome), sample type (swab/saliva), control type (human, internal control non-human origin or both) demonstrated a significant difference in mean sensitivity with ANOVA p-values of 0.91, 0.18, 0.59 and0.46 respectively. 3.3 FDA Reference panel We then compared the reported means and the differences between EUA LoD and the reference panel LoD to investigate sources of intra-test variability. Of the 247 tests evaluated in this study, 130 (63.1%) out of the 206 developers of SARS-CoV-2 nucleic acid tests contacted by the FDA took part in this challenge. There was a significant difference between the mean LoD values reported in the EUA documentation (mean = 9417 copies/mL) with those reported from the reference panel (mean = 43750 copies/mL) (p <0.0001). (Figure 2 ) LoD was similar across methods, number of targets, type of material (i.e., live virus, inactivated virus, extracted RNA, synthetic transcript(s), or synthetic whole viral genome), and the control type (human, internal control non-human origin or both) when using the reference panel, in agreement with our initial findings. The parameters mentioned above did not statistically significantly contribute to the observed differences (Tukey's HSD p-value: 0.54, 0.49, 0.65 and 0.63 for method, number of targets, type of material and control type respectively). Thus, the reason for the difference between EUA and reference panel remains unexplained.Figure 2 Violin plots of EUA and FDA reference panel LoD p-value<0.0001 Figure 2 3.4 Intra-test analysis Finally, a comparison of the LoD values reported in EUA to those reported in the reference panel within the same test was performed (Figure 3 A). In almost all cases, the LoD for the reference panel was higher than the LoD for the EUA, and a paired t-test showed this trend was statistically significant (p-value: <0.0001). Additionally, we looked at how these values compare against previously reported data. [14] In their study of presymptomatic, asymptomatic, and mildly symptomatic SARS-CoV-2 infections, Jones et al estimated viral loads, via a Bayesian regression, of individuals’ first positive test result. When looking at EUA LoD alone, no test had a higher LoD than the mean first test value of 8.91 × 105 GCE/mL, while 20 had a higher LoD than the mean 1st test value minus 1 standard deviation, estimated for this study to be 1.33 × 103 GCE/mL, suggesting that ∼8.1% of positive tests observed in that study would be missed by these tests. (Figure 3B) For tests involved in the FDA reference panel, each reported LoD (EUA or FDA reference panel) was below the mean 1st test viral load reported by Jones et al; however, 52 (40%) of these devices (Figure 3C) had a reported FDA reference panel LoD above the mean minus one standard deviation value again suggesting that ∼16% of positive tests observed in the Jones et al study would be missed by these tests.Figure 3 Reported LoD in EUA and FDA reference panel. A- Tests were numbered 1-130 from lowest to highest EUA LoD (x-axis) with GCE/mL as the y-axis. LoD values reported in EUA are plotted in blue, LoD values reported in FDA Reference Panel are plotted in orange. B&C- EUA LoD relative to 1st test viral load. Gray and gold represent first test mean viral load and mean-1 standard deviation viral load as calculated from Jones et al. B- LoD values as reported in EUA. Tests were numbered 1-247 from lowest to highest EUA LoD (x-axis) with GCE/mL as the y-axis. C- LoD values as reported in FDA reference panel results. Tests were numbered 1-130 from lowest to highest by FDA reference panel LoD (x-axis) with NDU/mL as the y-axis. Figure 3: 4 Discussion Our data indicate that new test EUAs resulted in a plethora of new tests (n=290) for the detection of SARS-Co-V2. The data show extensive variability in their reported sensitivities (LoD) of nucleic acid tests. While antigen tests were excluded from this study due to the limited number of EUA-approved tests, the reported values (Table 1B) are consistent with previous studies with the average LoD s being approximately 103-times less sensitive for these devices though not to the extent (105-times less sensitive) found in the Mak study. [16] [17] The mean LoD of tests did not show a significant difference when assessed by the material used for LoD, sample type, number of targets, or control type. For those tests that engaged in FDA reference panel testing, the mean LoD reported for that study was significantly different than the mean of LoD reported in EUAs. Lastly, while most of these tests are sensitive enough to detect SARS-CoV-2 at levels seen by Jones et al based upon their EUA reported LoD, 40% of the tests performing reference panel testing reported an LoD higher than 1.33 × 103 GCE/mL, which is one standard deviation below the mean first test viral load. It should be noted that, in their study, Jones et al calculated viral load based upon cycle threshold (Ct) value which provides a vague estimate of viral load and these formulae are not applicable between laboratories. These findings are of note considering that viral load and disease severity have been shown to be unrelated and that patients with low viral loads are capable of shedding active viruses. [18], [19], [20] We observed a new test EUA rate of 26 EUAs per month through October 2020 followed by a halving of that rate through the remainder of this study. While this slowing of new EUAs overlapped with the largest spike in new cases in the US, it is important to note that this is not a count of total SARS-CoV-2 tests performed nor a representation of total sites performing such testing. Additionally, this decrease in the pace of EUAs may be attributed to efforts to increase testing capacity, through the licensing of tests already granted EUA, sample pooling, or increasing access to testing through at-home collection. Several of the EUAs omitted from this study were from new testing facilities licensing existing EUAs from manufacturers or validation of the use of at-home collection devices. Additionally, other EUAs omitted from this study were for sample pooling to increase the throughput of an existing EUA – these were omitted as samples from a pool testing positive were then run individually. When looking at the current gold standard method RT-PCR, these assays have demonstrated the ability to detect the virus at levels lower than 100 copies per milliliter of transport media. [21] Our investigation was challenged by a lack of a common unit of measurement. Given the difference in analytes between antigen and nucleic acid tests this could be anticipated, since published materials for antigen tests often list the sensitivity of the device in nanograms per microliter of a control peptide rather than reporting viral copy number. [16, 22, 23] Additionally, values such as Tissue Culture Infectious Dose 50, Plaque Forming Units, Nucleic Acid Detectable Units or Genome Copy Equivalents are not necessarily interchangeable and necessitate calculations to arrive at a common unit of measure. This is similar to FDA approval for influenza, where no set unit of measurement is required and thus can be reported as Tissue Culture Infectious Dose50, Plaque Forming Units, Nucleic Acid Detectable Units, or Genome Copy Equivalents. [24] There is also no set minimum for LoD of the influenza virus but rather guidance that analytical sensitivity/limit of detection be reported as the level at which gives a 95% detection rate confirmed in at least 20 replicates. While influenza material is readily available and a list of at least 28 strains is provided to developers, SARS-CoV-2 test developers can choose the preferred material from which to perform their LoD study thus adding another variable to consider when comparing tests. As suggested in the background for the FDA reference panel, a lack of a common testing material can further convolute comparison, though we were unable to demonstrate this as a reason for the significant difference in LoD values between EUA and the FDA reference panel. Likewise, none of the parameters investigated for this study were able to elucidate the variability in the tests’ sensitivities. Regarding the intra-test variability between EUA listed LoD and that reported for the FDA reference panel, one manufacturer did state in their EUA documentation that the matrix used for the FDA reference panel, Minimal Essential Media -the only transport media used for the reference panel study, was not evaluated as part of their interfering substances study and may lead to a decrease in sensitivity. While this may be the case and matrix effects cannot be overlooked, it is certainly interesting to note that, based upon LoD values returned from the FDA reference panel, 52 of the 130 (40%) devices would not be able to detect positive samples from samples outside the -1SD of the mean 1st test viral load, which was estimated here to be 1.33 × 103 GCE/mL. Further research using a more standardized testing material with a common unit of measurement would help compare test sensitivity amongst SARS-CoV-2 tests. Even in the absence of set LoD minimums for test approval, agreement on a standard sample type and matrix as well as a common unit of measurement would allow for greater confidence in comparison of tests for SARS-CoV-2. While this alone is not likely to alleviate the wide variability in LoD reported here, having a direct comparison between tests can help guide decisions surrounding which test to choose. While it may be difficult to imagine a more rapid and coordinated response towards test development given the demand for such testing was higher than ever before, a push towards the standardization of how LoD is reported and improvements in the process for providing a consistent testing material (even if it is suboptimal e.g. synthetic transcripts in place of live virus, or a less common sample media such as minimal essential media) will help to better gauge test performance between tests. Further study is needed to make direct comparisons between these devices or to determine the impacts of reduced test sensitivity on clinical practice or public health. 5 Limitations This study was limited to information available through the FDA website https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2 for the devices listed in supplemental table s1. These values represent a snapshot in time over the course of the pandemic that continues to evolve. Author Statement Blommel, Joseph H Conceptualization, Methodology, Formal analysis, Investigation, Data Curation, Writing - Original Draft Jenkinson, Garrett Formal analysis Binnicker, Matthew J Writing - Review & Editing Karon, Brad S Writing - Review & Editing Boccuto, Luigi Writing - Review & Editing Ivankovic, Diana S Writing - Review & Editing Sarasua, Sara M Writing - Review & Editing Kipp Benjamin R Writing - Review & Editing Author Contributions Statement Blommel, Joseph H: Conceptualization, Methodology, Formal analysis, Investigation, Data Curation, Writing - Original Draft Jenkinson, Garrett: Formal analysis, Writing - Review & Editing Binnicker, Matthew J: Writing - Review & Editing Karon, Brad S; Writing - Review & Editing Boccuto, Luigi; Writing - Review & Editing Ivankovic, Diana S; Writing - Review & Editing Sarasua, Sara M; Writing - Review & Editing Kipp Benjamin R; Writing - Review & Editing Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors CRediT authorship contribution statement Joseph H Blommel: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft. Garrett Jenkinson: Formal analysis, Writing – review & editing. Matthew J Binnicker: Writing – review & editing. Brad S Karon: Writing – review & editing. Luigi Boccuto: Writing – review & editing. Diana S Ivankovic: Writing – review & editing. Sara M Sarasua: Writing – review & editing. Benjamin R Kipp: Writing – review & editing. DISCLOSURE M.J. Binnicker is a scientific advisory board member for DiaSorin Molecular and Mammoth Biosciences. Appendix Supplementary materials Image, application 1 Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.diagmicrobio.2022.115880. ==== Refs Bibliography 1 Dong, E., H. Du, and L. Gardner, An interactive web-based dashboard to track COVID-19 in real time. (1474-4457 (Electronic)). 2 Mitchell, S.L., et al., Understanding, Verifying, and Implementing Emergency Use Authorization Molecular Diagnostics for the Detection of SARS-CoV-2 RNA. LID - 10.1128/JCM.00796-20 [doi] LID - e00796-20. (1098-660X (Electronic)). 3 Genzen, J.R., Regulation of Laboratory-Developed Tests. (1943-7722 (Electronic)). 4 U. S. Food and Drug Administration Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) 2021 [cited 2021 5/3/2021]; Available from: https://www.fda.gov/media/135659/download 5 Russek-Cohen, E., et al., FDA perspectives on diagnostic device clinical studies for respiratory infections. (1537-6591 (Electronic)). 6 U.S. Food and Drug Administration. Template for Developers of Molecular Diagnostic Tests 2021 [cited 2021 11/12]; Available from: https://www.fda.gov/media/135900/download. 7 [Government] Office of the Federal Register, National Archives and Records Administration Office of the Federal Register N.A.a.R.A. 42 CFR 493 - LABORATORY REQUIREMENTS 2011 Office of the Federal Register, National Archives and Records Administration [Government]EditorSeptember 30 8 Patel N.V. Why the CDC botched its coronavirus testing 2020 [cited 2021; Available from https://www.technologyreview.com/2020/03/05/905484/why-the-cdc-botched-its-coronavirus-testing/ Accessed 02/09/2021 9 U. S. Food and Drug Administration In Vitro Diagnostics EUAs- Molecular Diagnostic Tests for SARS-CoV-2 2021 Available from https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2 Accesed 01/26/2021 10 U. S. Food and Drug Administration In Vitro Diagnostics EUAs - Antigen Diagnostic Tests for SARS-CoV-2 2021 Available from https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-antigen-diagnostic-tests-sars-cov-2 Accesed 01/26/2021 11 U. S. Food and Drug Administration SARS-CoV-2 Reference Panel Comparative Data 2021 Available from: https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-reference-panel-comparative-data Accessed 9/9/2021 12 ATCC Is it possible to determine from the TCID[50]how many plaque forming units to expect? 2021 Available from https://www.atcc.org/support/technical-support/faqs/converting-tcid-50-to-plaque-forming-units-pfu?matchtype=&network=g&device=c&adposition=&keyword=&gclid=EAIaIQobChMI-qu1oufy9QIVOx-tBh0BtwSREAMYASAAEgLnJPD_BwE Accessed 9/9/2021 13 Sender, R.A.-O., et al., The total number and mass of SARS-CoV-2 virions. LID - 10.1073/pnas.2024815118 [doi] LID - e2024815118. (1091-6490 (Electronic)). 14 Jones T.C. Estimating infectiousness throughout SARS-CoV-2 infection course Science 373 6551 2021 15 Campbell, M.R. and M.J. Binnicker, Analytic and Clinical Performance of Major Commercial Severe Acute Respiratory Syndrome Coronavirus 2 Molecular Assays in the United States. Clinics in Laboratory Medicine. 16 Mak G.C. Evaluation of rapid antigen test for detection of SARS-CoV-2 virus Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 129 2020 104500 -104500 17 Yamayoshi, S.A.-O., et al., Comparison of Rapid Antigen Tests for COVID-19. LID - 10.3390/v12121420 [doi] LID - 1420. (1999-4915 (Electronic)). 18 Ra, S.H., et al., Upper respiratory viral load in asymptomatic individuals and mildly symptomatic patients with SARS-CoV-2 infection. (1468-3296 (Electronic)). 19 Glenet, M., et al., Asymptomatic COVID-19 Adult Outpatients identified as Significant Viable SARS-CoV-2 Shedders. (2045-2322 (Electronic)). 20 Arons, M.M., et al., Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. (1533-4406 (Electronic)). 21 Arnaout R. SARS-CoV2 Testing: The Limit of Detection Matters. bioRxiv: the preprint server for biology 2020 131144 2020.06.02. 22 Grant B.D. SARS-CoV-2 Coronavirus Nucleocapsid Antigen-Detecting Half-Strip Lateral Flow Assay Toward the Development of Point of Care Tests Using Commercially Available Reagents Analytical Chemistry 92 16 2020 11305 11309 32605363 23 Nelson P.P. Current and Future Point-of-Care Tests for Emerging and New Respiratory Viruses and Future Perspectives Frontiers in cellular and infection microbiology 10 2020 181 -181 32411619 24 U.S. Food and Drug Administration. Guidance for Industry and FDA Staff: Establishing the Performance Characteristics of In Vitro Diagnostic Devices for the Detection or Detection and Differentiation of Influenza Viruses 2011 5/3/2021]; Available from: https://www.fda.gov/media/71519/download.

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==== Front Asian J Psychiatr Asian J Psychiatr Asian Journal of Psychiatry 1876-2018 1876-2026 Published by Elsevier B.V. S1876-2018(22)00407-5 10.1016/j.ajp.2022.103409 103409 Article Long Term Neuropsychiatric Consequences In COVID-19 Survivors: Cognitive Impairment and Inflammatory underpinnings Fifteen Months After Discharge He Danmei abc1 Yuan Minlan ad1⁎ Dang Wen abc Bai Lin a Yang Runnan a Wang Jingyi a Ma Yao a Liu Bo a Liu Shiyu a Zhang Simai bc Liao Xiao a Zhang Wei abcd⁎ a Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, China b West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China c Med-X Center for Informatics, Sichuan University, Chengdu, China d Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China ⁎ Correspondence to: Mental Health Center, West China Hospital of Sichuan University, Dianxin South Road No.28, Chengdu 610041, China 1 These authors contributed equally: Danmei He and Minlan Yuan. 15 12 2022 15 12 2022 1034098 10 2022 8 12 2022 12 12 2022 © 2022 Published by Elsevier B.V. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Emerging evidence shows that cognitive dysfunction may occur following coronavirus disease 19 (COVID-19) infection which is one of the most common symptoms reported in researches of “Long COVID”. Several inflammatory markers are known to be elevated in COVID-19 survivors and the relationship between long-term inflammation changes and cognitive function remains unknown. Methods We assessed cognitive function and neuropsychiatric symptoms of 66 COVID-19 survivors and 79 healthy controls (HCs) matched with sex, age, and education level using a digital, gamified cognitive function evaluation tool and questionnaires at 15 months after discharge. Venous blood samples were collected to measure cytokine levels. We performed correlation analyses and multiple linear regression analysis to identify the factors potentially related to cognitive function. Results The COVID-19 survivors performed less well on the Trails (p = 0.047) than the HCs, but most of them did not report subjective neuropsychiatric symptoms. Intensive care unit experience (β = -2.247, p < 0.0001) and self-perceived disease severity (β = -1.522, p = 0.007) were positively correlated, whereas years of education (β = 0.098, p = 0.013) was negatively associated with the performance on the Trails. Moreover, the abnormally elevated TNF-α levels (r = -0.19, p = 0.040) were negatively correlated with performance on the Trails in COVID-19 group. Conclusion Our findings suggest that COVID-19 survivors show long-term cognitive impairment in executive function, even at 15 months after discharge. Serum TNF-α levels may be an underlying mechanism of long-term cognitive impairment in patients recovering from COVID-19. Keywords COVID-19 cognitive function systematic inflammation Long-COVID ==== Body pmcBackground Coronavirus disease 19 (COVID-19)2 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)3 , primarily causes respiratory symptoms, with fever and cough with or without sputum being the most common manifestations in symptomatic patients. However, the finding that the virus has the potential to cause central nervous system (CNS)4 damage suggests a possible role for the virus in the development of long-term neuropsychiatric sequelae (Kumar et al., 2021, Tandon, 2022). Growing evidence suggests that there is a high frequency of persistent neuropsychiatric symptoms after the initial illness including fatigue, cognitive dysfunction, sleep disorders, mood disorder, and anxiety disorders that often refers to as ‘Long-COVID’(Badenoch et al., 2022, Hampshire et al., 2021). There are several mechanisms through which SARS-CoV-2 could damage the CNS, including direct invasion and indirect infection (Alvarez et al., 2022, Du et al., 2021, Iodice et al., 2021, Kumar et al., 2021). SARS-CoV-2 can invade the nervous system through the recognition of the virus’s spike proteins by cell membrane receptors (Amruta et al., 2021; Du et al., 2021). Another possible mechanism that the virus can indirectly infect the nervous system is the cytokine storm which refers to an uncontrolled excessive inflammatory reaction. It starts locally and spreads further in the body through systemic circulation. (Jose and Manuel, 2020). However, it is unclear which is the dominant mechanism that underlies the neuropsychiatric sequelae. Several inflammatory markers, including interleukin (IL)5 -1β, IL-6, interferon (IFN)6 -γ, tumor necrosis factor (TNF)-α7 , chemokine interferon-γ inducible protein-10, Monocyte chemoattractant protein-1, and macrophage inflammatory protein 1-α, and T helper 2 cytokines, including the IL-4, IL-10, and IL-1 receptors, are elevated in the serum of patients with COVID-19 during the cytokine storm particularly related to the illness (Coperchini et al., 2020, Mehta et al., 2020). The persistence of the SARS-CoV2 and extension and amplification of the inherent immune mechanism will cause the dysfunction of immune response once the human immune system could not produce an appropriate immune response to the virus. This will lead a high inflammatory state of cytokine storm. (Pelaia et al., 2020) Previously, systemic inflammation has been shown to lead to cognitive decline, suggesting that COVID-19 survivors could experience cognitive deficits in the following years (Gorelick, 2010, Poletti et al., 2022). It is known from previous pandemics that there are not only acute effects of the viral infection but also long-term sequelae such as depressed mood, anxiety symptoms, insomnia, loss of smell, ageusia, fatigue, and headache due to the virus infection itself as well as social effects due to quarantine, social distancing, and lockdown (Han et al., 2022, Kumar et al., 2021, Méndez et al., 2022). The COVID-19 pandemic has prompted many countries to adopt restraining measures to mitigate the spread of the disease (Nogueira et al., 2021). As the disease has a high level of transmissibility, the patients with COVID-19 are required to stay in isolated units. In Wuhan, patients with mild symptoms received treatment in temporary quarantined hospital facilities, whereas those with more severe symptoms received treatment from a designated hospital for more aggressive therapy (Hu et al., 2020). Isolation has been shown to influence cognitive function (Wang et al., 2022). Some earlier studies found significant differences between patients with COVID-19 and matched control groups via self-report questionnaires on various measures, indicating short-term memory loss, trouble focusing attention, and concentration impairment/disorder in the patients (Amin-Chowdhury et al., 2021, González-Hermosillo et al., 2021, Klein et al., 2021). However, most of the existing studies have focused on assessing patients at 5 days to one year of follow-up after discharge from the hospital (Ceban et al., 2022, Miskowiak et al., 2022). Research focusing on neuropsychiatric consequences over one year is limited and should be investigated (Kawakami et al., 2022). Furthermore, changes in the levels of inflammatory factors in people who recovered from COVID-19 and their relationship with cognitive function remain unknown. Moreover, most of the existing studies rely on patients’ complaints in medical records or self-reported symptoms via telephone to evaluate and describe neuropsychiatric symptoms and neurocognitive function. Few studies have evaluated the neurocognitive function of COVID-19 survivors using integrated tools in which both self-reported questionnaires and neuropsychological tests were used. In summary, SARS-CoV-2, which causes neuronal damage, can have a prolonged negative impact on cognitive function, daily functioning, and quality of life. It is important to understand the neuropsychiatric consequences as millions of individuals have been affected and more unfound. Similarly, evaluating cognitive consequences following COVID-19 is essential, particularly by evaluating the capacity of an individual to work effectively, participate in daily family activities, or make reasoned decisions (Kumar et al., 2021). This study aimed to evaluate the cognitive function and neuropsychiatric symptoms in patients who recovered from COVID-19 at 15 months of follow-up after their discharge from hospital, and to investigate the potential associated factors, including systematic inflammation. We assessed the cognitive function of COVID-19 survivors using THINC-integrated tool (THINC-it)8 , which is a digital, gamified cognitive function evaluation tool (Harrison et al., 2018, Zhang et al., 2020). Using this tool, we evaluated comprehensive neuropsychiatric/cognitive function in COVID-19 survivors after 15 months and in matched healthy controls (HC). Methods Study Design and Participants This was an observational cross-sectional study. We recruited 66 patients hospitalized for SARS-CoV-2 infection who were willing to participate in this study. Voluntary COVID-19 survivors who visited the second outpatient clinic, West China Hospital, Sichuan University, about fifteenth-month after their discharge from April 2021 to August 2021 were enrolled in the study. Healthy volunteers were recruited from nearby communities between August 2021 and December 2021. All subjects gave written informed consent. The Patients with COVID-19 Group The criteria for enrollment of patients with COVID-19 were as follows: (1) patients who were hospitalized and willing to participate in the follow-up process, and (2) participants who signed an informed consent form and were able to understand and complete the tests. The exclusion criteria were as follows: (1) Patients have some neurological diseases such as cerebrovascular disease, neurodegenerative diseases, encephalitis, and traumatic brain injury which may cause cognitive impairment based on MRI examination (3-T MRI system Philips Achieva) (2) patients who could not understand or read the informed consent form, and (3) patients who is taking psychotropic medicines. Finally, we recruited 66 COVID-19 survivors aged 13 to 66 years old into the study. HC Group In total, 79 healthy participants matched with sex, gender, and education level were recruited voluntarily. Both male and female participants aged between 17 and 61 years were included. Clinical examination eliminated cognitive impairment caused by physical illness, as well as family history of psychiatric disorders. We excluded participants who were pregnant or lactating women and those who had hearing or visual impairments. Assessment Demographic Data and Basic Clinical Information Demographic data, including age, sex, marital status, educational background, smoking history, occupation, and religion were collected. Meanwhile, routine clinical data, including length of hospital stay, isolation time, duration of nucleic acid positivity, and self-perceived disease severity were collected. The self-perception of disease severity was registered on an ordinal scale. Neuropsychiatric Interview The Mini International Neuropsychiatric Interview (MINI version 5.0.0)9 (Si et al., 2009) was conducted to determine the mental health diagnoses of all participants. The results were evaluated by a trained physician. In addition, the severity of anxiety, depression symptoms, and post-traumatic stress disorder (PTSD)10 symptoms was self-reported using the Generalized Anxiety Disorder Assessment (GAD-7)11 (He et al., 2010) Patient Health Questionnaire-9 (PHQ-9)12 (Sun et al., 2017) and a 4-item Post-traumatic Stress Disorder Checklist for Diagnostic and Statistical manual of Mental disorders-5 scale (PCL-5)13 (Fung et al., 2019) for the COVID-19 group. Cognitive Assessment Cognitive assessment was performed using a digital, simplified Chinese version of the THINC-it tool, which has been proven to have good reliability and validity in the Chinese adult population (Liu et al., 2021). It includes a 5-item Perceived Deficits Questionnaire for Depression (PHQ-5D)14 , Spotter, Symbol Check, Codebreaker, and Trails (Hou et al., 2020, Zhang et al., 2020). The validity of the four objective test sections of the THINC-it tool (Spotter, Symbol Check, Codebreaker, and Trails) was used to evaluate the subjunctive’s attention/concentration, executive function, working memory, and processing speed. The five consistent criterion tests were the Deficits Questionnaire for Depression (PDQ-5D), Reaction time paradigm (RTI)15 , Digit Symbol Substitution Test (DSST)16 , Trail Making Test-Part-B (TMT-B)17 , and One-back Task (1-back)18 (Zhang et al., 2020). RTI was selected as a measure of attention and executive function; 1-back paradigm was selected to test the attention, memory, and reaction speed of the participants; DSST was chosen to identify the executive function, processing speed, and attention/concentration; and TMT-B was selected to assess the executive function of the participants. In addition to these four objective measures of cognition, the PHQ-5D questionnaire was included as a subjective measure of general cognitive function, including attention/concentration, retrospective and prospective memory, and planning/organization, using a 5-points ordinal categorical response scale to reflect the frequency of experiencing a specific cognitive problem in the past 7 days (Harrison et al., 2018, Lam et al., 2018). Social Support Scale and Discrimination Evaluation Xiao revised a Chinese version of the social support scale based on the relevant information (Xiao, 1994). Its validity and reliability have been previously confirmed (Liu et al., 2008). The social support scale contains 10 items, including 3 objective support, 4 subjective support, and 3 support utilizations. The score varies from 12 to 65 points, with a higher score representing greater social support and diversity of social networks (Su et al., 2012). We also gathered information regarding discrimination factors, including being ostracized by neighbors, family members, relatives, and friends, and being insulted by others. All the above factors were registered on an ordinal scale assigning degrees of “none,” “somewhat,” “moderate,” “severe,” and “extraordinarily severe.” Serum Sample Collection and Analysis Venous blood samples (5 ml) were collected from each patient. The blood samples were centrifuged at 3500 r/min for 15 min, and serum was extracted for analysis. Cytokines in the serum/plasma were measured by a multiplexed flow cytometric assay using a human cytokine (kit catalog number: HSTCMAG-28SK) on a Luminex ® system (MAGPX ® WITH xPONENT, version 4.2, Merck Millipore, USA). In serum/plasma, measurements of interferon-inducible T cell alpha chemoattractant (I-TAC), granulocyte-macrophage colony-stimulating factor (GM-CSF)19 , fractalkine, IFN-γ, IL-10, macrophage inflammatory protein-3α (MIP-3α)20 , IL-2(p70), IL-13, IL-17A, IL-β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, IL-8, MIP-1, MIP-β, and TNF-α were performed. The analysis was performed according to the manufacturer’s instructions (MILLIPLEX Analyst 5.1, Merck Millipore, USA). The samples were measured in duplicates. The range of the standard curves for all measured cytokines was pg/ml. Statistical analysis In this study, the COVID-19 survivors and HC group were matched by propensity score matching to control for covariates including age, sex, and years of education. All the collected data were analyzed using the R (version 4.1.1) package with an alpha set for significance at p < 0.05, which represents an acceptable probability of Type I error in a statistical test. The Shapiro–Wilk method was used to assess the normality of continuous variables. T-tests were used for normally distributed data, and non-parametric Mann–Whitney U tests were applied for continuously skewed data. Categorical data were analyzed using the chi-square test. An association test was conducted using the Spearman method if the data were not normally distributed. Multiple linear regression analysis was used to explore factors related to cognitive function. Outlier and influential points were detected before all analyses. The sample size with adequate power was calculated by GPower (version 3.1.9.7). For non-normally distributed data, effect size r were estimated (Fritz et al., 2012). Demographic data and basic clinical information were displayed as frequencies and expressed as percentages (n, %). In the cognitive test, Symbol Check and Codebreaker were negatively associated with the severity of cognitive impairment; however, the scores of Spotter and Trails showed the opposite trend. To maintain the direction of each test result consistently, the results of PDQ-5D, Spotter, and Trails were converted into standard z-scores and multiplied by -1, so that the results of each sub-part of THINC-it would follow a trend where the higher the score, the better the cognitive function (McIntyre et al., 2017, Zhang et al., 2020). A multiple linear regression model was used to assess the independent predictors of the test scores for significantly different cognitive functions. We included 13 independent variables, including age, sex, years of education, length of hospital stay, nucleic acid test positive time, isolation time, self-perception of disease severity, being ostracized by family, neighbors, and community, being verbally abused, social support score, PHQ-9 score, and GAD-7 score. All categorical independent variables were recoded into dummy variables, which were used in the regression analysis to represent subgroups of the sample in the model. Result Demographic information and clinical characteristics The demographic information, cognitive performance, and neuropsychiatric data of the participants are presented in Table 1. In total, 66 patients hospitalized for COVID-19 and 79 HC volunteers were included in the present study after adjusting for age, sex, and educational background. There were no significant differences in age, sex, or education. Only 4 COVID-19 survivors had a MINI diagnosis consistent with depression and anxiety and most COVID-19 survivors did not report subjective neuropsychiatric symptoms. The COVID-19 group performed less well in the Trails with a small effect size (r = 0.21, p = 0.047) than the HC group.Table 1 Demographics and cognitive performance of the study population. Table 1 No. (%) Characteristic COVID-19 (n=66) HC (n=79) 95% CI P-value Age (median [IQR]), y 35.50 [26.25, 46.00] 29.00 [25.00, 39.00] / 0.104a Gender 0.496b Female 23 (34.8) 33 (41.8) Male 43(65.3) 46(58.2) Marriage Status / 0.013b Single 21 (31.8) 43 (54.4) Divorced 2 (3.0) 4 (5.1) Married 43 (65.2) 32 (40.5) Education Background Years of education (median [IQR]), y 15.00 [9.75, 16.00] 15.00 [15.00, 16.00] / 0.088a Primary school 4 (6.1) 3 (3.8) Junior high school 13 (19.7) 11 (13.9) Senior high school 7 (10.6) 1 (1.3) College 15 (22.7) 25 (31.6) Undergraduate 22 (33.3) 26 (32.9) Graduate 5 (7.6) 13 (16.5) Smoking History / 0.334b Non-smoker 49 (74.2) 55 (69.6) Occasionally smoking 3 (4.5) 7 (8.9) Smoker 7 (10.6) 13 (16.5) Smoking cessation 7 (10.6) 4 (5.1) Occupation / 0.079b Full-time or part-time job 53 (80.3) 56 (70.9) Retired or Jobless 4 (6.1) 7 (8.9) Students 6 (9.1) 16 (20.3) Others 3 (4.5) 0(0.0) Religion / 0.982b Have religion 6 (9.1) 6(7.5) THINC-it test Response time of Nback (median [IQR])c 50.98 [44.38, 59.00] 49.83 [42.53, 59.05] / 0.435a Response time of DSST (median [IQR]) 118.88[117.64,119.53] 119.10[118.23,119.51] / 0.362a The composite z-score of PDQ-5D (median [IQR]) 0.07 [-0.54, 0.68] 0.10 [-0.51, 1.02] / 0.767a Correct number of Symbol Check (median [IQR]) 21.50 [13.00, 29.00] 24.00 [13.50, 33.00] / 0.236a Correct number of Codebreaker (mean (SD)) 40.41±14.44 41.41±17.86 -6.30 to 4.31 0.711d The composite z-score of Spotter (mean (SD)) 0.03±0.98 0.00±1.01 -0.29 to 0.36 0.843d The composite z-score of Trail (median [IQR]) 0.23 [0.04, 0.33] 0.33 [0.01, 0.47] / 0.047a Neuropsychiatric test PHQ-9 score (median [IQR]) 0.00 [0.00, 0.00] / / / GAD-9 score(median [IQR]) 0.00 [0.00, 0.00] / / / PCL-5 score (median [IQR]) 0.00 [0.00, 0.00] / / / M.I.N.I teste Major depression disorder (n) 4 0 / / General anxiety disorder (n) 3 0 / / a The analysis was conducted by Mann-Whitney U test. b The analysis was conducted by χ2 test. c IQR: Interquartile range d The analysis was conducted by Two sample T test. e Only 4 patients were diagnosed with depression or anxiety disorders (3 MDD patients are comorbid with anxiety disorders) The clinical characteristics of the COVID-19 survivors are displayed in Table 2. The median length of hospital stays, isolation time of hospitalized survivors, and duration of nucleic acid positivity were 20.50 (14.25–30.00), 45.00 (30.00–60.00), and 20.00 (10.00–30.00) days, respectively. The majority of the survivors’ self-perceived disease severity was general and mild. Furthermore, participants rarely had the experience of intensive care unit (ICU) stay, and none of them had extraordinarily severe ostracization by neighbors, community, family members, relatives, or friends.Table 2 Clinical characteristics of the study COVID-19 survivors. Table 2 No. (%) Clinical characteristics COVID-19 (n=66) Length of hospital stays (median [IQR]) 20.50 [14.25, 30.00] Isolation time (median [IQR]) 45.00 [30.00, 60.00] Duration of nucleic acid positivity (median [IQR]) 20.00 [10.00, 30.00] Social support score (mean (SD)) 40.21 (7.25) Self-perceived disease severity Particularly severity 0 (0.0) Severe 5 (7.6) Somewhat severe 4 (6.1) General 18 (27.3) Mild 39 (59.1) Experience of ICU stay Yes 5 (7.6) Ostracized by neighbors and community None 39 (59.1) Somewhat 19 (28.8) Moderate 5 (7.6) Severe 3 (4.5) Extraordinary severe 0 (0.0) Ostracized by family members None 0 Somewhat 1 (1.5) Moderate 0 Severe 0 Extraordinary severe 0 Insulted by others None 47 (71.2) Somewhat 14 (21.2) Moderate 5 (7.6) Severe 0 (0.0) Extraordinary severe 0 (0.0) Multiple Linear Regression for the Prediction of Cognitive Function To streamline the presentation of the results, Table 3 reports the findings from the linear multiple regressions. The associations between the basic clinical data, discrimination data, and cognitive function are summarized in Table 3. In the model, the results of multiple linear regression indicated that the four predictors explained 32.76% of the variance (R2 = 0.328, F (20,38) = 2.584, p = 0.004). Multiple linear regression analysis revealed a significant association between ICU experience (β = -2.247, p <0.0001), years of education (β = 0.098, p = 0.013), and self-perception of disease severity (somewhat severe) (β = -1.522, p = 0.007). The factors of ICU stay and self-perceived disease severity were negatively associated with cognitive function. In contrast, years of education was positively associated with executive function.Table 3 Variables to predict the composite z-score of Trail. Table 3Variables β Std. error t-value P-value (Intercept) -0.546 0.628 -0.531 0.598 Experience of ICU stay (Yes)a -2.247 0.262 -3.579 P<0.0001*** Gender (Female) -0.110 0.047 -0.422 0.675 Age 0.017 0.018 0.355 0.724 Social support score -0.028 0.038 -1.596 0.117 Years of education 0.098 0.004 2.580 0.013* Isolation time 0.000 0.013 0.056 0.956 Length of hospital stay -0.006 0.015 -0.465 0.644 Duration of nucleic acid positivity 0.014 0.279 0.920 0.362 Self-perceived disease severity (general) 0.149 0.542 0.534 0.596 Self-perceived disease severity (Somewhat severe)b -1.522 0.632 -2.809 0.007** Self-perceived disease severity (severe) 1.197 1.099 1.893 0.065 Ostracized by family members (somewhat) -0.809 0.379 -0.736 0.466 Insulted by others (somewhat) 0.241 0.469 0.636 0.528 Insulted by others (moderate) 0.225 0.293 0.479 0.634 Ostracized by neighbors and community (somewhat) 0.181 0.585 0.617 0.541 Ostracized by neighbors and community (moderate) 0.453 0.651 0.774 0.443 Ostracized by neighbors and community (severe) -0.343 0.529 -0.526 0.601 PHQ-9 score 0.397 0.110 0.749 0.458 GAD-7 score -0.092 0.628 -0.836 0.407 Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1 Residual standard error: 0.8504 on 45 degrees of freedom Multiple R-squared: 0.5345, Adjusted R-squared: 0.3276 F-statistic: 2.584 on 20 and 38 DF, p-value: 0.004166 a : The reference variable is experience of ICU stays (NO) b : Self-perceived disease severity (mild) Associations between neuropsychiatric symptoms, inflammatory factors, and the cognitive test There is no statistically significance between scores for depression/anxiety/PTSD and cytokine levels and cognition. Comparison tests revealed significant differences after false discovery rate (FDR)21 correction between the COVID-19 (n = 55) and HC groups (n = 79) with regard to the I-TAC (adjusted p = 0.021), IL-8 (adjusted p < 0.0001), and TNF-α (adjusted p < 0.0001). The HC groups show higher I-TAC level (87.68±32.56) compared with COVID-19 group (33.95±9.59) in follow-up. Similarly, the IL.8 level is 18.58±11.54 for HC groups which is higher than COVID-19 group (6.55±6.51). However, the TNF-α is 8.39±1.76 which is elevated in COVID-19 group than in HC group (6.58 ± 1.76). Eleven COVID-19 survivors did not participate in blood sample collection. Moreover, the correlation analyses indicated that TNF-α levels were negatively correlated with the composite z-score of the Trails after FDR correlation (Spearman’s Rho; r = -0.19, p = 0.040) ( Fig. 1).Fig. 1 Association analysis between the composite z-score of Trail and inflammatory factors. The matrix diagram shows the correlation coefficient and significance level after FDR correction. The TNF-α level is statistically significant correlated with the composite z-score of Trail. (r = -0.19, p = 0.040). The “*” represents significance level, and the more of it, the more significance. Fig. 1 Discussion To our knowledge, this is the first study on neurocognitive evaluation using the THINC-it tool for COVID-19 survivors in a 15-month follow-up time. Our analysis exhibited differences in the performance on the Trails, which evaluates executive function, compared with the HC group at 15-months of follow-up. A potential correlation between serum TNF-α levels and executive function has also been reported. In hospitalized COVID-19 survivors, executive function was negatively correlated with the experience of ICU stay and self-perceived disease severity. These associations were independent of age, sex, and years of education. Cognitive deficit is one of the most common symptoms reported in research into Long COVID. Those who experienced “post-COVID-19 syndrome”/ “post-acute sequalae SARS-CoV-2”/ “Long COVID” following the COVID-19 infection may have cognitive dysfunction (Guo et al., 2022). Based on our understanding of the mechanism of the virus in the CNS and the emerging evidences available, one can expect to have a variety of cognitive consequences of COVID-19 infection including attention, dysexecutive symptoms and hypoperfusion (Kumar et al., 2021). In this study, COVID-19 survivors were admitted for a clinical physical examination to rule out cognitive impairment due to physical illness. We examined the objectively cognitive function of the 66 hospitalized COVID-19 survivors 15 months after hospital discharge, as well as in 79 recurred healthy participants based on age, sex, and educational background. We reported the differences in executive function between the two groups. Our results are in line with the results of a previous study that reported a significant difference in executive function between patients with COVID-19 and a healthy control group (Johnsen et al., 2021). Similarly, another study showed that the most pronounced impairments in patients with COVID-19 were seen in verbal learning and executive function evaluated using TMT-B, based on age, sex, and education, compared to a matched HC group (Miskowiak et al., 2021). We did not find any group differences in attention, memory, reaction speed, or processing speed, which is contrary to earlier research (Ferrucci et al., 2021). A previous study using the Montreal Cognitive Assessment indicated an improvement in cognitive function from discharge time to 6 months of follow-up, while another study showed a greater increase in duration to complete the TMT-B at follow-up time in patients with COVID-19 compared to healthy controls (Douaud et al., 2022, Nersesjan et al., 2022). We can only speculate that the possible reason for the difference in results from previous studies might be that the cognitive function of COVID-19 survivors improved over time, and most of the earlier evaluations were performed using objective tools. Further, we found that the experience of ICU stay and self-perceived disease severity were negatively associated with cognitive function. Patients with COVID-19 who had experienced ICU stay showed worse executive function at 15 months of follow-up. This result was in line with that from an earlier study which indicated that new or worse cognitive impairment commonly occurs and persists in survivors of ICU stay (McLoughlin et al., 2020). The COVID-19 survivors suffered some degree of isolation and discrimination; however, no significant correlation between discrimination or other social isolation factors and cognitive function have been identified. One possible reason might be that most of the discrimination faced by the patients with COVID-19 was mild, and none of them had experienced extraordinarily severe discrimination. As shown in Table 2, they received adequate social support from family members, friends, and society. Another possible reason is that the privacy of patients in Sichuan is well-protected and a certain degree of psychological education is provided to them, making them less vulnerable to social isolation and discrimination. SARS-CoV-2 can damage the nervous system through indirect infection such as cytokine storm which refers to an uncontrolled excessive inflammatory reaction (Du et al., 2021). In current study, we demonstrated that there were differences in I-TAC, IL-8, and TNF-α levels after FDR correction between the two groups. Our finding is consistent with the higher levels of inflammatory factors reported in other studies (Heneka et al., 2020, Huang et al., 2020). In contrast, we did not find any differences in the levels of IL-13, IL-1b, IL-6, IL-23, fractalkine, MIP-3a, IL-17A, IL-5, IFN-γ, GM-CSF, IL-7, IL-4, IL-21, MIP-1a, IL-2 between the COVID-19 and HC groups. Furthermore, there was a significant correlation between the serum TNF-α levels and executive function at 15 months of follow-up. A pervious study showed the systemic inflammation was a predict factor to the neurocognitive performance (Mazza et al., 2021). Inflammatory markers including TNF-α, TNF-β, IL-1β, IL-4, IL-6, IL-8, and IL-13 was found to be correlated with post-acute sequelae of COVID-19 (Schultheiss et al., 2022). Pro-inflammatory mediators can compromise the permeability of BBB via upregulation of cyclooxygenase-2 and activation of matrix metalloprotease (Dehghani et al., 2022). This enables cytokines to enter the CNS, causing microglial activation and oxidative stress, leading to the development of synergistic cognitive impairment (Baker et al., 2021). TNF-α is a prototypic proinflammatory cytokine that is crucial in initiating and sustaining the inflammatory response (Belarbi et al., 2012). Large amount of evidences show that TNF is a main mediator of secondary CNS damage after acute injury and under conditions of chronic inflammation (Probert, 2015). It exerts both homeostatic and pathophysiological effects in the CNS (Montgomery and Bowers, 2012). In healthy adults, TNF is constitutively expressed at low level, and has regulatory functions on crucial physiological processes while in pathological ones, astrocytes and mainly microglia release large amounts of TNF-α (Olmos and Lladó, 2014, Probert, 2015). Over release of TNF-α pathologically can be involved in the process of increased apoptosis and decreased neuroplasticity of nerve cells through neurotoxicity and lead to cognitive impairment(Olmos and Lladó, 2014). In an earlier study, compared with wild-type mice, TNF-α deficient mice demonstrate a decreased latency in finding the underwater platform in the Morris water maze testing. This suggests enhanced hippocampal memory function in TNF-α knock-out mice (Golan et al., 2004). Moreover, Fiore et al. conducted the same assessments to invest whether endogenous brain TNF-α elevation in transgenic mice was associated with changes in learning capabilities; overexpression of TNF-α impaired hippocampal learning/memory function, indicating a suppressive role for high-level TNF-α in cognition (Fiore et al., 2000). However, we did not find any correlation between depression/anxiety/PTSD scores and cytokine levels. This is in line with an earlier study which evaluate the relationship between psychiatric symptoms and hematological inflammatory markers. This may because that most COVID-19 survivors recovered from psychiatric symptoms, thereby inflammation is not a significant contributor to psychiatric morbidity in patients with COVID-19 in the long term. (Swami et al., 2022) The current study was an observational cross-sectional study that evaluated the cognitive functions of hospitalized patients with COVID-19 at 15 months of follow-up, and its related risk factors. However, this study has some limitations. First, we could not gather the information which is related to the cognitive impairment, including prolonged hypoxia, requirement for ventilatory support, and steroid therapy from the hospitals. Second, although existing studies have shown that systemic or CNS inflammation can cause psychiatric symptoms and cognitive deficits, we did not find any correlation between depression/anxiety/PTSD symptoms and cognition. This may be because only 4 COVID-19 survivors in present study had symptoms of depression or anxiety. Third, the blood sample was collected only once at follow-up visiting so that we could not determine whether inflammatory levels remain correlated with cognitive decline over time. A further study on longitudinal changes in neuropsychiatric symptoms, cognitive function and inflammatory levels would be necessarily. Conclusions In conclusion, we observed that COVID-19 survivors remain subtle cognitive impairment compared with healthy ones, especially on executive function at 15-month from hospital discharge. Additionally, the experience of ICU stay and self-perceived illness severity were associated with executive function. The serum TNF-α level continued to be abnormal compared with matched HC and was correlated with executive function in COVID-19 survivors even at 15 months after recovery. This study provides evidence of long-term cognitive function impairments in patients with COVID-19, and its relationship with inflammatory profiles. Funding This work was supported by China National Key Research and Development Program (2020AAA0105005), Department of Science and Technology of Sichuan Province (Grant numbers 2020YFS0582, 2020YFS0231), 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant number ZYJC21004), the National Natural Science Foundation of China (Grant numbers 81871061), and by Postdoctoral Foundation of West China Hospital (Grant number 2020HXBH041 to M.Y.). Acknowledgements The authors would like to thank all the participants, as well as all facilitators that contributed to this research and especially Minlan Yuan. Ethics Approval and Consent to Participate The research processes adhered to the Declaration of Helsinki (2008) Ethical Principles for Medical Research Involving Human Subjects and were approved by the Medical Ethics Committee of West China Hospital, Sichuan University. Besides, all the voluntary subjects gave written consents and were informed they were at liberty to withdraw from the study at any time, with an additional examination. Consent for Publication Not applicable Authors’ contributions DMH collected data on patients who came to the hospital for follow-up visits, analyzed data collected, and wrote the manuscript. RLY, LB, JYY, XL, BL, SYL, and SMZ collected patients’ follow-up data as well. MLY designed this research and the revised the draft critically for important intellectual content. WZ is the peer reviewer and designed this research. All authors read and gave the final approval of the version to be published. Declaration of Interest None. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 2 COVID-19: The Coronavirus disease 19 3 SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 4 CNS: Central Nervous System 5 IL-: Interleukin- 6 IFN-: Interferon- 7 TNF-α: Tumor Necrosis Factor alpha 8 THINC-it: THINC-Integrated Tool 9 MINI: Mini International Neuropsychiatric Interview 10 PTSD: Post-traumatic stress disorder 11 GAD-7: Generalized Anxiety Disorder Assessment 12 PHQ-9: Patient Health Questionnaire-9 13 PCL-5: Post-traumatic Stress Disorder Checklist for Diagnostic and Statistical manual of Mental disorders-5 scale 14 PHQ-5D: 5-item Perceived Deficits Questionnaire for Depression 15 RTI: Reaction time paradigm 16 DSST：Digit Symbol Substitution Test 17 TMT-B: Trail Making Test-Part-B 18 1-back: One-back Task 19 GM-CSF: Granulocyte-macrophage Colony-stimulating Factor 20 MIP: Macrophage Inflammatory Protein 21 FDR: false discovery rate ==== Refs REFERENCES Alvarez M. 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Psychiatric morbidity among patients attending the post-COVID clinic and its association with hematological inflammatory markers Asian J Psychiatr 78 2022 103293 Tandon R. Moving beyond COVID Asian J Psychiatr 73 2022 103178 Wang Z.J. Shwani T. Liu J. Zhong P. Yang F. Schatz K. Zhang F. Pralle A. Yan Z. Molecular and cellular mechanisms for differential effects of chronic social isolation stress in males and females Molecular psychiatry 27 2022 3056 3068 35449296 Xiao S.Y. Theoretical foundations and research applications of the Social Support Scale The Journal of clinical psychiatry 4 1994 98 100 Zhang W. Zhu N. Lai J. Liu J. Ng C.H. Chen J. Qian C. Du Y. Hu C. Chen J. Hu J. Wang Z. Zhou H. Xu Y. Fang Y. Shi C. Hu S. Reliability and Validity of THINC-it in Evaluating Cognitive Function of Patients with Bipolar Depression Neuropsychiatric disease and treatment 16 2020 2419 2428 33116541

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Asian J Psychiatr. 2022 Dec 15;:103409

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==== Front Sens Actuators B Chem Sens Actuators B Chem Sensors and Actuators. B, Chemical 0925-4005 0925-4005 The Author(s). Published by Elsevier B.V. S0925-4005(22)01808-1 10.1016/j.snb.2022.133165 133165 Article Lab-on-a-chip for the easy and visual detection of SARS-CoV-2 in saliva based on sensory polymers Arnaiz Ana ac1 Guirado-Moreno José Carlos a1 Guembe-García Marta a Barros Rocio b Tamayo-Ramos Juan Antonio b Fernández-Pampín Natalia b García José M. a Vallejos Saúl a⁎ a Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza de Misael Bañuelos s/n, 09001 Burgos, Spain b International Research Center in Critical Raw Materials for Advanced Industrial Technologies (ICCRAM), R&D Center, Universidad de Burgos, Plaza de Misael Bañuelos s/n, 09001 Burgos, Spain c Universidad Politécnica de Madrid, Calle Ramiro de Maeztu, 7, 28040, Madrid, Spain ⁎ Corresponding author. 1 These authors contributed equally 15 12 2022 15 12 2022 1331653 8 2022 1 12 2022 12 12 2022 © 2022 The Authors 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The initial stages of the pandemic caused by SARS-CoV-2 showed that early detection of the virus in a simple way is the best tool until the development of vaccines. Many different tests are invasive or need the patient to cough up or even drag a sample of mucus from the throat area. Besides, the manufacturing time has proven insufficient in pandemic conditions since they were out of stock in many countries. Here we show a new method of manufacturing virus sensors and a proof of concept with SARS-CoV-2. We found that a fluorogenic peptide substrate of the main protease of the virus (Mpro) can be covalently immobilized in a polymer, with which a cellulose-based material can be coated. These sensory labels fluoresce with a single saliva sample of a positive COVID-19 patient. The results matched with that of the antigen tests in 22 of 26 studied cases (85% success rate). Graphical Abstract Keywords Peptide substrate fluorimetry immobilization COVID-19 paper-supported coating pandemics ==== Body pmc1 Introduction At the beginning of 2022, the SARS-CoV-2 virus caused one of the most severe pandemics in the history of humanity and claimed the lives of more than 6 million people [1], [2], [3]. After two years of the pandemic, we now know that in the initial stages, where the virus advances rapidly, early detection methods for those infected and the isolation of these people are the most useful tools against the virus's progression [4], [5]. Since the pandemic, polymerase chain reaction (PCR) and antigen detection tests have been the most widely used methods for detecting infected people. However, these methods belong to entirely different families, and each of them has advantages and disadvantages concerning the other. The choice of detection method is usually based on the rush for the result (antigens) or the desired precision and sensitivity (PCR). PCRs belong to the group of nuclear acid-based detection methods, and antigen tests to the group of protein-based detection methods [6]. On the one hand, nuclear acid-based detection methods, such as PCR or Loop-Mediated Isothermal Amplification (LAMP), require an amplification process in which a few DNA strands can be replicated to produce a much larger sample. This amplification process makes the sensitivity of these methods very high. Within this group, we could include aptamer-based detection methods [7]. Unlike DNA, aptamers are single-stranded chains made of 20-80 nucleotides. With them, receptors can be synthesized for specific targets of the coronavirus, such as protein N and protein S [8]. On the other hand, the most relevant protein-based detection methods are called antigen and antibody tests [9]. These systems are composed of a rapid immunoassay kit (Enzyme-Linked ImmunoSorbent, ELISA, or lateral flow kit) in which a protein is detected by antigen-antibody interaction. However, most methods start with taking a sample using a swab, an invasive process that is uncomfortable and unpleasant. Some commercially available kits are non-invasive and work with a saliva sample, but they require a large saliva sample and an additional experimental procedure based on a lateral flow test. One of the most promising techniques for detecting these types of viruses is a subgroup of the protein-based detection methods called protein function-based detection methods [6], [10], [11], [12], [13]. They are based on using a peptide substrate to detect an enzyme closely related to the coronavirus, in this case, the Mpro protein [6]. Mpro (also called 3CLpro), is a cysteine hydrolase-like protease essential in viral replication that cleavages polyproteins and generates the corresponding functional proteins necessary for virion formation [14]. This protease has been well characterised for its possible role as a therapeutic target against the SARS-Cov2 virus [15], [16], [17]. For example, the peptide substrates designed for Mpro can be chemically modified with fluorophores and quenchers (FRET pairs), so that the interaction with the target enzyme generates a visual response, i.e., an OFF-ON fluorescence change [18]. Furthermore, this response is specific for the Mpro of SARS-CoV-2 and other highly similar Mpro (such as SARS-CoV) [15], [16]. Considering all ordinary citizens and children, we believe that developing a non-invasive, visual, and simple detection method for respiratory viruses is worthy, not only for coronavirus but also for other present and future viruses. In this work, we have applied our knowledge in detecting species of interest to develop a polymer that becomes fluorescent in the presence of the Mpro protein, indicative of the presence of SARS-CoV-2. Unlike the published works concerning the detection of this enzyme [10], [11], [12], [13], our proposal remains on the synthesis of a linear polymer that can be applied as a coating on a cellulose-based support. The user must only apply a single saliva sample above the smart label and check the fluorescence after the established time with the naked eye or, more precisely, with a smartphone. 2 Experimental 2.1 Materials All materials and solvents were commercially available and used as received unless otherwise indicated. The following materials and solvents were used: fluorogenic peptide substrate Dabcyl-KTSAVLQSGFRKME-Edans (GenScript, N-Terminus: DABCYL, ≥95.0%, additional information in SI-Section S1), methylmethacrylate (MMA) (Merck, 99%), 1-vinyl-2-pyrrolidone (VP) (Acros Organic, 99%), 4-aminostyrene (SNH2) (TCI, 98%), glutaraldehyde aqueous solution (VWR, 25%), ethanol (VWR-Prolabo, 99.9%), methanol (VWR-Prolabo, 99.9%), diethyl ether (VWR-Prolabo, 99.9%), dimethylsulfoxide (VWR, 99%), acetonitrile (VWR, 99.9%), dimethylformamide (Supelco, 99.9%) distilled water, acetonitrile (VWR, 99.9%), dimethylsulfoxide-d 6 (VWR, 99.8%), 5-aminonaphthalene-1-sulfonic acid (Alfa Aesar, 90%), Mpro 3CL protease from coronavirus SARS-CoV-2 (Sigma), recombinant MERS-CoV 3CL protease, CF (R&D Systems), Trizma (Aldrich, 99.5%), NaCl (VWR, 98%), Ethylenediaminetetraacetic acid (EDTA) (VWR, 99.8%), dithiothreitol (DTT) (TCI, 98%), filter paper in reams (Filter Lab, 73 g/m2). Azo-bis-isobutyronitrile (AIBN, Aldrich, 98%) was recrystallized twice from methanol. The tissues and the reagents employed in the In vitro EpiDerm™ skin irritation test (EPI-200-SIT) were provided by MatTek In Vitro Life Science Laboratories: EpiDerm™ tissues (EPI-200-SIT), DMEM medium (EPI-100), 5% sodium dodecyl sulfate (SDS) solution (TC-SDS-5%), MTT-100 assay kit (MTT-100), which include the following components: MTT concentrate (MTT-100-CON), MTT diluent (MTT-100-DIL) and extractant solution (MTT-100-EXT). DPBS (Dulbecco’s Phosphate-Buffered Saline) was provided by Corning. 2.2 Instrumentation and methods 1H and 13C{1H} NMR spectra (Avance III HD spectrometer, Bruker Corporation, Billerica, Massachusetts, USA) were recorded at 300 MHz for 1H and 75 MHz for 13C using deuterated dimethyl sulfoxide (DMSO-d6) at 25°C as solvent. The powder X-ray diffraction (PXRD) patterns were obtained using a diffractometer (D8 Discover Davinci design, Bruker Corporation, Billerica, Massachusetts, USA) operating at 40 kV, using Cu(Kα) as the radiation source, a scan step size of 0.02°, and a scan step time of 2 s. The polymers thermal characterization was performed by thermogravimetric analysis (Q50 TGA analyzer, TA Instruments, New Castle, DE, USA) with 10–15 mg of sample under synthetic air and nitrogen atmosphere at 10°C·min−1; and differential scanning calorimetry, with 10–15 mg of the sample under a nitrogen atmosphere at a heating rate of 10°C min−1 (Q200 DSC analyzer, TA Instruments, New Castle, DE, USA). Infrared spectra (FTIR) were recorded with an infrared spectrometer (FT/IR-4200, Jasco, Tokyo, Japan) with an ATR-PRO410-S single reflection accessory. Enzymatic activity assays were performed using a Synergy HT microplate reader (BioTek®, Winooski, Vermont, USA), measuring fluorescence with 360/40–460/40 nm excitation/emission filters. Digital photographs were taken with a smartphone (Mi 9, Xiaomi, Pekín, China). Solution fluorescence spectra were recorded using a F-7000 Hitachi Fluorescence spectrophotometer (Hitachi, Tokyo, Japan). A rectangular 10 mm cuvette was used for the fluorescence measurements, measuring all data at 25ºC ± 0.1 ºC. 2.3 Design of sensory polymers The design of the polymers was carried out thinking about the application as solid sensory material. Our hypothesis relies on the fact that the virus synthesised the protease Mpro when it starts replicating inside infected cells, so, as a respiratory virus, it could be detected in a saliva sample. First, we believe that a water-soluble polymer does not fit our work for one main reason: the user could inadvertently suck on the sensor tag, ingesting small amounts of polymer. Therefore, the polymer must contain a high enough amount of a hydrophobic monomer, such as methyl methacrylate, so the resulting copolymer is insoluble in water. Second, certain hydrophilicity of the material may favour the interaction between the Mpro enzyme and the substrate, which is why a specific mol% of the hydrophilic monomer 1-vinyl-2-pyrrolidone was included in the formulations. Therefore, two polymers were designed with different hydrophilicity. Finally, the polymers must have functional groups that serve as anchors for the immobilization of the peptide substrate ( Fig. 1a, characterization available in SI-Section S1). In our case, this immobilization occurs through the aniline side groups provided by the monomer 4-aminostyrene. All the monomers provide polarity to the final copolymers, which we believe is necessary to favour the affinity with the chosen support, i.e., cellulose paper.Fig. 1 Preparation of sensory labels: a) chemical structure and schematic view of the fluorogenic peptide substrate for SARS-CoV-2 main protease; b) graphical abstract of the sensory labels preparation procedure containing covalently anchored substrates; and c) graphical abstract of the sensory labels preparation procedure containing non-covalently anchored substrates. Fig. 1 2.4 Synthesis of polymers Linear polymers were prepared by radical co-polymerization of the commercially available monomers 1-vinyl-2-pyrrolidone (VP), methyl methacrylate (MMA) and 4-aminostyrene (SNH2) in different molar ratios, following the experimental procedure described below. The amounts of each monomer, specified in Table 1, were dissolved in DMF and the solution was added to a round-bottom pressure flask. Subsequently, radical thermal initiator AIBN was added, and the solution was sonicated for 10 min and heated overnight at 60°C, under a nitrogen atmosphere, and without stirring. The solution was then dropwise added to diethyl ether (100 mL) with magnetic stirring, yielding the desired copolymers as whitish precipitates. Finally, polymers were purified in a Soxhlet apparatus with diethyl ether as the washing solvent to eliminate DMF traces. The characterization of polymers can be found in the electronic supporting information (SI-Section S2).Table 1 Copolymers´ formulations indicating monomers´ mol%. The table shows the amounts of monomers, solvent (DMF), and radical thermal initiator (AIBN) used in different co-polymerizations. Table 1Image 1 Copolymers 3 and 4 were prepared as blanks of copolymers 1 and 2, respectively. These blanks are highly relevant for the storage stability study depicted in Section3.2, and the understanding of the importance of the peptide to be covalently anchored to the copolymers. The followed methodology gives rise to polymers with relatively low molecular weight so that the viscosity of coating solutions does not reach high values. These low viscosities can be obtained by carrying out the polymerization with high concentrations of the thermal radical initiator (0.1 M). The resulting copolymers are compatible with coating techniques such as drop-, spray- or dip-coating but incompatible with bar coating. 2.5 Preparation of sensory labels The preparation of the sensory labels by drop coating is schematically shown in Fig. 1b. 50 mg of copolymers 1 or 2 were dissolved in acetonitrile (1 mL). Then, the resulting solution was deposited twice (2 × 10 μL) on the surface of a filter paper disc (6 mm diameter, 28 mm2), and the solvent was evaporated at 60 °C for 10 min. Analogously, 8 mm disks were prepared specifically for cytotoxicity assays. After that, the substrate for Mpro was immobilized following two steps. Firstly, the coated paper discs were dipped in an aqueous solution of glutaraldehyde (5%), and left overnight at 25°C. Then, the discs were washed by dipping them in distilled water for 10 min, and the process was repeated 5 times until the glutaraldehyde odour finally disappeared [19]. Secondly, the discs were dipped in a substrate solution (50 μM in ethanol), and left overnight at 25°C. Finally, several dip washes were carried out with absolute ethanol (3 × 10 minutes), 75% ethanol (1 × 10 min), 50% ethanol (1 × 10 min), 25% ethanol (1 × 10 min), distilled water (2 × 10 min), and 20 mM Tris-HCl pH 7.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT buffer (2 × 10 min). Sensory labels 1 and 2 were air-dried and stored in zip bags. The video included as supporting information (SI-Video) explains the complete preparation procedure of the sensory labels. Supplementary material related to this article can be found online at doi:10.1016/j.snb.2022.133165. The following is the Supplementary material related to this article Video 1. Video 1 Additionally, sensory labels (3 and 4) without covalently anchored substrates were also prepared, as depicted in Fig. 1c. In this case, the coating solutions contain 0.042 mg of the substrate (50 μM) and 2.21 mg of copolymer 3 or 4. 2.6 Preliminary enzyme tests and storage stability study Measurements were carried out in a microplate reader with 96-well plates, including a 6 mm diameter sensory label at the bottom of each well and 20 μL of a 0.5 μM solution of Mpro in buffer (negative controls were performed with 20 μL of 20 mM Tris-HCl pH 7.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT buffer). The assay was carried out at the optimum enzyme temperature (30ºC), and the fluorescence emission at 460 nm was recorded over time (15, 30, 60, 120, 180, and 240 min). Measuring conditions: excitation slit = 40 nm; emission slit = 40 nm; excitation wavelength = 360 nm. The stability of sensory labels with and without covalently anchored substrates was studied over time. All labels were room stored in zip bags without more care, and enzyme tests were performed at 1, 7, 14, 28 and 60 days. The limit of detection (LOD) was estimated in vitro for the sensory label 1 and 2 using different concentrations of Mpro enzyme (from 0 to 1 µM) after 1 h of incubation with the sensory labels. We estimated the limit of detection (LOD) by the following equation: LOD=3.3xSD/s, where SD is the standard deviation of blank sample and s is the slope of the calibration curve in the region of low Mpro content, respectively. 2.7 In vitro Skin Irritation Test The skin irritation test was performed according to the in vitro EpiDerm™ skin irritation test (EPI-200-SIT, MatTek In Vitro Life Science Laboratories, 2020) after confirming the inability of the sensors to interfere with and/or to reduce the MTT following the guideline recommendations. Upon receipt, the tissues were inspected for damage according to the manufacturer´s instructions, transferred to 6-well plates prefilled with 0.9 mL of assay medium (EPI-100-NMM). and incubated at optimal conditions (37 ºC ± 1 ºC, 5 ±1% CO2, 90% ± 10% RH) for 1 h. Then, the tissues were transferred to a freshly prepared medium and incubated overnight (18 ± 3 h) at optimal conditions to release transport-stress, after which the tissues were exposed to the sensors for 1 h (37 ºC ± 1 ºC, 5 ± 1% CO2, 90% ± 10% RH). As negative and positive controls, the tissues were exposed to DPBS or 5% SDS, respectively. Three tissues were used per test material and controls. After the exposure, tissues were washed 15 times with DPBS, blotted in a sterile blotting paper, dried with a sterile cotton-tipped swab, transferred to a 6-well plate with 0.9 mL culture medium and incubated at optimal conditions for 24 ± 2 h. Finally, the culture medium was removed, fresh medium was added, and the tissues were subsequently incubated again for 18 ± 2 h at optimal conditions. Tissue viability after exposure to the sensors was determined using the MTT viability assay, following procedures described in the OECD guideline Test Nº 439. At the end of the 18 ± 2 h incubation, the tissues were transferred to a 24-well plate containing 0.3 mL of a MTT solution at 1 mg mL−1, and incubated for 3 h at optimal conditions. After this step, tissues were rinsed twice with DPBS, and formazan crystals were solubilized by adding 2 mL of isopropanol (MTT-100-EXT) for 2 h at RT with agitation. At the end of the extraction period, tissues were pierced with an injection needle, and the extract ran into the well from which the insert was taken. Afterwards, the tissues were discarded, and the extraction solutions were homogenized and transferred to a 96–well plate. Tissue viability is reported as % of negative control, measuring the OD of each isopropanol extract in duplicate at 570 nm by using a plate reader (BioTek Synergy HT). Isopropanol alone was used as a blank. The viability % of each tissue was calculated relative to negative control using the following equation:(1) % Viability tissue = [ODtissue / Mean ODNC] x 100% 2.8 Tests with subjects. Proof of concept The tests with COVID patients and controls were authorized by the bioethics committee of the University of Burgos on April 22, 2022 (Ref. IO 05/2022). All the participants in this study were informed of the entire procedure and signed an informed consent document. Due to the restrictions, and the responsibility we had with a virus as harmful as SARS-CoV-2, we decided the patients themselves would pick up the kit, and carry out the tests at home. This study was conducted with 26 subjects (14 men and 12 women). Among the participants, there were 15 patients (mild symptoms or asymptomatic patients) and 11 controls confirmed with antigen tests. The age range was from 23 to 69 years, and the tests were performed between 1 and 7 days after the first symptoms, or first positive result with PCR/antigen test. All tests were performed between 8:00 p.m. and 9:00 p.m., and for security reasons, they were not collected and analyzed until 12 hours later. The participants did not eat, drink or smoke during the 10 min before the test, and they first performed an antigen test on themselves (Boson Biotech, Hotgen, or Deepblue). They then discarded a saliva sample and placed four separate saliva samples over four sensory labels (2 made with copolymer 1, and another 2 with copolymer 2) contained in 2 Petri dishes, so that the discs looked completely covered by saliva. This step was done without forcing a cough, or a tear in the throat, just spitting up naturally. The Petri dishes remained open overnight, and finally, saliva excess was removed with a tissue, and the Petri dishes were sealed with parafilm. Since the patients kept the tests during the first 12 h, in this case, we could not follow the response of the material with a fluorimeter. However, as it is a visual sensor, photographs of all the sensory labels were taken once received under 365 nm light illumination, always in the same dark room, and always replicating the same lighting conditions, since the photographs were taken on different days. For that, two lamps were placed at 23 cm from the discs and at a 45-degree angle. The smartphone was placed at 20 cm from the disks without tilting. However, from the final user's point of view (1 single photo), it is unnecessary to be so careful with the lighting conditions. It is only required to see the difference in fluorescence between the positive and negative control with the naked eye and take the photo under these conditions. Each photo contained 3 discs, a positive control, a negative control, and the test disc, and the measurements were carried out by duplicate. G parameter (form RGB digital colour space) were extracted from discs in photographs using the smartphone app “Colorimetric Titration”, and the G parameters of the negative and positive control were assigned as 0 and 100 G%, respectively. Thus, Gtest% values were obtained with the following equation:(2) Gtest% = (Gtest−Gneg) / (Gpos−Gneg) × 100 In this way, values above 55 were considered positive tests for COVID, while values below 45 were considered negative. The range between 45-55 G% was considered borderline and would require a repeat test. 2.9 Selectivity/specificity study To study the substrate specificity for Mpro SARS-CoV-2 of our sensory labels two analyses were performed. Similarity matrix percentage and multiple alignments of amino acid sequences from 3CL proteases of different human coronaviruses were performed using MUSCLE program [20], and displayed by ESPript 3.0 web server [21]. In addition, a phylogenetic tree was obtained from Phylogeny.fr software [22]. Amino acid sequences of Mpro or 3CL protease from human coronaviruses were obtained from NCBI database (SARS-CoV: pdb|3V3M|A; SARS-CoV-2: YP_009742612.1; MERS-CoV: pdb|7D3C|A; HCoV-OC43: YP_009924323.1; HCoV-HKU1: YP_009944273.1; HCoV-NL63: pdb|7E6R|A and HCoV-229E: AGT21366.1). Then, in vitro analyses were developed to determine the kinetic parameters of the Mpro 3CL proteases from SARS-CoV-2 and MERS-CoV. These parameters were determined using different substrate concentrations ranging from 2.5 to 40 μM and 100 nM of the respective enzyme in a final volume of 100 μl. Initial velocities were determined from the linear part of the curve and converted to the amount of hydrolysed substrate per unit of time (μM/min). Kinetic parameters were obtained using the Michaelis-Menten equation in OriginPro Program software. Edans standard curve was performed using known amounts (0-40 µM) in reaction buffer 20 mM Tris-HCl pH 7.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT and the fluorescence was measured at 30 °C using an excitation filter of 360/40 nm and an emission filter of 460/40 nm. To study the in vitro functionality and selectivity, a 6 mm diameter of the sensory labels 1 and 2 discs were placed at the bottom of 96-well plates and 20 µl of 0.5 µM solution of Mpro from SARS-CoV-2 and MERS-CoV in 20 mM Tris-HCl pH 7.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT buffer were added. Fluorescence was recorded at 30 and 60 minutes after enzyme addition. 3 Results and discussion 3.1 Characterization of copolymers The four synthesized copolymers were characterized by infrared spectroscopy, 1H and 13C nuclear magnetic resonance, thermogravimetric analysis, differential scanning calorimetry, and powder X-ray diffraction. As shown in SI-Section S2, copolymers 1 and 2 show aromatic proton signals between 6.2 and 6.8 ppm in the 1H-NMR spectra, confirming the presence of aniline side groups in the polymer structure. On the other hand, 13C-NMR and FT-IR spectra show typical signals of random copolymers prepared with 1-vinyl-2-pyrrolidone and methyl methacrylate. FT-IR spectra of copolymers 2 and 4 (MMA 95 mol%) contain typical peaks of PMMA at 1718 and 1138 cm−1, assigned to C=O stretching and -O-CH3 stretching vibrations, respectively [23]. Signals related to PVP are only appreciable at FT-IR spectra of copolymer 1 and 3, in which the broad band assigned to the O–H stretching vibration can be shown between 3060 – 3703 cm-1, probably related to water molecules associated with the copolymer´s hydrophilicity [24]. Other characteristic peaks of PVP can also be seen at 1665 cm-1 (carbonyl group), and at 1021 cm-1 (C–N stretching) [25]. The most relevant information came from the PXRD and the polymers' thermal analysis. Thus, the PXRD spectra indicate that the separation between chains is not affected by the introduction of the aniline side groups in the polymer structure since the values of 2θ MAX do not vary significantly. In the same way, concerning thermal analysis, copolymers 1 and 3 do not present significant differences in the values of T 5, T 10 and Tg. However, copolymer 2 has T 5 and T 10 values 16 and 12 °C higher than copolymer 4, respectively. Therefore, our interpretation is that adding aniline groups improves the interaction between chains through H bonds with the carbonyl groups of the rest of the comonomers, which improves the material's thermal properties. This can also be seen in the behaviour of the Tg, which increases 5 °C when only 0.5% mol of vinylaniline is introduced in the copolymer formulation. 3.2 Response time and storage stability of sensory labels Fluorescence emission was measured at a fixed wavelength, and three replicates were performed for each measurement in 96-well plates to obtain statistically robust data, and the fluorescence data were transformed into enzymatic activity data through the following equation:(3) RFUs=Fsensor+enzyme−Fsensor, where “RFUs” are the relative fluorescence units, and “F” is the emitted fluorescence. The enzyme tests that were carried out with the sensory labels showed that an OFF-ON fluorescence process occurs when exposed to the Mpro enzyme, as shown in Fig. 2a. The system reached equilibrium 180 min after the enzyme addition for all sensory labels except the Nº3, in which the response time was 30 min. However, after half an hour, the response is intense enough to be detected with the naked eye. These experiments were performed with an enzyme concentration of 0.5 µM, but the LODs of the sensory labels 1 and 2 are 0.177 µM (6.018 µg/mL) and 0.396 µM (13.4 µg/mL), respectively.Fig. 2 Enzyme tests carried out in 96-well plates, including a 6 mm diameter sensory label at the bottom of each well and 20 μL of a 0.5 μM solution of Mpro in 20 mM Tris-HCl pH 7.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT buffer. Experimental conditions: temperature = 30ºC, λex = 360 nm, λem = 460 nm, excitation slit = 40 nm, emission slit = 40 nm. (a) Response time study of sensory labels 1-4, by monitoring the fluorescence at 15, 30, 60, 120, 180, and 240 min; image of a sensory label 1 before and after interaction with Mpro. (b) Storage stability study of sensory labels 1, 3 and free peptide by measuring the fluorescence response at 60 min after 1, 7, 14, 28 and 60 days of storage using zip bags. Data are means ± standard error of 3 independent replicates. Fig. 2 The stability study (Fig. 2b) showed that sensory labels with covalently anchored substrates, such as sensory label 1, have a longer shelf-life and remain suitable for at least two months after preparation (black line). However, as we have shown in previous works [26], this stability is not exhibited when using labels with substrate dispersed (not covalently anchored, as sensory label 3), showing the same behaviour as the free peptide substrate (green and pink lines, respectively). Additionally, results for sensory labels 2 and 4 were equivalent. Therefore, our interpretation is that the polymeric chains exert a protective effect only on the covalently anchored substrates. This fact is one of the novel keys of this study since this kind of substrates are usually unstable, so they are not used in the preparation of sensory materials. 3.3 Cytotoxicity assays In vitro EpiDerm™ skin irritation test (MatTek) is a test compliant with the OECD Test Guideline (TG) No. 439 to evaluate the skin irritation potential of the test chemicals in the context of identification and classification of skin irritation hazards according to the EU and Classification Harmonized System of Classification and Labelling Chemicals, GHS, (R38 / Category 2 or no label). Thus, an irritant is predicted if the mean relative tissue viability of three individual tissues exposed to the test substance is reduced below 50% of the mean viability of the negative controls. As shown in Fig. 3, sensory labels 1 and 2 did not reduce the viability by over 50% when compared with the controls. Therefore, according to the EU and Globally Harmonized System of Classification and Labelling Chemicals, GHS, (R38/ Category 2 or no label), none of them could be considered irritants in the conditions tested.Fig. 3 EpiDermTM tissues were exposed to sensory labels 1 and 2 for 1 h. The viability was analysed by MTT assay, and it is expressed as a percentage of negative control. Data represented the mean ± standard error of 3 independent replicates. Differences were established using a one-way ANOVA followed by a multiple comparisons test (Tukey test) and considered significant when p ≤ 0.05. The same letter indicates no significant differences between treatments. Fig. 3 3.4 Selectivity/Specificity of the sensory labels The most common human respiratory viruses are influenza A and B, syncytial, rhinoviruses, adenoviruses, and coronaviruses. Among them, only rhinoviruses and coronaviruses use their 3C-like proteases to replicate [27]. However, the 3C-like proteases of rhinoviruses only have a 20% homology with the protease studied in this work, they recognize a substantially different peptide sequence (LEVLFQ/GP) than that of the SARS-CoV-2, and their active site is made up of three amino acids instead of two as is the case of coronaviruses [28], [29], [30]. Therefore, the specificity and selectivity studies were carried out with viruses from the coronaviruses group. Seven human coronaviruses (HCoV) have been described until now, the endemic viruses HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1 and the epidemic viruses MERS-CoV, SARS-CoV, and SARS-CoV-2. HCoV-OC43 and HCoV-229E are included in the alphacoroviruses genera, while HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV, and SARS-CoV-2 are members of the betacoronaviruses genera [31], [32]. To study the specificity of our labels, the encoding amino acid sequences of the 3C-like proteases of these seven coronaviruses were obtained and aligned. Figure S8 (SI-Section S3) summarizes the multiple alignment results, showing the highly conserved residues of the catalytic site of the proteases (blue), the strictly equal residues in all the sequences (red), and the residues belonging to the same group of amino acids (yellow). The residues of catalytic site (blue) and those around them (red) are conserved, although their positions are slightly displaced. For instance, while in SARS-CoV and SARS-CoV-2 this catalytic dyad is located at residues Hys41 and Cys145, in MERS-CoV it is located at residues Hys41 and Cys148 [33]. The results of the identity matrix (Table S1, SI-Section S3) show that the alpha genera viruses are those with the lowest degree of conservation and, therefore, the lowest similarity with the rest of the coronaviruses. Consequently, on the one hand, we can conclude that the amino acid sequences of the 3C-like protease of SARS-CoV-1 and SARS-CoV-2 are practically identical (96.08% of similarity). On the other hand, the similarity between SARS-CoV-2 and MERS-CoV is quite lower (~50%), and even lower when comparing SARS-CoV-2 with the rest of the coronaviruses as previously reported [12], [33]. The phylogenetic tree analysis also supports these results, in which coronaviruses are sorted by genera (Figure S9 , SI-Section S3). SARS coronaviruses 1 and 2 have evolved separately from the rest of the betacoronaviruses. In fact, the MERS-CoV, HCoV-HKU1 and HCoV-OC43 viruses seem to have the same evolutionary origin, highly influenced by their zoonotic origin (from animals to humans), and definitively they have evolved differently and have adapted to their new niche [32], [33]. Accordingly, we performed the enzymatic analyses summarized in Table S2 (SI-Section S4), showing the kinetic parameters obtained for Mpro 3CL proteases from SARS-CoV-2 and MERS-CoV using the substrate Dabcyl-KTSAVLQSGFRKME-Edans. As expected, KM of the Mpro from SARS-CoV-2 is lower than KM of the Mpro from MERS-CoV, i.e., 43.02 ± 3.23 µM and 117.06 ± 10.61 µM values, respectively. This parameter indicates that the Mpro-SARS-CoV-2 presents a higher affinity for the substrate than Mpro-MERS-CoV. In addition, the Mpro-MERS-CoV's enzymatic efficiency (Kcat/KM) is remarkably lower than the Mpro-SARS-CoV-2, confirming our in silico studies and previous reports from other authors [12], [33], [34]. Regarding the tests with sensory labels, the Mpro-SARS-CoV-2 has higher activity than the Mpro-MERS-CoV, which means a higher fluorescence emission when performing fluorescence analysis in the microplate reader, and also higher visual response with the naked eye, as shown in Figure S10. 3.5 Proof of concept. Saliva test with 26 subjects (15 patients and 11 controls) This study was carried out with 26 subjects, 15 COVID patients, and 11 controls. It is a relatively small number to be considered a medical study, but large enough for a work in which the main claim and novelty is the strategy of preparing these new virus sensors straightforwardly, only anchoring a fluorogenic peptide substrate to a polymer and then using this sensory polymer as a coating for paper. For example, Fig. 4 shows the results of Subject #4 (asymptomatic), who tested positive for COVID with the antigen test and our sensory labels 1 and 2. The figures for the rest of the subjects are included in the SI-Section S5.Fig. 4 Results for Subject #4 testing with sensory label coated with copolymer 1 (sensory label 1), sensory label coated with copolymer 2 (sensory label 2), and antigen test. The image shows the real photograph and the cropped image. Each photo contains 2 negative controls, 2 positive controls, and 2 replicates. Fig. 4 The COVID patients generated fluorescence in the sensory labels to the naked eye, while the negative cases did not. To assign a numerical value to that response, the digital colour of each label was analysed in two different digital colour spaces (RGB and HSV), and we found G parameter from the RGB colour space was the one that best distinguishes between patients and controls. Considering the G parameter of the negative control as 0 G%, and the G parameter of the positive control as 100 G%, Subject #4 gave a G% result greater than 55 (75 G% for sensory label 1 and 157 G% for sensory label 2), so the result was positive for COVID in line with the antigen test. Table 2 shows the results for all subjects.Table 2 Results of the study with 26 subjects, testing COVID with sensory label 1, sensory label 2, and antigen test. The table shows the mean ± standard error of 2 replicates of the G% extracted from photographs, and calculated with the equation Gtest% = (Gtest-Gneg) / (Gpos-Gneg) × 100 (Eq. 3). Table 2Image 2 Image 3 The risk of making a mistake in the experimental procedure was high and difficult to control since all the responsibility lies within the participants. Despite this, our sensory label 1 and the used antigen tests provided the same result in 21 of the 26 cases (81%), which suggests that our proposed idea can be a leading methodology for the industrial production of this type of sensors in the short term. Furthermore, from a comparative point of view, the success rate of self-testing antigen tests is 82.5% [35], very similar to the result obtained with our material. Sensory label 1 has better results than sensory label 2 (85% match with antigen test versus 65%). Our interpretation is that the greater hydrophilicity of copolymer 1 makes the environment generated for the reaction with the Mpro enzyme more appropriate. Regarding the non-satisfactory results of sensory label 1, we must underline that result for subject #17 is on the borderline, that is, the subject should have repeated the test. The other four unsuccessful cases are one false positive (subject#8) and three false negatives (subjects #13, #14 and #20). In the case of the false positive, he/she presented symptoms compatible with COVID, and therefore there may be interference with some other rhinovirus. This interference problem can be addressed by increasing the length of the substrate peptide, i.e., making it much more specific for Mpro. Regarding the false negatives, we believe some other substance in the saliva may be quenching the fluorescent signal through deactivation processes. We think that this could be improved by including a tooth and tongue brushing 10 min before the test, but in our case could not be carried out since it is contraindicated in many of the antigen tests. 4 Conclusions Early detection methods are essential tools against the spread of infectious diseases, as seen in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused pandemic with the width spread use of rapid and reliable immunoassay to qualitatively detect antibodies against the virus. Herein, we report on a strategy to prepare an easy-to-use protein function-based detection method using saliva of potentially infected people, based on peptide substrate containing a FRET pair (fluorophore and quencher) to detect the Mpro protein. Specifically, we have chemically anchored the Mpro substrate to linear polymers with different hydrophilicity, and coated cellulose supports with it to prepare the sensory labels. Results show that the higher hydrophilicity of the copolymer, the higher performance of the sensory labels. Upon contacting the sensor with the saliva (Mpro is present in infected people, as demonstrated), the OFF-ON fluorescence response allows for the qualitative visual detection of the infection (LOD = 0.177 µM for sensory label 1). Moreover, a picture of the sensors provides a quantitative and statistical infection result. The advantages of these sensors are that they can be easily prepared, inexpensively, quickly, and in high quantities. Even more relevant is the proposed methodology that can be applied to detecting saliva or other body fluids and expired air for virus and bacterial infections. Open Data Open Data is available at https://riubu.ubu.es/handle/10259/5684 (Dataset of the work " Lab-on-a-chip for the easy and visual detection of SARS-CoV-2 based on a sensory polymer"). Supporting Information Characterization of the fluorogenic peptide substrate for Mpro; characterization of polymers; amino acid sequence analyses of Mpro 3C-like main proteases of human coronaviruses; in vitro comparative analysis of Mpro-SARS-CoV-2 and Mpro-MERS-CoV; proof of concept with 26 participants; explanatory video. CRediT authorship contribution statement Ana Arnaiz: Methodology, Validation, Formal analysis, Investigation, Writing - Original Draft, Jose Carlos Guirado-Moreno: Methodology, Conceptualization, Validation, Investigation, Resources, Marta Guembe-García: Validation, Investigation, Writing - Original Draft, Rocio Barros: Methodology, Validation, Formal analysis., Juan A. Tamayo-Ramos: Validation, Formal analysis, Investigation, Supervision, Natalia Fernández-Pampín: Methodology, Validation, Formal analysis, José M. García: Conceptualization, Methodology, Writing - Review & Editing. Supervision, Funding acquisition, Saul Vallejos: Conceptualization, Funding acquisition, Project administration, Methodology, Investigation, Writing - Original Draft, Writing - Review & Editing, Supervision. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Ana Arnaiz (F) completed her PhD in Biotechnology and Genetic Resources in Plants and Associated Microorganisms at the Universidad Politécnica de Madrid in 2019. In addition, she has a postdoctoral Margarita Salas Grant at the University of Burgos to expand her research in the development of sensory polymeric materials oriented to detect biological targets. José Carlos Guirado-Moreno (M) received her Master's degrees in drug discovery and advanced chemistry at the University of Alcalá de Henares (Spain, 2018) and the University of Burgos (Spain, 2019), respectively. He started his PhD in Advanced Chemistry in 2019, and his research interests include smart polymers with applications in biomedicine and food safety. Dr. Marta Guembe-García (F) received her PhD in Advanced Chemistry at the University of Burgos, Spain, in 2021. In addition, she has a postdoctoral Margarita Salas Grant at the University of Pavia (Italy) to expand her research in the development of smart materials with different applications in analytical chemistry. Dr. Rocío Barros (F) has a degree in Environmental Biology and a PhD in Environmental Science. She is Head of the ICCRAM – Environmental, Sustainability and Toxicology Research Group and collaborates in several H2020 / HE Projects, coordinating GREENER Project. She has been involved in more than 25 European projects mainly related to developing different environmental technologies for soil, water and air treatment. Dr. Juan Antonio (M) Tamayo has PhD in Molecular Microbiology and is the scientific leader of the Toxicology Research line. He has achieved 24 publications in top sciences journals (h-index=12, i-10 index=13, total citations=744), 2 patents, and participation in more than 20 R&D projects at national and international level. He is the Coordinator of the on-going DIAGONAL Project, H2020-MSCA-RISE NANOGENTOOLS. Natalia Fernández-Pampín (F) is a PhD student that currently works as a researcher at the International Research Center in Critical Raw Materials (ICCRAM), University of Burgos. Her project thesis is focused on the study of the antitumoral and antimicrobial properties of new metal Pt(II),Ir(III),Ru(II) and Rh(III) complexes. Since 2021,she has been part of the Environmental,Sustainability and Toxicological Research Group at ICCRAM,where she is involved in studying the toxicity of nanomaterials employing human cell lines,3D Reconstructed Human Epidermis (RhE) and different prokaryotic and eukaryotic microorganisms as in vitro models. Prof. José Miguel García (M) is Full Professor at the Department of Chemistry at the University of Burgos, Spain. He carried out his doctoral studies at the Institute of Polymer Science & Technology, Spanish National Research Council (CSIC), receiving his PhD in Chemistry at the Complutense University of Madrid, Spain in 1995. Prof. Garcia is a co-author of 120+ peer-reviewed scientific publications and has a number of patents, along with co-author books and book chapters. His principal research areas are high-performance materials, functional polymers, and sensory polymers as sensing materials for food, biomedical, environmental, and civil security applications. Dr. Saúl Vallejos (M) received his PhD in Chemistry in 2014 from the University of Burgos, Spain. Now he is a postdoc researcher at the Department of Chemistry, University of Burgos. Dr. Vallejos is the author/co-author of 45+ peer-reviewed scientific publications and has 22 patents, along with co-author books and book chapters. His research interests are functional polymers with receptor motifs as sensory materials for anions, cations, and neutral molecules. Appendix A Supplementary material Supplementary material Data availability No data was used for the research described in the article. Acknowledgements We gratefully acknowledge the financial support provided by all funders. Author Saul Vallejos coordinates the project leading to these results, which has received funding from "La Caixa" Foundation, under agreement LCF/PR/PR18/51130007. This work was supported by the Regional Government of Castilla y León (Junta de Castilla y León) and by the Ministry of Science and Innovation MICIN and the European Union NextGenerationEU PRTR. Author Jose Miguel García received grant PID2020-113264RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe”. Ana Arnaiz received funding from Ministerio de Universidades-European Union in the frame of NextGenerationEU RD 289/2021 (Universidad Politécnica de Madrid). Finally, all the authors want to thank the support provided by City Hall of Villadiego “Ayuntamiento de Villadiego” when looking for participants for the proof of concept. Competing interests The authors declare no competing interests. Appendix A Supplementary data associated with this article can be found in the online version at doi:10.1016/j.snb.2022.133165. ==== Refs References 1 Arroyo-Marioli F. Bullano F. Kucinskas S. Rondón-Moreno C. 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==== Front Eur J Med Chem Eur J Med Chem European Journal of Medicinal Chemistry 0223-5234 1768-3254 Elsevier Masson SAS. S0223-5234(22)00923-0 10.1016/j.ejmech.2022.115021 115021 Research Paper Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors Previti Santo a∗ Ettari Roberta a Calcaterra Elsa a Di Maro Salvatore b Hammerschmidt Stefan J. c Müller Christin d Ziebuhr John d Schirmeister Tanja c Cosconati Sandro b∗∗ Zappalà Maria a a Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d’Alcontres 31, 98166, Messina, Italy b DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy c Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, 55128, Mainz, Germany d Institute of Medical Virology Justus Liebig University, Gießen Schubertstr. 81, 35392, Gießen, Germany ∗ Corresponding author. Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Italy. ∗∗ Corresponding author. 15 12 2022 15 12 2022 1150218 11 2022 30 11 2022 11 12 2022 © 2022 Elsevier Masson SAS. All rights reserved. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Despite several major achievements in the development of vaccines and antivirals, the fight against SARS-CoV-2 and the health problems accompanying COVID-19 are still ongoing. SARS-CoV-2 main protease (Mpro), an essential viral cysteine protease, is a crucial target for the development of antiviral agents. A virtual screening analysis of in-house cysteine protease inhibitors against SARS-CoV-2 Mpro allowed us to identify two hits (i.e., 1 and 2) bearing a methyl vinyl ketone warhead. Starting from these compounds, we herein report the development of Michael acceptors targeting SARS-CoV-2 Mpro, which differ from each other for the warhead and for the amino acids at the P2 site. The most promising vinyl methyl ketone-containing analogs showed sub-micromolar activity against the viral protease. SPR38, SPR39, and SPR41 were fully characterized, and additional inhibitory properties towards hCatL, which plays a key role in the virus entry into host cells, were observed. SPR39 and SPR41 exhibited single-digit micromolar EC50 values in a SARS-CoV-2 infection model in cell culture. Graphical abstract Image 1 Keywords COVID-19 SARS-CoV-2 Mpro inhibition Antiviral activity Michael acceptors Peptide-based inhibitors ==== Body pmc1 Introduction At the end of 2019, a few cases of a new coronavirus (CoV) were recorded in Wuhan (China) [1]. In February 2020, the International Committee on Taxonomy of Viruses named the newly emerged human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the ‘coronavirus disease 19’ (COVID-19) [2,3]. To date (November 2022), over 643 million cases of COVID-19 were reported worldwide, resulting in dramatic consequences in terms of public health, economy, and social life [[4], [5], [6]]. The impressive commitment made by the scientific community led to several vaccines preventing the severe form of the disease and a small set of drugs for inpatient treatment [[7], [8], [9], [10]]. Despite the SARS-CoV-2 pandemic is now better controlled in terms of the number of cases, hospitalization, and deaths, the fight against COVID-19 is still ongoing. The risk of COVID-19 reinfection, the possible onset of new variants resistant to vaccines and drugs, and the effectiveness and durability of both vaccine- and infection-induced antibodies remain relevant concerns for the coming years [[11], [12], [13], [14], [15], [16]]. In the last two years, many articles reported the inhibitory properties of several classes of molecules towards SARS-CoV-2 main protease, also known with the acronyms of SARS-CoV-2 Mpro and 3-CLpro (i.e., picornavirus 3C-like protease) [[17], [18], [19], [20], [21]]. The enormous efforts led to precious information concerning the minimum requirements for the inhibition, and several crystal structures of SARS-CoV-2 Mpro bound with potent inhibitors were deposited in the Protein Data Bank (PDB) [[22], [23], [24]]. Structurally, SARS-CoV-2 Mpro is a homodimer composed of two protomers that consist of three domains, namely I, II, and III, with the catalytic dyad Cys145-His41 located in a cleft between the domains I and II [25]. Recently, we reported the results of a virtual screening campaign against SARS-CoV-2 Mpro using an our in-house library of peptidic and non-peptidic ligands characterized by different types of electrophilic warheads [26], initially developed as inhibitors of rhodesain, a cysteine protease of Trypanosoma brucei rhodesiense [[27], [28], [29], [30], [31], [32], [33]]. Starting from the N3-SARS-CoV-2 Mpro complex (PDB: 7BQY) [23], the 106 in-house compounds were docked into the binding site of SARS-CoV-2 Mpro. In accordance with the predicted binding free energy values, fifteen of them were selected for biological evaluation [26]. Among them, the dipeptidyl inhibitors 1 and 2 showed IC50 values in the micromolar range towards the viral cysteine protease (Chart 1). The two compounds share the methyl vinyl ketone warhead, homophenylalanine (hPhe), and an aliphatic amino acid (i.e., cyclohexylalanine (Cha) and Leu) at the P1 and P2 positions, respectively, and a phenyl ring at the P3 site bearing an electron-withdrawing group (EWG) at the para position. Covalent docking-based experiments showed that the methyl vinyl ketone warhead of both dipeptides lends itself well to the formation of a covalent adduct with the catalytic Cys145 (Fig. 1 ).Fig. 1 Predicted binding mode of compound 1. The protein is represented as a yellow surface while the ligands as blue sticks. Fig. 1 The CO group could establish an H-bond with the NH group of Gly143 of SARS-CoV-2 Mpro, meanwhile, the peptide backbone of the two inhibitors is involved in a series of H-bonds and van der Waals interactions with the target, as we reported [26]. Docking analysis confirmed the importance of hydrophobic residues at the P2 site, while the aromatic ring at the P3 position fits well in the S3 pocket. Conversely, the hPhe residue lodged in the P1 site did not seem to establish tight interaction with the P1 site, as confirmed by molecular dynamics (MD) simulations [26]. Our compounds mainly differ from the potent SARS-CoV-2 Mpro inhibitors in an aromatic residue being present at the P1 site, which substitutes the Gln residue known to be required for strong binding affinity [21]. We, therefore, decided to design a new series of peptide-based Michael acceptors (SPR35-SPR44) bearing a Gln pentatomic surrogate at the P1 site, since this unnatural amino acid is common in the most potent SARS-CoV-2 Mpro inhibitors (Chart 2). A panel of seven aliphatic amino acids was introduced at the P2 position, to explore the effect of different aliphatic side chains on the binding affinity. In particular, linear, branched, and cyclic amino acids were inserted, in agreement with the most promising results reported in the literature [34]. Along with Leu (SPR37), the bulkier tert-butyl alanine (Tba) was introduced (SPR40), as well as the rigid analog tert-Leu (Tle, SPR36). To evaluate the role of the branched side chain of Leu, the linear isomer of Leu and Val, namely Norleucine (Nle, SPR38) and Norvaline (Nva, SPR35), respectively, were inserted. Considering its linear side chain, Nle could fit well into the S2 pocket, while Nva perfectly mimics the side chain length of Leu without ramification. The presence of the cyclic analog of Leu, namely cyclopropylalanine (Cpa), as well as the bulkier Cha, provided inhibitors with great inhibitory properties [24,35], and for this reason, both residues were incorporated in SPR39 and SPR40, respectively. The carbobenzyloxy (Cbz) group was introduced as the N-capping at the P3 position, both because its presence was found to be well-tolerated in our virtual screening analysis (Fig. 1) and is part of potent SARS-CoV-2 Mpro inhibitors, such as GC376, UAWJ9-36-3, and UAWJ9-36-1 [36,37]. Lastly, the methyl vinyl ketone warhead of our lead compounds 1 and 2 was maintained: to our knowledge, no Michael acceptors carrying the methyl vinyl ketone warhead were rationally developed for SARS-CoV-2 Mpro inhibition to date. Validation of this electrophilic moiety as a valuable warhead capable of inhibiting SARS-CoV-2 Mpro was one of the purposes of this structure-activity relationship (SAR) study from the outset. Considering the promising predicted binding free energy values of some methyl vinyl ester warhead-containing compounds in our in-house database [26], this warhead was also evaluated in derivatives carrying the bulkier residues at the P2 position, such as Nle, Tba, and Cha (i.e., SPR42, SPR43, and SPR44, respectively). Therefore, we herein report the synthesis, biological evaluation, and docking studies of a series of peptide-based Michael acceptors SPR35-SPR44 targeting SARS-CoV-2 Mpro. 2 Results and discussions 2.1 Synthesis of SPR35-SPR44 The novel Michael acceptors SPR35-SPR44 were synthesized in solution following the Boc-chemistry procedures. With this approach, the peptide backbone was initially synthesized from C- to N-terminus, and the warheads were introduced in the last step (Scheme 1 ). Indeed, the Weinreb amide at the C-terminal portion is well suited to be reduced in the corresponding aldehyde, which by Wittig reaction provided the desired final compounds, as we recently reported [38]. The commercially available ester 3 was hydrolyzed in alkaline conditions and the resulting acid 4 was coupled with N,O-dimethylhydroxylamine hydrochloride in the presence of TBTU and NMM as coupling reagent and base, respectively. The use of the most common bases employed in coupling reactions, such as DIPEA and TEA, gave lower yields. Subsequently, the Boc protecting group was removed by treatment with TFA, and the resulting trifluoroacetate 6 was coupled with the N-Cbz amino acids 7a-g. Lastly, the N-Cbz-dipeptides 8a-g were treated with LiAlH4, and the Wittig reaction between the resulting aldehydes and the appropriate Wittig reagents (i.e., 1-(triphenylphosphoranylidene)-2-propanone and methyl (triphenylphosphoranylidene)acetate for ketone and ester warheads, respectively) gave the final compounds SPR35-SPR44.Scheme 1 Reagents and conditions: i) NaOH, MeOH, H2O, −5 °C–0 °C, 1 h; ii) TBTU, NMM, 0 °C, 30 min, then N,O-dimethylhydroxylamine hydrochloride, rt, on; iii) 30% TFA in DCM, 0 °C–rt, TLC monitoring; iv) 7a-g, TBTU, NMM, 0 °C, 30 min, then 6, rt, on; v) LiAlH4, dry THF, −10 °C, TLC monitoring; vi) DCM, appropriate Wittig reagent, rt, 2 h. Scheme 1 2.2 Biological investigation After an initial screening for the inhibitory activity against SARS-CoV-2 Mpro at 20 μM, K i values were determined for compounds with a percentage of inhibition >90% (Table 1 ). Nirmatrelvir and SARS-CoV-2 Mpro inhibitor 11a [24] were used as positive controls, and DMSO was used as negative control (solvent control). The K i values of 3.15 ± 0.42 nM and 8.32 ± 0.90 nM obtained for Nirmatrelvir and 11a, respectively, were in agreement with those reported in the literature [24,39], which proved the accuracy of these biological assays. With the exception of SPR35 and SPR36, the vinyl ketone derivatives SPR37–SPR41 showed K i values in the sub-micromolar range against SARS-CoV-2 Mpro, ranging from 0.184 μM to 0.416 μM. In particular, the Cha-analogs SPR41 exhibited the best K i value towards the target, meanwhile, SPR38 and SPR39, which carry Nle and Cpa, respectively, exhibited comparable binding affinity. The presence of Leu and Tba (i.e., SPR37 and SPR40, respectively) led to a slight loss of affinity. The similar activities shown by SPR38 and SPR41, which carry two deeply different side chains in terms of the steric hindrance (i.e., linear and cyclic, respectively) at the P2 site, suggest a limited specificity towards bulky aliphatic amino acids at the S2 pocket. On the other hand, the Nva-containing analog SPR35 showed a higher K i value that lies in the low micromolar range, while the Tle derivative SPR36 exhibited only a low percentage of inhibition at the screening concentration. It is interesting to note as the reduction of the side chain size negatively influences the inhibitory properties towards SARS-CoV-2 Mpro: in fact, Nva derivative SPR35 exhibited a binding affinity almost 7-fold lower with respect to the Nle analog SPR38, which only differs for the length of the side chain (n-propyl vs n-butyl, respectively). Furthermore, an increased loss of affinity was observed in the presence of a rigid tert-butyl side chain of SPR36. All in all, the incorporation of aliphatic amino acids with bulky and hindering side chains at the P2 site, irrespective of whether they are linear, cyclic, or branched, led to inhibitors with sub-micromolar binding affinities towards SARS-CoV-2 Mpro. In contrast, the presence of small or constrained side chains, incorporated both in SPR35 and SPR36, resulted in loss or lack of activity, indicating that Nva and Tle do not fit well into the S2 pocket.Table 1 Biological evaluation of novel SPRs towards SARS-CoV-2 Mpro and selectivity assessment. Table 1Compounds EWG AA Ki (μM) or % of inhibition at 20 μM SARS-CoV-2 Mpro hCatL hCatB SPR35 Image 2 Nva 1.77 ± 0.16 – – SPR36 Tle 33 ± 2% – – SPR37 Leu 0.386 ± 0.055 – – SPR38 Nle 0.260 ± 0.066 1.92 ± 0.10 11.1 ± 1.2 SPR39 Cpa 0.252 ± 0.028 3.38 ± 0.20 7.88 ± 0.65 SPR40 Tba 0.416 ± 0.058 – – SPR41 Cha 0.184 ± 0.025 0.252 ± 0.018 14.4 ± 1.2 SPR42 Image 3 Nle 29 ± 4% – – SPR43 Tba 50 ± 5% – – SPR44 Cha 47 ± 2% – – Nirmatrelvir – – 0.003 ± 0.0004 – – 11a – – 0.008 ± 0.0009 – – Completely different results were obtained with the vinyl methyl ester derivatives SPR42–SPR44: none of the three analogs showed significant inhibition at the screening concentration, which suggests that the vinyl methyl ester warhead poorly reacts with the catalytic cysteine. The ester analogs SPR42–SPR44 share the binding site recognition with potent inhibitors SPR38–SPR39 and SPR41, thus, the lack of activity is clearly related to the different warheads. Considering the appreciable inhibitory properties of vinyl methyl ketone derivatives, the most promising Michael acceptors were selected for the biological evaluation towards a panel of cysteine proteases. SPR38, SPR39, and SPR41 showed no inhibition at 100 μM against SARS-CoV-2 papain-like protease (PLpro), which plays a crucial role in processing viral polyproteins [40]. This result was expected as the peptide-based recognition moiety of the most potent PLpro inhibitors incorporates different amino acids [41]. Similarly, no inhibitory activity against dengue virus NS2B/NS3 serine protease was observed at 100 μM. Regarding to human cathepsins (hCats), the three selected compounds were assayed towards hCatL and hCatB: both human cysteine proteases resulted to be sensitive to SPRs inhibition in the micromolar range, meanwhile, SPR41 exhibited hCatL inhibition in the sub-micromolar range. As well-known, hCatL mediates the cleavage of SARS-CoV spike protein, which is necessary for the endosomal entry route of the virus into host cells [42,43]. Similarly, hCatL plays the same role in the SARS-CoV-2 infection, enhancing the virus entry [[42], [43], [44], [45]]. In COVID-19, the plasma levels of hCatL resulted to be higher in patients with severe disease with respect to the ones with non-severe form [42]. Hence, high plasma levels of circulating hCatL were found to be directly correlated with the disease progression and its severity. The antiviral effect of hCatL inhibitors was widely reported in the literature [[46], [47], [48]], meanwhile, dual inhibition of SARS-CoV-2 Mpro and hCatL could provide a synergistic antiviral effect in vivo [49,50]. Simultaneous inhibition of two valid targets involved in two different cellular and/or viral pathways could provide huge advantages compared to the antiviral agents directed against a single target, as widely reported in the literature in several research fields of drug discovery and medicinal chemistry [[51], [52], [53], [54]]. In light of all these data, the inhibitory properties of SPR38–SPR39 and SPR41 towards hCatL could lead to positive effects in terms of antiviral activity in vivo, similarly to the potent dual inhibitor MPI8 [49]. Lastly, the three assayed Michael acceptors showed moderate inhibition against hCatB: whilst SPR38 and SPR39 exhibited K i values almost 2- and 6-fold higher compared to those observed for the hCatL inhibition, SPR41 resulted to be mildly selective towards hCatL, with a selectivity index (SI = K i hCatB/K i hCatL) of 57. To test the nature of the ligand's mode of inhibition of Mpro and hCatL, dilution assays were performed as described previously [55,56]. Solutions with inhibitor concentrations of 5 x IC50 were prepared to ensure potent inhibition. After incubation, samples were diluted to achieve inhibitor concentrations of 0.1 x IC50. Enzyme activities were recorded before and after dilution (Fig. 2 ). In the case of non-covalent or reversible-covalent binding, the enzyme activity should recover after dilution. Since neither Mpro nor hCatL showed recovering enzyme activities for none of the tested compounds, we propose a covalent irreversible binding mode. Based on these findings, we sought to determine the kinetic parameters for this mechanism of inhibition. Despite the results, indicating a covalent irreversible binding mode, time-dependent measurements did not show a curvature significant enough to be deconvoluted to the kinetic parameters K i, k inact, and k 2nd. (Fig. S1). Therefore, we hypothesized, that this binding mechanism depends on a bi-phasic mechanism of inhibition as previously published for dipeptidyl enoates [57]. In this case, high inhibitor concentrations led to an irreversible inhibition, whereas lower concentrations yielded the observation of a reversible binding mode.Fig. 2 A) Dilution assay with SPR38 (blue), SPR39 (green), SPR41 (purple), and a DMSO (white) treated reference against SARS-CoV-2 Mpro. Bar chart of the relative enzyme activities, demonstrating no significant activity recovering after dilution. B) Dilution assay with SPR38 (blue), SPR39 (green), SPR41 (purple), and a DMSO (white) treated reference against hCatL. Bar chart of the relative enzyme activities, demonstrating no significant recovering activity after dilution. Fig. 2 Our experimental setup of dilution assays is not suitable for Nirmatrelvir as a reversible control substance. Since it exhibits a low IC50 value, the resulting concentrations of Nirmatrelvir would be way lower than the enzyme concentration. Therefore, to further demonstrate the covalent irreversible reaction mode of SPRs, we performed a dialysis assay as previously described [55,56]. To do so, Mpro was incubated for 60 min with inhibitor concentrations of 10-fold the IC50 value for the most potent inhibitors SPR39, SPR41, and Nirmatrelvir as a reversible control substance and performed dialysis for 25 h. Enzyme activities of samples drawn at several time points were recorded (Fig. 3 ). Due to its high affinity and covalent reversible binding mode, Nirmatrelvir was dialyzed very slowly, so that after 25 h of dialysis, only 50% of enzymatic activity was recovered. However, dialysis of SPR39 and SPR41 did not show recovering enzymatic activities, further supporting their covalent irreversible binding mode.Fig. 3 Dialysis assay of SPR39, SPR41, and Nirmatrelvir, the latter used as a covalent reversible control substance. Means of relative activities are depicted as bar chart, errors of technical duplicates are indicated. Fig. 3 Lastly, the antiviral activities of the three selected Mpro inhibitors were assessed using Huh-7-ACE2 cells infected with SARS-CoV-2. Except for SPR38, which was proven to be unstable and toxic, SPR39 and SPR41 exhibited single-digit micromolar EC50 values when SARS-CoV-2 replication was tested in cell culture so that the observed antiviral activity is consistent with the Mpro inhibition (Table 2 ).Table 2 Antiviral and cytotoxicity evaluation of the most promising SARS-CoV-2 Mpro inhibitors. Table 2Cmpd Huh-7-ACE2 cells infected EC50 (μM) Huh-7-ACE2 cells CC50 (μM) SI SPR38 18.5 ± 6.5 60.9 ± 11.5 3 SPR39 1.5 ± 0.3 100 66.6 SPR41 1.8 ± 0.1 14.5 ± 3.4 8 Nirmatrelvir <0.01 >100 >10.000 As can be noted, the antiviral activities of the three assessed compounds were not in perfect correlation with the SARS-CoV-2 Mpro inhibition. Despite that, our results are comparable with those reported in several SAR studies aimed at the development of novel anti-COVID-19 agents [20,58,59]. The discrepancy between the enzymatic inhibitory properties and cellular effects is usually ascribed to the low permeability of cell membranes. The design of suitable carrier-linked prodrugs and the incorporation into liposomes or nanocarriers could improve the membrane crossing, resulting in increased concentrations of inhibitors within cells, where SARS-CoV-2 Mpro is located [60,61]. Lastly, the cytotoxicity towards the same uninfected cell line was evaluated: SPR39, which carries Cpa at the P2 site, exhibited a CC50 value of 100 μM, resulting in a SI of 66.6, whereas the Cha-containing analog SPR41 was shown to be more cytotoxic. 2.3 Docking studies Molecular modeling studies were indeed instrumental to identify the lead compounds 1 and 2 as SARS-CoV-2 Mpro inhibitors [26] that were subjected to a first round of optimization in the present study. Here, the same theoretical procedure was also used to provide at molecular level information on the binding pose of the most interesting compound and rationalize the obtained structure-activity relationship (SAR) data. In particular, the covalent docking protocol available with the AutoDock4 (AD4) docking software named “flexible side-chain method” [62] was employed to predict the binding pose of SPR39 in the Mpro X-ray structure having PDB code 7BQY [23]. This compound was selected considering its promising biological activity in in vitro and cell-based experiments. As expected, the calculated binding position strongly resembles to one already reported for its close lead analog 6. More precisely, the predicted covalent adduct with the enzyme Cys145 residue allows to form an additional H-bond with the backbone NH of Gly143 (Fig. 4 ). The ligand Gln pentatomic surrogate at the P1 site is lodged in the S1 pocket forming a double H-bond with His163 and Glu166 just like the N3 peptide co-crystallized in the 7BQY structure. On the other hand, the P2 Cpa residue is well inserted in the S2 pocket establishing favorable hydrophobic interactions with the side chains of His41, Met49, Met165, and Asp187. In this position, different chemically related substituents were explored (Chart 1) resulting in comparable potencies (Table 1) except for the Tle one, that proved to be detrimental for enzyme inhibition. In this case, it is possible to postulate that the intrinsic rigidity of the Tle side chain might negatively influence the ligand/enzyme recognition or formation of the covalent adduct. The P3 side chain is lodged in a cleft made up of Met165, Leu167, Pro168, Gln189, and Gln192. Here the terminal phenyl ring might establish hydrophobic contacts with the aforementioned residues as well as π-stacking interactions with the surrounding π-faces of the backbone amides.Fig. 4 Predicted binding mode of SPR39 into the X-ray SARS-CoV-2 Mpro structure. The protein is represented as yellow surface and white sticks, and the ligand as green sticks. H-bond interactions are represented as dashed yellow lines. Fig. 4 To probe the stability of these interactions molecular dynamics (MD) simulations were also attained of the AD4 SPR39-SARS-CoV-2 Mpro predicted complex. This structure was subjected to a 100 ns long MD simulation and results analyzed by examining the ligand root mean square deviations and fluctuations (L-rmsd and L-rmsf, respectively) to profile the modifications in the ligand atom positions. As reported in Fig. 5 A , the AD4 predicted binding mode is very stable throughout the entire production run. Analysis of the main ligand fluctuations broken by atom demonstrates that the P3 site is the most flexible one while the rest of the molecule, including the P2 site, is adopting a stable conformation (Fig. 5B). Interestingly, the same site in the parent compound 6 was experiencing a high degree of flexibility in previously run MD simulations [26] thereby further underscoring the viability of our design hypothesis. The reason for this stable binding conformation can be ascribed to the stability of the ligand-enzyme interactions as evidenced when plotting the interaction fraction of the protein-ligand contacts throughout the simulation (Fig. 5C and D).Fig. 5 (A) rmsd (Å) plot of SPR39 over time (ns). (B) L-rmsf plot broken down by atom corresponding to the reported two-dimensional structure of SPR39. (C and D) Protein interactions of SPR39 throughout the simulation categorized into H-bonds, hydrophobic, ionic, and water bridges. Fig. 5 Chart 1 The best inhibitors identified from our in-house database. IC50 values against SARS-CoV-2 Mpro are indicated. Chart 1 Chart 2 Design of SPR35-SPR44. Abbreviations: Nva, norvaline; Tle, tert-leucine; Leu, leucine; Nle, nor-leucine; Cpa, cyclopropyl alanine; Tba, tert-butyl alanine; Cha, cyclohexylalanine. Chart 2 3 Conclusion In this paper, we report the development of novel peptide-based Michael acceptors targeting SARS-CoV-2 Mpro. With a few exceptions, analog bearing a vinyl methyl ketone warhead showed K i values in the sub-micromolar range against the target (SPR38–SPR41), while the vinyl methyl ester derivatives SPR42–SPR44 did not inhibit the viral cysteine protease. These data highlight the key role played by the vinyl methyl ketone warhead, which strongly reacts with the catalytic Cys of SARS-CoV-2 Mpro. The side chain size of the aliphatic amino acids at the P2 site was found to be crucial for the binding affinity: analogs containing relatively bulky amino acids, such as Cha, Nle, Cpa, and Tba proved to be more potent compared to derivatives carrying small and rigid side chains at this position. Interestingly, appreciable inhibitory properties against hCatL were observed for SPR38, SPR39, and SPR41. Considering the key role played by hCatL in the viral entry into cells, the dual inhibition of hCatL and SARS-CoV-2 Mpro could lead to a synergistic antiviral effect in vivo. The three fully characterized vinyl methyl ketone Michael acceptors showed a bi-phasic mechanism of inhibition towards both SARS-CoV-2 Mpro and hCatL: in fact, whilst reversible binding mode was detected at low inhibitor concentration at a 30 min timescale, irreversible inhibition at higher concentrations was observed. Lastly, SPR39 and SPR41 showed single-digit micromolar antiviral activity, and SPR39 exhibited moderate selectivity towards infected cells (SI = 66.6). All in all, peptide-based Michael acceptors bearing a vinyl methyl ketone warhead and bulky aliphatic amino acids at the P2 site were found to strongly inhibit SARS-CoV-2 Mpro, and an antiviral effect in the low micromolar range was observed. Based on the promising findings described herein, further SAR studies aiming to improve binding affinity, antiviral activity, and cytotoxicity will be carried out. 4 Experimental section 4.1 Chemistry Reagents and solvents were purchased from several commercial suppliers. TBTU, N,O-dimethylhydroxylamine hydrochloride, TFA, and Cbz-amino acids were obtained from Fluorochem. N-Methyl morpholine were purchased from VWR. TFA, LiAlH4, methyl (triphenylphosphoranylidene) acetate, and methyl (triphenylphosphoranylidene)-2-propanone were obtained from Merck, as well as silica gel 60 F254 plates and silica gel (200–400 mesh) employed for TLC and column chromatography, respectively. All the TLC were treated with an ethanol solution of phosphomolybdic acid hydrate (15%), which was obtained by Fluorochem, meanwhile, TLC in which aldehydes were evaluated, were treated with 2,4-dinitrophenylhydrazine TLC stain. All the 1H and 13C spectra were performed on a Varian 500 MHz, operating at 499.74 and 125.73 MHz for 1H and 13C, respectively. Deuterated solvents, namely CDCl3 and MeOD, were obtained from Merck and the signal of the solvents was used as the internal standard. Splitting patterns are described as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m), and broad singlet (bs). Chemical shifts are expressed in ppm and coupling constants (J) in Hz. Elemental analyses were performed on a C. Erba model 1106 (elemental analyzer for C, H, and N) apparatus, and ±0.4% of the theoretical values were found. 4.1.1 (S)-2-((tert-Butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid (4) In a round bottom flask (A), the commercially available Boc-cGln-OMe 3 (1 eq.) was dissolve in MeOH (0.7 mL/mmol) and cooled down up to −5 °C with ice/salt bath. Meanwhile, an aqueous solution of NaOH (4 eq., same volume of MeOH) was prepared, cooled down and added dropwise to the flask A over 10 min, keeping the temperature below 0 °C. The reaction was maintained in stirring and the temperature was constantly monitored (not more than 2–3 °C). After 1 h, TLC monitoring (EtOAc/light petroleum, 7:3. R f starting material: 0.30 in this mixture) showed the disappearance of the starting material, the pH was neutralized up to 7 with 1 M HCl and methanol was removed in vacuo. Subsequently, 1 M HCl was added up to pH 1, and the organic phase was extracted with EtOAc (x 3), washed with brine (x 3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was used for the next step without further purification. Consistency = white foamy powder. R f = 0.0 in EtOAc/light petroleum (7:3). Yield: 74%. 1H NMR (500 MHz) in CDCl3, δ = 1.44 (s, 9H), 1.83–1.97 (m, 2H), 2.13–2.24 (m, 1H), 2.38–2.49 (m, 1H), 2.57–2.66 (m, 1H), 3.34–3.46 (m, 2H), 4.33–4.41 (m, 1H), 5.69 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H). 13C NMR (125 MHz) in CDCl3, δ = 27.74, 28.31, 33.79, 37.98, 41.00, 52.05, 80.05, 155.79, 174.82, 181.17. NMR data are in agreement with those already reported in the literature [63]. 4.1.2 tert-Butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (5) In a round-bottom flask, the acid 4 (1 eq.) was dissolved in DCM (10 mL/mmol) and stirred at 0 °C. TBTU (1.2 eq.) and NMM (2 eq.) were added, and the reaction was maintained in stirring for 30 min at 0 °C. After this time, N,O-dimethylhydroxylamine hydrochloride (1.1 eq.) was added portion-wise, and the pH was checked (>8). The reaction was vigorously stirred at rt on. After this time, DCM vas removed in vacuo, and the resulting residue was dissolved in EtOAc washed with 1 M HCl (x 2), NaHCO3 saturated solution (x 2), and brine (x 2), dried over Na2SO4, and concentrated. The crude was purified using EtOAc/MeOH 9:1 as the eluent mixture. Consistency = pale yellow poder; Yield = 86%; R f = 0.62 in EtOAc/MeOH 9:1.1H NMR (500 MHz) in CDCl3, δ = 1.43 (s, 9H, Boc), 1.63–1.71 (m, 1H), 1.78–1.88 (m, 1H), 2.10 (t, J = 11.1 Hz, 2H), 2.44–2.55 (m, 2H), 3.21 (s, 3H), 3.31–3.36 (m, 2H), 3.79 (s, 3H), 4.67 (t, J = 8.3 Hz, 1H), 5.48 (d, J = 8.8 Hz, 1H), 6.44 (s, 1H). 13C NMR (125 MHz) in CDCl3, δ = 28.07, 28.48, 32.37, 34.45, 38.13, 40.42, 49.44, 61.74, 79.75, 155.91, 172.69, 179.95. NMR data are in agreement with those already reported in the literature [63]. 4.1.3 (S)-1-(Methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-aminium 2,2,2-trifluoroacetate (6) In a round-bottom flask, intermediate 5 was dissolved in DCM (5 mL/mmol) at 0 °C and an equivalent volume of TFA was added dropwise and the resulting solution was vigorously stirred. The reaction was monitored through TLC (eluent mixture EtOAc/MeOH 9:1) and maintained in stirring until the disappearance of the starting material (around 1 h). After that, DCM was easily removed in vacuo, and the resulting suspension was further evaporated with toluene, chloroform, and diethyl ether. The obtained white powder was used for the next step without purification. Consistency = white powder; Yield = 93%; R f = 0.0 in EtOAc/MeOH 9:1.1H NMR (500 MHz) in MeOD, δ = 1.79–1.89 (m, 1H), 1.89–1.98 (m, 1H), 2.04 (ddd, J = 15.0, 5.0, 2.8 Hz, 1H), 2.43–2.36 (m, 1H), 2.74–2.83 (m, 1H), 3.26 (s, 3H), 3.36–3.41 (m, 2H), 3.82 (s, 3H), 4.40 (dd, J = 9.5, 2.8 Hz, 1H). 13C NMR (125 MHz) in MeOD, δ = 29.58, 32.59, 33.24, 41.92, 42.06, 52.45, 62.38, 161.26, 181.62. 4.1.4 General procedure for the synthesis of intermediates 8a-g In a round bottom flask (A), the commercially available Cbz-amino acids 7a-g (1.5 eq.) were dissolved in DCM (10 mL/mmol) and cooled down up to 0 °C with an ice bath. TBTU (1.5 eq.) and NMM (2 eq.) were added, and the reaction was kept in vigorously stirring for 30 min. Meanwhile, the trifluoroacetate salt 6 (1 eq.) was suspended in DCM (10 mL/mmol) and NMM (2eq.) was added at 0 °C. The pH was checked (>8) and the resulting solution was added dropwise to the flask A. After that, the reaction was left in stirring at rt on. Subsequently, DCM vas removed in vacuo, and the residue was dissolved in EtOAc and washed with 1 M HCl (x 2), NaHCO3 saturated solution (x 2), and brine (x 2), dried over Na2SO4, and concentrated in vacuo. The obtained crude was purified using the appropriate eluent mixture below described. 4.1.4.1 Benzyl ((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopentan-2-yl)carbamate (8a) In this reaction Cbz-Nva-OH 7a was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 71%; R f = 0.24 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.80–0.93 (m, 3H), 1.26–1.43 (m, 2H), 1.49–1.84 (m, 4H), 2.05–2.20 (m, 1H), 2.26–2.48 (m, 2H), 31.7 (s, 3H), 3.18–3.28 (m, 2H), 3.78 (s, 3H), 4.21–4.32 (m, 1H), 4.79–4.91 (m, 1H), 5.05 (d, J = 12.1 Hz, 1H), 5.08 (d, J = 12.0 Hz, 1H), 5.74 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 11.2 Hz, 1H), 7.18–7.36 (m, 5H), 7.72 (d, J = 7.5 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 13.85, 18.74, 28.18, 33.23, 35.50, 38.40, 40.48, 48.59, 53.54, 54.76, 61.62, 66.84, 128.06, 128.10, 128.53, 136.47, 156.09, 171.83, 172.46, 180.02. 4.1.4.2 Benzyl ((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (8b) In this reaction Cbz-Tle-OH 7b was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 60%; R f = 0.33 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 1.01 (s, 9H), 2.10–2.21 (m, 1H), 2.30–2.48 (m, 2H), 3.19 (s, 3H), 3.21–3.33 (m, 2H), 3.80 (s, 3H), 4.12 (d, J = 9.5 Hz, 1H), 4.74–4.84 (m, 1H), 5.06 (d, J = 12.4 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 5.67 (d, J = 9.5 Hz, 1H), 6.68 (s, 1H), 7.27–7.36 (m, 5H), 7.87 (d, J = 6.3 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 26.66, 28.46, 32.43, 32.79, 35.10, 38.71, 40.57, 49.36, 61.67, 62.63, 66.89, 128.08, 128.15, 128.57, 136.56, 156.38, 171.02, 171.81, 180.01. 4.1.4.3 Benzyl ((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (8c) In this reaction Cbz-Leu-OH 7c was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 76%; R f = 0.45 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.86 (t, J = 6.0 Hz, 6H), 1.40–1.51 (m, 1H), 1.52–1.75 (m, 4H), 2.03–2.14 (m, 1H), 2.22–2.43 (m, 2H), 3.12 (s, 3H), 3.14–3.23 (m, 2H), 3.72 (s, 3H), 4.22–4.30 (m, 1H), 4.78–4.86 (m, 1H), 4.99 (d, J = 12.6 Hz, 1H), 5.03 (d, J = 11.9 Hz, 1H), 5.66 (d, J = 8.6 Hz, 1H), 6.86 (s, 1H), 7.16–7.30 (m, 5H), 7.66 (d, J = 7.6 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 21.88, 23.09, 24.68, 28.11, 32.25, 33.26, 38.36, 40.49, 42.28, 48.48, 53.51, 61.58, 66.81, 127.99, 128.05, 128.48, 136.47, 156.11, 171.83, 172.92, 180.11. 4.1.4.4 Benzyl ((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8d) In this reaction Cbz-Nle-OH 7d was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 79%; R f = 0.36 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.80 (t, J = 6.6 Hz, 3H), 1.20–1.30 (m, 4H), 1.50–1.59 (m, 1H), 1.60–1.68 (m, 1H), 1.68–1.80 (m, 2H), 2.05–2.14 (m, 1H), 2.26–2.42 (m, 2H), 3.12 (s, 3H), 3.73 (s, 3H), 4.17–4.24 (m, 1H), 4.79–4.87 (m, 1H), 5.00 (d, J = 12.6 Hz, 1H), 5.04 (d, J = 12.1 Hz, 1H), 5.65 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 7.17–7.31 (m, 5H), 7.59 (d, J = 7.6 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 14.00, 22.43, 27.56, 28.23, 33.06, 33.31, 38.39, 40.49, 48.59, 53.53, 55.00, 61.64, 66.87, 128.07, 128.11, 128.54, 136.52, 156.11, 171.86, 172.46, 180.03. 4.1.4.5 Benzyl ((S)-3-cyclopropyl-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8e) In this reaction Cbz-Cpa-OH 7e was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 77%; R f = 0.35 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.01–0.11 (m, 2H), 0.32–0.48 (m, 2H), 0.65–0.79 (m, 1H), 1.51–1.82 (m, 4H), 2.05–2.20 (m, 1H), 2.25–2.49 (m, 2H), 3.07–3.28 (m, 2H), 3.17 (s, 3H), 3.78 (s, 3H), 4.27–4.39 (m, 1H), 4.80–4.94 (m, 1H), 5.06 (d, J = 13.1 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 5.79 (d, J = 8.0 Hz, 1H), 6.67–6.75 (bs, 1H), 7.20–7.36 (m, 5H), 7.65 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 4.39, 4.51, 7.31, 28.25, 33.44, 38.11, 38.38, 40.47, 48.57, 53.53, 55.50, 61.65, 66.82, 127.76, 128.07, 128.53, 136.55, 155.97, 171.80, 172.17, 180.00. 4.1.4.6 Benzyl ((S)-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (8f) In this reaction Cbz-Tba-OH 7f was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 73%; R f = 0.34 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.80–0.97 (s, 9H), 1.37–1.50 (m, 1H), 1.60–1.84 (m, 2H), 2.05–2.18 (m, 1H), 2.23–2.47 (m, 2H), 2.67–2.75 (m, 1H), 3.15 (s, 3H), 3.14–3.35 (m, 2H), 3.75 (s, 3H), 4.22–4.35 (m, 1H), 4.76–4.91 (m, 1H), 5.03 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 11.8 Hz, 1H), 5.73 (d, J = 8.8 Hz, 1H), 6.92 (bs, 1H), 7.12–7.33 (m, 5H), 7.61 (d, J = 7.6 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 28.09, 29.71, 30.57, 33.39, 38.31, 38.62, 40.44, 46.35, 48.38, 52.97, 61.56, 66.80, 127.93, 128.02, 128.46, 136.50, 155.80, 171.79, 173.37, 180.02. 4.1.4.7 Benzyl ((S)-3-cyclohexyl-1-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8g) In this reaction Cbz-Cha-OH 7g was used as the acid. Eluent mixture: EtOAc/MeOH, 19:1. Consistency = pale yellow solid; Yield = 83%; R f = 0.40 in EtOAc/MeOH 19:1.1H NMR (500 MHz) in CDCl3, δ = 0.76–1.00 (m, 2H), 1.03–1.26 (m, 3H), 1.26–1.40 (m, 1H), 1.41–1.52 (m, 1H), 1.53–1.85 (m, 7H), 2.06–2.23 (m, 2H), 2.29–2.49 (m, 2H), 3.18 (s, 3H), 3.20–3.29 (m, 2H), 3.78 (s, 3H), 4.22–4.37 (m, 1H), 4.81–4.94 (m, 1H), 5.05 (d, J = 12.5 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.54 (d, J = 8.3 Hz, 1H), 6.51 (s, 1H), 7.18–7.39 (m, 5H), 7.54 (d, J = 7.8 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 26.14, 26.32, 26.51, 28.27, 32.43, 33.39, 33.85, 34.03, 38.36, 38.69, 40.49, 40.79, 48.51, 52.92, 61.65, 66.89, 128.05, 128.13, 128.56, 136.53, 156.13, 171.84, 172.99, 180.00. 4.1.5 General procedure for the warhead incorporation in SPR35-SPR44 In a round-bottom flask, the intermediate 8a–g (1 eq.) was solubilized in dry THF (20 mL/mmol), cooled down to −10 °C with an ice/salt bath, and vigorously stirred. LiAlH4 (1 eq.) was added each 30 min until the TLC monitoring (DCM/MeOH 19:1) did not show the presence of starting material (usually, 2 or 3 eq. of LiAlH4 were added). Cold temperature was kept. Aldehydes were detected by the treatment of the TLC with 2,4-dinitrophenylhydrazine TLC stain. Afterwards, the unreacted LiAlH4 was quenched with 1 M KHSO4 and the ice-bath was removed. The suspension was moved in a separatory funnel, DCM was added, and the two phases were separated. The organic phase was further extracted with DCM (x 3). Subsequently, the merged organic phases were washed with NaHCO3 saturated solution (x 2), 1 M KHSO4 (x 2) and brine (x 2), dried over Na2SO4 and concentrated. The obtained residues were used for the next step without further purification. In a round-bottom flask, the aldehydes were solubilized in DCM (5 mL/mmol) and the appropriate Wittig reagent (1 eq.) was added in one portion. The reaction was stirred at rt for 2 h. After that, the solvent was removed in vacuo and the desired products were purified by column chromatography using the appropriate eluent below described. 4.1.5.1 Benzyl ((S)-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)pentan-2-yl)carbamate (SPR35) In this reaction 8a and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 41% (two steps). R f = 0.30 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.89–0.97 (m, 3H), 1.30–1.44 (m, 2H), 1.55–1.70 (m, 2H), 1.72–1.87 (m, 2H), 1.99–2.11 (m, 1H), 2.22 (s, 3H), 2.29–2.39 (m, 1H), 2.39–2.48 (m, 1H), 3.21–3.35 (m, 2H), 4.28–4.38 (m, 1H), 4.53–4.61 (m, 1H), 5.09 (s, 2H), 5.64 (d, J = 8.7 Hz, 1H), 6.16 (d, J = 15.9 Hz, 1H), 6.41 (s, 1H), 6.65 (dd, J = 16.0, 6.0 Hz, 1H), 7.26–7.36 (m, 5H), 7.93 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 13.88, 18.90, 27.66, 28.66, 35.08, 35.71, 38.64, 40.66, 49.44, 54.92, 67.01, 128.08, 128.26, 128.65, 129.88, 136.49, 146.26, 156.25, 172.53, 180.31, 198.33. Elemental analysis for C23H31N3O5, calculated: C, 64.32; H, 7.27; N, 9.78; found: C, 63.98; H, 7.33; N, 9.86. 4.1.5.2 Benzyl ((S)-3,3-dimethyl-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)butan-2-yl)carbamate (SPR36) In this reaction 8b and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. In this reaction methyl (triphenylphosphoranylidene)-2-propanone was used as the Wittig reagent. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 27% (two steps). R f = 0.25 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.93 (s, 9H), 1.43–1.55 (m, 1H), 1.63–1.74 (m, 1H), 2.04–2.13 (m, 1H), 2.13–2.20 (m, 1H), 2.16 (s, 3H), 2.20–2.38 (m, 2H), 4.12 (d, J = 9.7 Hz, 1H), 4.39–4.50 (m 1H), 5.02 (s, 1H), 5.63 (d, J = 9.7 Hz, 1H), 6.15 (d, J = 16.2 Hz, 1H), 6.59 (dd, J = 16.0, 6.2 Hz, 1H), 6.63 (s, 1H), 7.21–7.32 (m, 5H), 7.99 (d, J = 6.9 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 26.81, 27.50, 28.46, 29.82, 34.99, 38.45, 40.65, 49.50, 62.61, 67.00, 127.99, 128.26, 128.65, 130.40, 136.49, 146.32, 156.54, 171.14, 180.17, 198.43. Elemental analysis for C24H33N3O5, calculated: C, 64.99; H, 7.50; N, 9.47; found: C, 65.24; H, 7.67; N, 9.34. 4.1.5.3 Benzyl ((S)-4-methyl-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)pentan-2-yl)carbamate (SPR37) In this reaction 8c and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 31% (two steps). R f = 0.30 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.94 (s, 3H), 0.96 (s, 3H), 1.44–1.59 (m, 1H), 1.59–1.74 (m, 2H), 1.73–1.85 (m, 2H), 1.99–2.09 (m, 1H), 2.23 (s, 3H), 2.31–2.50 (m, 2H), 4.30–4.39 (m,1H), 4.49–4.59 (m, 1H), 5.10 (s, 2H), 5.47 (d, J = 8.7 Hz, 1H), 6.16 (d, J = 15.8 Hz, 1H), 6.24 (s, 1H), 6.65 (dd, J = 16.0, 6.7 Hz, 2H), 7.27–7.35 (m, 5H), 7.94 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 22.07, 23.17, 24.97, 27.68, 28.78, 35.07, 38.64, 40.67, 42.62, 49.57, 53.74, 67.06, 128.06, 128.27, 128.66, 129.92, 136.49, 146.24, 156.28, 172.97, 180.29, 198.36. Elemental analysis for C24H33N3O5, calculated: C, 64.99; H, 7.50; N, 9.47; found: C, 65.17; H, 7.41; N, 9.30. 4.1.5.4 Benzyl ((S)-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)hexan-2-yl)carbamate (SPR38) In this reaction 8d and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 19% (two steps). R f = 0.27 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.86–0.91 (m, 3H), 1.29–1.35 (m, 3H), 1.37–1.50 (m, 1H), 1.58–1.69 (m, 1H), 1.72–1.86 (m, 4H), 1.99–2.06 (m, 1H), 2.22 (s, 3H), 2.31–2.48 (m, 1H), 3.26–3.32 (m, 2H), 4.25–4.33 (m, 1H), 4.51–4.61 (m, 1H), 5.10 (s, 2H), 5.57 (d, J = 8.2 Hz, 1H), 6.16 (d, J = 15.9 Hz, 1H), 6.19 (s, 1H), 6.65 (dd, J = 15.9, 5.3 Hz, 1H), 7.26–7.37 (m, 5H), 7.93 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 14.06, 22.49, 27.61, 27.68, 28.49, 33.28, 35.10, 38.55, 40.64, 49.21, 55.06, 66.97, 128.03, 128.24, 128.63, 129.84, 136.46, 146.31, 156.24, 172.53, 180.31, 198.34. Elemental analysis for C24H33N3O5, calculated: C, 64.99; H, 7.50; N, 9.47; found: C, 64.73; H, 7.67; N, 9.28. 4.1.5.5 Benzyl ((S)-3-cyclopropyl-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)propan-2-yl)carbamate (SPR39) In this reaction 8e and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. In this reaction methyl (triphenylphosphoranylidene)-2-propanone was used as the Wittig reagent. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 43% (two steps). R f = 0.21 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.06–0.16 (m, 2H), 0.41–0.50 (m, 2H), 0.66–0.75 (m, 1H), 1.59–1.69 (m, 2H), 1.75–1.88 (m, 1H), 1.98–2.08 (m, 1H), 2.23 (s, 3H), 2.30–2.50 (m 2H), 3.24–3.38 (m, 2H), 4.31–4.40 (m, 1H), 4.52–4.61 (m, 1H), 5.11 (s, 2H), 5.63 (d, J = 9.0 Hz, 1H), 6.06 (s, 1H), 6.17 (d, J = 16.1 Hz, 1H), 6.65 (d, J = 15.7 Hz, 1H), 7.28–7.39 (m, 5H), 7.95 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 4.54, 4.66, 7.44, 27.69, 28.96, 35.01, 38.08, 38.69, 40.69, 49.83, 55.78, 67.04, 128.12, 128.27, 128.66, 130.03, 136.50, 146.07, 156.16, 172.31, 180.34, 198.34. Elemental analysis for C24H31N3O5, calculated: C, 65.29; H, 7.08; N, 9.52; found: C, 65.40; H, 7.19; N, 9.37. 4.1.5.6 Benzyl ((S)-4,4-dimethyl-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)pentan-2-yl)carbamate (SPR40) In this reaction 8f and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 56% (two steps). R f = 0.20 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.96 (s, 9H), 1.45 (dd, J = 14.4, 9.2 Hz, 1H),1.57–1.64, (m, 1H), 1.74–1.82 (m, 2H), 2.05 (ddd, J = 14.2, 11.9, 5.0 Hz, 1H), 2.21 (s, 3H), 2.28–2.37 (m, 1H), 2.38–2.46 (m, 1H), 3.22–3.32 (m, 2H), 4.32–4.40 (m, 1H), 1.45–4.57 (m, 1H), 5.10 (s, 2H), 5.51 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 16.0 Hz, 1H), 6.46 (s, 1H), 6.63 (dd, J = 16.0, 5.5 Hz, 1H), 7.27–7.34 (m, 5H), 7.88 (d, J = 7.0 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 27.68, 28.62, 29.85, 30.71, 35.12, 38.56, 40.65, 46.83, 49.41, 53.17, 67.03, 127.96, 128.24, 128.64, 129.98, 136.52, 146.17, 155.97, 173.52, 180.32, 198.40. Elemental analysis calculated for C25H35N3O5: C, 65.62; H, 7.71; N, 9.18; found: C, 65.79; H, 7.57; N, 9.10. 4.1.5.7 Benzyl ((S)-3-cyclohexyl-1-oxo-1-(((S,E)-5-oxo-1-((S)-2-oxopyrrolidin-3-yl)hex-3-en-2-yl)amino)propan-2-yl)carbamate (SPR41) In this reaction 8g and 1-(triphenylphosphoranylidene)-2-propanone were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 25:1. Consistency = pale yellow solid; Yield = 45% (two steps). R f = 0.23 in EtOAc/MeOH 25:1.1H NMR (500 MHz) in CDCl3, δ = 0.84–1.03 (m, 2H), 1.09–1.25 (m 3H), 1.31–1.39 (m, 1H), 1.46–1.54 (m, 1H), 1.61–1.72 (m, 5H), 1.77–1.85 (m, 3H), 1.99–2.08 (m, 1H), 2.24 (s, 3H), 2.31–2.40 (m, 1H), 2.40–2.48 (m, 1H), 3.24–3.36 (m, 2H), 4.30–4.39 (m, 1H), 4.50–4.62 (m, 1H), 5.09 (d, J = 12.5 Hz, 1H), 5.13 (d, J = 12.3 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 6.21 (s, 1H), 6.66 (dd, J = 16.0, 5.0 Hz, 1H), 7.28–7.38 (m, 5H), 7.91 (d, J = 6.9 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 26.21, 26.39, 26.51, 27.68, 28.81, 32.73, 33.81, 34.28, 35.06, 38.63, 40.67, 41.01, 49.56, 53.17, 67.03, 128.04, 128.26, 128.66, 129.91, 136.55, 146.22, 156.24, 173.05, 180.33, 198.32. Elemental analysis calculated for C27H37N3O5: C, 67.06; H, 7.71; N, 8.69; found: C, 67.32; H, 7.53; N, 8.44. 4.1.5.8 (S,E)-Methyl 4-((S)-2-(((benzyloxy)carbonyl)amino)hexanamido)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoate (SPR42) In this reaction 8d and methyl (triphenylphosphoranylidene)-acetate were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 100:1. Consistency = pale yellow solid; Yield = 38% (two steps). R f = 0.34 in EtOAc/MeOH 100:1.1H NMR (500 MHz) in CDCl3, δ = 0.81–0.92 (m, 3H), 1.27–1.38 (m, 4H), 1.55–1.68 (m, 2H), 1.73–1.87 (m, 4H), 1.97–2.07 (m, 1H), 2.30–2.48 (m, 2H), 3.71 (s, 3H), 4.24–4.34 (m, 1H), 4.52–4.60 (m, 1H), 5.09 (s, 2H), 5.61 (d, J = 8.2 Hz, 1H), 5.93 (d, J = 15.7 Hz, 1H), 6.23 (s, 1H), 6.83 (dd, J = 15.7, 5.3 Hz, 1H), 7.27–7.37 (m, 5H), 7.85 (d, J = 6.9 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 14.04, 22.52, 27.67, 28.64, 33.37, 35.10, 38.60, 40.64, 49.35, 51.75, 55.07, 67.01, 120.84, 128.13, 128.25, 128.64, 136.50, 147.80, 156.21, 166.79, 172.41, 180.29. Elemental analysis calculated for C24H33N3O6: C, 62.73; H, 7.24; N, 9.14; found: C, 62.87; H, 7.02; N, 8.96. 4.1.5.9 (S,E)-Methyl 4-((S)-2-(((benzyloxy)carbonyl)amino)-4,4-dimethylpentanamido)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoate (SPR43) In this reaction 8f and methyl (triphenylphosphoranylidene)-acetate were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 100:1. Consistency = pale yellow solid; Yield = 29% (two steps). R f = 0.33 in EtOAc/MeOH 100:1.1H NMR (500 MHz) in CDCl3, δ = 0.96 (s, 9H), 1.43 (dd, J = 14.4, 9.3 Hz, 1H), 1.57–1.66 (m, 1H), 1.74–1.83 (m 2H), 2.02 (ddd, J = 14.3, 11.9, 5.3 Hz, 1H), 2.30–2.46 (m, 2H), 3.20–3.35 (m, 2H), 3.72 (s, 3H), 4.25–4.36 (m, 1H), 4.47–4.58 (m, 1H), 5.10 (s, 2H), 5.40 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 15.6 Hz, 1H), 6.15 (s, 1H), 6.82 (dd, J = 15.7, 5.6 Hz, 1H), 7.27–7.36 (m, 5H), 7.77 (d, J = 7.2 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 28.78, 29.87, 30.74, 35.14, 38.57, 40.63, 46.83, 49.52, 51.75, 53.20, 67.08, 120.99, 128.08, 128.24, 128.63, 136.53, 147.70, 155.98, 166.84, 173.43, 180.27.43Elemental analysis calculated for C25H35N3O6: C, 63.41; H, 7.45; N, 8.87; found: C, 63.59; H, 7.60; N, 8.72. 4.1.5.10 (S,E)-Methyl 4-((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoate (SPR44) In this reaction 8g and methyl (triphenylphosphoranylidene)-acetate were used as the intermediate and Wittig reagent, respectively. Eluent mixture: EtOAc/MeOH, 100:1. Consistency = pale yellow solid; Yield = 35% (two steps). R f = 0.26 in EtOAc/MeOH 100:1.1H NMR (500 MHz) in CDCl3, δ = 0.84–0.99 (m, 3H), 1.09–1.24 (m, 3H), 1.29–1.38 (m, 1H), 1.57–1.73 (m, 7H), 1.73–1.84 (m, 1H), 2.02 (ddd, J = 14.2, 12.0, 5.3 Hz, 1H), 2.30–2.46 (m, 2H), 3.22–3.34 (m, 2H), 3.72 (s, 3H), 4.29–4.38 (m, 1H), 4.50–4.60 (m, 1H), 5.08 (d, J = 12.6 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.45 (d, J = 8.4 Hz, 1H), 5.93 (d, J = 15.7 Hz, 1H), 6.16 (s, 1H), 6.83 (dd, J = 15.6, 5.3 Hz, 1H), 4.27–4.37 (m, 5H), 7.80 (d, J = 6.9 Hz, 1H). 13C NMR (125 MHz) in CDCl3, δ = 26.19, 26.34, 26.54, 28.72, 32.76, 33.79, 34.26, 35.12, 38.56, 40.64, 41.10, 49.36, 51.75, 53.13, 67.02, 120.85, 128.10, 128.25, 128.64, 136.55, 147.79, 156.22, 166.81, 172.97, 180.31. Elemental analysis calculated for C27H37N3O6: C, 64.91; H, 7.46; N, 8.41; found: C, 64.83; H, 7.22; N, 8.67. 4.2 Biological evaluations 4.2.1 Enzyme expression and preparation 4.2.1.1 SARS-CoV-2 Mpro The expression of SARS-CoV-2 Mpro was performed exactly as described previously [26]. Briefly, pMal-c2 plasmid DNA (New England Biolabs) containing the entire SARS-CoV-2 Mpro coding sequence flanked, at the 5′ end, by a short sequence specifying the 5 C-terminal residues of nonstructural protein 4 and, at the 3′ end, 6 histidine codons at the 3’ end. The plasmid construct was transformed in Escherichia coli (E. coli) BL21-Gold (DE3) (Agilent Technologies, Santa Clara, CA, USA) cells. After growing the bacterial culture in LB medium with ampicillin to an OD600 of ∼0.5 and induction with isopropyl-β-d- thiogalactopyranoside (IPTG), Mpro was produced at 18 °C for 16 h. Cell pellets obtained by centrifugation were resuspended in lysis buffer (20 mM Tris−HCl pH 7.8, 150 mM NaCl, 20 mM imidazole) and lysed by sonication (Sonoplus HD 2200; Bandelin, Berlin, Germany). The cleared lysate was subjected to immobilized metal affinity chromatography (IMAC) on a HisTrap HP 5 ml column (Cytiva Europe GmbH, Freiburg im Breisgau. Germany). After washing with IMAC buffer A (20 mM Tris−HCl pH 7.8, 200 mM NaCl, 20 mM imidazole), Mpro was eluted with IMAC buffer B (20 mM Tris−HCl pH 7.8, 200 mM NaCl, 500 mM imidazole). The collected fractions containing Mpro, were subjected to a gel filtration step (HiLoad 16/600 Superdex 75 pg column; GE Healthcare, Chicago, IL, USA) in SEC buffer (20 mM Tris−HCl pH 7.8, 150 mM NaCl, 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM dithiothreitol (DTT)). After dilution to 10 μM and adjustment to 10% (v/v) glycerol, Mpro was shock frozen in liquid N2 and stored at −80 °C. 4.2.1.2 SARS-CoV-2 PLpro The SARS-CoV-2 PLpro was prepared exactly as described previously [64]. 4.2.1.3 Dengue virus NS2B/NS3 The glycine linked dengue virus 2 NS2B/NS3 protease was prepared exactly as described previously [65]. 4.2.1.4 hCatL and hCatB Human cathepsins B in this study was purchased from Calbiochem (Merck Merck KGaA, Darmstadt, Germany). Human Cathepsin L was purchased by Sigma Adrich (St. Louis, Missouri, USA). 4.2.2 Enzyme activity assays 4.2.2.1 Enzyme inhibition assays Nirmatrelvir was purchased from AOBIUS (Gloucester, Massachusetts, USA). 11a was purchased from BIOMOL GmbH (Hamburg, Germany). Inhibitory activity was determined using either a FRET-substrate (SARS-CoV-2 Mpro) [26] or fluorogenic AMC-substrates (NS2B/NS3 [65], PLpro [64], hCatL [66], and hCatB [67]). Assays were performed in white flat-bottom 96-well microtiter plates (Greiner bio-one, Kremsmünster, Austria) on a TECAN Infinite F2000 PRO plate reader (Agilent Technologies, Santa Clara, USA) for SARS-CoV-2 Mpro or a TECAN Spark 10M (Agilent Technologies) for assays using AMC-substrates. As a general procedure, inhibitors were dissolved as 20 mM DMSO-stock solutions. Substrates were also dissolved in DMSO. For more detailed information for each assayed enzyme see (Table S2). After an initial screening at 20 μM for SARS-CoV Mpro or 100 μM for all other proteases, IC50 values of active inhibitors were determined. Therefore. half-logarithmic dilution series of active inhibitors were prepared (eg. final concentrations: 100, 30, 10, 3, 1, 0.3, 0.1 μM, and DMSO as control). For each well, 185 μL of the respective buffer was supplemented with 5 μL of the enzyme-solutions, followed by 10 μL of the Inhibitors. Reactions were initiated without further incubation by addition of 5 μL of the substrate-solutions and vigorous mixing. Measurements were performed in at technical triplicates. The fluorescence was recorded in intervals of 30 s for 10 min at 25 °C (EDANS: λex 335 nm; λem 493 nm; AMC: λex 380 nm; λem 460). IC50 values were calculated with GraFit (Version 6.0.12; Erithacus Software Limited, East Grinstead, West Sussex, UK) [68] by fitting the enzymatic activities against the respective inhibitor concentration to the four-parameter equation. To correct for substrate competition, K i values calculated by the Cheng-Prusoff equation. 4.2.2.2 Dilution assay Experiments shifting the inhibitor concentrations from 5-fold the respective IC50 to 0.1-fold the IC50, were performed for SARS-CoV-2 Mpro and hCatL mainly as described previously [55,56]. The 5-fold IC50 solutions were as described for enzyme activity assays without addition of the substrate but with 50-fold the SARS-CoV-2 Mpro or 10-fold the hCatL concentration. Samples were incubated for 60 min at rt to ensure potent inhibition. After incubation, one sample per enzyme was diluted 50-fold to achieve inhibitor concentrations of 0.1-fold the IC50. Enzymatic activities of 58.5 μL samples initiated with 1.5 μL of the respective substrate concentration were recorded in triplicates before and after dilution and were normalized to similar treated control experiment with DMSO instead of inhibitor solutions. 4.2.2.3 Dialysis assay Experiments extracting unbound or reversibly bound inhibitors from SARS-CoV-2 Mpro were performed using a custom-built dialysis chamber allowing the parallel examination of five samples mainly as described previously [55,56]. In brief, a dialysis membrane (cut off 13 kDa MW) connected the sample containing wells with a chamber of continuously flowing assay buffer supplemented with 7.5% (v/v) DMSO (flowrate: ∼200 mL/h). Samples were prepared similar to the enzymatic activity assay conditions without substrate (5-fold the volumes). To potently inhibit SARS-CoV-2 Mpro activity, inhibitors were used at a concentration 10-fold the IC50. To compensate for loss of enzymatic activity during dialysis, SARS-CoV-2 Mpro was used in a final concentration of 250 nM, exceeding the concentration of Nirmatrelvir, so that activity could not be fully inhibited by Nirmatrelvir. Activity control measurements were performed using pure DMSO instead of the inhibitor solutions. Hence, 975 μL reaction mixtures were incubated for 60 min at rt to allow covalent reaction (if possible). After that, the first samples (t = 0 min) were drawn, and the rest was put in the wells of the dialysis device. Samples of 58.5 μL were drawn in duplicates at seven different time points (0, 30, 60, 150, 300, 600 and 1500 min). Enzymatic cleavage reactions were initiated by the addition of 1.5 μL of substrate solution in a final concentration of 25 μM. Fluorescence was recorded over 10 min as described for enzymatic activity assays. 4.2.3 Cell-based antiviral activity and cytotoxicity assays 4.2.3.1 Cells and viruses Huh-7 cells overexpressing human angiotensin-converting enzyme 2 (ACE2) (Huh-7-ACE2; kindly provided by Friedemann Weber, Institute of Virology, Justus Liebig University Giessen) were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and antibiotics (100 U/mL penicillin and 100 μg/mL streptomycin) at 37 °C in an atmosphere containing 5% CO2. The SARS-CoV-2 isolate Munich 929 [69] was kindly provided by Christian Drosten (Institute of Virology, Charité-Universitätsmedizin, Berlin). 4.2.3.2 Cell toxicity Cytotoxic concentrations 50% (CC50) of the compounds used in antiviral activity assays were determined using MTT assays as described previously [70]. 4.2.3.3 Antiviral activity To determine effective concentrations 50% (EC50) of the respective compounds, Huh-7-ACE2 cells were inoculated with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 plaque-forming units (pfu) per cell. After incubation for 1 h at 33 °C, the virus inoculum was replaced with fresh cell culture medium containing the test compounds at the indicated concentration. After 23 h at 33 °C, the cell culture supernatants were collected and virus titers were determined by virus plaque assay as described previously [64]. 4.3 Molecular modeling methods 4.3.1 Docking AutoDock4 (AD4) was employed for molecular docking calculations [71]. The formation of the covalent adduct between ligand and protein was modeled using the covalent docking protocol devised by Bianco et al. known as the “flexible side chain method” [62]. Using the Maestro suite, the ligand SPR39 was modeled with two extra atoms where the alkylation would take place. Namely, a sulfur and a carbon atom, in order to match the corresponding atoms Cys145 of the protein. The Mpro X-ray structure having PDB code 7BQY was downloaded from the RCSB PDB database and prepared for docking using the protein preparation wizard, part of the Schrödinger suite [72]. The overlay of the ligand with the reactive cysteines was attained using the scripts offered by the AD4 website. The AutoGrid4 software was used to prepare the protein grid maps using the ligand atom types as probes. The enzyme grid box with a size of 60 Å × 60 Å × 60 Å and 0.375 Å spacing was centered on the coordinates of the cognate c7BQY o-crystal ligand. The docking calculations were performed by treating the modified cysteine/ligand residue as flexible. The Lamarckian Genetic Algorithm (LGA) was employed for the docking simulations. 100 runs of LGA were executed. The docking run consisted of 20 million energy evaluations using the Lamarckian genetic algorithm local search (GALS) method. The GALS method evaluates a population of possible docking solutions and propagates the most successful individuals from each generation into the subsequent generation of possible solutions. A low-frequency local search according to the method of Solis and Wets is applied to docking trials to ensure that the final solution represents a local minimum. The docking experiment was performed with a population size of 150, and 300 rounds of Solis and Wets local search were applied with a probability of 0.06. A mutation rate of 0.02 and a crossover rate of 0.8 were used to generate new docking trials for subsequent generations, and the best individual from each generation was propagated over the next generation. All the other settings were left at their default value. The docking results from the calculation were clustered on the basis of root-mean-square deviation (solutions differing by less than 2.0 Å) between the Cartesian coordinates of the atoms and were ranked on the basis of free energy of binding (ΔGAD4). Finally, the SPR39 docking pose with the best-predicted ΔGAD4 was selected. All the images were rendered using the UCSF Chimera X software [73]. 4.3.2 Molecular dynamics simulations The complex obtained from the docking results was subjected to a molecular dynamics (MD) simulation by means of the Desmond module of the Schrödinger software package [74,75]. As a first step, the system builder panel was used to prepare the system for the MD calculation. Each complex was embedded in a parallelepiped box by solvating it with TIP3P water model [76]. The initial −3 negative charge was neutralized using 3 Na+ ions. Then, the system was equilibrated by employing the NPT ensemble with the default Desmond protocol that includes eight steps. The first 7 are short simulations known as the equilibration phase, where the system temperature is gradually increased and the solute is partially restrained. After the first 7 steps, the equilibrated systems were subjected to the 100 ns MD final production run with PBC conditions and NPT ensemble. The system was set to 300 K temperature and 1 atm pressure throughout the simulation utilizing the Martyna−Tobias−Klein barostat [77] and Nose−Hoover chain thermostat [78]. The OPLSe force field [79] was used for all the MD simulation steps. Author contribution SP: Investigation, synthesis, methodology, characterization, writing—original draft, and validation; RE: Validation, review, and editing; EC: Synthesis; SDM: Design, molecular docking, editing, validation and funding acquisition; SH: Enzyme preparation, enzymatic activity assays, dilution assays, dialysis assays; CM: cytotoxicity and antiviral assays; JZ: review and editing, funding acquisition; T.S.: Validation, review, and editing; SC: Design, molecular docking, editing, validation and funding acquisition; MZ: Validation, Funding acquisition, Supervision, review, and editing. All authors have read and agreed to the published version of the manuscript. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data The following is the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Data availability Data will be made available on request. Acknowledgements This study was funded by Italian Ministry of University and Research (project n° FISR2020IP_00850) and the 10.13039/100009139 German Center for Infection Research (DZIF, TTU Emerging Infections to J.Z.). SH thanks Sabine Maehrlein for fruitful discussions and technical support for enzymatic assays. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2022.115021. ==== Refs References 1 Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 2020 497 506 31986264 2 Gorbalenya A.E. Baker S.C. Baric R.S. de Groot R.J. Drosten C. Gulyaeva A.A. Haagmans B. Lauber C. Leontovich A. Neuman B. 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==== Front Socioecon Plann Sci Socioecon Plann Sci Socio-Economic Planning Sciences 0038-0121 0038-0121 Elsevier Ltd. S0038-0121(21)00087-2 10.1016/j.seps.2021.101095 101095 Article Has the COVID-19 pandemic changed food waste perception and behavior? Evidence from Italian consumers Amicarelli Vera a Lagioia Giovanni a Sampietro Stefania b Bux Christian a∗ a Department of Economics, Management and Business Law, University of Bari Aldo Moro, Bari, Italy b Department of Statistical Sciences, University of Padova, Padova, Italy ∗ Corresponding author. 11 6 2021 8 2022 11 6 2021 82 101095101095 22 12 2020 16 4 2021 8 6 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Food waste represents a multi-sectoral issue and influences the economy, society and environment. Considering that over 50% of food waste is generated from household consumption, the issue has been included among the 17 Sustainable Development Goals, with the aim of halving its quantity by 2030. However, the COVID-19 pandemic imposed several variations in the agri-food industry in terms of food manufacturing, storage and distribution, changing at the same time food access, food consumption and food waste behavior. The present paper, through an online-based questionnaire among 831 respondents from Italy and the application of the cumulative logit model, investigates consumer behavior after the lockdown with reference to unpredictable lifestyles, improvements in smart food delivery and never-experienced time management. Results illustrate that always-at-home consumers (forced to stay at home 24 h a day) are more likely to perceive food waste and reduce its amount, whereas discontinuous smart working makes food purchase, preparation and consumption activities even more stressful and complex. Furthermore, smart food delivery tends to increase consumers’ awareness of meals, improving buying decisions and indirectly reducing food waste generation. The unjustifiable prevalence of household food waste represents a major barrier to the achievement of food security, health insurance and hunger reduction, but also the most promising entry point to stress in the achievement of private and public benefits. Thus, the active role of education among young generations must be enhanced. Keywords Food waste Covid-19 pandemic Cumulative logit model Household consumption behaviour Food waste education ==== Body pmc1 Introduction Food waste represents a multi-sectoral issue and produces significant impacts on the economy, society and environment all over the world [1,2]. Indeed, each year more than 1.3 billion tons of food, equal to approximately one-third of global food production, is wasted along the whole food supply chain [3,4]; [101]. Under financial, social and environmental perspective on global scale, full costs associated to food waste have been assessed in approximately USD 1 trillion per year, to which environmental costs (USD 700 billion) and social costs (USD 900 billion) must be added [5], while food waste carbon footprint has been estimated in over 3.3 Gigatons (Gt) of CO2e each year (6% of global GHG emissions) [[5], [6], [7]]. In the European Union (EU), more than 140 million tons (Mt) of food is wasted each year [8] of which approximately 24% is from harvesting and post-harvesting production, 23% from industrial transformation, 5% at the distribution level, 9% from food service and 39% from households [9,10], estimated in over 140 billion euros in terms of financial costs [11], less than 520 million MJ in terms of nutritional losses [12] and over 170 Mt of CO2eq (3% of global EU emissions) released in the atmosphere [13]. In Italy, food waste is estimated at approximately 8.5 Mt per year, resulting in loss in over 15 billion euros and roughly 8.5–14.5 Mt of CO2eq [14]. To reduce food waste impacts and address economic, environmental and societal concerns, impressive initiatives have been adopted in the field of resource use efficiency, reduction of supply chain disruptions, food donations and food waste valorization [15]. At the international level, the United Nations has included food waste among the 17 Sustainable Development Goals (SDGs), pursuing the challenge of reducing hunger and enhancing responsible consumption and production [16,17]. The main aim is to halve per capita global food waste at retail and consumer level, as well as to reduce food losses along agricultural, post-harvest and manufacturing stages by 2030. At the EU level, as a consequence of the adoption of Closing the loop – An EU action plan for the Circular Economy [18], the monitoring framework for the circular economy has included food waste among the 10 circular economy indicators [19,20]. Furthermore, through the adoption of the Farm to Fork Strategy (part of the European Green Deal), the EU imposed on the entire community actions for sustainable food consumption and food loss and waste prevention. The latter highlights the opportunities coming from the implementation of such actions for agri-food operators and final consumers [21], such as the general improvement of economic development, food safety, food security and climate change. Indeed, although upstream stages of the food supply chain (harvesting and post-harvesting, industrial manufacturing) should be monitored, the EU focuses on food waste occurring through retail, food service and household consumption (downstream stages) [1], where roughly 70 Mt of food is wasted each year [22]. The unjustifiable prevalence of food waste in households represents a major barrier to the achievement of food security, health insurance and hunger reduction, but also the most promising entry point to stress in the achievement of private and public benefits [23,24]. Nowadays, the COVID-19 pandemic still represents a social, health and financial challenge all over the world, affecting all economic and industrial sectors, significantly the agri-food industry in terms of food manufacturing and consumption [25,26]. Worldwide, the World Health Organization [27] confirmed more than 120 million cases and over 2.6 million deaths (18th March 2021), of which European ones amount to over 34%. In Italy, more than 3.2 million cases and approximately 103,000 deaths have been registered (18th March 2021). In terms of socioeconomic consequences, from March 2020 onwards, entire countries adopted different forms of social distancing with the aim of limiting disease infection diffusion. This lockdown period upset life, work and food consumption habits among households [28,29]. People, forced to stay at home (24 h a day) or experiencing smart working, had enough time to discover food planning and food storage techniques, adopt food diets, increase time assigned for eating, improve cooking skills and familiarize themselves with food domestic appliances. Moreover, the fear of not finding enough food (resources) in the medium-long term played a significant role in changing domestic habits [30]. In the light of these premises, this paper investigates current attitudes, awareness and behavioral patterns related to food waste reduction in domestic consumption during the COVID-19 pandemic. Through an online-based questionnaire and applying the cumulative logit model (CLM) to analyze data, the authors investigate Italian consumer behavior following the COVID-19 lockdown with reference to unpredictable lifestyles, improvements in smart food delivery and never-experienced time management. The originality of this paper lies in the investigation of food waste perception and behavior through a hypothesis approach, based on a series of variables such as employment status, smart working experience, smart food delivery, food diets and sport activities, useful to identify and propose new paths for sustainable food consumption at home. 2 Literature review: consumer behavior and effects of the pandemic The role of households in the reduction of food waste is crucial [31,32]. In recent decades, a plethora of studies have focused on food waste issue determinants, measurement and opportunities. Despite one of the first analyses conducted on the issue dating back to 1974 [33] and the first waste definition being presented in 1975 [34], the vast majority of studies have followed the publication of the first report on food loss and waste assessment along the food supply chain in 2011 [1]. The most recent studies in the field of household food consumption/waste investigated general drivers and barriers to food waste reduction [35,36], as well as particular domestic practices to reduce its amount (e.g., food preparation planning, improvement of storage conditions) [37,38]. Furthermore, some authors have analyzed how to address international policies [39] and intervention programs [24], identifying in leftover management, education campaigns and date-labelling awareness some of the key points to emphasize [40], but only a few have stressed the unavoidable link between environmental impacts (e.g., resource depletion, greenhouse gas emissions) and food waste [41,42]. In terms of households' food waste behavior, some studies have analyzed individual and potential variables associated with the issue [43,44], recognizing a set of behavioral patterns (e.g., purchasing attitude, consumer perception) that could enhance food waste management at home [[45], [46], [47]]. However, even if the role of households' food waste in times of crisis has been under-researched before the pandemic [48], numerous studies have analyzed households' behavioral changes induced by the COVID-19 all around the world. At first glance, all authors highlighted an almost homogeneous behavior among consumers, either in European [30,49,50], American [51,52], Asian [53,54] or African [55,56] realities, estimating effects almost comparable between countries. According to Ben Hassen et al. [55], consumers shifted toward healthier diets, increasing domestic products consumption and changing modality of acquiring food toward online shopping. Indeed, Alaimo et al. [49] and Laguna et al. [50] examined the significant role of online food shopping during the pandemic in Italy and Spain, while either Jribi et al. [56] or Roe et al. [52] stressed the need to improve households’ skills and management practices to reduce the day-to-day food waste both in Tunisia and America. Further, Brizi and Biraglia [53] investigated the gender role and the psychological variables correlated with stockpiling and food waste processes in India, while Shi et al. [54] emphasized the role of food safety knowledge toward sustainable food consumption behaviors among Chinese consumers. 3 Methodology In line with the Commission Delegated Decision (EU) 2019/1597 of May 3, 2019 [57], which states that “the amount of food waste within a stage of the food supply chain shall be established by measuring food waste generated by a sample of households in accordance with any of the following methods or a combination of those methods or any other method equivalent in terms of relevance, representativeness and reliability,” the authors adopted the questionnaire methodology to analyze food waste behavior among households. As Møller et al. [9] stated, questionnaires are structured and formal ways to collect quantitative or qualitative data among all actors of the agri-food sector, from producers to consumers, and are cost effective, usually standardized, accessible and easy to read. The questionnaire-based analysis conducted in the present study followed systematic steps: (1) literature analysis on the Web of Science (WoS) Core Collection; (2) hypothesis development and questionnaire drafting; (3) sampling strategy and data collection; and (4) statistical approach and data analysis. Furthermore, considering the food waste definition as one of the main criticalities in food waste studies, the authors adopted that proposed by FAO [58]: food waste is the “the masses of food lost or wasted in the part of food chains leading to edible products going to human consumption,” referring to food originally destined for human nutrition but later discarded or reused for other purposes [59]. 3.1 Literature background on food waste questionnaire-based studies To begin the analysis and gain a better understanding of domestic food consumption and wastage, the authors conducted a brief but comprehensive literature review on food waste questionnaire-based studies using the WoS Core Collection. In the last five years (2015–2020), several authors have successfully applied questionnaires, in all forms (by e-mail, by telephone, electronically or in person), in food waste studies. In the downstream stages, Willersinn et al. [60] applied a standardized 8-page questionnaire sent by e-mail to investigate the potato supply chain in Switzerland, Hartikainen et al. [61] utilized 21 different questionnaires to analyze primary production in Nordic countries, and Baker et al. [62] conducted in-depth interviews to understand primary production in Northern and Central California. In the upstream stages, some authors have measured food waste quantities in food services [63,64] and the hospitality sector [65], while others have investigated household behavior and major food waste drivers [66,67], as well as food waste quantities [68]. However, even though one study has already detected the effects of the lockdown on food waste during the COVID-19 pandemic [30], none has analyzed attitudes, awareness and behavioral patterns of domestic food waste with reference to the role of smart working, time management and smart food delivery. 3.2 Hypothesis development The drafting of a clear and logical questionnaire (wording, clarity, interpretation) was based on three main pillars: a) the use of an investigative technique that avoids distribution of the object investigated; b) the elaboration of simple questions to speed up participation during compilation; and c) the use of direct questions to avoid excessive space for participants' and researchers’ interpretations [69]. Thus, to pursue the overall aim of the study and test the weight of selected household variables on food waste generation, the authors developed the following hypotheses:Hypothesis 1 (H1): Sociodemographic variables (age, gender, job, financial status, education, household size) and employment status have a direct effect on food waste perception (FWP) and food waste behavior (FWB). Hypothesis 2 (H2): Smart working (from 14th October to 14th November 2020) has a direct effect on FWP and FWB. Hypothesis 3 (H3): Smart food delivery (from 14th October to 14th November 2020) has a direct effect on FWP and FWB. Hypothesis 4 (H4): Food diets (voluntary or mandatory) and sport activities have a direct effect on FWP and FWB. Fig. 1 illustrates the extended hypothesis development.Fig. 1 Extended hypothesis development and study design (Source: Personal elaboration by the authors). Fig. 1 In terms of FWP, the authors investigated the impact (positive or negative) of selected items (e.g., sociodemographic variables, smart working, smart delivery, food diets and sport activities) on households' social and environmental awareness of food waste issues. In terms of FWB, the authors examined the impact of the abovementioned items on the self-reported quantities of food waste in seven food categories: fruit, vegetables, rice and pasta, meat and meat-based products, fish and fish-based products, milk and dairy products, bread and baked products, and prepared meals (including takeout and delivered food) [59]. Participants’ reported quantities referred to the month prior to the compilation (from 14th October to 14th November 2020). 3.3 Questionnaire drafting, sampling strategy and data collection The questionnaire (available on demand) consisted of 29 single-option queries divided among four sections: a) sociodemographic characteristics (ten questions); b) general shopping habits in the last month (four questions); c) time management and domestic activities in the last month (eight questions); and d) food consumption and food wastage in the last month (seven questions). To increase the significance of qualitative and quantitative information, the authors added to dichotomous questions (yes or no) also 7-point Likert scale questions, because they appear to be more suited to electronic distribution and offer more accurate records of participants’ evaluations [70,71]. As discussed by Joshi et al. [72], the 7-point Likert scale (from not at all to very much) provides more varieties of options which could increase the probability of meeting the objective reality of people, offering more independence to respondents and allowing them to pick the exact option rather the closest one [73]. The questionnaire was written in Italian and realized in Google Forms, an online platform useful to create questionnaires, receive fast answers and analyze data in multimodal formats [74,75]. The questionnaire link was disseminated online from 14th November 2020 to 30th November 2020 on social media (e.g., Instagram, LinkedIn, Facebook) and distributed via e-mail. Participants were asked to sincerely respond to a questionnaire on household food waste and share the survey as much as possible. Due to the restrictions imposed by the health emergency, but still in line with previous literature [30,76], the distribution of the questionnaire link followed the non-probabilistic snowball method. Indeed, as discussed by Cohen and Ariely [77], the snowball sampling represents a widely applied method in Internet research, either guaranteeing security under pandemic conditions or reaching as many respondents as possible requiring the minimal planning and human resources [49]. However, being a nonrandom technique, it does not guarantee representation and is vulnerable to sampling biases (e.g., risk of self-selection, internal and external validity limitations). Nevertheless, the large number of participants (n = 831) overcame such a limit. All respondents were asked to consent to data processing only for academic purposes. 3.4 Statistical approach and data analysis To select the most suitable statistical method to analyze collected data, the authors preliminarily conducted an explorative analysis using descriptive statistical tools (e.g., box plots, bar plots, scatter plots). Second, the authors applied the CLM. The model, initially introduced by McCullagh [78], is suitable to analyze response variables on an ordinal scale, for which the stochastic ordering can be defined using the distribution function [79]. Considering Yi as the random variable that describes the response of the ith subject in an ordered manner, with qualitative response variables on an ordinal scale, it is possible to define the following equation [1]:[1] Pr(Yi≤j)=πi1+…+πijwithj=1,…,candπij=Pr(Yi=j) Cumulative logit is the logit transformation of the cumulative probability, according to the following equation [2]:[2] logit[Pr(Yi≤j)]=logPr(Yi≤j)1−(Yi≤j)=logπi1+…+πijπij+1+…+πic.withj=1,…,c−1 Thus, the applied CLM can be defined as follows [3]:[3] logit[Pr(Yi≤j)]=αi+xiβwithj=1,…c−1andα1≤α2≤…≤αc−1 The parameters αj represent intercept parameters, while the vector β contains the regression coefficients with respect to the further covariates. In order to choose the most suitable exploratory variables (covariates), the authors applied the stepwise approach [80] and created three different models: the first one enclosing all variables; the others, though considering the four hypotheses, deleting the less significant variables from time to time on the basis of coefficients p-value, consistency and adherence to the topic [81]. To compare the three models, the authors calculated the Akaike information criterion (AIC) [82] to measure their statistical quality. The authors used a 5% level of statistical significance, illustrating the p-value of variables in all tables. Data were processed using R 3.6.3 software (https://www.r-project.org). 4 Results 4.1 Sample characteristics The sample was composed of 831 respondents from Italy (Table 1 ). In line with several studies [30,76], the majority of respondents were females (69.8%), while men represented a slighter quota (30.2%). The ratio is justified because women are still traditionally the main ones responsible for home management, family care and culinary activities [83,84]. In terms of age, respondents were heterogeneously distributed, with higher percentages of young people between 18 and 25 (24.1%) and adults between 46 and 55 years old (21.4%). The majority of households were made up of 4 or more people (43.1%).Table 1 Sociodemographic characteristics of the sample. Table 1Sociodemographic characteristics Categories Percentage (%) Gender Female 69.8 Male 30.2 Civil status Single 48.5 Married 43.2 Divorced 6.5 Widower 1.8 Age 18–25 24.1 26–35 20.9 36–45 15.6 46–55 21.4 56–65 11.4 Over 65 6.7 Households composition 1 9.9 2 25.6 3 21.5 4 or more 43.1 Residence area Big city (over 100,000 inhabitants) 50.8 Small city (10,000–100,000 inhabitants) 34.4 Town (fewer than 10,000 inhabitants) 14.8 Education Elementary school 0.6 Middle school 3.5 Diploma 39.5 Bachelor's or master's degree 42.1 Master, Ph.D. 14.3 Financial status Hard 4.2 Humble 29.8 Good 61 Excellent 5 Employment situation Employed 56.5 Unemployed 8.1 Housemaker 5.3 Retired 7.4 Student 22.8 Smart working experience Yes 64.9 No 35.1 (Source: Personal elaboration by the authors). Regarding smart working, participants were asked to answer based on their experience following the COVID-19 lockdown (Q10. Due to the COVID-19 pandemic, have you experienced smart working or smart studying?). Approximately 65% of respondents answered affirmatively. Of those, roughly 44% had performed half smart working on a monthly basis, approximately 27% less than half and more than 27% engaged completely in smart working. Overall, these values are almost in line with Italian trends [85], which have estimated that, on average, approximately 37% of workers were able to work from home in last quarter of 2020, with the highest peak at the beginning of the pandemic (47%). The explorative analysis through descriptive statistical tools (e.g., box plots, bar plots, scatter plots) highlighted the reverse effect in the field of FWP and FWB with reference to employment situations and smart working experience (Table 2 ).Table 2 Employment situations, smart working experience and food waste. Table 2Employment status FWP FWB Total (a) (b) (c) (d) (a) (b) (c) (d) Housemaker 3 5 11 25 21 18 3 2 44 Unenployed 9 18 13 27 22 26 15 4 67 Employed 64 64 154 187 186 220 46 17 469 Retired 1 3 17 40 39 21 1 0 61 Student 43 45 52 50 43 102 12 33 190 Smart working experience FWP FWB Total (a) (b) (c) (d) (a) (b) (c) (d) Never 38 42 76 117 117 115 33 8 273 <50% 23 29 39 62 49 72 18 14 153 >50% 42 43 74 88 87 101 37 22 247 Always 21 24 56 57 51 83 15 9 158 (a) Not at all, to a small extent, to some extent; (b) To a moderate extent; (c) To a significant extent; (d) To a large extent, very much. (Source: Personal elaboration by the authors). 4.2 Food waste perception cumulative logit model results The CLM is suitable for the analysis of ordinal response data, considering at the same time the ranked order inherent in ordinal response data, the adjustment of confounding variables and the assessment of effect modification on a modest sample size [86]. As previously stated, the authors applied the stepwise approach and created three different models. The first model included all variables related to sociodemographic characteristics (i.e., gender, age, civil status, households composition, region and province of residence, residence area in terms of size, education, financial status, employment situation), general shopping habits (i.e., price care, food purchase frequency, food purchase place, food delivery), time management and domestic activities (i.e., smart working experience, average smart working hours, sport activities) and food consumption and wastage behavior (i.e., mandatory and voluntary recycling, mandatory and voluntary diet, environmental issues care, food waste apps knowledge, change in food waste perception after the COVID-19 lock down). On the basis of coefficients p-value, consistency and adherence to the topic, the covariates were reduced in the passage from the first to the second model, and from the second to the third, until the elimination of some variables (i.e., age, civil status, region and province of residence and education). Further, the AIC has been calculated to compare the models, highlighting the following results: (a) first model = 1191.045; (b) second model = 1183.84; (c) third model = 1176.094. Therefore, the authors have selected the third one. The FWP-CLM response variable was ordered on a 7-point Likert scale and regarded sensitivity and perception toward food waste in light of the COVID-19 pandemic (Q25. How sensitive are you to food waste?). Table 3 illustrates the main FWP-CLM results. The groups of covariates are related to sociodemographic variables (H1), smart working experience (H2), food purchase frequency and habits, smart delivery (H3), food diets and sport activities (H4), general attitudes toward food waste and environmental issues, food waste app knowledge (e.g., ToGoodToGo) and individual perception of changes in food consumption following the COVID-19 lockdown.Table 3 Food waste perception cumulative logit model (FWP-CLM). Table 3Food Waste Perception Cumulative Logit Model (FWP-CLM) Coefficients Estimate P-value Significance Gender Ref. Male 0.2327 0.2627 Residence area Small city (10,000–100,000 inhabitants) 0.0564 0.8118 Town (fewer than 10,000 inhabitants) 0.1437 0.6734 Financial status Humble 0.0150 0.9798 Good 0.0221 0.9695 Excellent −1.1096 0.1134 Employment situation Unemployed 1.2343 0.0484 * Employed 0.7058 0.2159 Retired 0.1945 0.8270 Student 1.8048 0.0024 ** Smart working experience Yes 1.1266 0.1220 Smart working (average) Less than 50% −1.6342 0.0320 * More than 50% −1.5935 0.0347 * Always 1.6624 0.0302 * Price care (ratio quantity/price) Yes −0.8221 0.0011 ** Food purchase frequency 2-3 times a week 0.5806 0.0047 ** 4-5 times a week −0.3906 0.3843 Every day 0.2091 0.6409 Food purchase place Local market −1.6688 0.0150 * Retail shop (e.g., bakery, butchery) −0.1613 0.6527 Supermarket −0.0224 0.9368 Online 0.1460 0.8765 Food delivery 2-3 times a week 1.2423 0.00004 *** 4-5 times a week −0.2596 0.7653 Every day 1.2046 0.5235 Recycling Voluntary organic recycling −0.5936 0.0578 . Mandatory organic recycling −0.4539 0.1181 Food diet Voluntary −0.5506 0.0078 ** Mandatory −0.3124 0.2365 Sport activities Yes 0.0520 0.7934 Environmental issues care Yes −1.6423 0.00003 *** Food waste apps knowledge Yes −0.1984 0.3259 Change in food consumption after the Covid-19 lock down Not at all 0.5334 0.0924 . To a small extent 0.6618 0.0464 * To some extent 0.3653 0.2632 To a moderate extent 0.0122 0.9704 To a significant extent −0.0848 0.8339 To a large extent −1.2413 0.83391 Significance at 0 (***). Significance at 0.001 (**). Significance at 0.01 (*). Significance at 0.05 (.). (Source: Personal elaboration by the authors). In terms of sociodemographic variables, employment status (H1) was estimated as a significant variable. Unemployed people are more likely to perceive food waste consequences (estimate: 1.2343, p-value: 0.0484), as are students (estimate: 1.8048, p-value: 0.0024). In general, individuals from such categories are between 18 and 35 years old, thus belonging to younger generations compared with older ones. Furthermore, smart working experience (H2) revealed its significance in terms of FWP. Based on exploratory studies [87], the authors believed that a novel work-life balance would cause additional food waste at final consumption. Considering an average monthly basis of smart working, the authors assessed that people working from home for less than 50% of their work are less likely to perceive food waste (estimate: −1.6342, p-value: 0.0320), while their sensitivity slightly increases if smart working increases to more than 50% (estimate: −1.5935, p-value: 0.347). The lack of organization, not-always-precise work scheduling and professional stress due to the pandemic have potentially diverted workers’ attention from food waste issues [88]. On the contrary, people experiencing smart working all day long revealed a greater awareness of food waste (estimate: 1.6624, p-value: 0.0302), demonstrating how stability and time management at home help individuals to consider consumption and waste consequences. Considering food purchasing habits, the authors estimated that people buying huge quantities of food at greater/discounted prices (price care) are more likely not to consider food waste issue (estimate: −0.8221, p-value: 0.0011). Moreover, consumers whose food purchase frequency ranges between 2 or 3 days a week are more aware of food waste (estimate: 0.5806, p-value:0.0047). In general, food purchase place revealed no significance in terms of FWP. In terms of food delivery (H3), the FWP-CLM highlighted that consumers using smart delivery (e.g., apps) 2 or 3 days a week are more likely to be aware of food waste issues (estimate: 1.2423, p-value: 0.00004), especially in light of the fact that home delivery food is highly portioned and more expensive compared with raw ingredients [89]. Lastly, according to H4 (food diets and sport activities), the authors estimated that consumers adopting a voluntary diet are less likely to perceive food waste (estimate: −0.5506, p-value: 0.0078), in line with previous studies on the topic [90]. Furthermore, participants were asked to declare their awareness of food waste environmental issues (Q27. Are you aware of food waste environmental consequences, such as water or energy consumption and greenhouse gas emission?). The application of the FWP-CLM to the dichotomic answer (yes or no) showed that consumers living in small towns with fewer than 10,000 inhabitants are less likely to understand food waste environmental consequences (estimate: −1.8361, p-value: 0.0434), while those adopting a mandatory healthier diet (estimate: 1.4197, p-value: 0.0917) and buying food through food waste-reduction apps (estimate: 2.0481, p-value: 0.0002) are more likely to understand food waste environmental issues. 4.3 Food waste behavior cumulative logit model results The FWB-CLM response variable was ordered on a 7-point Likert scale (from not at all to very much) and regarded self-reported quantities of food waste for seven food categories (fruit, vegetables, rice and pasta, meat and meat-based products, fish and fish-based products, milk and dairy products, bread and baked products, prepared meals) in the last month. Participants were asked to assess food waste quantities (Q28. How much food do you think you have wasted on average in the last month?). Because each category was positively correlated with another, the authors assumed similar food waste behaviors among food categories. Fig. 2 illustrates results according to Kendall rank correlation coefficient.Fig. 2 Correlation between eight food categories (Source: Personal elaboration by the authors). Fig. 2 It is estimated that all food commodities are positively correlated, above all fruits and vegetables (0.67), rice, pasta, meat and meat-based products (0.66), as well as meat, meat-based products, fish and fish-products (0.78). Being pasta one of the most representative staple food in the Mediterranean diet [91], its correlation is on average over 0.50 with all food commodities (excluded fruits and vegetables). Considering that the study did not aim to quantify food waste but to qualify participants’ behavior, the authors applied the FWB-CLM to the average reported waste in each category. Table 4 illustrates the main FWB-CLM results. It is important to highlight that the FWB-CLM applies the same variables as the FWP-CLM. Basically, the two models behave in opposite ways (an increase in FWP-CLM corresponds to a decrease in FWB-CLM), with only a few exceptions.Table 4 Food waste behavior cumulative logit model (FWB-CLM). Table 4Food Waste Behavior Cumulative Logit Model (FWB-CLM) Coefficients Estimate P-value Significance Gender Ref. Male −0.4244 0.0528 . Residence area Small city (10,000–100,000 inhabitants) −0.2261 0.3618 Town (fewer than 10,000 inhabitants) −0.4062 0.2593 Financial status Humble −0.1098 0.7357 Good −0.0451 0.9408 Excellent −0.2302 0.7502 Employment situation Unemployed −2.1337 0.0017 ** Employed −1.1212 0.0713 . Retired −0.4261 0.6523 Student −2.0883 0.0012 ** Smart working experience Yes 0.4686 0.5439 Smart working (average) Less than 50% −0.6166 0.4426 More than 50% −0.5856 0.4632 Always −0.3352 0.6784 Price care (ratio quantity/price) Yes 0.2541 0.3350 Food purchase frequency 2-3 times a week −0.3520 0.1015 4-5 times a week −0.7263 0.1068 Every day −0.0546 0.9063 Food purchase place Local market 1.5492 0.0288 * Retail shop (e.g., bakery, butchery) 0.4500 0.2346 Supermarket 0.4559 0.1273 Online 0.2989 0.7658 Food delivery 2-3 times a week −0.5087 0.1059 4-5 times a week −0.9457 0.2832 Every day −1.1521 0.5466 Recycling Voluntary organic recycling −0.6517 0.0514 . Mandatory organic recycling 0.6521 0.0329 * Food diet Voluntary −0.0756 0.7272 Mandatory −0.0644 0.8119 Sport activities Yes 0.2787 0.1811 Environmental issues care Yes −0.1091 0.7971 Food waste apps knowledge Yes 0.0094 0.9643 Change in food consumption after Covid-19 lock down Not at all −0.5253 0.1249 To a small extent −1.802 7.48e-07 *** To some extent −1.7332 1.01e-06 *** To a moderate extent −1.6609 3.20e-06 *** To a significant extent −1.5975 0.0001 *** To a large extent −0.6151 0.1516 Significance at 0 (***). Significance at 0.001 (**). Significance at 0.01 (*). Significance at 0.05 (.). (Source: Personal elaboration by the authors). In terms of sociodemographic variables, employment status (H1) represents a significant item. In fact, unemployed consumers tend to waste less food (estimate: −2.1337, p-value: 0.0017) than do employed individuals (estimate: −1.1212, p-value: 0.0713), as well as students (estimate: −2.0883, p-value: 0.0012). The FWB-CLM confirms the FWP-CLM results, because those who perceive food waste the most are the same as those who declared a lower quantity of food waste. Considering the smart working experience (H2), no significant results were associated with food waste self-assessment, nor with food diets and sport activities (H3). In terms of organic recycling, the authors assessed that consumers voluntarily adopting a separate waste collection are more likely to waste lower amounts of food (estimate: −0.6517, p-value: 0.0514) compared with those who are forced (estimate: 0.6521, p-value: 0.0329). The most interesting result of the FWB-CLM is regarding the ordinal responses related to participants' change in food consumption following the COVID-19 lockdown. Even though FWP did not immediately change due to the pandemic—cognitive control is a process that unfolds over time [92]—food waste behavior did. Indeed, all consumers reporting a change in food consumption during the pandemic are more likely to waste less food, as shown by those who declared a moderate change (estimate: −1.6609, p-value: 0.00000101) and a large one (estimate: −1.5975, p-value: 0.0001). Basically, unpredictable lifestyles changed consumers’ behaviors faster than their perceptions. 5 Discussions In light of previous results and considering that possible effects of the COVID-19 pandemic on FWP and FWB have been difficult to predict, the following key concepts can be discussed. First, the authors estimated that sociodemographic variables in general and employment status in particular have a significant impact on FWP and FWB, confirming H1 as an interesting point of reflection. Moreover, smart working and smart delivery, contextualized in a novel and unpredictable work-life balance (H2, H3), defined new horizons, paths and reflections on domestic food waste. In addition, variables such as food diets (voluntary or mandatory) and sport activities (H4) were analyzed, demonstrating a slight significance toward food waste awareness. It has been demonstrated that changes in food consumption (e.g., food purchase planning, storage operations, increased time allotted for eating, improved cooking skills, familiarity with domestic appliances) due to the COVID-19 pandemic directly modified FWB, reducing on average the self-assessed quantities of food waste. Indeed, even if not yet metabolized, the fear of reduced medium-to long-term food availability led consumers to preserve resources and manage them in a more sustainable way, thus unexpectedly reducing food waste. Table 5 synthesizes FWP and FWB effects with regards to hypothesis development and variables significance.Table 5 Effects on FWP and FWB according to hypothesis development. Table 5Hypothesis Independent variable Effect on FWP Effect on FWB H1 Unemployment Yes (+) Yes (−) Student status Yes (+) Yes (−) H2 Smart working (<50%) No N/S Smart working (>50%) Slight (+) N/S Smart working (always) Yes (+) N/S H3 Smart food delivery (2–3 times a week) Yes (+) N/S H4 Food diets No N/S Sport activities N/S N/S N/S = Not significant. (Source: Personal elaboration by the authors). It is necessary to proceed step by step. The results reveal a high likelihood of young generations of students (18–25 years old) and unemployed people (up to 45 years old) to reduce food waste. Indeed, both unemployed and students registered a sharp perception toward food waste issues, as well as a strong inclination toward its reduction. Among others, individuals from these categories were forced to stay at home during the COVID-19 lockdown and represent one of the few examples of always-at-home consumers (24 h a day). The accessibility of novel time management had a positive effect in the field of food waste reduction. Consumers could improve food purchase programming, storage operations and eating choices, showing the importance of time management during households’ operations. People who spent more time at home, with the chance to plan culinary and food activities, tended to improve their perception of food waste and reduce, on average, its quantity. However, these circumstances were registered only among people spending all their time at home, whereas they are not valid for those who engaged in smart working part time (more or less 50%). Contrary to what was assumed, smart working activities made family management and food purchase, preparation and consumption operations even more stressful and complex, thus leading to increased food waste. Not surprisingly, consumers who carried out discontinuous smart working reported a lower perception of food waste, demonstrating their lack of time to plan and establish food habits. Furthermore, the results highlight that price care in terms of quantity/price ratio and smart food delivery have significant effects on consumers' attitudes. Consumers more interested in buying discounted products (e.g., products on offer, family-size packages) and consumers affected by compulsive shopping, on average, show a low perception of food waste, displaying an unwise and inattentive attitude toward grocery shopping [93]. The key factor is simply buying too much food, especially during the pandemic, where the fear of not finding foodstuff rules. Home delivery, especially through digital apps (e.g., Deliveroo, Just Eat, Uber Eats) and social tools (e.g., Telegram), is relevant in the field of food waste perception, in particular among people ordering food 2 or 3 times a week. In line with previous studies [94,95], smart food delivery tends to increase consumers’ awareness of products and improve buying decisions, thus reducing unappreciated meals, especially through high-definition photographs and precise food descriptions. Furthermore, the higher cost of food represents a crucial variable toward food waste reduction. It is a strong assumption, but if food is valued more, then its importance will probably increase. An irrational element of reflection concerns the adoption of food diets, both voluntary and mandatory. Food diets, generally including intrinsic shopping and portion size planning, should determine a higher perception of food waste, although the contrary has been estimated. These results necessitate further attention regarding the opportunity of transmission of food waste contents among people adopting diets. In the field of organic recycling, the authors assessed that people adopting mandatory separate collection still do not exhibit sustainable behavior in terms of food waste. Thus, it would be advisable to educate them to adopt more virtuous consumption behaviors. FWP and FWB act in the opposite way. An increase in perception corresponds with a decrease, on average, in food waste production. Previous studies [96,97] stated the importance of educational and awareness campaigns toward food waste reduction, demonstrating how positive changes in perception, in the medium and long term, affect waste behaviors. However, the advent of the COVID-19 pandemic highlighted an opposite trend, showing how human beings, placed in conditions of extreme difficulty, change habits even before perceiving their effects. Indeed, considering that all outdoor food service facilities have been limited, as well as all grocery shopping opportunities, the authors would have expected a sharp increase in food waste generation due to the sudden changes in food habits and all related negative emotions, psychological burdens [98] and stockpiling processes [53]. However, as already confirmed by previous studies [87], the so-called “stock effect” has been counterbalanced by the “I-stay-at-home effect,” which helped consumers to improve households’ skills, storage practices and management activities to reduce day-to-day food [52]. In terms of domestic managerial suggestions, several opportunities in the field of food waste perception and reduction are related to households’ time management. Among others, considering the disruption in the agri-food supply chain, the commitment to consume food at home and the impossibility of moving beyond local borders, one possibility could concern the rediscovery of local (e.g., regional provincial) culinary habits and traditions, especially in the context of the Italian gastronomic culture. The Italian food culture has always relied on endogenous resources, products and ingredients and is based on reuse as a paradigm, combining raw materials to avoid leftovers and take advantage of seasonality, availability and zero-kilometer products. Furthermore, the increase in time allotted to domestic activities (e.g., food planning, preparation, storage) is essential to promote sustainable practices, allowing, for instance, the precise portioning of food while storing and food storage organization based on the expiration date. Indeed, the availability of previously weighted resources—in line with household needs—at the moment of storage could reduce consequential exaggerated portions, leftovers or undesirable meals. Moreover, the greater availability of time and the smart working experience enable better management in terms of food purchasing, with the consequence that it is possible to re-experience the opportunities of local markets and their related social, economic and environmental benefits. On the side of policy implications, the active role of education must be enhanced. Indeed, the direct involvement of consumers is essential to pursue sustainable development and address climate change, but it is crucial to intervene through education, youth engagement and social innovation. As proposed by the European Commission [99], young generations and students have the potential to become ambassadors for sustainable behaviors, green consumption and environmental protection, along with ordinary citizens and families. To achieve the SDGs in general, and food waste reduction in particular, it is essential to teach people about the sources and consequences of food waste, as well as inspire their commitment to solving the issue, developing a common attitude and correcting detrimental habits. For instance, it could be useful to implement continuous mapping and measurement of food waste quantities, drivers and disposal routes, along with introducing social and digital technologies (e.g., games, training courses, webinars) to educate and inform about criticalities, progress and future perspectives. 5.1 Theoretical implications, limitations and future research Under a theoretical perspective, the present research contributes to enrich the literature on food waste perception and behavior with reference to new scenarios imposed by the pandemic (i.e., smart working, smart food delivery, novel time management), confirming past trends and adding new insights after the COVID-19 pandemic. However, it presents intrinsic limitations. First, although questionnaires are cost-effective, can be standardized and represents one of the most diffused methodologies to reach high numbers of people, they are subject both to the risk of self-selection, approximation or undervaluation by respondents. Indeed, in the absence of coaching, participants are usually unaware of the differences inherent in the concepts of perception-behavior and are somehow confused during food waste assessment [100]. Further, the snowball sampling technique, being a nonrandom methodology, has not guaranteed generalizations and is susceptible to some sampling biases (e.g., validity limitations). However, the application of the CLM to analyze four hypotheses, and the adoption of some tricks (e.g., 7-point Likert scale) to reduce possible vulnerabilities, offered robust statistical evidence, revealing interesting interconnections between changes in lifestyle during the pandemic and food waste production. In the light of previous results and considering that young generations of students (18–25 years old) have a high likelihood to reduce food waste, the authors are intended to apply the causal research in order to verify the extent and nature of cause-and-effect relationships between new educational systems, food waste perception and food waste behavior. Indeed, the authors are interested in addressing young people to value food, highlighting their role of healthy carriers within and between generations. 6 Conclusions The paper investigated the current attitudes, awareness and behavioral patterns of Italian food consumers during the COVID-19 pandemic, with particular regard to smart working, time management and smart food delivery. To sum up, the greater the time available and the greater the ability to manage it, the greater the attention paid to food waste. The pandemic period has offered people the opportunity (or has forced them) to pause, thus boosting time availability and offering opportunities to adopt diets, increase consumption of domestic products, become familiar with online shopping, improving at the same time cooking skills and domestic management practices. Indeed, always-at-home consumers decreased more likely the amount of food waste compared to partial smart workers, demonstrating the influence of time availability on better food habit planning and programming. However, the question about the future is obligatory: What will happen when the pandemic period ends? Of course, several efforts in education, food supply chain management, national and international policies, research and food consumption habits must continue to pursue the SDGs. The authors are convinced that one of the biggest challenges to reduce food waste at home, since it is not possible to donate leftovers to charities, is to educate people from an early age, for example introducing update lessons on domestic economics. It is crucial to learn today to not waste tomorrow, as well as to educate future generations on food waste hidden burdens. In a world ravaged by the COVID-19 pandemic, it is important to understand the potential for food waste reduction through local culture, education and consumer behavior. Nowadays, time is one of the most critical variables to reach the goal of sustainability. CRediT authorship contribution statement Vera Amicarelli: Conceptualization, Methodology, Data Curation, Writing – review&editing, Supervision, Giovanni Lagioia: Conceptualization, Supervision, Stefania Sampietro: Methodology, Software, Formal analysis, Christian Bux: Conceptualization, Methodology, Data Curation, Software, Writing – original draft, Writing – review&editing. Vera Amicarelli, Ph.D. in Commodity Science, is Associate Professor at Department of Economics, Management and Business Law (DEMDI) at the University of Bari Aldo Moro, Italy. She teaches Industrial Ecology, Quality theory and technique and Resource and waste management. She is author of more than 80 papers published on scientific journals and academic volumes. Her current research interests are focused on Material Flow Analysis, Environmental Indicators and Circular Economy. Her main academic activities are related to Erasmus + exchange program. She is in the working group for DEMDI course of study qualification. Since 2018 she is member of ICESP (Italian Circular Economy Stakeholders Platform) and form 1998 of Italian Commodity Science Academy (AISME). Christian Bux is Ph.D. student in Economics and Management at University of Bari Aldo Moro, Department of Economics, Management and Business Law. His main field of interest is the relationship between natural resources, commodity production/consumption and environmental management systems. He is author of more than ten papers published on scientific journals and academic volumes. His doctoral research project regards food loss and waste management, Circular Economy and Material Flow Analysis. Christian Bux is corresponding author (christian.bux@uniba.it). Giovanni Lagioia, Ph.D. in Commodity Science, is Full Professor of Commodity Science, Commodity Science of Natural Resources and Environmental Certification Systems at the Department of Economics, Management and Business Law of the University of Bari. He is author of more than 150 papers published on the main scientific journals and academic volumes. His principal field of study regards impacts of commodity production and consumption and environmental management systems. Since 2018 he is Director of the Department of Economics, Management and Business Law, University of Bari Aldo Moro, Italy. Stefania Sampietro is M.Sc Candidate at the University of Padova, Department of Statistical Sciences, in the field of demography and childlessness. She is interested in social statistics and statistics applied to marketing, with regards to event history analysis and its holistic approach (sequence analysis). ==== Refs References 1 Gustavsson J. Cederberg C. Sonesson U. Van Otterdijk R. Meybeck A. Global food losses and food waste. Extent, causes and prevention 2011 Food and Agriculture Organization of the United Nations (FAO) Rome, Italy 2 Corrado S. Caldeira C. Eriksson M. Hanssen O.J. Hauser H.-W. van Holsteijn F. Liu G. Ostergren K. 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Threat of COVID-19 and emotion- al state during quarantine: positive and negative affect as mediators in a cross-sectional study of the Spanish population PloS One 15 2020 e0235305 99 European Commission Enabling citizens to act on climate change, for sustainable development and environmental protection through education, citizen science, observation initiative, and civic engagement 2020 100 Quested T.E. Palmer G. Moreno L.C. McDermott C. Schumacher K. Comparing diaries and waste compositional analysis for measuring food waste in the home J Clean Prod 262 2020 121263 101 United Nations Environment Programme Food waste index report 2021 2021 United Nations Environment Programme Publications Nairobi, Kenya

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Socioecon Plann Sci. 2022 Aug 11; 82:101095

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Socioecon Plann Sci

10.1016/j.seps.2021.101095

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==== Front J Thorac Cardiovasc Surg J Thorac Cardiovasc Surg The Journal of Thoracic and Cardiovascular Surgery 0022-5223 1097-685X Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery S0022-5223(20)32566-6 10.1016/j.jtcvs.2020.09.003 Commentary Commentary: The changing role of the Thoracic Surgery Residents Association over time Suzuki Yota MD Okereke Ikenna MD ∗ Division of Cardiothoracic Surgery, University of Texas Medical Branch, Galveston, Tex ∗ Address for reprints: Ikenna Okereke, MD, Division of Cardiothoracic Surgery, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555. 4 9 2020 9 2021 4 9 2020 162 3 929930 30 8 2020 30 8 2020 1 9 2020 © 2020 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery. 2020 The American Association for Thoracic Surgery Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmc Yota Suzuki, MD, and Ikenna Okereke, MD Central Message The Thoracic Surgery Residents Association has played a major role in providing guidance to trainees since its inception in 1997. It has adapted its function as training has changed over time. See Article page 917. The Thoracic Surgery Residents Association (TSRA) is a robust and active organization led by trainees. As described by the current members of the TSRA in their article,1 the TSRA was established in 1997 with a mission of representing the interests and needs of resident physicians in thoracic surgery specialty. The role and activity of the TSRA has expanded over the years, in concert with the changing nature of thoracic training programs. The introduction of integrated thoracic programs has had a significant influence on the training structure for thoracic surgeons. The age and level of surgical experience of trainees has decreased significantly,2 and the gap between faculty and junior thoracic residents has widened. A communication from the TSRA sent to a postgraduate year 6 through 8 in 1997 would likely focus on very different ideas than an e-mail message sent to a postgraduate year 1 during 2020. The authors address the role of the TSRA in reducing this gap and acclimating young trainees to become better able to succeed during their training. TSRA offers online publications targeting young trainees, mentorship by senior residents at multiple institutions, and a variety of social media podcasts and programming. Although there has been a high level of satisfaction expressed by integrated program residents with their programs,3 supporting their training with help from organizations like the TSRA will maximize the benefit of training. In addition, the ongoing pandemic has shown that the use of virtual conferencing will play a pivotal role in training over the next decade. The TSRA has responded by scheduling multiple virtual meetings this year. To assist students who are applying to thoracic surgery training programs, the TSRA is planning meet-and-greet sessions to answer questions applicants may have about the process. Given that applicants at institutions without training programs will not be able to do away rotations this year, the efforts by the TSRA will be important to give those applicants a fair chance during the match process. It has been shown that using virtual means to correspond with trainees during the pandemic can be effective.4 Sharing the knowledge, experience, and mindset of members of the TSRA will be helpful for these applicants and current trainees. Providing an environment for bidirectional communication is important and among the best attributes of the TSRA. Although many organizations provide advice to students and residents, having guidance from a group of similar-aged, current trainees allows for a different perspective and level of mentorship. The TSRA has accomplished significant achievements since 1997, and has been able to adapt as the paradigm of thoracic surgery training has shifted during the past 2 decades. Continuing to adapt will be important for the organization over the next several decades. Disclosures: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. ==== Refs References 1 Brescia A.A. Lou X. Louis C. Blitzer D. Coyan G.N. Han J.J. The Thoracic Surgery Residents Association: past contributions, current efforts, and future directions J Thorac Cardiovasc Surg 162 2021 917 927.e5 33051070 2 Zhu Y. Goldstone A.B. Woo Y.J. Integrated thoracic surgery residency: current status and future evolution Semin Thorac Cardiovasc Surg 31 2019 345 349 30954666 3 Tchantchaleishvili V. Lapar D.J. Stephens E.H. Berfield K.S. Odell D.D. Denino W.F. Current integrated cardiothoracic surgery residents: a Thoracic Surgery Residents Association survey Ann Thorac Surg 99 2015 1040 1047 25624055 4 Monday L.M. Gaynier A. Berschback M. Gelovani D. Kwon H.Y. Ilyas S. Outcomes of an online virtual boot camp to prepare fourth-year medical students for a successful transition to internship Cureus 12 2020 e8558 32670695

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J Thorac Cardiovasc Surg. 2021 Sep 4; 162(3):929-930

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J Thorac Cardiovasc Surg

10.1016/j.jtcvs.2020.09.003

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==== Front Mar Pollut Bull Mar Pollut Bull Marine Pollution Bulletin 0025-326X 1879-3363 Elsevier Ltd. S0025-326X(21)00497-5 10.1016/j.marpolbul.2021.112463 112463 Research Article Impact of the COVID-19 crisis: Analysis of the fishing and shellfishing sectors performance in Galicia (Spain) Fernández-González Raquel a⁎ Pérez-Pérez Marcos I. a Pérez-Vas Raisa b a Department of Applied Economics, ERENEA-ECOBAS, University of Vigo, Lagoas-Marcosende s/n, 36310 Vigo, Spain, b Departament of Finance and Accounting, Intellectual capital and internacional company-ECOBAS, University of Vigo, Lagoas-Marcosende s/n, 36310 Vigo, Spain, ⁎ Corresponding author at: Lagoas-Marcosende s/n, 36310 Vigo, Spain. 26 5 2021 8 2021 26 5 2021 169 112463112463 30 1 2021 30 4 2021 4 5 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The COVID-19 crisis has had consequences in every area of the Spanish economy. The fisheries and shellfishing sectors in Galicia have been significantly affected due to the measures taken to curb the pandemic. In particular, the closure of the HORECA channel and the confinement of the population have adversely affected the production of fresh fish and shellfish. In this study, a three-stage analysis of the management of the pandemic in Spain has been carried out (confinement, “new normality” and closure of the HORECA channel). The direct and indirect effects of the pandemic have been considered, as well as other factors independent of it, which usually influence production. The results show a decrease in catches, revenue and average price (euros/kg) at first sale of Galician fish and shellfish products over the three study periods, with an incidence level that varies between phases, species, fleet segments and sectors. Keywords COVID-19 Fishing Shellfishing Galicia Spain ==== Body pmc1 Introduction The Spanish economy has been strongly affected by the COVID-19 crisis. The impact of coronavirus disease 2019 has gone beyond the health field to the economic and social sphere, given the measures adopted by the central and regional governments to curb the pandemic (Pak et al., 2020). These measures have resulted in the restriction of people movements and the paralysis of a large part of economic activities (López and Rodó, 2020; Royo, 2020). As a result of the temporary cessation of non-essential activities in the Spanish economy, the European Central Bank forecasts negative GDP growth of −11% for this country in 2020 (European Commission, and Directorate-General for Economic and Financial Affairs, 2020). The adoption of these measures responds to the application of Article 10 of Royal Decree 463/2020 under the provisions of Organic Law 4/1981, which considers health crises as a justified cause for declaring a state of alarm (Henríquez et al., 2020). Thus, in Spain, since March 14, 2020, economic activity was suspended except for those sectors providing security services and performing functions of “supplying the population and the essential services themselves” (Real Decreto 463/2020, 2020). The state of alarm situation lasted for three months, until the risk of expansion of the pandemic was minimized (Codagnone et al., 2020). Its termination was decided by each of the Spanish regions to which the corresponding competences were transferred. In the case of the region of Galicia, the regional government ordered the termination of the State of Alarm on June 15, 2020 (Orden SND/520/202, 2020). After a period without restrictions both for the mobility of the population and for the performance of economic activities, the worsening of the health situation due to the COVID-19 led to the declaration of a second state of alarm in Spain. In the case of the Galician region, the activities considered as non-essential suffered a discriminated paralysis from November 7 to December 3, 2020 (Rodríguez-Antón and Alonso-Almeida, 2020). The Galician fishing and shellfishing sectors were legally considered essential activities by the central government, so they were authorized to maintain their activity without restrictions during the two periods of application of the state of alarm. However, given the reduction in sales, part of the Galician fishing fleet, especially the small-scale segment, decided to limit its activity, while shellfishing activities were practically paralysed in Galicia. It is important to point out that the Galician fishing and shellfishing sectors have great importance in the Galician economy, much more so than in other Spanish coastal regions (Garza-Gil et al., 2017; Piñeiro-Antelo et al., 2019; Surís-Regueiro and Santiago, 2018). In 2016, both industries directly generate 16,559 full-time jobs and €525 million of GVA (Galician Institute of Statistics database (IGE), 2020). Given the importance of the fishing and shellfishing sectors in Galicia, numerous studies have analyzed the problems that have affected this industry. Some of the most relevant issues related to the performance of this sector are poaching (Ballesteros and Rodríguez-Rodríguez, 2019; Ballesteros et al., 2020), oil spills (Caballero-Miguez and Fernández-González, 2015; Domínguez and Loureiro, 2013; Garza-Gil et al., 2006; García Negro et al., 2009; Surís-Regueiro et al., 2007) and conflicts between fishing and other activities (Fernández et al., 2016; Fernández-González et al., 2020; Perez de Oliveira, 2013; Pita and Freire, 2016). However, studies on the consequences of coronavirus disease 2019 are scarce. The aim of this paper is to analyse the consequences of the economic crisis derived from the COVID-19 in the Galician fishing and shellfishing sectors, establishing three periods of study. These three temporal phases analyzed correspond to the first state of alarm, which involves the confinement of the population and the paralysation of the non-basic activities (March 14th - June 15th), the period of “new normality” without restrictions to any of the Spanish productive sectors (June 16th - November 6th) and, finally, a period of reduced population movement and closure of the HORECA channel in the municipalities with a higher incidence of COVID-19, and limitation of capacity and opening hours in the remaining municipalities (November 7th - December 3rd). Moreover, fishery production is subject to high variability caused by a multiplicity of factors (biological, climatic or institutional) that cannot be ignored in the evaluation of the effects of COVID-19. For this reason, these factors have been included in the analysis. In addition, special consideration will be given to the evolution of the HORECA sector, since it is one of the main distribution channels of the fishing and shellfishing production in Galicia (Rodríguez and Ramudo, 2015; Santiago and Surís-Regueiro, 2018). 2 Galician fishing and shellfishing sector Galicia is one of the main maritime regions in Spain, which is also the most important fish and shellfish producing country in the EU (Claret et al., 2012; Garza-Gil et al., 2017; Vázquez-Rowe et al., 2011). Within the group of European regions that are highly dependent on fishing, Galicia occupies the first position (Salz and Macfadyen, 2007; Surís-Regueiro and Santiago, 2014). The Spanish fishing fleet landed 908,162 tons in 2017, which represented 16.73% of the EU total, and 304,785 tons of the Spanish total landings corresponded to Galicia (European Commission, 2020b). The Galician fishing fleet is the most important regional fleet in the EU (8.3% of the total European gross tonnage [GT] and 38.7% of the total Spanish GT), and it operates in national, European, international, and some non-EU countries waters (Afundación, 2019). In 2020, according to the fishing vessels registration of the Galician regional Government (Xunta de Galicia, 2020a), the fleet consists of 4313 vessels, with a total capacity of 129,009 GT and 255,682 kW (kW). The classification of the Galician fishing fleet distinguishes three major groups of vessels according to their harvesting zone: small-scale fishing fleet (Spanish waters of the Cantabrian-Northwest fishing ground), offshore fishing fleet (non-Spanish EU waters), and large-scale fishing fleet (international waters and waters of third countries engaged with the EU in fishing agreements) (Ministerio de Agricultura, 2020a). The small-scale fishing fleet is the most numerous with 96% of the vessels. However, it only represents 33% of the total capacity of the Galician fleet in terms of GT. The reason for this is the predominance of small-scale vessels, especially in the minor gears modality (3841 vessels). Other fishing methods used in the small-scale fishing fleet are purse seining (152 vessels), bottom trawling (54 vessels), surface longlining (52 vessels), bottom longlining (20 vessels) and gillnetting (24 vessels), with an estimated number of crew members of 8798 (Xunta de Galicia, 2020a). The offshore fishing fleet consists of 71 vessels, representing 15.7% of the total tonnage, and it includes 48 bottom longliners and 23 trawlers. This fleet operates, mostly, in the NEAFC Regulatory Area, specifically in the Grand Sole fishing grounds. The estimated total employment is 861 people. Finally, the large-scale fishing fleet is composed of 99 vessels that accumulate 51.7% of the total GT owing to their large size. This fleet operates in fishing grounds spread around the world, which include the waters of Norway (2 cod trawlers), the NAFO area (15 freezer trawlers), the Southwest Atlantic (Argentina and the Falkland Islands) and Northwest Africa (Morocco, Mauritania, Senegal, Cape Verde and Guinea Bissau) (13 freezer trawlers). There are also 68 surface longliners specialized in catching swordfish and a freezer purse seiner catching tuna, all of them operating both in the Atlantic and in various areas of the Indian and the Pacific Oceans. The large-scale fishing fleet employs an estimated number of crew members of 1058 people (Xunta de Galicia, 2020a). European hake (Merluccius merluccius, Merlucciidae) is by far the main species landed, in terms of value, by the Galician fleet. This fact makes Spain the largest market in the world for this species (Amigo-Dobaño and Garza-Gil, 2011). There exist 65 fish markets located in the different fishing ports of the Galician coast, where first sale of fish and shellfish takes place (Afundación, 2019). Furthermore, the freezing, canning and marketing subsectors complete the fish and seafood production chain in Galicia (Sobrino Heredia and Oanta, 2019). 3 Methodology 3.1 Phases description The study of the evolution of catches and revenue in the Galician fishing and shellfishing sector during the COVID-19 pandemic has been divided into three phases. The first phase (March 14–June 15, 2020) began with the declaration of the first state of alarm (Real Decreto 463/2020, 2020), in which the population is confined and non-essential economic activities are paralysed. Fishing and shellfishing were two of the activities considered essential and, therefore, authorized by the Spanish Central Government to continue their activity (Real Decreto 463/2020, 2020). However, the HORECA sector had to cease its business, blocking one of the most important distribution channels in the sector (EUMOFA, 2020b). This was a damage to the fishing and shellfishing industry, even more serious in the latter case, since the shellfish sector decided to almost completely paralyse its activity because its main commercial channel was not active (Consellería do mar, 2020a). The second phase (June 16–November 6, 2020) was characterized by an improvement in the epidemiological situation in Spain, allowing the central government to end the state of alarm. In this way, a scenario of “new normality” was established, and all the productive sectors could restart their activity (Orden SND/520/202, 2020; Resolución del DOG n° 115 de 2020/6/13 Diario Oficial de Galicia, 2020). This measure resulted in the reopening of the HORECA channel, allowing the revitalisation of shellfish farming and the improvement of income in the fisheries sector. However, the start of a second wave of the pandemic resulted in the declaration of a new state of alarm on 25 October, which was extended until May 2021 (Real Decreto 926/2020, 2020; Real Decreto 956/2020, 2020). This measure ended the situation of “new normality” that characterized this second phase. During the third phase (November 7–December 3, 2020), the Galician regional government, using the powers granted by the central government (Real Decreto 926/2020, 2020), adapted the national declaration of the state of alarm to its territory (Decreto 178/2020, 2020; Decreto 179/2020, 2020). The fishing and shellfishing sectors were able to continue their activity because they were considered as key industries for food supply (Orden del DOG n° 223-Bis, 2020). In contrast, the discriminated closure of the HORECA sector was declared and its activity was ceased in 60 municipalities with a high incidence of COVID-19 (the main cities and 53 other municipalities, representing 60% of the Galician population). The stoppage of activity in this sector lasted approximately one month (November 7–December 3, 2020) (Decreto 202/2020, 2020). This second closure of the HORECA channel caused the demand for fish and shellfish to fall once again. 3.2 Data The data used in this study were obtained from the fish and shellfish database of the Galician regional government. This database, Pesca de Galicia, publishes daily data on the catches, revenue and average price of first sale of a total of 286 species in the 65 fish markets of Galicia. For this analysis, all the species of fish or shellfish from all the Galician fish markets were selected (Xunta de Galicia, 2020c). Once the three study phases had been established, between 2015 and 2020, the average volume of the main species landed in all the fish markets of Galicia was determined for the six-year period. Then, the top ten species of fish and shellfish caught between 2015 and 2020 were selected for a comparison between production in 2020 and the average production in 2015–2019. For each phase, catches, revenue and average price of first sale were analyzed for the species in 2020 and for the average 2015–2019. In addition, the variation percentages between the two periods were calculated for each of these magnitudes. On the other hand, another analysis of the fish and shellfish species in the three phases of the pandemic has been carried out. In this case, according to their average price per kg, the species have been classified by quartiles. Both the time range (2020–2015) and the variables (catches, revenue and average price of first sale) are the same as in the previous analysis described. 4 Results 4.1 First phase (March 14th – June 15th) During the first state of alarm, the fish and shellfish landings decreased its volume by 19.49%, its first sale revenue by 26.63% and its first sale average price by 8.87% compared to the average of the period 2015–2019. In view of this situation, the Galician regional government estimated that the economic losses during this phase were: €25 million at first sale level, about €60 million for the lack of activity, and more than €500 million for the whole maritime industry (EUMOFA, 2020a). The economic impact of the pandemic on Galician fishing and shellfishing sectors was not even mitigated by the large drop in the spot price of crude oil, which directly affects the price of marine fuel. Until September 2020, its price was down 30% compared with the same period of 2019 (EUMOFA, 2020b). In this phase, the HORECA channel was closed, negatively affecting the commercialisation of fish and shellfish species. It is important to point out that the damage was even more severe in the higher value products, which are preferably marketed by this channel. Therefore, the demand for this type of products decreased during those three months. In contrast, the demand for more affordable products, traditionally with a higher percentage of sales for domestic consumption, suffered a smaller decrease (Revista Mar 600, 2020). These products are agglutinated in quartile two and three, while those in the last quartile are of very low quality and are normally not destined for domestic consumption or the HORECA channel, but for industrial uses. Another consequence of the closure of HORECA was the temporary reduction of activity in the fisheries and shellfish sectors. In order to alleviate the negative consequences of the temporary business slowdown, the central government enabled wage indemnity for producers with a reduction of 75% or more of their revenue. In this first phase, 3266 applications were submitted in Galicia, distributed as follows: Vilagarcía (1422), Vigo (967) and A Coruña (877). Shellfishing sector was the most affected, with 2454 applications, almost tripling the number of requests for fishing sector (Revista Mar 603, 2020). 4.1.1 Fishing sector Regarding the impact of COVID-19 on fishing, small-scale and offshore fishing fleets have performed worse than large-scale fishing fleet (EUMOFA, 2020b). The explanation for this lies in the fact that small-scale and deep-sea vessels land fresh fish; whereas large-scale vessels land frozen fish that does not need to be marketed immediately. This characteristic of the large-scale fishing fleet has benefited it since during the first state of alarm in Spain, the production of frozen fish increased by 24% and its revenue by 28% compared to 2019 (Industria Conservera 140, 2020). In the case of small-scale fishing, the activity has been reduced, trying to adapt to the decrease in demand (European Commission, 2020a). As a result, the drop in prices in the ports with small-scale fishing fleets was pronounced (Revista Mar 600, 2020). The main ten fish species caught by the Galician fleet at this first stage are shown in Table 1 . Eight of them decreased both in catch volume and in revenue. The most pronounced declines are those of the Atlantic chub mackerel (Scomber colias, Scombridae) and the bogue (Boops boops, Sparidae). This can be largely attributed to the biology of these species, which were less abundant this year (Xunta de Galicia, 2020b). The abundance and catches of Atlantic chub mackerel have increased in recent years, but with oscillations (Villamor et al., 2017).Table 1 Catches, revenue and average price (euros/kilogram) of first sale of fish catches in Galicia. First phase (March 14th – June 15th). Table 1 March 14th - June 15th (2020) March 14th - June 15th (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/kg) Average catch (Kg) (2019–2015) Average revenue (€) (2019–2015) Average price (€/kg) Catch Revenue Average price (€/kg) Most caught species European hake (Merluccius merluccius, Merlucciidae) 7,327,046.84 21,899,286.54 2.99 8,221,440.18 30,014,516.57 3.65 −10.88% −27.04% −18.13% Atlantic mackerel (Scomber scombrus, Scombridae) 8,004,830.69 8,297,773.51 1.04 7,344,591.32 7,408,349.57 1.01 8.99% 12.01% 2.77% Blue whiting (Micromesistius poutassou, Gadidae) 5,954,970.67 3,038,911.18 0.51 6,023,670.76 4,052,181.06 0.67 −1.14% −25.01% −24.14% Atlantic horse mackerel (Trachurus trachurus, Carangidae) 4,233,730.19 4,157,465.66 0.98 5,191,563.14 4,796,489.57 0.92 −18.45% −13.32% 6.29% Atlantic chub mackerel (Scomber colias, Scombridae) 615,647.73 374,626.05 0.61 4,283,548.34 2,767,285.53 0.65 −85.63% −86.46% −5.81% Bogue (Boops boops, Sparidae) 777,534.20 349,836.25 0.45 2,461,041.98 1,061,065.67 0.43 −68.41% −67.03% 4.36% Blackbellied angler (Lophius budegassa, Lophiidae) 2,061,474.99 7,908,002.53 3.84 2,128,112.78 10,699,588.25 5.03 −3.13% −26.09% −23.70% Megrim (Lepidorhombus whiffiagonis, Scophthalmidae) 1,664,974.67 6,458,852.13 3.88 2,035,911.01 7,675,318.63 3.77 −18.22% −15.85% 2.90% European pilchard (Sardina pilchardus, Clupeidae) 1,607,125.99 2,164,391.35 1.35 815,365.40 1,068,164.82 1.31 97.11% 102.63% 2.80% Atlantic pomfret (Brama brama, Bramidae) 579,678.50 1,355,297.64 2.34 619,441.52 1,508,534.39 2.44 −6.42% −10.16% −4.00% Rest of Fish 3,496,048.41 12,340,089.54 3.53 5,228,085.33 17,401,666.33 3.33 −33.13% −29.09% 6.05% Total Fish 36,323,062.88 68,344,532.38 3.50 44,352,771.75 88,453,160.39 4.25 −18.10% −22.73% −17.67% Quartiles Q1 854,400.82 6,680,099.76 8.63 1,545,207.27 11,474,597.72 10.12 −44.71% −41.78% −14.68% Q2 12,517,298.14 40,539,378.22 3.08 12,946,425.34 49,616,677.57 3.83 −3.31% −18.29% −19.56% Q3 3,150,670.26 4,775,008.76 1.55 3,352,684.59 6,165,862.53 2.08 −6.03% −22.56% −25.53% Q4 19,800,693.66 16,350,045.64 0.56 26,508,454.54 21,196,022.57 0.94 −25.30% −22.86% −40.29% On the contrary, European pilchard (Sardina pilchardus, Clupeidae) considerably increased the volume of catches, because the Spanish-Portuguese shared quota rised by 76.9% with respect to 2019 (Resolución de 24 de abril de 2020, 2020; Resolución de 30 de junio de 2020, 2020). This increment was possible by a slight recovery in the European pilchard biomass detected by ICES (ICES (International Council for the Exploration), 2020b). As far as Spain is concerned, this means that it could increase its European pilchard catches to 6400 tons (Ministerio de Agricultura, 2020b). Another species that also increases its catch volume, although to a lesser extent, is Atlantic mackerel (Scomber scombrus, Scombridae). The reason for this is the 71% increase in the fishing quota compared to 2019, as TACs and swaps were increased (European Commission, 2020b). Although in this phase there was a slight increase in the volume of catches in relation to the previous campaign, the heavy increase in catches of this species was postponed until the third phase of this study since, in view of the fall in market prices, shipowners reduced the daily catch limit until the Christmas season (Revista Mar 601, 2020). 4.1.2 Shellfishing sector The shellfish catches suffered a much greater reduction than the fish catches during confinement. The explanation for this is that the HORECA channel, which had stopped its activity, is the main sales channel for shellfish products. As a result of the severe drop in demand, the prices of shellfishing products fell by 96% in the first month of the state of alarm (Consellería do mar, 2020b). Faced with this scenario, most shellfish producers chose not to continue with their activity and their various associations proposed to the government to declare the obligatory cessation of their activity in order to benefit from government COVID-19 subsidies (Revista Mar 601, 2020). The low level of shellfish activity meant that prices in the first two quartiles remained constant because supply adjusted to existing demand, which was reduced by the closure of the HORECA channel. However, in the third quartile of shellfish products, the average price per kg increases. This is because this quartile includes species destined for the canning industry whose demand did not decrease. In fact, until June 2020, the production of canned products in Spain increased by 15% and its turnover by 16% compared to 2019 (Industria Conservera 140, 2020). In the case of quartile four, the weak demand for these lower value products did not allow that drop in production were offset by significant price increases. At this phase, only one of the ten main shellfish species increased in catch volume and revenue (Table 2 ). This species is the northern shortfin squid (Illex illecebrosus, Ommastrephidae), which is currently experiencing high variability in its abundance. The distribution and abundance of cephalopods in Galician waters have been described as strongly influenced by oceanographic phenomena, in particular the upwelling (Rocha et al., 1999). The remaining nine species suffered strong declines with respect to the 2015–2019 period, due to both the paralysis of the shellfishing sector after the HORECA channel closure and other biophysical factors that explain the differences between species.Table 2 Catches, revenue and average price (euros/kilogram) of first sale of shellfish catches in Galicia. First phase (March 14th – June 15th). Table 2 March 14th - June 15th (2020) March 14th - June 15th (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/Kg) Average catch (Kg) Average revenue (€) Average price (€/Kg) Catch Revenue Average price (€/Kg) Most caught species Japanese carpet Shell (Ruditapes philippinarym, Veneridae) 371,956.86 3,383,475.13 9.10 589,408.86 5,244,666.84 8.68 −36.89% −35.49% 4.79% Common octopus (Octopus vulgaris, Octopodidae) 277,059.28 1,989,236.87 7.18 397,531.11 2,915,240.47 7.71 −30.31% −31.76% −6.85% Common cockle (Cerastoderma edule, Cardiidae) 103,013.79 821,907.61 7.98 254,288.09 1,409,532.54 5.71 −59.49% −41.69% 39.66% Northern shortfin squid (Illex illecebrosus, Ommastrephidae) 240,037.88 761,130.44 3.17 214,884.97 485,861.00 2.41 11.71% 56.66% 31.54% Sea urchin (Paracentrotus lividus, Parechinidae) 146,116.05 930,469.49 6.37 214,221.91 1,129,396.13 5.37 −31.79% −17.61% 18.71% Common cuttlefish (Sepia officinalis, Sepiidae) 170,305.32 1,253,166.22 7.36 189,112.53 1,229,026.97 6.60 −9.94% 1.96% 11.48% Lesser Flying Squid (Todaropsis eblanae, Ommastrephidae) 80,037.65 235,981.14 2.95 192,316.60 423,786.56 2.39 −58.38% −44.32% 23.43% Curled octopus (Eledone cirrhosa, Octopodidae) 82,795.52 197,517.75 2.39 173,962.93 283,516.38 1.86 −52.41% −30.33% 28.77% Pullet carpet Shell (Venerupis pullastra, Veneridae) 53,328.45 850,826.44 15.95 162,183.07 2,392,862.17 14.74 −67.12% −64.44% 8.18% Razor Shell (Ensis magnus, Pharidae) 75,624.05 485,619.29 6.42 135,896.87 11,09,149.58 8.15 −44.35% −56.22% −21.21% Rest of Shellfish 636,161.67 3,564,674.39 10.49 1,014,558.16 7,798,862.14 10.82 −37.30% −54.29% −3.08% Total Shellfish 2,236,436.52 14,474,004.77 9.92 3,538,365.09 24,421,900.79 10.14 −36.79% −40.73% −2.17% Quartiles Q1 146,823.70 2,840,478.76 28.02 343,910.63 7,109,093.09 28.34 −57.31% −60.04% −1.14% Q2 1,251,199.56 9,805,782.69 7.63 1,802,606.53 14,161,024.82 7.62 −30.59% −30.76% 0.03% Q3 428,872.23 1,368,803.00 4.08 606,542.91 2,157,057.48 3.53 −29.29% −36.54% 15.59% Q4 409,541.03 458,940.32 1.08 785,305.02 994,725.41 1.06 −47.85% −53.86% 2.72% The meteorological factor is one of those biophysical factors that regularly and unevenly affect shellfish production. In particular, rainfall causes salinity fluctuations that alters the vital parameters and distribution of bivalve molluscs (Pourmozaffar et al., 2019). The heavy rainfall in the winter of 2020 produced a significant drop of the water salinity level that mainly affected bivalves, especially pullet carpet shell (Venerupis pullastra, Veneridae) and common cockle (Cerastoderma edule, Cardiidae). For this reason, the mortality rate in the main common cockle bank of Galicia increased to 67% (La Voz de Galicia, 2020a). The razor shell (Ensis magnus, Pharidae) and the Japanese carpet shell (Ruditapes philippinarym, Veneridae), more resistant to this type of change, decreased their production to a lesser extent. 4.2 Second phase (June 16th - November 6th) During the “new normality” phase, total fish and shellfish landings fell by 16.15% in volume and 13.99% in first sales revenue with respect to the average for 2015–2019. On the other hand, the average first sale price increased by 2.57%. The opening of the HORECA channel during this period had a positive effect on the fisheries and shellfish sectors in Galicia. The percentages of variation in the catches and revenue of the higher priced species, included in the first quartiles of fish and shellfish, increased. At the same time, there is a decrease in average prices per kg. This contrasts with the reduction in catches and revenue in most other quartiles of fish and shellfish products. Even so, the effect of the reopening of the hospitality industry was less than expected as a result of the partial capacity restrictions on catering establishments and the lower level of attendance. 4.2.1 Fishing sector As previously mentioned, European pilchard catches grew in 2020 owing to the increase in the joint quota with Portugal. Despite the slight increase in catches in this second period, there is a notable drop in turnover and an even greater decrease in the average price per kg. compared to the 2015–2019 period (Table 3 ). The explanation for this is that the COVID-19 forced to cancel all the saint festivities associated with the highest peak in annual European pilchard consumption (EUMOFA, 2020a).Table 3 Catches, revenue and average price (euros/kilogram) of first sale of fish catches in Galicia. Second phase (June 16th – November 6th). Table 3 June 16th - November 6th (2020) June 16th - November 6th (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/Kg) Average catch (Kg) Average revenue (€) Average price (€/Kg) Catch Revenue Average price (€/Kg) Most caught species Atlantic horse mackerel (Trachurus trachurus, Carangidae) 2,222,3012.79 16,653,392.82 0.75 18,539,810.94 12,861,098.25 0.71 19.87% 29.49% 5.63% Atlantic chub mackerel (Scomber colias, Scombridae) 3,339,184.98 2,033,513.30 0.61 20,351,815.04 8,613,222.28 0.47 −83.59% −76.39% 29.79% European hake (Merluccius merluccius, Merlucciidae) 9,293,866.69 35,777,738.72 3.85 11,938,106.15 50,394,891.60 4.22 −22.15% −29.01% −8.77% Blue whiting (Micromesistius poutassou, Gadidae) 9,299,725.64 5,815,230.38 0.63 8,249,172.53 5,764,834.43 0.72 12.74% 0.87% −12.50% Blackbellied angler (Lophius budegassa, Lophiidae) 2,749,474.19 14,046,306.51 5.11 2,822,849.78 16,168,480.99 5.73 −2.60% −13.13% −10.82% Megrim (Lepidorhombus whiffiagonis, Scophthalmidae) 2,551,287.55 9,570,691.75 3.75 2,748,135.25 11,360,593.93 4.13 −7.16% −15.76% −9.20% European pilchard (Sardina pilchardus, Clupeidae) 2,378,604.69 3,651,845.03 1.54 2,326,131.56 4,636,253.89 2.03 2.26% −21.23% −24.14% European anchovy (Engraulis encrasicolus, Engraulidae) 6,233,031.35 6,850,973.08 1.10 1,494,005.71 2,307,075.59 1.71 317.20% 196.95% −35.67% Bogue (Boops boops, Sparidae) 1,082,768.50 388,469.16 0.36 2,096,218.75 758,174.87 0.34 −48.35% −48.76% 5.88% Albacore (Thunnus alalunga, Scombridae) 1,662,135.40 6,309,446.42 3.80 1,863,844.76 7,521,782.13 4.06 −10.82% −16.12% −6.40% Rest of Fish 7,548,578.18 25,945,174.00 4.22 8,291,267.96 26,272,221.53 4.52 −8.96% −1.24% −6.64% Total Fish 68,361,669.96 127,042,781.17 4.09 80,721,358.43 146,658,629.50 4.37 −15.31% −13.38% −6.41% Quartiles Q1 4,498,743.93 28,815,400.67 10.49 3,673,060.23 26,058,063.05 10.85 22.48% 10.58% −3.31% Q2 15,521,392.83 57,251,387.19 3.42 18,362,196.70 76,620,289.80 3.80 −15.47% −25.28% −10.05% Q3 4,823,875.38 7,965,713.18 1.74 6,246,847.30 12,376,169.54 2.07 −22.78% −35.64% −15.66% Q4 43,517,657.82 33,010,280.13 0.80 52,439,254.20 31,604,107.10 0.88 −17.01% 4.45% −8.92% The most striking data from this period is that of the European anchovy (Engraulis encrasicolus, Engraulidae), which triples its capture. This is explained by two main factors. The first one is the biological factor, since its biomass increased by 44% with respect to 2019 (ICES (International Council for the Exploration), 2020a). European anchovy has been characterized as a highly variable species in terms of abundance, with a recovered stock after the Bay of Biscay fishery was closed between 2006 and 2010 (Santos et al., 2013). This species has a very irregular catch history in Galicia, and it is only fished in Galician waters in years when its biomass is high. Otherwise, its capture is restricted to Cantabrian waters (Fernández-González et al., 2019). The second one is a market factor. The decline in demand, caused by the closure of the HORECA channel, resulted in the Cantabrian fishing sector reducing catches to avoid a large drop in the price of the species. While in June 2019 80% of the quota had already been caught, in the same period of 2020 it was reduced to less than 60% (Revista Mar 603, 2020). Since the European anchovy is a species whose migration takes place from the east to the west of the Cantabrian Sea, this meant that the Galician fleet was able to catch more anchovies. Moreover, the large increase in European anchovy catches in Galicia resulted in a 35% decrease in the average price per kg. at the first sale. Most of the European anchovy production is destined for the canning industry, which requires large specimens. However, the small size of the specimens caught was not valid, in most cases, to supply the national canning industry (Revista Mar 603, 2020). The alternative was to export the surplus catches to Italy and Morocco. But, because of the COVID-19 pandemic, the borders were closed and this was not possible. The increase in the supply on the domestic market brought down the price of this species (EUMOFA, 2020a; La Voz de Galicia, 2020c). There is another species that shows a relative improvement in the tons caught in the second phase of the pandemic. The increase in Atlantic horse mackerel (Trachurus trachurus, Carangidae) catches is due to the approval, by the European Commission, of the increase in fishing quotas for Spain through the quotas retained in 2019. Thus, since August 2020, Spain can fish 7944 tons more Atlantic horse mackerel than those first stipulated for 2020 (Commission implementing regulation (EU) 2020/1155, 2020). 4.2.2 Shellfishing sector Despite the reopening of the hospitality industry in this period, the performance of the shellfish sector is well below that of previous years, which only improves for two species: Japanese carpet shell and northern shortfin squid (Table 4 ). This is because Japanese carpet shell is a species resistant to the salinity variation produced by winter rains and northern shortfin squid is a species with high variability in terms of abundance.Table 4 Catches, revenue and average price (euros/kilogram) of first sale of shellfish catches in Galicia. Second phase (June 16th – November 6th). Table 4 June 16th - November 6th (2020) June 16th - November 6th (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/Kg) Average catch (Kg) Average revenue (€) Average price (€/Kg) Catch Revenue Average price (€/Kg) Most caught species Common cockle (Cerastoderma edule, Cardiidae) 717,386.27 4,964,182.68 6.92 1,287,589.03 8,099,640.57 6.23 −44.28% −38.71% 11.08% Japanese carpet shell (Ruditapes philippinarym, Veneridae) 1,228,108.92 11,915,155.91 9.70 1,183,394.93 10,065,068.33 8.39 3.78% 18.38% 15.61% Common octopus (Octopus vulgaris, Octopodidae) 185,403.35 1,640,931.63 8.85 874,403.85 6,559,347.68 7.58 −78.80% −74.98% 16.75% Pullet carpet shell (Venerupis pullastra, Veneridae) 256,879.36 4,547,399.57 17.70 380,590.43 5,198,414.19 13.93 −32.51% −12.52% 27.06% Razor shell (Ensis magnus, Pharidae) 265,926.15 2,447,935.41 9.21 271,260.16 2,669,099.89 9.81 −1.97% −8.29% −6.12% Lesser Flying squid (Todaropsis eblanae, Ommastrephidae) 30,414.65 89,512.17 2.94 252,633.61 538,815.33 2.55 −87.96% −83.39% 15.29% Banded carpet shell (Venerupis rhomboides, Veneridae) 127,275.15 1,341,544.22 10.54 193,530.50 1,706,862.00 8.95 −34.24% −21.40% 17.77% Northern shortfin squid (Illex illecebrosus, Ommastrephidae) 175,375.31 580,354.97 3.31 167,826.44 412,248.46 2.62 4.50% 40.78% 26.34% Gooseneck barnacle (Pollicipes pollicipes, Pollicipedidae) 129,869.21 3,913,009.88 30.13 167,442.54 4,127,670.08 24.72 −22.44% −5.20% 21.89% Grooved carpet shell (Ruditapes decussatus, Veneridae) 110,398.94 2,757,366.17 24.98 148,629.69 4,089,765.58 27.98 −25.72% −32.58% −10.72% Rest of Shellfish 932,230.98 7,597,504.87 9.08 1,043,324.04 7,444,504.05 10.48 −10.65% 2.06% −13.36% Total Shellfish 41,59,268.29 41,794,897.48 9.54 5,970,625.24 50,911,436.16 10.59 −30.34% −17.91% −9.92% Quartiles Q1 742,492.00 15,255,185.80 24.31 638,075.69 13,699,519.82 28.80 16.36% 11.36% −15.57% Q2 2,787,796.97 24,871,438.71 9.20 3,815,819.91 32,111,579.90 8.90 −26.94% −22.55% 3.32% Q3 422,299.87 1,475,330.05 4.09 1,041,379.75 4,415,738.85 3.52 −59.45% −66.59% 16.15% Q4 206,679.45 192,942.92 1.03 475,349.89 684,597.58 1.13 −56.52% −71.82% −8.28% Among the species whose records are worsening is the common cockle, whose decrease in production is attributable to three main factors. The first factor is the decrease in quota, which is reduced by 10–7 kg/day for shellfishermen. This decrease is attributable to the low demand for common cockles as a result of the pandemic. Although the largest buyer of this species in 2020 is the canning industry, its purchases are not as plentiful as in previous years, as consumers prefer lower-priced canned foods. The second factor is the closure of the main fish farm for this species because of the high levels of toxin detected. The closure began on September 28, 2020 and continued throughout this second phase (Confraría de Pescadores de Noia, 2020). On the other hand, the effects of the drop in salinity caused by winter rains on common cockle production are prolonged during this phase, as is the case with pullet carpet shell and banded carpet shell, whose production decreases by more than 30%. The decreasing production of common octopus (Octopus vulgaris, Octopodidae) is in line with the general trend of the year and continues throughout the third phase of this analysis. Its causes are still unknown. Among the hypotheses being considered are the variations observed in oceanographic conditions and water temperature, and the increase in the population of Atlantic mackerel and whiting, natural predators of the common octopus (La Voz de Galicia, 2020e). The same applies to the lesser flying squid (Todaropsis eblanae, Ommastrephidae), whose production has decreased throughout the year. 4.3 Third phase (November 7th - December 3rd) In this phase, total fish and shellfish landings fell by 17.67% in volume and 13.54% in revenue at first sale with respect to the average 2015–2019. In addition, the average price at first sale increased by 5.02%. The effect of the new closure of the HORECA channel in the municipalities with a higher incidence of COVID-19 and the limitation of capacity and opening hours in the remaining municipalities, can be clearly seen in the evolution of the first quartile of fishing pro However, in the case of seafood products, the negative effect of the closure of the hospitality industry is less than in the first phase This is because, unlike the first state of alarm, the shellfishing sector did not stop its activity during this phase. The much shorter scheduled duration of this HORECA closure, just before the Christmas period when revenues are raised at the highest levels of the year, encouraged shellfishermen to maintain activity. 4.3.1 Fishing sector During this phase, the effect of the Christmas season, which usually leads to an increase in production and turnover in the fishing sector, was not noticeable. Only two of the top 10 fish species raised their catches, in both cases resulting from an increase in quotas. This benefited both the offshore fishing fleet and the small-scale fishing fleet (Table 5 ). As far as the offshore fishing fleet is concerned, blackbellied angler (Lophius budegassa, Lophiidae) is the species that increased its quota due to swaps with France, Belgium and the Netherlands (Council Regulation (EU) 2020/123, 2020; Ministerio de Agricultura, 2020c). However, the new closure of the hospitality industry reduced the demand for this species, leading to a decrease in price and total revenue. As far as the small-scale fishing fleet is concerned, the Atlantic mackerel doubled its landings in this period following a 41% increase in the Spanish quota for this species. In addition, a quota swap with the Netherlands obtained 1700 tons more of Atlantic mackerel for 2020 (Council Regulation (EU) 2020/123, 2020; Resolución de 8 de abril de 2020, 2020). The initial quota was distributed among the Cantabrian-Northwest regions and, subsequently, the swap was assigned among them according to the same distribution criteria.Table 5 Catches, revenue and average price (euros/kilogram) of first sale of fish catches in Galicia. Third phase (November 7th – December 3rd). Table 5 November 7th - December 3rd (2020) November 7th - December 3rd (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/Kg) Average catch (Kg) Average revenue (€) Average price (€/Kg) Catch Revenue Average price (€/Kg) Most caught species Atlantic horse mackerel (Trachurus trachurus, Carangidae) 1,856,037.90 1,750,123.17 0.94 2,476,671.78 1,731.671.64 0.70 −25.06% 1.07% 34.67% European hake (Merluccius merluccius, Merlucciidae) 1,778,813.72 8,277,949.04 4.65 2,330,544.90 10,220,365.34 4.43 −23.67% −19.01% 4.97% Blue whiting (Micromesistius poutassou, Gadidae) 1,375,768.74 1,267,373.92 0.92 1,425,022.31 1,227,610.10 0.90 −3.46% 3.24% 2.22% Atlantic chub mackerel (Scomber colias, Scombridae) 312,583.96 164,247.48 0.53 815,155.03 389,891.47 0.60 −61.65% −57.87% −12.25% Blackbellied angler (Lophius budegassa, Lophiidae) 698,790.85 3,211,886.03 4.60 631,885.76 3,832,369.31 6.09 10.59% −16.19% −24.47% Megrim (Lepidorhombus whiffiagonis, Scophthalmidae) 415,278.25 1,868,825.67 4.50 458,129.59 2,309,716.57 5.07 −9.35% −19.09% −11.17% Bogue (Boops boops, Sparidae) 386,792.54 147,143.64 0.38 404,955.53 127,298.75 0.33 −4.49% 15.59% 15.85% Atlantic pomfret (Brama brama, Bramidae) 173,140.35 427,781.50 2.47 206,406.83 470,525.97 2.43 −16.12% −9.08% 1.48% Swordfish (Xiphias gladius, Xiphiidae) 130,237.00 799,915.72 6.14 175,342.70 1,003,185.62 5.74 −25.72% −20.26% 7.01% Atlantic mackerel (Scomber scombrus, Scombridae) 227,421.14 293,366.35 1.29 112,044.95 154,253.41 1.40 102.97% 90.18% −7.73% Rest of Fish 1,073,363.48 4,068,970.95 6.55 1,249,561.61 4,494,659.27 8.06 −14.10% −9.47% −18.77% Total Fish 8,428,227.93 22,277,583.47 6.26 10,285,721.00 25,961,547.45 7.64 −18.06% −14.19% −18.03% Quartiles Q1 301,180.07 2,565,651.64 18.32 1,017,679.13 6,880,188.80 22.90 −70.41% −62.71% −20.00% Q2 3,199,176.13 14,655,106.80 3.87 3,075,842.59 13,650,005.65 3.99 4.01% 7.36% −3.15% Q3 649,199.96 1,343,710.53 2.19 611,544.71 1,422,343.04 2.70 6.16% −5.53% −18.84% Q4 4,278,671.77 3,713,114.50 0.80 5,580,654.57 4,009,009.97 0.98 −23.33% −7.38% −18.46% On the contrary, the great decrease in the captures volume of the Atlantic chub mackerel, with respect to the captures average of the 4 previous years, can be explained by the lower abundance of this species for biological causes, since it is a species with a high variability (Xunta de Galicia, 2020b). 4.3.2 Shellfishing sector As far as the shellfishing sector is concerned, the increase in several species is remarkable, the most notable being the northern shortfin squid (Table 6 ). In 2020, the production of this species almost doubled compared to the average value of catches in the previous four years (Xunta de Galicia, 2020c). This phenomenon is linked to the strong variations in the annual abundance of this species, since it is a species very sensitive to environmental changes (NOAA Fisheries, 2020).Table 6 Catches, revenue and average price (euros/kilogram) of first sale of shellfish catches in Galicia. Third phase (November 7th – December 3rd). Table 6 June 16th - November 6th (2020) June 16th - November 6th (2015–2019) Variation in catches. Revenue and average price (2015–2019)/2020 Catch (Kg) Revenue (€) Average price (€/Kg) Average catch (Kg) Average revenue (€) Average price (€/Kg) Catch Revenue Average price (€/Kg) Most caught species Common cockle (Cerastoderma edule, Cardiidae) 211,327.08 1,239,915.83 5.87 581,603.55 2,829,557.92 4.72 −63.66% −56.18% 24.47% Japanese carpet shell (Ruditapes philippinarym, Veneridae) 216,899.86 2,107,647.43 9.72 254,831.63 2,143,014.76 8.36 −14.89% −1.65% 16.27% Common octopus (Octopus vulgaris, Octopodidae) 113,063.54 912,358.14 8.07 224,324.30 1,611,527.80 7.54 −49.60% −43.39% 7.06% Northern shortfin squid (Illex illecebrosus, Ommastrephidae) 335,707.69 673,718.48 2.01 117,001.49 263,600.15 2.35 186.93% 155.58% −14.47% Atlantic spinous spider crab (Maja brachydactyla, Majidae) 261,369.07 2,018,402.07 7.72 157,550.49 1,310,817.26 8.76 65.90% 53.98% −11.87% Lesser Flying Squid (Todaropsis eblanae, Ommastrephidae) 16,556.75 33,657.43 2.03 132,220.42 253,974.87 2.20 −87.48% −86.75% −7.73% Pullet carpet shell (Venerupis pullastra, Veneridae) 74,529.94 1,317,597.29 17.68 99,867.05 1,520,456.95 15.45 −25.37% −13.34% 14.45% Sea urchin (Paracentrotus lividus, Parechinidae) 90,678.70 720,456.05 7.95 77,119.41 508,175.73 7.13 17.58% 41.77% 11.56% Queen scallop (Aequipecten operculares, Pectinidae) 93,393.45 271,860.92 2.91 58,437.22 188,873.69 3.37 59.82% 43.94% −13.65% Banded carpet shell (Venerupis rhomboides, Veneridae) 33,884.80 364,621.90 10.76 56,523.25 499,234.31 9.74 −40.05% −26.96% 10.43% Rest of Shellfish 291,711.56 2,889,745.35 10.99 304,889.35 3,189,668.36 12.53 −4.32% −9.40% −12.34% Total Shellfish 1,739,122.44 12,549,980.89 10.39 2,064,368.16 14,318,901.81 11.51 −15.76% −12.35% −9.70% Quartiles Q1 183,244.79 3,513,113.70 27.60 161,655.62 3,249,000.73 31.12 13.36% 8.13% −11.30% Q2 786,707.57 6,613,656.98 8.44 778,001.52 6,539,335.63 8.81 1.12% 1.14% −4.24% Q3 378,024.44 1,661,308.11 4.35 800,587.51 3,904,228.92 4.54 −52.78% −57.45% −4.34% Q4 391,145.64 761,902.10 1.27 324,123.51 626,336.54 1.55 20.68% 21.64% −18.09% On the other hand, the increase in the production of queen scallop (Aequipecten operculares, Pectinidae) is a consequence of the increase in the permits to exploit this species. This is since the Galician Fisheries Ministry granted temporary permits to king scallop (Pecten maximus, Pectinidae) fishers to collect queen scallop, being common the fishing gear for both species. The king scallop is a high-priced seafood, mainly commercialized by the HORECA channel. Therefore, the closure of the catering business in the pandemic seriously affected its demand, increasing its stock by 20% compared to 2019. In order not to saturate the market, the shellfishers chose to stop catching this seafood and focus their activity on a lower-priced bivalve such as the scallop fishers (La Voz de Galicia, 2020b). The Atlantic spinous spider crab (Maja brachydactyla, Majidae) also experienced a significant increase in production and, to a lesser extent, in revenue, given that the price fell by almost 12%. The increase in the volume captured corresponds to a probable increase in its biomass after the interruption in production during the first state of alarm, which had an effect similar to a fishery closure. On the contrary, the species with a more pronounced decrease in their captures were the lesser flying squid, the octopus and the cockle. The first two species followed the trend maintained throughout the year, whose possible causes were described in phase two. On the other hand, the cockle continued to be affected by the presence of toxins in Galician waters which, as specified above, forced the closure of the most important cockle extraction banks. This closure was extended until December 30th, 2020 (INTECMAR, 2020). In addition, the heavy autumn rains caused a drop in the level of water salinity that raised the cockle mortality rate (La Voz de Galicia, 2020d). On the other hand, the new closure of the hospitality industry had a negative effect on the demand for this species (EUMOFA, 2020b; FAO, 2020). 5 Conclusions The impact of the COVID-19 on the Galician fishing and shellfishing sectors has been significant in the three periods analyzed. The inter-annual comparison carried out has shown appreciable differences in terms of catches, revenue and average price at first sale. Each one of the phases of study (confinement, new normality and closure of the HORECA channel) presents some differentiating characteristics determining a diverse performance for the fishing and shellfishing sectors. Although in the first two stages the shellfishing sector suffers a greater fall in volume and turnover than the fishing sector, in the third period this trend is reversed due to the Christmas season. When the analysis of the COVID-19 impact is focused on the main target species, great differences between them can be noticed. The confluence of direct and indirect effects of the pandemic with other factors explain these variations. Firstly, we can observe the direct effects of the pandemic in the closure of the hospitality industry, which acted as a brake on the marketing of higher value products, and in the border closures, which meant the interruption of exports and imports of all types of seafood products. Second, there exist indirect effects of the pandemic on the preferences of consumers, who bought more frozen or canned products during the confinement period, and on the fishing and shellfishing sector, that adopted strategies such as changing the target species or delaying the time of capture to deal with the economic effects induced by the pandemic (Aldaco et al., 2020). Finally, other factors, completely independent of the pandemic, are observed throughout the studied time series. These aspects, of a biological, oceanographic and meteorological nature, are superimposed to the pandemic direct and indirect effects and determine the differences observed in the behavior of the diverse species and sectors. The highest incidence of COVID-19 is observed in the fishing and shellfishing products included in the quartile with the highest average price, which are the most commercialized through the HORECA channel. Therefore, its closure had a strong impact on these products in the first and third phases of the study. On the other hand, the period of new normality meant a partial recovery of the fishing and shellfishing sectors, but without reaching the same performance of previous years. The fleet segment most affected in the three periods is the small-scale fishing fleet, which captures shellfish (with a higher average price than fish) in much greater proportion than the offshore fishing fleet, which mostly lands fresh fish. On the other hand, the large-scale fishing fleet, which lands exclusively frozen products, has hardly been directly affected by the pandemic. The COVID-19 pandemic has created an unprecedented situation in all areas of the economy. In the specific case of fishing and shellfishing, which are themselves subject to a high variability because of multiple factors, the pandemic introduces a new distorting element, whose study opens up a wide field of research. This work represents a contribution in this line, circumscribed to a geographical area with a high economic dependence on fishing and shellfishing. At the present time, the pandemic situation persists, and greater economic effects on these activities are foreseeable. Further studies will be needed to update the results obtained in this article. The results derived from the analysis in this paper provide interesting insights for decision-makers. As demonstrated in this study, there exists a high variability in the results (catch, revenue, average price) for the different sectors and species during the COVID-19 pandemic. This shows the need for differentiated management for each species according to their specific characteristics, since the incidence of the pandemic varies between sectors and species. Decision-makers must be aware of this complexity, which requires flexibility in the measures adopted and rapid response capacity. It is important that decision-makers include stakeholders in the process of management, decision-making and design of the institutional framework applied to natural resources. The constant need to collect information of various kinds makes it essential to ensure a fluid and uninterrupted collaboration. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments The authors would like to thank Juan Carlos López Rodríguez for his contributions to this article. This study was possible thanks to the financial support from 10.13039/501100010801 Xunta de Galicia (ED431C2018/48 and ED431E2018/07) and from the 10.13039/501100003329 Ministry of Economy and Competitiveness (RTI2018-099225-B-100). Also, Raquel Fernández-González thanks for financial support of the Postdoctoral Program Xunta de Galicia under grant ED481B2018/095 and Raisa Pérez-Vas gratefully acknowledges funding under grant ED481A-2018/341 from the Programa Predoctoral Xunta de Galicia. ==== Refs References Afundación A Economía Galega. Informe 2018, first ed., Afundación Obra Social ABANCA, Santiago de Compostela 2019 Aldaco R. Hoehn D. Laso J. Margallo M. 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The Chub Mackerel (Scomber colias) in the Atlantic Spanish Waters (ICES Divisions 8.c and 9.a): biological, fishery and survey data Working Document to WGWIDE 2017 2017 Xunta de Galicia Rexistro de buques pesqueiros https://www.pescadegalicia.gal/rexbuque/ 2020 Xunta de Galicia Anuario de Pesca de Galicia 2019 https://www.pescadegalicia.gal/Publicaciones/AnuarioPesca2019/index.htm 2020 Xunta de Galicia Estatísticas: Primeira venda de productos frescos. Venda nas lonxas https://www.pescadegalicia.gal/estadisticas/ 2020

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==== Front Mar Pollut Bull Mar Pollut Bull Marine Pollution Bulletin 0025-326X 1879-3363 Elsevier Ltd. S0025-326X(21)00531-2 10.1016/j.marpolbul.2021.112497 112497 Article Personal protective equipment (PPE) pollution driven by the COVID-19 pandemic in Cox's Bazar, the longest natural beach in the world Rakib Md. Refat Jahan a⁎ De-la-Torre Gabriel E. b Pizarro-Ortega Carlos Ivan b Dioses-Salinas Diana Carolina b Al-Nahian Sultan c a Department of Fisheries and Marine Science, Faculty of Science, Noakhali Science and Technology University, Noakhali, Bangladesh b Universidad San Ignacio de Loyola, Av. La Fontana 501, Lima 12, Lima, Peru c Bangladesh Oceanographic Research Institute, Ramu, Cox's Bazar, Bangladesh ⁎ Corresponding author. 16 5 2021 8 2021 16 5 2021 169 112497112497 8 4 2021 7 5 2021 11 5 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The extensive use of personal protective equipment (PPE) driven by the COVID-19 pandemic has become an important contributor to marine plastic pollution. However, there are very few studies quantifying and characterizing this type of pollution in coastal areas. In the present study, we monitored the occurrence of PPE (face masks, bouffant caps, and gloves) discarded in 13 sites along Cox's Bazar beach, the longest naturally occurring beach in the world. The vast majority of the items were face masks (97.9%), and the mean PPE density across sites was 6.29 × 10−3 PPE m−2. The presence of illegal dumping sites was the main source of PPE, which was mainly located on touristic/recreational beaches. Fishing activity contributed to PPE pollution at a lower level. Poor solid waste management practices in Cox's Bazar demonstrated to be a major driver of PPE pollution. The potential solutions and sustainable alternatives were discussed. Keywords Mask Coronavirus Plastic Waste Management Bangladesh ==== Body pmc1 Introduction The outbreak of the novel coronavirus disease (COVID-19) by the end of 2019 (Xu et al., 2020) was declared a global health emergency by the World Health Organization (WHO) on January 30 of 2020 (Saadat et al., 2020). The worldwide spread of the virus led to intensive measures to prevent the transmission of the virus, such as lockdowns, border closures, enforced use of personal protective equipment (PPE), among others (Alfonso et al., 2021; Siam et al., 2020). Initially, it was reported that the reduction of greenhouse gas emissions, limited pressure on touristic destinations, and the absence of humans in natural habitats may have caused a positive impact on the environment (Rume and Islam, 2020). However, these were short-term effects. The immense increase in the demand for face masks, face shields, gloves, and other forms of PPE poses a great challenge to solid waste management (Rhee, 2020), which could lead to long-term environmental impacts. Marine litter, one of the most severe forms of environmental pollution, threatens the wellbeing of marine biodiversity (Miranda-Urbina et al., 2015). The vast majority of litter entering the ocean (estimated ~80%) comes from land-based sources and anthropogenic activities (Cordova and Nurhati, 2019; Jambeck et al., 2015). Marine litter encompasses many types of materials but is mostly composed of synthetic plastics (Hidalgo-Ruz and Thiel, 2015). Conventional plastics are strong, cheap, and persistent materials synthesized from fossil fuels (Andrady, 2011). Their massive production, use, and incorrect disposal or mismanagement have turned plastics into one of the most challenging environmental issues of current times (De-la-Torre et al., 2021b). The ongoing COVID-19 pandemic exacerbated plastic pollution due to the increase in demand for plastic-based PPE and constraints to efficient waste management (Adyel, 2020; Patrício Silva et al., 2021). Fadare and Okoffo (2020) and Aragaw (2020) determined that surgical face masks found in an urban drainage and natural lake, respectively, consisted of polypropylene (PP) and high-density polyethylene (HDPE), two of the most commercially available plastic polymers. Other types of PPE may be composed of polyacrylonitrile, polystyrene (PS), polycarbonate (PC), or polyesters (Potluri and Needham, 2005). Recent studies have reported the occurrence of PPE polluting cities, beaches, and rivers (Ammendolia et al., 2021; Ardusso et al., 2021; Cordova et al., 2021), which demonstrates the arrival of this new form of plastic pollution in the environment. Moreover, the breakdown of PPE items may produce secondary microplastics (MPs, <5 mm), which are a serious concern to aquatic organisms by inducing ecotoxicological effects upon ingestion (Aragaw and Mekonnen, 2021a). MPs interact with contaminants in the environment, such as volatile organic compounds, heavy metals, pharmaceuticals, and emerging contaminants (Torres et al., 2021), serving as a carrier of xenobiotics and potentially exacerbating detrimental effects on marine biota (Bhagat et al., 2021). Like most forms of plastic pollution, PPE could severely impact the environment and marine biota. De-la-Torre and Aragaw (2021) discussed and identified the knowledge gaps regarding PPE pollution in the marine environment, such as their suitability as a source of MPs, the potential transport of alien invasive species (AIS), sorption of chemical contaminants, and magnitude of PPE pollution worldwide. The objectives of the present article were to determine the abundance, characteristics, and distribution of PPE, namely face masks, gloves, and bouffant caps, polluting the longest natural beach in the world, Cox's Bazar, Bangladesh. To achieve this, a 12-week monitoring program was carried out on 13 beaches along the coast of Cox's Bazar. Each sampling site was characterized by its main activities (tourism, fishing, or fishing + tourism). 2 Materials and methods 2.1 Study area Cox's Bazar District, Chittagong Division, is located in east Bangladesh, home to the longest natural beach in the world (Mahamud and Takewaka, 2018). Cox's Bazar coast is a sandy beach expanding about 125 km along the coast of the Bay of Bengal. This place is known for its natural landscapes and subject to notorious national and international tourism and fishing activities (Rahman et al., 2020). The presence of hotels, gastronomic premises, and cultural and religious events poses a significant burden on solid waste management along the coast of Cox's Bazar beach. Previous studies have demonstrated that MPs are already polluting Cox's Bazar (Rahman et al., 2020), which elucidates the anthropogenic influence on these areas. To have a better overview of PPE pollution in Cox's Bazar, we have monitored 13 sampling sites (Fig. 1 ) for 12 consecutive weeks. These sites are well distributed and representative of almost the entire coast of Cox's Bazar beach. Based on field observations, were have determined the main activities carried out in each site, categorized as tourism (including recreational activities), fishing, or both tourism and fishing activities. This categorization will allow us to determine the influence of the activities carried in Cox's Bazar over the pollution with PPE associated with the COVID-19 pandemic.Fig. 1 Map of the sampling sites in Cox's Bazar, Bangladesh. Fig. 1 2.2 Sampling strategy For the sake of standardization, PPE monitoring followed our previous study carried out on the coast of Peru (De-la-Torre et al., 2021). In brief, several transects were established for each sampling site that allowed the beach to be completely surveyed (up to ~2 m into vegetation). Observers walked along each transect and visually identified PPE, which were categorized as face masks, face shields, bouffant caps, and gloves. Some recreation/touristic beaches are subject to solid waste dumping. The litter dumpsites were also checked carefully to identify PPE reaching the ocean from this source. Sampling campaigns covering the 13 sites were carried out weekly during 12 consecutive weeks from November 2020 to January 2021. The area covered in each sampling site was estimated using Google Earth (https://www.google.com/earth/) (Table 1 ). These values were used to calculate the PPE density in each sampling site as described by Okuku et al. (2020):C=n/a where C is PPE density (PPE m−2), n is the number of PPE, and a is the covered area (m2).Table 1 Coordinates, activities, and areas covered of the 13 sampling sites. Table 1Code Coordinates Activity Area covered S1 20.918018, 92.223913 Fishing and tourist 18,690 m2 S2 20.998981, 92.191373 Fishing and tourist 12,258 m2 S3 21.077660, 92.132420 Fishing 45,066 m2 S4 21.154814, 92.066642 Fishing and tourist 33,456 m2 S5 21.181083, 92.049206 Tourist 74,581 m2 S6 21.206303, 92.048947 Tourist 28,761 m2 S7 21.300112, 92.041482 Fishing 74,281 m2 S8 21.315069, 92.037589 Fishing and tourist 36,048 m2 S9 21.366336, 92.018106 Tourist 13,826 m2 S10 21.410881, 91.985406 Tourist 52,577 m2 S11 21.423341, 91.974897 Tourist 42,816 m2 S12 21.426620, 91.971975 Tourist 22,240 m2 2.3 Statistical analysis PPE density was expressed in PPE m−2 ± standard deviation. Sampling sites were grouped by activity (tourism, fishing, or tourism + fishing) to determine its influence on the PPE density. The Gaussian distribution of the datasets was invalidated by Shapiro-Wilk normality tests. To compare the PPE density among activities, a Kruskal-Wallis test followed by Dunn's multiple comparison test was conducted. The significance level was set to 0.05 for all the analyses. Statistical tests and graphs were performed using GraphPad Prism (version 8.4.3 for Windows). 3 Results All of the sampling sites in Cox's Bazar beach were contaminated with PPE. An absolute total of 29,254 PPE items was counted across sites during the 12 weekly sampling campaigns (Fig. 2a), most of the time accumulating near fishing or litter dumping sites (Fig. 2b,c). The vast majority of the items were face masks, accounting for 97.2% of the total, followed by gloves (1.3%), and bouffant caps (0.79%) (Fig. 3a). No face shields were found on any site. The total amount of PPE per week increased over time up to the 10th week (Fig. 3b).Fig. 2 a) Examples of surgical face masks, a glove and plastic bouffant cap found in different sampling sites along Cox's Bazar beach, b) evidence of plastic pollution near fishing sites, and c) evidence of large solid waste dumping sites within the beach. Fig. 2 Fig. 3 a) Proportion of face masks, face shields, gloves, and other PPE. b) Weekly evolution of the total number of PPE across sampling sites. Fig. 3 The mean PPE density across sites was 6.29 × 10−3 PPE m−2 and ranged from 3.16 × 10−4 PPE m−2 in S5 to 2.18 × 10−2 PPE m−2 in S12. Fig. 4 displays a boxplot with the PPE density of the 12 sampling weeks per site. As observed, the highest densities are found in touristic beaches, with the exception of S5. According to the Kruskal-Wallis test, PPE density varied significantly (Chi-square = 53.57, p < 0.0001) among different activities. Specifically, the sites where only touristic or recreational (T) activities are carried out, demonstrated a significantly higher PPE density (p < 0.001) than those where only fishing (F) or fishing and touristic (F + T) activities are carried out together, as revealed by the Dunn's multiple comparison test (Fig. 5 ).Fig. 4 Box plot diagram of the PPE density among sampling sites. Fig. 4 Fig. 5 Box plot of the PPE density for the three different activities. F + T: Fishing and tourism. F: Exclusively fishing. T: Exclusively tourism or recreational. Letters indicate significant differences according to Dunn's multiple comparisons test. Fig. 5 4 Discussions Overall, the results found in the present study show higher PPE pollution than in other reports. In our previous research, we found a total of 138 PPE items in 12 beaches from the metropolitan city of Lima, Peru, after 12 sampling campaigns (De-la-Torre et al., 2021). In this study, however, the number of PPE items was ~212 times higher, despite having similar sampling methods and number of sampling campaigns. It should be noted that the 13 sites in the present study encompass 516,683 m2 of sampled area, while in Lima only 110,757 m2 and including three control sites (non-touristic sites of difficult access) with almost no PPE pollution. Given the influence of various methodological factors in the number of PPE, we suggest PPE density (PPE m−2) as a more precise unit of measurement. The dominance of face masks (97.9%) among different PPE types is in accordance with the PPE composition in Lima (87.7%) (De-la-Torre et al., 2021). In the Cilincing and Marinda rivers, Indonesia, face masks of different types (cotton, sponge, and medical masks) were the most frequent PPE found (Cordova et al., 2021). However, in streets and recreational trails from the city of Toronto, Canada, the mean proportion of face masks was 32% (Ammendolia et al., 2021). The PPE density found in Cox's Bazar beach (3.16 × 10−4–2.18 × 10−2) was similar to that of Toronto (urban areas) but larger than in Lima (Table 2 ). There are insufficient studies currently available to have a complete reference frame on the magnitude of the PPE pollution and density.Table 2 Mean and range of PPE densities across studies. Table 2Country City Area PPE density (PPE m−2) Reference Mean Range Bangladesh Cox's Bazar Beach 6.29 × 10−3 3.16 × 10−4–2.18 × 10−2 This study Peru Lima Beach 6.42 × 10−5 0–7.44 × 10−4 (De-la-Torre et al., 2021) Chile Nationwide Beach 6.00 × 10–3a – (Thiel et al., 2021) Kenya Kwale and Kilifi Beach – 0–5.6 × 10−2 (Okuku et al., 2020) Persian Gulf Bushehr Beach – 7.71 × 10−3–2.70 × 10−2 (Akhbarizadeh et al., 2021) Canada Toronto Urban 1.01× 10−3 0–8.22 × 10−3 (Ammendolia et al., 2021) a Only face masks were counted. The results of the statistical analyses suggest that touristic beaches are the most polluted with PPE. On the touristic beaches, multiple recreational and cultural events and gatherings are carried out constantly, where about 2 million tourists are expected to visit during peak season (between November and March) (Dey et al., 2013). It is plausible that these activities, along with the lack of environmental awareness, could induce higher rates of incorrect disposal of PPE. However, the most notorious source of PPE within beach areas is illegal dumping and waste burning, as depicted in Fig. 2c. The vast majority of PPE in highly polluted sites are attributed to the presence of illegal dumping sites, and most of these are located in touristic sites (except for S5). Waste generation in Chittagong has been increasing continuously, despite municipal solid waste management systems being not sufficient to treat and adequately dispose all of it. Due to weak institutional capacity and a limited budget for waste management (Chowdhury et al., 2013), plastic pollution driven by the COVID-19 pandemic in Cox's Bazar is likely to exacerbate. Other sites that included fishing activities showed generally lower PPE densities. As shown in Fig. 2b, the areas in the vicinity of artisanal fishing harbors were highly polluted with various objects, such as broken fishing lines, fabrics, wood pieces, and paint particles, but a reduced number of PPE items. Additionally, illegal dumping sites were less frequent in fishing areas, resulting in lower PPE densities. Recent studies determined that the outer and inner layers of common surgical face masks are made of PP and polyethylene (PE), respectively (Aragaw, 2020; Fadare and Okoffo, 2020). The vast majority of commercially available face masks are made of PP due to its low cost and low melt viscosity for facile processing (Chua et al., 2020), although several other materials, such as PS, PC, PE, and polyester, may also be used in face masks. Gloves, on the other hand, are made of latex, nitrile, or PVC (De-la-Torre and Aragaw, 2021), while surgical bouffant caps generally consist of woven textiles, like cotton and cotton-polyester layers (Behera and Arora, 2009). Each disposable N95 and surgical face mask contain approximately 9 and 4.5 g of PP, respectively (Akber Abbasi et al., 2020), and an additional 2 g in the N95 filter (Liebsch, 2020). Likewise, earloops are mostly made of PA (Battegazzore et al., 2020). Based on the chemical identity of most PPE materials, its contribution to plastic pollution becomes evident. The potential effects of PPE pollution in coastal environments are diverse. It has been suggested that face masks may be notable sources of MPs in the form of fibers (Aragaw, 2020; Fadare and Okoffo, 2020). The occurrence of microplastics in Cox's Bazar has already been demonstrated (Rahman et al., 2020), with fragments and fibers among the most abundant MP types. With the large amount of PPE wastes introduced to the beach, we hypothesize that MP pollution may become more pronounced, especially in areas with high PPE densities. However, the extent of the contribution of PPE to MPs in the environment remains unknown. Regardless, MPs are considered as contaminants of concern due to their ubiquitous presence in the environment (De-la-Torre et al., 2020b; Dioses-Salinas et al., 2020; Garcés-Ordóñez et al., 2020; Hidalgo-Ruz et al., 2012) and the likeliness of being ingested by organisms of various taxa (De-la-Torre et al., 2020a; Ory et al., 2017; Santillán et al., 2020). Additionally, open plastic burning as shown in the illegal dumping sites could lead to the formation of new types of plastic pollutants, such as pyroplastics and plastiglomerates (Corcoran et al., 2017; Turner et al., 2019). Also, plastic litter is known to harbor sessile organisms, which could be transported to foreign locations and turn into AIS (Rech et al., 2018a, Rech et al., 2018b). In our previous study conducted in Peru, we found a KN95 face mask colonized by macroalgae of the Rhodophyta division in an area of high presence of fouled marine litter (De-la-Torre et al., 2021, De-la-Torre et al., 2021a), which suggests the suitability of PPE as an artificial substrate for benthic organisms. However, none of the PPE found in the present study showed evidence of colonization. PPE may also interact with local biota through entanglement or ingestion. Hiemstra et al. (2021) reviewed these reports, showing photographic evidence of fish entrapped in surgical gloves, bird entangled in a face mask, and different PPE incorporated in bird nests from different locations. The face mask use guidelines provided by the Department of Operational Support of the United Nations indicate that medical face masks (mostly single-use) are recommended for medical personnel, while the general public must opt for reusable cloth masks (UN, 2020). However, from our observations, it was evident that the vast majority of PPE items in Cox's Bazar were single-use surgical face masks (Fig. 2). We were unable to determine a precise number of face mask types (surgical, cloth, N95, etc.) during the sampling campaigns since most of these were indistinguishable in the presence of larger partially burned litter in dumping sites. Regardless, we recommend prioritizing reusable over single-use face masks as an economic and simple way to reduce face mask waste generation. Incorrectly disposed face masks could carry pathogenic microbiota, including the SARS-CoV-2 virus, thus becoming fomites (materials or objects that carry infection) (van Doremalen et al., 2020), and may be treated as hazardous waste (Dharmaraj et al., 2021a). As a potential solution to the increasing face mask waste generation, Aragaw and Mekonnen, 2021a, Aragaw and Mekonnen, 2021b and Jung et al. (2021) proposed and reported preliminary results of using thermo-chemical processes for recycling. In brief, PP wastes are converted into gas and liquid fuels through pyrolysis. Additionally, Dharmaraj et al., 2021a, Dharmaraj et al., 2021b reviewed the conversion of various medical wastes through pyrolysis. Another alternative to prevent synthetic plastic waste generation is the use of degradable plastics. Biobased and biodegradable plastics have been extensively studied for their environmentally friendly properties, biocompatibility, and formation of composite materials (Ccorahua et al., 2017; Torres et al., 2019). Several studies developed N95 nano-porous filters based on degradable plastics, such as polybutylene succinate (PBS) and polylactic acid (PLA), through electrospinning (Choi et al., 2021; He et al., 2020). Also, Vaňková et al. (2020) fabricated PLA-based respirators by 3D printing. Although some fully biobased disposable masks are commercially available (Selvaranjan et al., 2021), the available market for this type of product is still very limited. Other preliminary studies incorporated surgical face masks as additives to pavements base/subbase (Saberian et al., 2021) and as a source of porous carbon for electrochemical applications (Hu and Lin, 2021). 5 Conclusions The COVID-19 pandemic has turned the tide in favor of marine plastic pollution. However, the studies reporting pollution with PPE in coastal areas are very few. Here, we reported the results from a large-scale PPE monitoring study along the coast of Cox's Bazar, the longest naturally occurring beach in the world. Large numbers of PPE (a total of 29,254 PPE items) were found, out of which 97.9% were face masks. However, after calculating the area-based PPE density (PPE m−2), our results are comparable to those in the literature. The most notorious source of face masks was illegal dumping sites in most touristic/recreational beaches. This evidences the poor solid waste management practices and lack of environmental awareness in beachgoers. The potential impacts of PPE in marine environments are the formation of MPs, harboring transportation of potentially invasive species, and entanglement or ingestion by larger organisms. This is one of the very few articles to report PPE pollution in coastal environments. It is necessary to display important research efforts in order to have a better understanding of the magnitude and impact of PPE pollution across different environmental compartments and organisms. CRediT authorship contribution statement Md. Refat Jahan Rakib: Project administration, Visualization, Funding acquisition, Formal Analysis, Resources, Investigation, Writing Original – Draft and review. Carlos Ivan Pizarro-Ortega: Formal Analysis, Writing – Original Draft, Data Curation. Diana Carolina Dioses-Salinas: Investigation, Data Curation, Formal Analysis, Writing Original – Draft. Sultan Al-Nahian: Data curation, Resources. Gabriel Enrique De-la-Torre: Conceptualization, Methodology, Software, Writing – Original Review & Editing, Supervision. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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Increased plastic pollution due to COVID-19 pandemic: challenges and recommendations Chem. Eng. J. 405 2021 126683 10.1016/j.cej.2020.126683 32834764 Potluri, P., Needham, P., 2005. Technical textiles for protection, in: Textiles for Protection. Elsevier Ltd, pp. 151–175. doi:10.1533/9781845690977.1.151. Rahman S.M.A. Robin G.S. Momotaj M. Uddin J. Siddique M.A.M. Occurrence and spatial distribution of microplastics in beach sediments of Cox’s Bazar, Bangladesh Mar. Pollut. Bull. 160 2020 10.1016/j.marpolbul.2020.111587 Rech S. Salmina S. Borrell Pichs Y.J. García-Vazquez E. Dispersal of alien invasive species on anthropogenic litter from European mariculture areas Mar. Pollut. Bull. 131 2018 10 16 10.1016/j.marpolbul.2018.03.038 29886925 Rech S. Thiel M. Borrell Pichs Y.J. García-Vazquez E. Travelling light: fouling biota on macroplastics arriving on beaches of remote Rapa Nui (Easter Island) in the South Pacific Subtropical Gyre Mar. Pollut. Bull. 137 2018 119 128 10.1016/j.marpolbul.2018.10.015 30503417 Rhee S.W. Management of used personal protective equipment and wastes related to COVID-19 in South Korea Waste Manag. Res. 38 2020 820 824 10.1177/0734242X20933343 32517547 Rume T. Islam S.M.D.U. Environmental effects of COVID-19 pandemic and potential strategies of sustainability Heliyon 6 2020 e04965 10.1016/j.heliyon.2020.e04965 Saadat S. Rawtani D. Hussain C.M. Environmental perspective of COVID-19 Sci. Total Environ. 728 2020 138870 10.1016/j.scitotenv.2020.138870 32335408 Saberian M. Li J. Kilmartin-Lynch S. Boroujeni M. Repurposing of COVID-19 single-use face masks for pavements base/subbase Sci. Total Environ. 769 2021 145527 10.1016/j.scitotenv.2021.145527 33736252 Santillán L. Saldaña-Serrano M. De-la-Torre G.E First record of microplastics in the endangered marine otter (Lontra felina). Mastozoología Neotrop 27 2020 211 215 10.31687/saremMN.20.27.1.0.12 Selvaranjan K. Navaratnam S. Rajeev P. Ravintherakumaran N. Environmental challenges induced by extensive use of face masks during COVID-19: a review and potential solutions Environ. Challenges 3 2021 100039 10.1016/j.envc.2021.100039 Siam M.H.B. Nishat N.H. Ahmed A. Hossain M.S. Stopping the COVID-19 pandemic: a review on the advances of diagnosis, treatment, and control measures J. Pathog. 2020 2020 9121429 10.1155/2020/9121429 33133697 Thiel M. de Veer D. Espinoza-Fuenzalida N.L. Espinoza C. Gallardo C. Hinojosa I.A. Kiessling T. Rojas J. Sanchez A. Sotomayor F. Vasquez N. Villablanca R. COVID lessons from the global south – face masks invading tourist beaches and recommendations for the outdoor seasons Sci. Total Environ. 147486 2021 10.1016/j.scitotenv.2021.147486 Torres F.G. Troncoso O.P. Pisani A. Gatto F. Bardi G. Natural polysaccharide nanomaterials: an overview of their immunological properties Int. J. Mol. Sci. 20 2019 5092 10.3390/ijms20205092 31615111 Torres F.G. Dioses-Salinas D.C. Pizarro-Ortega C.I. De-la-Torre G.E. Sorption of chemical contaminants on degradable and non-degradable microplastics: recent progress and research trends Sci. Total Environ. 757 2021 143875 10.1016/j.scitotenv.2020.143875 33310573 Turner A. Wallerstein C. Arnold R. Webb D. Marine pollution from pyroplastics Sci. Total Environ. 694 2019 133610 10.1016/j.scitotenv.2019.133610 31398639 UN, 2020. Use of Masks for UN Personnel in Non-healthcare Settings in Areas of COVID-19 Community Transmission. van Doremalen N. Bushmaker T. Morris D.H. Holbrook M.G. Gamble A. Williamson B.N. Tamin A. Harcourt J.L. Thornburg N.J. Gerber S.I. Lloyd-Smith J.O. de Wit E. Munster V.J. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1 N. Engl. J. Med. 382 2020 1564 1567 10.1056/nejmc2004973 32182409 Vaňková E. Kašparová P. Khun J. Machková A. Julák J. Sláma M. Hodek J. Ulrychová L. Weber J. Obrová K. Kosulin K. Lion T. Scholtz V. Polylactic acid as a suitable material for 3D printing of protective masks in times of COVID-19 pandemic PeerJ 8 2020 e10259 10.7717/peerj.10259 Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. Liu S. Zhao P. Liu H. Zhu L. Tai Y. Bai C. Gao T. Song J. Xia P. Dong J. Zhao J. Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir. Med. 8 2020 420 422 10.1016/S2213-2600(20)30076-X 32085846

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==== Front J Thorac Cardiovasc Surg J Thorac Cardiovasc Surg The Journal of Thoracic and Cardiovascular Surgery 0022-5223 1097-685X Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery S0022-5223(20)32680-5 10.1016/j.jtcvs.2020.09.080 Commentary Commentary: Two decades of innovation, leadership, and overcoming challenges, but more lies ahead Liou Douglas Z. MD ∗ Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, Calif ∗ Address for reprints: Douglas Z. Liou, MD, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Dr, Falk Building, Stanford, CA 94305. 28 9 2020 9 2021 28 9 2020 162 3 928929 16 9 2020 16 9 2020 17 9 2020 © 2020 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery. 2020 The American Association for Thoracic Surgery Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmc Douglas Z. Liou, MD Central Message The Thoracic Surgery Residents Association has an impressive record of enhancing education and providing leadership, and is poised to help guide the next generation of cardiothoracic surgery trainees. See Article page 917. Since its formation in 1997, the Thoracic Surgery Residents Association (TSRA) has had tremendous influence on cardiothoracic surgery training, as detailed by Brescia and colleagues.1 Considering the organization is run solely by surgeons in training under the guidance of the Thoracic Surgery Directors Association, the list of accomplishments is exceptional, particularly over the past decade. Among them are more than a dozen widely used educational publications, including review books, reference guides, and test preparation material. A podcast series created by TSRA offers free access to more than 100 unique cardiothoracic surgery topics and has more than 175,000 listens across the globe. More recently, the organization has focused on facilitating peer-to-peer mentorship among medical students, surgeons in training, and seasoned faculty through collaborative events at national meetings. These efforts provide a different avenue to attract young talent to our specialty, foster intellectual growth, and stimulate innovation. Many changes in cardiothoracic surgery occurred during the early TSRA era owing to declining interest in the specialty that largely stemmed from concerns about long-term job security.2 , 3 During that time of uncertainty, TSRA played an active role in helping to identify the problem through data collection and research studies involving surgical trainees across North America.4 , 5 Targeted interventions were undertaken over the next decade, including the introduction of an integrated cardiothoracic surgery residency program allowing direct matriculation from medical school that has returned cardiothoracic surgery training to a preeminent state.6 Since then, TSRA has maintained its vital role by continually assessing the quality and components of the cardiothoracic surgery education structure.7 , 8 One could argue that few, if any, other resident-led associations have had a comparable influence on the overall training and outlook of their specialty during such a daunting period. Challenges facing the current generation of cardiothoracic surgeons will differ significantly from those prior. Events in our society during the past few years—2020 in particular—have illustrated vividly many of the problems that medicine is facing, including health disparities among socioeconomic groups, gender inequality, and racial bias. Diversity, equity, and inclusion are part of the TSRA mission, and it is not surprising that the organization is already involved in examining some of these issues within our specialty.9 , 10 Although it is uncertain how these challenges will ultimately influence the practice of cardiothoracic surgery, we have come to expect that the TSRA will take the lead on confronting the issues. Disclosures: The author reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. ==== Refs References 1 Brescia A.A. Lou X. Louis C. Blitzer D. Coyan G.N. Han J.J. The Thoracic Surgery Residents Association: past contributions, current efforts, and future directions J Thorac Cardiovasc Surg 162 2021 917 927.e5 33051070 2 Salazar J.D. Ermis P. Laudito A. Lee R. Wheatley G.H. Paul S. Cardiothoracic surgery resident education: update on resident recruitment and job placement Ann Thorac Surg 82 2006 1160 1165 16928572 3 Vaporciyan A.A. Reed C.E. Erikson C. Dill M.J. Carpenter A.J. Guleserian K.J. Factors affecting interest in cardiothoracic surgery: survey of North American general surgery residents Ann Thorac Surg 87 2009 1351 1359 19379863 4 Sarkaria I.S. Carr S.R. Maciver R.H. Whitson B.A. Joyce D.L. Stulak J. The 2010 Thoracic Surgery Residents Association workforce survey report: a view from the trenches Ann Thorac Surg 92 2011 2062 2071 22115218 5 Cooke D.T. Kerendi F. Mettler B.A. Boffa D.J. Mehall J.R. Merrill W.H. Update on cardiothoracic surgery resident job opportunities Ann Thorac Surg 89 2010 1853 1859 20494038 6 Bui J. Bennett W.C. Long J. Strassle P.D. Haithcock B. Recent trends in cardiothoracic surgery training: data from the National Resident Matching Program J Surg Educ September 11, 2020 [Epub ahead of print] 7 Tchantchaleishvili V. Lapar D.J. Stephens E.H. Berfield K.S. Odell D.D. Denino W.F. Current integrated cardiothoracic surgery residents: a Thoracic Surgery Residents Association survey Ann Thorac Surg 99 2015 1040 1047 25624055 8 Nguyen T.C. Terwelp M.D. Stephens E.H. Odell D.D. Loor G. Lapar D.J. Resident. The perceptions of 2-year versus 3-year cardiothoracic training programs Ann Thorac Surg 99 2015 2070 2076 25863731 9 Stephens E.H. Robich M.P. Walters D.M. Denino W.F. Aftab M. Tchantchaleishvili V. Gender and cardiothoracic surgery training: specialty interests, satisfaction, and career pathways Ann Thorac Surg 102 2016 200 206 27157051 10 Ceppa D.P. Dolejs S.C. Boden N. Phelan S. Yost K.J. Doningon J. Sexual harassment and cardiothoracic surgery: #UsToo? Ann Thorac Surg 109 2020 1283 1288 31454525

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==== Front Clin Soc Work J Clin Soc Work J Clinical Social Work Journal 0091-1674 1573-3343 Springer US New York 860 10.1007/s10615-022-00860-0 Original Paper Exploring Shared Trauma in the Time of COVID: A Simulation-Based Survey Study of Mental Health Clinicians http://orcid.org/0000-0002-9277-6441 Asakura Kenta kasakura@smith.edu 1Kenta Asakura, MSW, LICSW, RSW, Ph.D., is an Associate Professor and Chair of the Practice Sequence at Smith College School for Social Work. He engages in a robust program of simulation-based research on clinical social work education and practice. Gheorghe Ruxandra M. 2 Rieger Danielle 3 Tarshis Sarah 2 Borgen Stephanie 4 D’Angiulli Amedeo 5 1 grid.263724.6 0000 0001 1945 4190 Smith College School for Social Work, Northampton, MA USA 2 grid.34428.39 0000 0004 1936 893X Carleton University School of Social Work, Ottawa, ON Canada 3 grid.34428.39 0000 0004 1936 893X Department of Psychology, Carleton University, Ottawa, ON Canada 4 Registered Social Worker, Ottawa, Canada 5 grid.34428.39 0000 0004 1936 893X Department of Neuroscience, Carleton University, Ottawa, ON Canada 15 12 2022 112 28 11 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. From fear of contracting the virus, isolation from physical distancing, to navigating lifework balance, the COVID-19 pandemic is expected to leave long-lasting psychosocial impacts on many. Shared trauma refers to similar psychological reactions to an extraordinary community event when experienced by both the clinicians and clients. We examined the experiences mong mental health clinicians in Canada and the United States (n = 196) in this online survey study during the second phase of the pandemic (Spring 2021). In addition to using traditional survey items (e.g., demographics, scales, and short answers), we also used video-recorded Simulated Clients (SC; i.e., professional actors) as a novel method to elicit the participants’ assessment of the SCs and the psychosocial impacts of the COVID-19 pandemic. Using shared trauma as a theoretical framework, we analyzed both quantitative and qualitative data. Quantitative results suggested that although these mental health clinicians certainly reported experiencing psychosocial impacts of the pandemic themselves, these shared experiences with client and general populations did not greatly impact how they understood the SCs. Qualitative results helped further contextualize the clinicians’ own personal and professional lives. Implications for clinical practice and further research related to shared trauma are discussed. Keywords Shared trauma Clinical social workers COVID-19 Pandemic Simulation Mixed-methods Online survey http://dx.doi.org/10.13039/100008095 Carleton University ==== Body pmcIntroduction There is rising concern that the COVID-19 global pandemic will generate long-lasting impacts on collective wellness. A mounting threat of social upheaval, economic decline, psychological hardship, and largescale health repercussions has imposed global turmoil of stress, grief, loss, and uncertainty—particularly for marginalized groups, namely Black, Indigenous, and People of Color (BIPOC) (Gianfrancesco et al., 2021; Lund, 2020; Sze et al., 2020), women (Cabarkapa et al., 2020; Danet Danet, 2021; Volk et al., 2021), parents and caregivers (Magruder et al., 2021; Volk et al., 2021), people with disabilities (Cieza et al., 2021; Shakespeare et al., 2021), and queer and trans people (Kamal et al., 2021; Ruprecht et al., 2020). At the forefront of the pandemic are health and social service workers. Since the onset of the pandemic, these workers have been in a unique position where they experience “the stress of [the] COVID-19 pandemic in their professional lives by providing services to clients who are often in states of crisis or adversity, while simultaneously experiencing the same trauma in their personal lives” (Holmes et al., 2021, p. 495). Various systematic reviews (Cabarkapa et al., 2020; Danet Danet et al., 2021; Lai et al., 2020) have found that frontline workers are more prone to various psychological impacts from COVID-19 than non-frontline workers, including vicarious trauma, stress-related disorders, depression, anxiety, sleep disturbances and burnout. To further contribute to relevant professional literature, the purpose of this mixed methods survey was to explore the experiences of traumatic stress among clinicians. Literature Review Shared Trauma According to trauma theory (Herman, 2015), traumatic stress is defined as common and normal reactions to extraordinary situations like the COVID-19 pandemic as well as natural disasters, terror attacks, violence, war and poverty (Ali et al., 2021; Holmes et al., 2021; Tosone et al., 2003, 2012). While primary trauma implies the direct exposure of trauma experienced by an individual (Finklestein et al., 2015), secondary trauma describes the potential of psychological distress experienced by clinicians when exposed to clients’ traumatic stories (Stamm, 1995). Shared trauma consists of both primary and secondary trauma when both clinicians and clients are exposed to the same traumatic event, which can have transformative or lasting impacts (Saakvitne, 2002; Tosone et al., 2003). In other words, shared trauma dually reflects a clinician’s personal and professional lives in their role as both a victim and a helper. Literature on shared trauma has been gaining prominence in social work over the last few decades. The term first emerged shortly after 9/11 to describe the joint distress of clinicians and clients after witnessing the attacks on the World Trade Center (Altman & Davies, 2002; Saakvitne, 2002; Tosone et al., 2003). Relevant literature documents clinicians’ heightened anxiety and fear for their own safety and their clients’ wellbeing during a crisis (Nuttman-Shwartz & Dekel, 2009; Saakvitne, 2002; Tosone et al., 2014). These scholars also highlighted clinicians’ capacity for empathy, compassion, connectedness, and professional growth as they experience shared trauma (Ali et al., 2021; Bauwens & Tosone, 2010; Tosone et al., 2021). Shared trauma has been since explored following events such as Hurricane Katrina (Tosone et al., 2014), conflict zones including the West Bank (Blome & Safadi, 2016), and the Gaza Strip (Dekel and Baum, 2010). Shared trauma is also now being discussed in the context of COVID-19 (Ali et al., 2021; Dempsey et al., 2021; Tosone et al., 2021). Tosone and colleagues (2021) reflected on the realities of social work students during the pandemic, highlighting the inevitability of interconnectedness with their clients as they experience similar emotions, struggles, fears, and resilience. Dempsey and colleagues (2021) also used a shared trauma lens to explore the impact of the pandemic on field education, student anxiety, and contingency plans to establish ways to better support students in a global crisis. Health and Wellbeing Among Mental Health Clinicians During COVID-19 The pandemic has exacerbated occupational challenges of mental health clinicians on a global level, including increased job demands, inadequate equipment, training or resources, and insufficient time to complete their work (Ashcroft et al., 2021; Ben-Ezra & Hamama-Raz, 2020). Recent pandemic-related studies on social workers in the United States and the United Kingdom (Greene et al., 2021; Holmes et al., 2021; Miller et al., 2021) found that social workers (n range = 181–1568) met the diagnostic criteria for peritraumatic distress (46%), posttraumatic stress disorder (PTSD) (range: 22–26.21%), depression (46.90%), and anxiety (47.28%). Researchers have also documented a considerable decline in self-care practices among social workers in the pandemic context (Miller & Reddin Cassar, 2021). Others, however, reported that greater engagement with self-care practices predicted a decrease in pandemic-related distress among social workers (Miller et al., 2021). Other scholars have argued that there might exist a relationship between social locations (i.e., privileges, marginalities) and the exacerbation of psychosocial impacts, especially for individuals who are BIPOC (Gianfrancesco et al., 2021; Lund, 2020; Sze et al., 2020), women (Cabarkapa et al., 2020; Danet Danet, 2021; Volk et al., 2021), parents and caregivers (Magruder et al., 2021; Volk et al., 2021), people with disabilities (Cieza et al., 2021; Shakespeare et al., 2021), and queer and trans people (Kamal et al., 2021; Ruprecht et al., 2020). One study empirically confirmed that social workers (n = 1568) who were married, heterosexual, physically healthier and more financially secure generally reported less distress than other clinicians (Miller et al., 2021). Qualitative studies on social workers and other health and social service providers have revealed more nuanced understandings of these pandemic-related experiences. The study of frontline healthcare workers (n = 103) conducted by Bender et al. (2021) explicated that while interpersonal connection was increasingly difficult due to quarantine and isolation protocols, emotional connectedness was nonetheless a supportive coping strategy that strengthened practitioners’ resilience during COVID-19. Exploring the ecological impacts of COVID-19 on health and human service workers (n = 531), Magruder and colleagues (2021) found that practitioners experienced impacts across various proximal and distal domains, including (1) interpersonal impacts, such as fear of infecting loved ones; (2) intrapersonal impacts, such as facing infection or hospitalization themselves; (3) organizational impacts, such as increased caseloads at work; (4) community impacts, such as isolation from community; and, (5) public policy impacts, such as uncertainty or frustration with governmental policy responses to COVID-19. To add, in the qualitative portion of a recent large-scale Canadian survey, social workers (n = 2470) reported experiencing the following nine themes:increased work-load; loss of employment; redeployment to new settings; early retirement; concern for personal health and safety; social workers in private practice seeing fewer clients; personal caregiving responsibilities; limiting recent graduates’ employment potential and social workers experiencing new opportunities. (Ashcroft et al., 2021, p. 1) For BIPOC social workers, these pandemic-related themes are often contextualized in relation to racial identity, social location, and professional experiences. Describing their experiences as Black American clinicians, Lipscomb and Ashley (2020) highlighted that they are navigating a “dual pandemic” (p. 221) defined not only by the COVID-19 pandemic, but also by repeated incidents of anti-Black racism. Alongside psychological distress, fear and emotional fatigue, they also identified difficulty sharing pain with other Black clients and discomfort working with white clients who offered their sentiments regarding race relations (Lipscomb & Ashley, 2020). The Current Study In this study, we explored whether and how mental health clinicians experienced shared trauma during the COVID-19 pandemic. While a considerable amount of research has been done on the pandemic and its impacts on frontline healthcare providers (e.g., Danet Danet et al., 2021), there is little known about social workers and other mental health clinicians from a shared trauma perspective in the context of COVID-19. While some have conceptually explored COVID-19-specific shared trauma about social work students in a higher education context (Dempsey et al., 2021; Tosone et al., 2021), there remains a dearth of work focused on shared trauma among practicing social workers and other mental health clinicians in the times of COVID. Empirical research on COVID-related shared trauma among frontline clinicians can contribute to social workers’ knowledge on whether and how shared trauma might impact clinicians’ response to client work, their own wellness, and clinical performance (Tosone et al., 2003). Furthemore, the nature of this global pandemic and its impact is ever changing and ongoing. By Spring 2021, mental health clinicians had already been living and working in the midst of the global pandemic for a year. This was also the time when vaccines were starting to be made available to mental health clinicians. While much of the relevant literature has focused on the experiences of healthcare workers in general (e.g., Perraud et al., 2022; Serrão et al., 2022), we are unaware of studies that explored mental health clinicians’ experiences during this particular time and context of the COVID, which is often known as the third wave (see Wu et al., 2021 for the Government of Canada classification). Given that the context of the pandemic and its impacts on clinicians are constantly developing, there remains a need for research that examines clinicians’ experiences at different waves and contexts of this pandemic. To address these existing gaps and needs identified in the current social work literature, we designed and conducted the current study in Spring 2021. Using both quantitative and qualitative data, the literature on shared trauma informed the following research questions (RQ): RQ1: What are the characteristics of clinician’s psychosocial functioning and coping during the pandemic?; RQ2: What are the relationships between clinician characteristics and their psychosocial coping and functioning?; RQ3: What are the relationships between clinician characteristics and their assessment of Simulated Clients (SCs)?; and, RQ4: How do clinicians experience pandemic impacts on their personal and professional lives? Method We conducted an online survey using Qualtrics from March 2021 to April 2021, which was during the third wave of the pandemic when vaccines were recently made available to healthcare workers. We recruited and surveyed mental health clinicians practicing in Canada and the United States about the psychosocial impacts of the pandemic on them. Participants were then asked to watch two separate video-recorded simulated case scenarios, in which two professional actors were trained to portray realistic SCs and provide a monologue about their situations for several minutes. We then asked participants to assess the SCs’ psychosocial functioning. This simulation method, a novel approach in social work research, is designed for participants to feel immersed in the scenario as if they are attending an actual session (Asakura et al. 2021). All research materials were approved by the university Institutional Review Board. Sampling Recruitment took place via professional listservs and social media groups subscribed by clinicians. A total of 196 clinicians completed all questions of the survey. Survey Measures Quantitative We surveyed participants’ demographic information, including age, gender, race, the country/state/province, years of practice, practice settings, and the highest education associated with the participant’s clinical license. To examine pandemic impacts, we adapted the questions from the COVID-19 Pandemic Mental Health Questionnaire (Rek et al., 2020, 2021) to be more reflective of the third wave of the pandemic when the study took place (e.g., adding a question about COVID-19 vaccine status; removing a question about stocking up on household supplies since it was no longer happening). Participants were asked the following questions (1) Have you or someone close to you tested positive for COVID-19? (yes/no); (2) Has a person close to you died due to COVID? (yes/no); and (3) current employment status (e.g., full-time, laid off due to COVID) and mode of practice (e.g., remote, in-person, hybrid). We also asked about anxiety, depression, sleep disturbance, and irritability or anger experienced in the past 14 days of survey responses. The average score produced excellent internal consistency, ⍺ = 0.83. Responses reflect an average endorsement of pandemic stress within the last 14 days, ranging from 1 = Not at all to 5 = Very much. Video-Recorded Simulations Traumatic stress manifests in many different ways across people’s emotional (e.g., shock, anger, irritability, helplessness), cognitive (e.g., impaired concentration), physical (e.g., fatigue, insomnia), and interpersonal (e.g., increased relational conflict) domains (Substance Abuse and Mental Health Services Administration [SAMHSA], 2014). Using the definitions and examples of typical trauma responses provided by SAMHSA (2014) and our practice experiences in the field, we drafted two simulation scenarios. The scenarios were then revised multiple times upon consultation with clinicians working in relevant fields (e.g., addiction, intimate partner violence, trauma therapy). We hired and worked with professional actors to enact the following scenarios: SC 1, Sophie: A 43-year-old white single woman, who presents emotional distress while raising three children, one of whom is currently in cancer treatment; and SC 2, Reggie: A 32-year-old Black man, who presents relationship distress with his white male partner. An approximately three-minute monologue was video-recorded using Zoom platform for each simulated scenario. Psychosocial Assessment Checklist Using SAMHSA’s (2014) trauma framework, we created a checklist for participants to identify the SCs’ psychosocial functioning in the following domains: emotional, cognitive, physical, and interpersonal. Responses reflect an average rating of the SCs’ functioning in the vignettes in the emotional, physical, cognitive, behavioral, and social domains, ranging from 1 = Least functioning to 5 = Most functioning. Scores were created for each psychosocial domain by averaging items within that domain. A rating of the SCs’ overall functioning was created by averaging the domain scores. For both vignettes, overall functioning scores produced excellent internal consistency, ⍺ = 0.77–0.78. Qualitative We asked a few qualitative questions in the survey. For the purpose of this article, we reviewed participants’ responses to the following question: “Please describe the ways in which your personal and professional life has been impacted by the COVID-19 pandemic.” Data Analysis Quantitative data analyses and assumption checks were analyzed using IBM SPSS v.27 software. All assumptions for each analysis were met and each analysis conducted is outlined in the results portion of this article. Qualitative data were analyzed using qualitative content analysis methods (Bengtsson, 2016; Elo & Kyngas, 2007; Hsieh & Shannon, 2005). Qualitative content analysis allows researchers to inductively summarize text data and identify categories (i.e., themes) on a descriptive level (Vaismoradi et al., 2013) and is appropriate for this study given the limited nature of online responses. Data were analyzed at two stages. We first coded the data independently by two research assistants. We regularly met as a team to review preliminary codes, while any coding disagreements were resolved at research team meetings. As a team, we then grouped these codes into categories. In making the reporting of results (i.e., impacts of COVID-19 onto the clinicians’ lives) accessible to readers, we grouped the categories relevant to either positive or negative impacts. Since the purpose of qualitative research is not to reveal a single ‘reality’ and is rather to interpret the data reflexively, we chose to take on an iterative, team-based process to coding and did not calculate intercoder reliability (i.e., Cohen’s kappa) (O’Connor & Joffe, 2020). To enhance trustworthiness of qualitative data analysis, we maintained individual field notes and reviewed them as a team, discussed preliminary codes as a team from multiple perspectives, took a team consensus on results, and provided sample quotes from participants to illustrate each category in writing up the results (Levitt et al., 2018). Results Quantitative Participant Characteristics The majority of participants were clinicians in Canada (80.1%). Participant age ranged from 24 to 71 years old with a mean of 39. Most were cisgender female (84.2%) and identified as white (72.5%). Due to the small proportion of minorities in this sample, ethnicity was examined as BIPOC or non-white (29.6%) or white (70.4%), wherein those who identified as mixed with white were categorized as BIPOC. Years of experience ranged from one to 20 years with a mean of nine. Sample characteristics are summarized in Table 1.Table 1 Participant demographics n % Gender  Cisgender woman 165 84.2  Cisgender man 26 13.3  Missing/Other 5 2.6 Ethnicity  White/Caucasian 144 73.5  Black Canadian/African American 19 9.7  Asian 10 5.1  South Asian 12 6.1  Indigenous 9 4.6  Middle Eastern/North African 5 2.6  LatinX 1 0.5  Mixed race 1 1.5  Other 2 1.0 Location  Canada 157 80.1  United States 39 19.9 Education  MSW 138 70.4  Other Masters (e.g., Counseling, Nursing) 30 15.3  Doctorate (e.g., PhD, PsyD) 19 9.7 MD 9 4.6 Scope of practice  Counseling 86 43.9  Healthcare 57 29.1  University and higher education 11 5.6  School 10 5.1  Children’s mental health 6 3.1  Government 3 1.5  Child welfare 3 1.5  More than 1 area of practice 6 3.1  Other 14 7.1 Setting type  Agency 122 62.2  Private practice 57 29.1  Both 6 3.1  Unspecified 11 5.6 Someone close to them tested positive for COVID-19 120 61.2 Someone close to them died of COVID-19 20 10.2 Vaccinated at time of study 107 54.6 Psychosocial Impacts To answer RQ 1 (What are the characteristics of clinicians’ psychosocial functioning and coping during the pandemic?), we analyzed participants’ answers to a series of questions relating to the psychosocial impacts of the COVID-19 pandemic. Responses were endorsed on a scale of 0 = Not at all to 4 = Very much. First, participants were asked to report recent psychosocial impacts relating to the pandemic that have occurred in the past 14 days. Most participants reported no or only slight effects relating to anxiety (73.5%), sleep disturbance (52.6%), or irritability (57.1%). Only 28% of participants endorsed recent feelings of depression. In fact, most participants (51.5%) reported being able to cope effectively with the stress caused by the pandemic. Most participants (63.3%) reported no urges or attempts to cope with substances. Most participants (61.7%) also reported no excessive urges to clean or disinfect to avoid contamination. Participants were asked about specific stressors over the course of the pandemic. While some participants reported worries about health (32.7%) and the future (33.7%), most of this sample had little or no financial (64.3%), job (69.9%), childcare (77.6%), housing (58.2%), or interpersonal conflicts (68.4%). When asked about recent stressors, participants generally reported moderate confidence in their government and healthcare system. To answer RQ2 (What are the relationships between clinician characteristics and their psychosocial coping and functioning?), a multiple linear regression was conducted to examine whether provider demographic factors of race, location, years of experience, and institutional setting affect participants’ psychosocial impacts of the pandemic. A nonsignificant model was found (see Table 2, Model 1). An ordinal logistic regression was conducted to examine whether participant demographic factors of race, location, years of experience and institutional setting affect participants’ ability to cope with stress during the pandemic. While a significant model was found (see Table 2, Model 2), no individual predictors significantly predicted the participants’ ability to cope with stress.Table 2 Regressions examining effects of clinician characteristics on clinician psychosocial functioning and assessment of SC overall functioning b SE R2 Model 1: clinician behavior F(5, 180) = 1.62 0.04  Intercept 8.47 1.35  White race 1.26 0.39  Canadian − 0.89 0.79  Years of practice − 0.03 0.05  Agency setting 1.5 1.18  Private practice setting 0.4 1.24 Model 2: clinician stress coping χ2(5) = 9.00 0.05  [Stress = 1] − 2.95* 0.7  [Stress = 2] − 1.45 0.64  [Stress = 3] 0.19 0.62  [Stress = 4] 1.85* 0.64  White race − 0.11 0.32  Canadian 0.12 0.36  Years of practice 0.02 0.02  Agency setting − 0.25 0.54  Private practice setting 0.6 0.57 Model 3: clinician behavior F(2, 193) = 3.16* 0.03  Intercept 12.07 1.27  Positive COVID test − 1.50* 0.6  Vaccinated − 0.02 0.59 Model 4: clinician stress coping F(2, 193) = 0.01 0  Intercept 3.54 0.34  Positive COVID test − 0.01 0.16  Vaccinated − 0.02 0.16 Model 5: overall functioning—Sophie F(2, 188) = 0.18 0  Intercept 2.84 0.09  Gender male − 0.02 0.13  White race − 0.06 0.1 Model 6: overall functioning—Reggie F(5, 187) = 1.09 0.01  Intercept 3.03 0.1  Gender male − 0.2 0.15  White race − 0.09 0.12 The reference group for race is non-white, for Canadian is United States, for gender male is gender female A linear regression was conducted to examine whether the participant’s vaccine status and whether the participant or someone close to them has tested positive with COVID-19 affects the provider’s psychosocial functioning. A significant effect was found (see Table 2, Model 3). Individuals who have themselves or someone close to them test positive for COVID-19 saw a decrease in their psychosocial functioning by 1.5 points (M = 9.62, min = 4, max = 20). While this difference was significant, it was a small effect. A linear regression was conducted to examine whether vaccine status and whether the participant or someone close to them has tested positive affected the provider’s recent ability to cope with stress. No significant effect was found (See Table 5, Model 4). To answer RQ3 (What are the relationships between clinician characteristics and their assessment of SCs?), a multiple linear regression was conducted to examine whether participants’ gender (male/female) and race (BIPOC/white) affected their perceptions of the overall functioning of Sophia and Reggie. For both vignettes, nonsignificant models were found (See Table 2, Models 5 and 6). For this sample, participants’ race and gender did not significantly impact their assessments of the SCs overall functioning. Chi-Square Tests of Independence were conducted to see whether differences in participants’ gender, race, and highest educational training affected their assessment of SCs on individual items. A Bonferroni adjustment was used to adjust for multiple tests; using a significance threshold of 0.001, there were only four significant differences found in this sample. In assessing Sophie, a greater proportion of men than women reported symptoms of difficulty connecting, χ2(1, N = 196) = 10.14, p = 0.001, V = 0.23, and anxiety, χ2(1, N = 196) = 11.64, p = 0.001, V = 0.25. In assessing Reggie, a greater proportion of white participants endorsed substance use issues, χ2(1, N = 196) = 13.98, p < 0.001, V = 0.27. No other significant differences were found. Qualitative Qualitative data were analyzed asking RQ4: How do clinicians experience pandemic impacts on their personal and professional lives? Examples of participant responses for each result (i.e., categories) is shown in Table 3. As shown in previous research (e.g., Danet Danet, 2021; Holmes et al., 2021; Miller et al., 2021), participant responses suggested mostly negative impacts. These negative impacts were as follows: (1) Exacerbated health risks and mental health vulnerabilities; (2) experiences of loss and grief; (3) increased dissonant responsibilities at work and home; (4) difficulties with personal-professional boundary management; and (5) distress over racial injustice in society. First, the pandemic seems to have exacerbated the participants’ risks and vulnerabilities related to health and mental health, such as contracting COVID-19, anxiety, depression, substance abuse. Next, these qualitative data suggested that the pandemic brought a variety of types of losses and grief. For example, participants reported losing loved ones, financial security, employment to a sense of connection with others, as well as associated feelings of grief. Furthermore, participants reported increased dissonant responsibilities in their personal and professional lives due to increased caseload, childcare and caregiving responsibilities at home. This was marked by the participants’ uneasy feelings of having to choose between equally important but sometimes conflicting priorities in their personal and professional lives. Additionally, participants in this survey reported difficulties managing boundaries between their personal and the professional lives. Specifically, the participants reported having to navigate similar experiences shared with clients during the pandemic, especially given that the sessions were taking place remotely from home. Finally, racial injustice exposed by the pandemic, such as state sanctioned violence against Black people, anti-Chinese/Asian sentiment, and reports of racial disparities of health outcomes, appeared to cause much distress in participants.Table 3 Sample qualitative responses Theme Sample quotes Negative impacts  (1) Exacerbated health risks and mental health vulnerabilities “It feels like life is ‘all work and no play’ right now. I have noticed an increase in my alcohol consumption and I experience anxiety or low mood/irritability several days a week (prior to the pandemic, this was not the case).” “Feeling emotionally and mentally burnt out because I feel more helpless and it’s hard for me to navigate this without my go to coping (gym, friends, family) and trying to help others navigate on top of that. Having a way harder time detaching and disconnecting. Have barely slept. Became very anxious when I haven’t struggled with anxiety before.”  (2) Experiences of loss and grief “Personally, due to the death of my husband, I have had to grieve in isolation which has been very difficult. I ache to have my family and friends around me, but it is not possible.” “Continued isolation from friends and family. Working from home (90% of time). Started an additional job due to financial struggles. Death of a family member. Increase work load that results in poor work life balance. Cancelled vacations and celebrations. A delay in starting our journey to family planning.”  (3) Increased dissonant responsibilities at work and home “It has felt incredibly overwhelming and stressful to have to be a support for clients while I am struggling to even support myself and my family. It is a time when there has been widespread struggles with mental health and therefore we have been needed more than ever but we too are negatively impacted by the same things impacting others. And because of the pandemic, the number of clients had increased, as has the severity of people’s symptoms. Oh and we are also trying to do home school or attend to our own family’s mental health struggles and it is just too much!” “It has been a difficult decision to send my other child back to school due to concerns about covid and some health issues that she has. The hardest part is questioning every decision and feeling like there is no decision that is the 'right' one. Always second guessing”  (4) Difficulties with personal-professional boundary management “I have shifted from working at the office everyday to working fulltime in my tiny apartment. There is no healthy separation between my work life balance. I am finding it increasingly difficult to maintain a boundary between the two.” “I also feel that lack of separation from home and work and engaging in emotional work while in the sacred space of home has impacted burnout and stress as well. Holding space for clients, hearing stories of trauma and walking out of my ‘office’ into my home, into a room with my children (during times of online learning) was extremely difficult.”  (5) Distress over racial injustice in society “I think that I have been more emotionally impacted by the Black Lives Matter movement and recent gun violence than be COVID-19.” “I have been concerned about the BLM movement, as I have seen how it has significantly impacted our working conditions and what my colleagues have had to endure for so many years. I also have been effected, being a South Asian female, as racism has been a part of my life as well.” Positive impacts  (1) Benefits of online support for client “Due to my work moving online I am now working with a broader population in the state. This now includes those who are typically in more insular and rural areas. In many ways, the shift to telework has increased access to mental health and substance use services. I am seeing people who might not have had access to these services otherwise. Further, I have heard reports from many of my patients that these services being online made it easier to reach out.”  (2) Greater access to self-care and personal or professional development “Quite a few clients who have anxiety or agoraphobia find it easier to be present in sessions with me because they are in their home/ safe place; they have increased communication with their other health care providers as well on account of this so the health care that they are able to receive is more fitted to their situation (this is accessibility related). It will be important to continue having services available remotely.”  (3) Greater awareness of structural inequality and privilege “I have been able to spend more time with my friends getting together outside for walks which I haven't been able to do in many years due to being far too focused on my work.” “Something that helped me so much was attending psychotherapy training and conferences online. Meeting and interacting with other professionals who did not know me was so great. I have a clinical supervisor and a clinical supervision group and all that helped but the trainings at least once a week and on occasion 3 times a week kept me sane.” “I have experienced much of the pandemic in a very privileged position. I am able to work from home, my partner is able to do the same and we live well together. I have been able to keep my job, and am financially stable. I recognize my privileged position daily.” “I am privileged to have maintained employment throughout this pandemic. Finances have been tight, however my work was able to move online. I also do not have children, so childcare was not an issue. I was also privileged enough to support the BLM protests and movement in my city while protecting my personal health.” Participants also shared several, perhaps inadvertently positive impacts on their personal and professional lives during the pandemic. These positive impacts were as follows: (1) Benefits of online support for clients; (2) greater access to self-care and personal or professional development; and (3) greater awareness of structural inequality and privilege. First, the shift to online therapy, triggered by the pandemic, allowed greater access to therapeutic services among clients with whom the participants could not have worked otherwise, such as those who live in rural areas or do not have accessible transportation. Second, the pandemic afforded the participants more time with their families and for their own self-care activities. Similarly, the pandemic offered them a greater accessibility to online resources for professional development (e.g., continuing education courses). Finally, the pandemic especially exposed various structural inequalities and provided participants with a learning opportunity about social problems (e.g., racial inequality) as well as their own personal and/or professional privileges. Discussion This mixed-methods survey explored experiences of shared trauma among mental health clinicians during the COVID-19 pandemic. This study offered a methodological innovation. We employed two video-recorded SC monologues as a way to elicit the participants’ clinical response. The use of SCs offered a novel, methodological advantage (Asakura et al. 2021) that allowed participants to share their immediate clinical assessment without ethical concerns of involving real clients during such a vulnerable time. Rather than inquiring retrospectively about their practice, this allowed us to survey clinicians about their practice while they too lived in the midst of the pandemic. This is a unique contribution of this study to the literature. Our quantitative results showed that clinicians might experience psychosocial impacts of the pandemic (e.g., sleep difficulties) similarly to client and general populations, as supported by previous research (e.g., Miller et al., 2021). While these experiences might not be necessarily traumatic (i.e., deeply distressing and impactful) for all clinicians, this certainly suggests that there is a shared experience between clinicians and general populations during the times of COVID-19. On the other hand, the majority of our participants reported coping relatively well with the pandemic. This is corroborated by previous literature that suggests that experienced and highly-trained clinicians may effectively utilize necessary coping skills even during times of distress (Bauwens & Tosone, 2010; Holmes et al., 2021; Tosone et al., 2014). Our results also showed little relationship between clinicians’ personal characteristics and the psychosocial impacts of the pandemic on them. Additionally, there was little relationship between clinicians’ experiences with the pandemic, their personal characteristics (e.g., race, location) and their clinical assessment of the two SCs. This suggests that the clinicians’ own experience during the pandemic might not necessarily act as a barrier in their professional ability to understand clients. This is certainly encouraging and might point to the professionalism that allows these clinicians to uphold their practice skills despite their shared experience of the pandemic. This might also be explained by the timing of data collection. Given that these clinicians already had a full year (since the onset of pandemic in Spring 2020) of involvement with clients while navigating the pandemic themselves, they might have had sufficient time and practice to foster a work-life balance by the time of this survey. Another possible explanation could be the sampling bias of our study. Given that white, cisgender individuals typically fare better during the pandemic than marginalized populations (Gianfrancesco et al., 2021; Kamal et al., 2021; Lund, 2020; Ruprecht et al., 2020; Sze et al., 2020), our sample—predominantly white and cisgender—could explain the results of minimal psychosocial impacts of the pandemic. To add, the majority of participants resided in Central Canada and their experiences might be context-specific to the political, social and economic climate of this location. Finally, it is also plausible that highly overwhelmed clinicians could not afford to participate in this time-consuming study in the first place due to their own personal time and capacity constraints. Interestingly, our quantitative data revealed that testing positive for COVID-19 or knowing someone who has tested positive for COVID-19 may elicit a decrease in clinician psychosocial functioning compared to those who were vaccinated, did not test positive, and did not know anyone who tested positive. Since the study was conducted in the midst of the pandemic and there was still so much unknown about the long-term effects of COVID, these participants may have felt more stressed as a result of this uncertainty. Despite the quantitative results, qualitative results showed a more nuanced understanding of the clinicians’ pandemic-related experiences, corroborated by previous empirical studies highlighting clinicians’ experiences with anxiety (Ashcroft et al., 2021; Greene et al., 2021), depression (Greene et al., 2021), and grief and loss (Holmes et al., 2021). Our qualitative results also revealed the impacts of the larger sociopolitical climate at the time of this study, including the Black Lives Matter Movement and anti-Asian sentiments, on clinician wellbeing. As corroborated in others’ work (Chae et al., 2021; Lipscomb & Ashley, 2020), the emotional distress and feelings of helplessness of clinicians exposed to anti-Black and anti-Asian racism were also revealed in the qualitative portion of our study. The strength of qualitative research lies in its ability to elicit participants’ complex thoughts and feelings that often cannot be captured in a quantitative survey alone. Without the qualitative aspect of this study, our results likely failed to fully understand these socio-political contexts of the pandemic and their psychosocial impacts on those working at the frontline. Our qualitative results add nuances to the existing relevant literature. The pandemic has generated feelings of increased dissonant responsibilities in clinicians’ personal and professional lives, marked by feelings of having to choose between equally important, but often conflicting, priorities (e.g., pressures to support clients while having to support themselves and their families). Clinicians also reported difficulties building and maintaining relationships with colleagues or accessing peer support in the remote working condition. Although our quantitative results showed that the majority of participants were relatively “doing well,” our qualitative results certainly suggest that clinicians’ own pandemic-related experiences remain a concern. From living and working in the same space, helping clients who share similar situations, to managing increased personal and professional responsibilities, these results suggest the importance of managing isolation and navigating a work-life balance during the pandemic. Especially given that self-care has been now added to the NASW Code of Ethics (Murray, 2021), to support clinicians in enhancing their self-care practices is a vital responsibility for those engage in clinical education, supervision, and clinical practice with helping professionals. As suggested by previous literature on shared trauma (Holmes et al., 2021), our results suggested that extraordinary events like the pandemic could provide constructive opportunities for clinicians. Our findings showed that remote working conditions afforded clinicians with new opportunities, such as having more time for continuing education, enhancing service access for hard-to-reach clients, and engaging in racial and social justice work. Despite the struggles participants reported, the pandemic also created an opportunity for further learning, enhanced empathy, compassion and connectedness in clients during this distressing time, which has also been echoed by others who study shared trauma (e.g., Bauwens & Tosone, 2010; Nuttman-Shwartz & Dekel, 2009). Clinicians are encouraged to keep these promising results in mind while supporting clients during distressing times. Limitations Several limitations must be taken into account when readers interpret the study results. While the online survey allowed us to recruit clinicians from various disciplines from two countries, there was no way to verify that respondents were licensed clinicians who met all of the study criteria. As well, despite our concerted efforts to recruit diverse participants, our sample was predominantly white, cis-women from Canada. Given how differently the pandemic impacted and was handled across states/provinces and countries, readers are cautioned to interpret our study results when discussing clinicians in other geographical and social contexts. This biased sampling occurred likely because initial recruitment reached potential participants through the research team’s local professional networks in our predominantly white mid-sized Canadian city, and we closed the survey when the first 200 responses were recorded. This was certainly a missed opportunity given the well-documented health disparities among marginalized groups during COVID-19 (Gianfrancesco et al., 2021; Lund, 2020; Sze et al., 2020). Additional target recruitment efforts (e.g., recruiting BIPOC clinicians first) are warranted in future research to better capture the experiences of those from marginalized communities. Given the urgent and constantly changing nature of the pandemic and its impacts, we were unable to locate a scale that fit perfectly for the purpose of this study. We used a newly developed scale on the pandemic impacts on mental health (Rek et al., 2020, 2021) by adapting some questions to better suit the pandemic context in which this study was conducted (i.e., the public was better informed of the virus by this point). These modifications were necessary for us to accurately capture participant response in this particular pandemic wave and context. The reliability of the modified scale (⍺ = 0.83) aligned with that of the original instrument (Rek et al., 2020, 2021). While face validity of the modified scale was ensured by those in the research team that worked in the field as frontline social workers, these modifications likely changed the construct validity of the scale. This is certainly a study limitation. Once more researchers have used this scale to conduct similar studies on mental health clinicians, a validation study can and should be conducted to further strengthen the scale. Doing so will contribute greatly to advancing research in this area. Another limitation of the study is the fixed nature of qualitative data collected in an online survey format. Unlike interview or focus group data, participant response could not be elaborated, which limited our ability to contextualize the data during analysis. We also were unable to engage in member-checks or participant feedback on results (Levitt et al., 2018). Finally, the survey did not include several important variables, such as parenting status, caregiving responsibilities, and ages of children—all of which could have impacted participants’ experiences with pandemic. At the time of this article, the COVID-19 pandemic is not yet behind us, and global crises will continue to impact the lives of clients and clinicians. Taking these limitations into account, further research on clinicians is needed to further advance our knowledge base of shared trauma. Conclusion This mixed-methods study surveyed 196 clinicians in Canada and the U.S. on their pandemic-related experiences during the third wave of the pandemic (Spring 2021). In addition to using traditional survey items (e.g., demographics, scales, and short answers), we also used video-recorded monologues of two SCs in order to elicit the clinicians’ assessment of SCs. Clinicians reported similar psychosocial impacts of the pandemic to client and general populations, though more than half of them reported coping well with the pandemic. Our study results on the participants’ assessment of SCs also suggests that clinicians’ pandemic-related experiences might not necessarily negatively impact clinical practice, and clinicians are relatively well-equipped to support clients well even in times of global distress. As we continue to live and work in the times of COVID-19, our study supports the importance of assisting clinicians in navigating a work-life balance and further developing empirically-grounded knowledge about shared trauma and its positive and negative impacts on clinicians. Funding This study was funded to Drs. Kenta Asakura and Amedeo D’Angiulli by Carleton University COVID-19 Rapid Response Research Grant, School of Social Work Evelyn Maud McCorkle Research Fund, and Faculty of Public Affairs Research Productivity Bursary. Declarations Conflict of interest All authors declare that we have no conflict of interest. Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 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Springer. 10.1007/978-3-030-61442-3_36 Vaismoradi M Turunen H Bondas T Content analysis and thematic analysis: Implications for conducting a qualitative descriptive study Nursing & Health Sciences 2013 15 3 398 405 10.1111/nhs.12048 23480423 Volk A Brazil K Franklin-Luther P Dane A Vaillancourt T The influence of demographics and personality on COVID-19 coping in young adults Personality and Individual Differences 2021 168 1 7 10.1016/j.paid.2020.110398 Wu J Scarabel F McCarthy Z Xiao Y Ogden NH A window of opportuynity for intensifying testing and tracing efforts to prevent new COVID-19 outbreaks due to more transmissible variants Canada Communicative Disease Report 2021 47 7/8 329 338 10.14745/ccdr.v47i78a06

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==== Front Eur Phys J E Soft Matter Eur Phys J E Soft Matter The European Physical Journal. E, Soft Matter 1292-8941 1292-895X Springer Berlin Heidelberg Berlin/Heidelberg 254 10.1140/epje/s10189-022-00254-7 Regular Article - Soft Matter UV light sensing and switching applications of dimeric smectic liquid crystals: comparative calculations Das Punyatoya 1 Jose T. Jaison 2 Ghosh Aritra 3 Praveen P. Lakshmi plpraveen_phy@vssut.ac.in 1 1 grid.449922.0 0000 0004 1774 7100 Department of Physics, Veer Surendra Sai University of Technology, Burla, Sambalpur, Odisha 768018 India 2 grid.448848.c 0000 0004 1766 2545 P.G. Department of Chemistry, Andhra Loyola College, Vijayawada, Andhra Pradesh India 3 grid.8391.3 0000 0004 1936 8024 College of Engineering, Mathematics and Physical Sciences, Renewable Energy, University of Exeter, Penryn, TR10 9FE UK 15 12 2022 2022 45 12 9814 10 2022 23 11 2022 © The Author(s), under exclusive licence to EDP Sciences, SIF and Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Two dimeric smectic molecules, namely α-ω-bis (4-n-pentylanilinebenzylidene-4′-oxy) butane (PABO4) and α-ω-bis (4-n-pentylanilinebenzylidene-4′-oxy) pentane (PABO5), have been considered for sensing UV light. The compounds’ optimization process has been performed through B3LYP hybrid functional together with basis set 6-31+G (d) using the input parameters from the crystallographer. The absorption of UV analysis of these compounds has been estimated, and the configuration interaction single-level method has been used to analyse the electronic transition features coupled with the calculation of excited states using semi-empirical Hamiltonian ZINDO. The CNDO/S, INDO/S together with CI approaches, has been utilized for comparative evaluation. The spectral-associated parameters have been summarized. The molecules discussed in this manuscript present several features, viz. the absorption range of the molecules that is sensitive to different wavelengths, the usage in flexible devices, offering the prospect for UV sensors. Further, the switching applications have been explored based on the oscillator strength data in various regions of wavelengths. Graphical abstract issue-copyright-statement© EDP Sciences, SIF and Springer-Verlag GmbH Germany, part of Springer Nature 2022 ==== Body pmcIntroduction The orientational ordering basically characterizes the liquid crystalline (LC) state [1]. The transitions among various mesophases are associated with transformations in the molecular local order [2], which are noticeable by various anisotropic properties [3]. Structural design and practicality are crucial facets in the engineering of LC molecules for managing the physical properties and constancy of mesophases [4]. The preliminary awareness of LC dimers [5–7] arose from their prospective use as model molecules that help in the understanding of complex polymeric systems. However, these dimers attained noteworthy attention as they exhibit fairly dissimilar behaviour to usual small molar mass LCs. The LC dimers consist of mesogenic blocks alienated by stretchy spacers, and end chains. It is composed of molecules containing two conformist mesogenic groups connected via a flexible spacer. Further, in a dimer system, the non-symmetry may be initiated by bonding two singular mesogenic units, altering the terminal chain length, using terminal groups, or by varying the spacer group length and parity [8]. Hence, the focus on this type of system is at a substantial level for their application potential. However, device applications based on these systems need special attention due to their rich phase structure, transition properties, and better viability. The extended aromatic structures favour intense optical absorption and related optical properties [9]. Such subtle and delicate sensitivity [10] is accountable for their operation as stimuli-responsive materials in various applications such as visualization, display, sensor, and switching technology [11]. Consequently, passionate research attempts are continuously initiated at implementing LCs [12, 13] as quick-response, sensitive, and minimum-cost materials for sensor applications. Further, now the liquid crystal biosensors are emerging [14, 15]. These light sensing based on LC devices act as unswerving platforms for identifying the chemical and bio-chemical processes [16, 17]. Recently, liquid crystal-based immunosensor [18] has been developed to detect anti-SARS-CoV-2 antibody for the diagnosis of past-COVID-19 infection. Therefore, sensing and switching applications based on LCs are high in demand. The smectic compounds are 2D (two-dimensional) liquids that contain a monomolecular stack of layers. The molecular positions in each of these are translationally more or less disordered. The LC dimer systems possess opto-electronic functionality [19] along with the self-organizing ability [20] in various continual mesophases that favours free defect films due to their conjugation degree. Therefore, they are very much functional for building optoelectronic and sensing devices. In this framework, the studies on LC dimers with better chromophores [21] have to be reported for both elementary science and realistic applications. This manuscript has been aimed toward the exploration of dimeric smectic molecules PABO4 and PABO5 for sensing UV light applications. The DFT method has been used for this intention and for the optimal geometries calculation. The convolution of absorption spectra has been made based on the time-dependent DFT theory [22] along with the CIS method [23]. The Hamiltonian ZINDO [24, 25] has been implemented for the calculation of excited states. The results estimated have been summarized and matched to the CNDO/S + CI [26] and INDO/S + CI approaches [27]. The stability of the compounds in the UV wavelength region and sensing capability has been studied. The spectral data have been reported. Both dimer molecules exhibit smectic behaviour as evident from the literature [28]. Methods The molecular UV spectra of PABO4 and PABO5 have been described by employing the DFT calculation method. These calculations are liable to estimate the ground-level properties with correctness [29, 30] closer to the post-HF approaches. The accuracy of excitation energies depends on the exchange–correlation function used. The hybrid functional execution suggests the consistent excitation of vertical energies together with analysis of charge transfer. Therefore, the structure-based aspects have been analysed via the ‘hybrid’ density B3LYP functionals [31–33] and ‘precise exchange’ in coupling with the gradient-suitable density functionals. Further, the structural optimization process has been performed via the DFT-B3LYP approach [34, 35], along with 6-31G+(d) basis set. The required structural, energy data and wave functions are studied by approximating the single-level configuration interaction (CI) of with π → π* excitations. This procedure has been widely accepted and sufficient to guesstimate the absorption spectra in UV-visible region. The SORCI (spectroscopy-oriented configuration interaction) method [31, 36] has been used for the DFT calculations. The DFT data has been matched up with the CNDO/S + CI and INDO/S + CI approaches. A modified version of QCPE 174 was executed for this. The crystallographic information files have been utilized for molecular construction [28]. Discussion of results Figure 1 shows the structures of PABO4, PABO5 molecules. The description of the UV absorption spectra is as follows:Fig. 1 Geometry of a PABO4 and b PABO5 molecules UV spectra UV spectroscopy is one of the primary techniques used to characterize molecules and their complexes. The logical elucidation of absorption spectra can offer important and often distinctive data about the structure and electronic properties of molecular assemblies. Model molecules of varying complexity can be utilized to infer these spectra. The general and simple view typically entails the analysis of absorption bands. Widespread handling using various computational approaches offers an extensive depiction of the electronic states of the molecular complex and the transitions between them [37–39]. One main centre of attention of this perception is the distinctive absorption spectral aspect that occurs with respect to the inclusion of end chains. The interpretation of these spectral aspects can be repeatedly analysed within the outline of a suitable model to construct a molecular database. The LC molecules consist of fixed aromatic conjugated blocks and absorption spectral analyses considered to be crucial that direct the necessary properties in the bulk phases of LC molecules. Absorption spectral profiles of PABO4 and PABO5 are shown in Fig. 2 and Fig. 3 using the above three methods, respectively. The comprehensive spectral feature data are given in Table 1. The data from the table indicated that PABO4 molecule reveals the highest absorption wavelength (corresponding to a large value of extinction coefficient) in the UV region at 220.51 nm, 296.09 nm, and 207.83 nm correspondingly using DFT, CNDO/S, and INDO/S data correspondingly. Similarly, in the UV region, the PABO5 reveals absorption highest wavelength at 205.86 nm, 306.05 nm, and 311.91 nm correspondingly with the DFT, CNDO/S, and INDO/S data correspondingly. All these electronic bands corresponding to the highest absorption wavelength are recognized as a consequence of the transition of HOMO → LUMO and are considered as π → π* molecular transitions.Fig. 2 UV absorption profile molecules PABO4 molecule using DFT, CNDO/S, and INDO/S methods Fig. 3 UV absorption profile molecules PABO5 molecule using DFT, CNDO/S, and INDO/S methods Table 1 The absorption bands (AB), extinction coefficients (EC), oscillator strength (f), vertical transition energy (EV), HOMO (H), LUMO (L) energies, and the band gap (Eg = ELUMO − EHOMO) of PABO4 and PABO5 molecules Molecule Method AB/nm EC* f EV/eV PABO4 DFT 201.17 1.02 0.39 6.15 220.51 1.70 0.43 5.60 301.95 0.96 0.92 4.11 330.08 0.19 0.18 3.75 350.00 0.29 0.29 3.54 H = − 7.74 eV, L = − 0.39 eV, Eg = 7.35 eV CNDO/S 203.51 1.59 0.25 6.04 296.09 1.66 1.30 4.15 H = − 8.44 eV, L = − 1.42 eV, Eg = 7.02 eV INDO/S 207.03 1.31 0.34 6.00 278.51 0.99 0.84 4.44 308.98 1.05 1.00 4.01 H = − 7.28 eV, L = − 0.34 eV, Eg = 6.94 eV PABO5 DFT 205.86 1.22 0.22 6.03 224.02 1.12 0.13 5.52 289.65 0.24 0.22 4.28 318.95 0.46 0.46 3.89 343.55 0.73 0.64 3.60 H = − 7.68 eV, L = − 0.55 eV, Eg = 7.13 eV CNDO/S 245.12 0.21 0.20 5.07 306.05 2.04 1.79 4.05 H = − 7.22 eV, L = − 0.48 eV, Eg = 6.82 eV INDO/S 209.37 0.92 0.03 5.94 252.73 0.32 0.31 4.91 311.91 1.17 0.88 3.99 H = − 7.22 eV, L = − 0.48 eV, Eg = 6.74 eV Bold value represents λmax/nm. *EC unit: 104 dm3 mol−1 cm−1 Upon comparing these wavelengths, one may notice that when we move from PABO4 to PABO5, the DFT data show a hypochromic effect (blue-shift), whereas both semiempirical approaches show a red-side move of wavelength with a hyperchromic effect. In general, the hypsochromically moved bands are in general deemed to be a sign of the strong coupling of excitons. The electronic excitation is not restrained to one of the chromophores and gets delocalised over the array of chromophores when the many chromophores are positioned in closer spatial propinquity. This is known as exciton coupling which is of fundamental importance and determines the functional properties of molecules for various types of devices. Hence, distinct absorption trends are expected for the molecules under analysis. The shifts towards the red wavelength side in this analysis are noticed owing to the lowering in transition (Table 1), whenever electron excitation occurs. Therefore, this leads to much dominant electrostatic interaction of absorption bands and further variation in charge distribution. This, in turn, enhances the delocalization of electrons. One more noteworthy aspect of this study is the extent and strength of chromophores during the coupling of excitons that induces n → π* type of transitions. It may be understood that the prime influencing factor for these type of transitions is controlled by the rigidity of molecular ring structure that further alters the remaining spectral features. UV light sensing applications The research studies and understanding of the procedures happening upon molecular irradiation with ultraviolet (UV) light are imperative as these procedures may direct to the dreadful conditions of molecules that hamper the device's performance. The photophysics and chemistry of the molecular chromophores have been considered comprehensively. The photophysical properties of mono-molecules are fairly well understood; however, the nature of the photo-initiated processes in several molecular chromophores is still under debate. The largest wavelength in the UV absorption region for PABO4 has been noticed to be 350 nm (DFT), 296.09 nm (CNDO/S), and 308.98 nm (INDO/S). The PABO5 molecule demonstrates the largest absorption wavelength in the UV region at 343.55 nm (DFT), 306.05 nm (CNDO/S), and 311.91 nm (INDO/S) (data of Table 1). The extinction coefficient values corresponding to these wavelengths are found to be greater for PABO5 molecule. Therefore, from the majority of the above data from Table 1, we may observe that below 400 nm, PABO5 molecule absorbs UV larger wavelength that revealing the more UV light sensing capability for this molecule. Hence, this molecule has been deemed to be greatly flexible for UV region electronic transitions. The visible display features of both molecules have been considered to be of great level since no absorption visible region has been observed for both the molecules. The exciton theory from the perturbation view may be understood by the conserved nature of chromophores by their individuality; the coupling trend of excitons is illustrated as a relation amid the transition fluctuating transition dipole moments that are localized. This kind of couple leads towards the splitting of the excited energy state which modifies the discrepancy in the absorption spectral features. The flexibility of transitions Computational evolution helps in establishing an unyielding direction in analysing the molecular transitions and properties of a targeted chromophore. Detailed study of the spectra in the UV–Vis region helps in understanding the details of the structure and their probable applications, and the analysis of the transition that is liable for the requisite absorption of light. For the occurrence of a transition, the dipole that oscillates should be excited through the electric field interaction along with the electromagnetic waves externally. The oscillator strength is estimated by depicting the coefficient of line absorption that helps to quantify the flexibility of transitions and their strength. Figure 4 illustrates the flexibility of transitions for PABO4 molecule based on the three methods as mentioned. The chosen region of wavelength is the same approximately for the plotting of the oscillator strength offset values. The DFT data reveal that the initial point of wavelength for PABO4 is 201.7 nm, and the final point is 309.04 nm, which shows the transitions are in the 100.1-nm region. In the same way, a UV region of 97.84 nm and 109.67 nm for PABO4 has been observed based on CNDO/S and INDO/S approaches. A similar view of PABO5 molecule from Fig. 5 indicates a UV region of 143.9 nm (DFT), 104.83 (CNDO/S), and 110.81 nm (INDO/S). Therefore, a wider region in terms of UV wavelength has been observed for PABO5 compared to PABO4 based on any chosen method. It has been noticed that sudden rise in the oscillator strength data at a specific wavelength for both the molecules. This enhances and induces the extinction coefficient data and spectral characteristics. This implies that the molecules under investigation are appropriate for light modulator devices.Fig. 4 Offset oscillator strength value as a function of wavelength of PABO4 using three methods Fig. 5 Offset oscillator strength values as a function of wavelength of PABO5 using three methods Switching applications In order to understand the switching applications, the oscillator strength data based on the DFT approach are analysed in Fig. 6. From the figure, one may notice that the lower left quadrant contains maximum data points with an oscillator strength value between 0 and 0.4 within the wavelength region of 200 nm to 280 nm. The lower right side quadrant contains oscillator strength data points with oscillator strength values between 0 and 0.4 with a wavelength region between 280 and 360 nm. Further, the top left and right quadrants contain a minimum number of oscillator strength data points from 0.6 to 1. The top left quadrant within a wavelength region 200 nm to 280 nm contains three data points, and the top right quadrant with a wavelength region contains two data points. The quadrant-wise analysis clearly indicates the transition flexibility of the molecules.Fig. 6 Analysis of wavelength versus oscillator strength in quadrant system using DFT method The DFT highest oscillator strength value for PABO4 molecule has been found to be 0.99 corresponding to 218.6 nm, and the minimum value has been found to be 0.001 corresponding to 279.5 nm. Therefore, the wavelength difference of 60.9 nm has been noticed for a relative oscillator strength value of 0.989. In the same way, PABO5 molecule exhibits the highest and lowest oscillator strength values of 0.64, 0.002 corresponding to 344 nm, 284.2 nm, respectively. Hence, the wavelength difference of 59.8 nm has been noticed for relative oscillator strength of 0.638. This analysis reveals that the minimum wavelength region has been found for PABO5 molecule confirming better switching applications. However, a better relative oscillator strength value has been noticed for the PABO4 molecule that revealing a better light modulation capability. The analysis of wavelength versus oscillator strength in quadrant system using CNDO/S and INDO/S methods is presented in Figs. 7 and 8, respectively. A similar analysis using INDO/S data is in clear agreement with the DFT data revealing PABO5 molecule to exhibit better switching and PABO4 molecule for better light modulation applications. However, CNDO/S method shows some discrepancy in agreeing on this result. The discrepancy in analysing the data of the electronic transitions of the compounds is in general implicit as a sign of the scope of charge estimation and distribution of molecules.Fig. 7 Analysis of wavelength versus oscillator strength in quadrant system using CNDO/S method Fig. 8 Analysis of wavelength versus oscillator strength in quadrant system using INDO/S method Components of energy The components of energy have been accounted for in Table 1. It is apparent from the data that all the energy components are moderately sensitive to the number of carbon atoms number in the linking group. The HOMO energies increment, the decrement in gaps of L–H and the transferred red side transition energies in general are featured in the enhanced interactions that are delocalized. The gap of L–H decrements from the table clarifies the features of red-shift of the compound. Moreover, the decreased gaps of L–H designate the many intermolecular prominent interactions, which are necessary to be promoted for spectral red-side shift. The relative end results disclose that the PABO5 molecule has a low value of band gap that causes greater conductivity compared to PABO4. Therefore, the lower gap confirms the eventual charge transport molecular interactions. Conclusions The current work on dimeric smectic compounds signifies that the PABO5 molecule shows a greater UV wavelength that confirms the UV higher stability. Further, lower than 400 nm, PABO5 absorbs a greater UV wavelength that signifies greater sensing capability in the UV region. The visible display features of both molecules have been considered to be of great level since no visible absorption region has been observed for both molecules. There is a sudden rise in the oscillator strength data at a specific wavelength for both the molecules. This enhances and induces the extinction values and spectral characteristics. This implies the molecules under investigation are appropriate for light modulator devices. This analysis reveals that the minimum wavelength region has been found for PABO5 molecule that confirms better switching applications. However, a better relative oscillator strength value has been noticed for PABO4 molecule revealing a better light modulation capability. Author contribution P.D., T.J.J., and A.G. did conceptualization, work design, and formulation of the problem; P.D., T.J.J., A.G., and P.L.P. performed formal analysis, investigation, and paper writing; P.L.P. done supervision and correcting the manuscript. Funding Nil. Data availability statement Not applicable. Declarations Conflict of interest The authors declare no conflict of interest. Novel Molecular Materials and Devices from Functional Soft Matter. Guest editors: Jean-Marc Di Meglio, Aritra Ghosh, Orlando Guzmán, P. Lakshmi Praveen. ==== Refs References 1. Patari S Chakraborty S Nath A Liq. Cryst. 2016 43 1017 10.1080/02678292.2016.1155767 2. Kumar BVNP Mattea C Stapf S Dabrowski R Liq. Cryst. 2017 44 1494 10.1080/02678292.2017.1290289 3. Kishor MH Mohan MLNM J. Electr. Mater. 2020 49 2311 10.1007/s11664-020-07944-y 4. Reddy MK Reddy KS Kumar BVNP Narasimhaswamy T Mol. Cryst. Liq. Cryst. 2014 593 1 10.1080/15421406.2013.858013 5. Ramakrishna DS Jose TJ Lakshmi Praveen P J. Mol. Struct. 2021 1236 130336 10.1016/j.molstruc.2021.130336 6. Walker R Pociecha D Stroey JMD Gorecka E Imire CT J. Mater. Chem. C 2021 9 5167 10.1039/D1TC00904D 7. Perju E Marin L Molecules 2021 26 2183 10.3390/molecules26082183 33920141 8. Viswanath LCK Senthil S Mol. Cryst. Liq. Cryst. 2017 656 12 10.1080/15421406.2017.1386518 9. Lakshmi Praveen P Ojha DP Phase Trans. 2014 87 641 10.1080/01411594.2013.879478 10. Lakshmi Praveen P Ojha DP J. Phys. Chem. Solids. 2012 73 57 10.1016/j.jpcs.2011.09.017 11. Kataoka M Okada H Liq. 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Chem. 2014 1040–1041 84 98 10.1016/j.comptc.2014.04.002 35. Lakshmi Praveen P Ojha DP J. Mol. Liq. 2014 194 8 10.1016/j.molliq.2014.01.002 36. Ojha DP Lakshmi Praveen P J. Phys. Chem. Solids 2012 73 57 10.1016/j.jpcs.2011.09.017 37. Das P Lakshmi Praveen P IOP Conf. Ser. Mater. Sci. Eng. 2020 798 012041 10.1088/1757-899X/798/1/012041 38. LakshmiPraveen P J. Mol. Liq. 2021 341 117424 10.1016/j.molliq.2021.117424 39. LakshmiPraveen P J. Mol. Liq. 2021 343 117620 10.1016/j.molliq.2021.117620

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Eur Phys J E Soft Matter. 2022 Dec 15; 45(12):98

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Eur Phys J E Soft Matter

10.1140/epje/s10189-022-00254-7

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==== Front Nervenarzt Nervenarzt Der Nervenarzt 0028-2804 1433-0407 Springer Medizin Heidelberg 1417 10.1007/s00115-022-01417-9 Leitthema Neurointensivmedizin und COVID-19 Neurointensive care medicine and COVID-19Dimitriadis Konstantinos konstantin.dimitriadis@med.uni-muenchen.de 12 Schmidbauer Moritz 1 Bösel Julian 3 1 grid.5252.0 0000 0004 1936 973X Neurologische Klinik, Universitätsklinikum LMU München, München, Deutschland 2 grid.5252.0 0000 0004 1936 973X Institut für Schlaganfall- und Demenzforschung (ISD), LMU München, Feodor-Lynen-Str. 17, 81377 München, Deutschland 3 grid.5253.1 0000 0001 0328 4908 Neurologische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland 15 12 2022 17 9 11 2022 © The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Die vorliegende Übersichtsarbeit fasst wichtige Erkenntnisse der Schnittstellen Corona-virus-disease-2019(COVID-19)-Pandemie und Neurologie mit Fokus auf Neurointensivmedizin zusammen. Insbesondere werden auf Prävalenz, Pathomechanismen und Auswirkungen neurologischer Manifestationen eingegangen. Die häufigsten Manifestationen schwer kranker Intensivpatienten sind zerebrovaskuläre Komplikationen, Enzephalopathien und die „intensive care unit-acquired weakness“ (ICUAW). Ein direkter, neurodestruktiver Effekt durch das Virus an sich konnte bisher nicht sicher nachgewiesen werden. Vielmehr kommen ursächlich durch die virale Infektion ausgelöste systemische inflammatorische Prozesse sowie Nebenwirkungen der intensivmedizinischen Therapie infrage. Die Auswirkungen der Pandemie auf Patienten mit neurologischen Erkrankungen und die Neurointensivmedizin sind weitreichend, aber noch nicht ausreichend untersucht. This review article summarizes important findings on the interfaces between the coronavirus disease 2019 (COVID-19) pandemic and neurology with an emphasis of the implications for neurointensive care medicine. More specifically, the prevalence, pathomechanisms and impact of neurological manifestations are reported. The most common neurological manifestations of critically ill COVID-19 patients are cerebrovascular complications, encephalopathies and intensive care unit-acquired weakness (ICUAW). A relevant direct pathophysiological effect by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) itself has not yet been established with certainty. In fact, indirect systemic inflammatory processes triggered by the viral infection and side effects of intensive care treatment are much more likely to cause the reported sequelae. The impact of the pandemic on patients with neurological disorders and neurointensive care medicine is far-reaching but not yet sufficiently studied. Schlüsselwörter SARS-CoV‑2 Neurologische Manifestationen Prävalenz Pathomechanismen Intensive care unit-acquired weakness Keywords SARS-CoV‑2 Neurological manifestations Prevalence Pathomechanisms Intensive care unit-acquired weakness ==== Body pmcIm Rahmen der Coronavirus-disease-2019(COVID-19)-Pandemie wurden neurologische Manifestationen (NM) beschrieben, die zunächst als direkter Effekt der viralen Infektion diskutiert wurden. Zum anderen kam es zu einer Reihe von Berichten über „neurologische Kollateralschäden“ verbunden mit COVID-19-assoziierten Therapien, den Impfstoffen, den fehlenden Ressourcen in der Versorgung anderer neurologischer Erkrankungen, der Umstrukturierung von neurologischen Stationen inklusive Neurointensivstationen sowie Einschränkungen in Forschung und Ausbildung. Ziel dieses Artikels ist ein Überblick über den Einfluss der COVID-19-Pandemie auf die oben genannten Aspekte mit besonderem Fokus auf die Neurointensivmedizin zu geben. Neurologische Manifestationen von COVID-19 Manifestationen und Prävalenz Das Spektrum und die Ausprägung der durch SARS-CoV‑2 verursachten Symptome variieren stark. Neben den beschriebenen allgemeinen Erkältungssymptomen bis hin zu respiratorischer Insuffizienz und Multiorganversagen wurden seit Beginn der Pandemie auch NM beschrieben. Seit einer initialen retrospektiven Arbeit [25] hat eine Reihe von Studien versucht, die NM zu charakterisieren. Heterogene Angaben zu Prävalenzen sind vor allem unterschiedlichen Bezugsgrößen geschuldet Die Angaben zur Prävalenz von NM variieren stark und wurde anfangs mit bis zu 82,5 % angegeben [7]. Wahrscheinliche Gründe für die Variabilität sind Unterschiede in der Definition von NM, der Genauigkeit der Befragung, der verwendeten Untersuchungsmodalitäten, mögliche Selektionsbias in der Erfassung des Kollektivs und Reporting-Bias bei soziokulturellen Unterschieden. Entscheidend für die heterogenen Angaben zur Prävalenz dürften aber vor allem die unterschiedlichen Bezugsgrößen der COVID-19-Gesamtkohorte sein. In einer Metaanalyse mit Einschluss von 350 Studien und 145.721 individuellen Patientendaten (89 % hospitalisierte Patienten) wurden 41 NM beschrieben (24 Symptome und 17 Diagnosen). Die am häufigsten berichteten Symptome waren Agitation (44 %), Abgeschlagenheit (32 %), Ageusie (21 %) und Myalgie (20 %), wohingegen die am meisten berichteten Diagnosen neuropsychiatrische Erkrankungen (24 %), Enzephalopathie (7 %), Schlaganfall (2 %; akuter ischämischer Schlaganfall (AIS) 1 %, intrazerebrale Blutungen (ICB) 0,31 %) und Myopathie (2 %) waren [30]. In Studien, die sich auf schwer betroffene COVID-19-Patienten konzentrierten, kristallisierten sich Enzephalopathien (am häufigsten mit Delir), zerebrovaskuläre Erkrankungen (AIS und ICB) und neuromuskuläre Erkrankungen („critical illness polyneuropathy and myopathy“, CIP/CIM) als die häufigsten NM heraus [10, 13, 20]. Des Weiteren leiden COVID-19-Patienten nach prolongiertem Intensivaufenthalt vermehrt an Dysphagie, was mit einer Verlängerung des Krankenhausaufenthaltes einhergeht [11, 12]. Beispiele typischer radiologischer Befunde von COVID-19-Intensivpatienten sind in Abb. 1 dargestellt. Kardiovaskuläre Erkrankungen Eine große Studie mit Einbezug der gesamten Bevölkerung in Schweden fand ein 2,1- bis 6,2fach erhöhtes Risiko von AIS bei COVID-19-Patienten [18]. Die Prävalenz für AIS bei COVID-19-Erkrankten wird zwischen 1–2,5 % angegeben [2]. Eine Hyperkoagulabilität im Rahmen eines „systemic inflammatory response syndrome“ (SIRS) mit Beteiligung des Endothels der großen und kleinen Gefäße wird dabei als Pathomechanismus postuliert. Passend zu der Hypothese konnte eine Korrelation zwischen Prävalenz und Schweregrad der Erkrankung gezeigt werden [10, 13, 32]. Die Frage, ob es sich dabei um einen SARS-CoV-2(„severe acute respiratory syndrome coronavirus 2“)-spezifischen Effekt handelt, bleibt jedoch unklar. Als Hinweis auf einen potenziell virusspezifischen Effekt zusätzlich zu einer systemischen Inflammation zeigte sich die Prävalenz für AIS bei COVID-19-Patienten im Vergleich zu ähnlich betroffenen Influenzaerkrankten signifikant höher [41]. Was COVID-19-Intensivpatienten betrifft, zeigt sich die AIS-Prävalenz jedoch vergleichbar zu anderen Kohorten kritisch kranker Patienten mit „acute respiratory distress syndrome“ (ARDS), Sepsis oder „extracorporeal membrane oxygenation“ (ECMO), sodass hier spezifische Effekte infrage gestellt werden müssen [10]. Auch bei hämorrhagischen Schlaganfällen (ICB und Subarachnoidalblutungen) finden sich diskrepante Angaben in der Literatur. In einigen größeren Kohortenstudien sowie Metaanalysen wird die Prävalenz zwischen 0,4 und 2 % angegeben [13, 32, 38]. Allerdings ist bei der Subgruppe der intensivpflichtigen COVID-19-Patienten mit hohem Anteil an ECMO-Verfahren eine deutlich höhere Prävalenz von 3–5 % beschrieben [10, 20]. Letzteres kann durch die positive Korrelation von Prävalenz und dem Schweregrad der Erkrankung bzw. dem hohen Anteil an ECMO-Verfahren mit entsprechender Antikoagulation erklärt werden [10, 13, 20, 41]. In anderen schwer kranken intensivpflichtigen Kohorten findet sich eine ähnliche Prävalenz [31]. Als Subgruppe der hämorrhagischen Schlaganfälle werden „microbleeds“ in MRT-Studien berichtet. Dabei war das Verteilungsmuster gemischt (lobär und tief) und zeigte passend zu der bereits beschriebenen Entität der „critical illness-associated cerebral microbleeds“ (CIAMs) eine Häufung im Bereich des Corpus callosum sowie juxtakortikal [33, 38]. Ähnlich wie für sonstige Intensivkohorten mit „microbleeds“ ergaben sich Korrelationen mit Hypoxämie, Invasivität der Beatmung und Schweregrad der Erkrankung, sodass eine SARS-CoV-2-spezifische Pathophysiologie auch hier unwahrscheinlich erscheint [1, 33, 38]. Enzephalopathie und Delir Enzephalopathie und Delir werden sehr häufig bei COVID-19 diagnostiziert. Die Prävalenz variiert zwischen 7 % und 69 % [2]. Die Aussagekraft der meisten Studien hierzu ist limitiert durch die Variabilität der jeweiligen Definitionen (insbesondere fehlende Differenzierung zwischen dem allgemeineren Begriff der Enzephalopathie und Delir), die Erfassung durch zumeist nicht ausgebildetes Personal und fehlende validierte Biomarker. In einer der wenigen prospektiven Studien mit Fokus auf Intensivpatienten (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19, PANDEMIC) bestehend aus 392 COVID-19-Patienten (70,7 % männlich, mittleres Alter 65,3 [±13,1], 48,5 % in der kritischen Phase der Erkrankung nach LEOSS [20]) wurde das klinische Syndrom einer Enzephalopathie als häufigste NM (46,2 %) beschrieben. Da ein erheblicher Teil der Patienten eingeschränkt beurteilbar war, muss allerdings eine höhere Dunkelziffer angenommen werden [10]. Als Prädiktoren für das Auftreten einer Enzephalopathie konnten in der Studie ARDS, Alter und Geschlecht identifiziert werden, was sich mit der aktuellen Literatur zu Prädiktoren für Delir weitgehend deckt. Insgesamt konnte auch in dieser Hinsicht bisher kein SARS-CoV-2-spezifischer Pathomechanismus identifiziert werden [2, 10]. Peripher-neurologische Erkrankungen In Zusammenhang mit COVID-19 dominieren in der Literatur zu peripheren neurologischen Erkrankungen Arbeiten zum Guillain-Barré-Syndrom (GBS) und zu CIP/CIM. Das GBS wurde insgesamt selten und meist in Form von Fallberichten/-serien berichtet. Statistisch und im Vergleich zu Vergleichskohorten konnte keine direkte Relation zu SARS-CoV‑2 gefunden werden [2, 40]. Anders als bei den bekannten GBS Auslösern Campylobacter jejuni und Zytomegalievirus (CMV) scheint SARS-CoV‑2 keine homologen Epitope zu entwickeln, um „molecular mimicry“ zu aktivieren [3]. Dadurch ist die biologische Plausibilität eines kausalen Zusammenhangs ebenfalls limitiert. Die CIP und CIM, oft zusammengefasst als „intensive care unit-acquired weakness“ (ICUAW), wurden bei 17,6 % der COVID-19-Intensivpatienten der PANDEMIC-Studie gefunden [10]. Nur ARDS konnte die Wahrscheinlichkeit des Auftretens erhöhen [10]. Auch hier scheint sich die Prävalenz und Ätiologie nicht relevant von anderen Intensiverkrankungen zu unterscheiden. Pathomechanismen Eine Vielzahl potenzieller Routen viraler Neuroinvasion wird für die Entstehung von NM postuliert. Viele Aspekte der zugrunde liegenden Pathomechanismen blieben jedoch unklar. Zum einen basieren viele Annahmen auf Studien mit deutlichen methodischen Schwächen (vor allem einer fehlenden adäquaten Kontrollgruppe), zum anderen ist anzunehmen, dass bei der Variabilität der berichteten NM unterschiedliche Mechanismen vorliegen. Grundsätzlich bestehen für NM im Rahmen von COVID-19 pathophysiologisch im Wesentlichen vier Optionen:direkte Schädigung des Nervengewebes durch das Virus an sich, indirekte Schädigung durch inflammatorische Prozesse, Schädigung als „Kollateralschaden“ (z. B. durch Therapien, Kreislauf- oder respiratorische Insuffizienz) oder Kombination der oben genannten Varianten. Für eine direkte Schädigung ist der Kontakt des Virus mit dem Nervengewebe erforderlich. Dafür gibt es theoretisch vier mögliche Wege, die schematisch in Abb. 2 und 3 dargestellt sind. Argumente aus der Literatur, die einen Neurotropismus des SARS-CoV-2-Virus stützen, basieren einerseits auf Tier‑, Liquor‑, Autopsie- und klinischen Daten zu den ebenfalls den humane Coronaviren (HCoV) zugehörigen Erregern der SARS- und MERS(„middle east respiratory syndrome“)-Pandemien [9]. Des Weiteren hat SARS-CoV‑2 für den Angiotensinkonversionsenzym 2(ACE2)-Rezeptor über das Spike-Protein S eine hohe Affinität und besitzt mit der „transmembrane protease serine 2“ (TMPRSS2) eine Möglichkeit zur Endozytose. Da Gliazellen und Neuronen ACE2 exprimieren, werden sowohl eine direkte Invasion als auch eine indirekte Schädigung durch Ausschaltung der neuroprotektiven Effekte des ACE2-Rezeptors als Gegenspieler für ACE postuliert [16]. Empirische Daten basierend auf einzelnen Fällen mit positivem PCR(„polymerase chain reaction“)-Nachweis für SARS-CoV-2-RNA im Liquor oder Parenchym nach Autopsie befeuerten zunächst die Theorie des Neurotropismus. Jedoch konnten im Verlauf der Pandemie diese Ergebnisse nicht bestätigt werden. In größeren Studien war nur in Ausnahmefällen die Liquor-PCR von Patienten mit NM positiv [10, 17, 34]. Ein positiver PCR-Nachweis in histologischen Schnitten von verstorbenen Patienten ist als Beweis für einen primären Befall des Nervengewebes nicht hinreichend, da die RNA aus Endothel‑, Immun- oder sonstige Blutszellen stammen könnte. Immunhistochemische Untersuchungen nach Autopsie wiesen nur einen sehr kleinen Anteil zytotoxischer T‑Zellen auf, was ebenfalls gegen eine Virusenzephalitis spricht. Zuletzt konnten elektronenmikroskopische Studien intakte Viruspartikel im Riechendothel, nicht aber in Nervengewebe nachweisen [4], sodass die Theorie des Neurotropismus von SARS-CoV‑2 noch nicht sicher bestätigt werden konnte. Für sekundäre Auswirkungen inflammatorischer Prozesse gibt es zahlreiche Nachweise Anders als für eine relevante primäre Schädigung gibt es für sekundäre Auswirkungen lokaler oder systemischer inflammatorischer Prozesse zahlreiche Nachweise. Diese betreffen sowohl das zentrale Nervengewebe als auch das periphere Nervengewebe und die Muskulatur. Eine wichtige Rolle dabei scheint dabei neben einer direkten Gewebeschädigung, z. B. der Muskulatur, eine Beteiligung des Endothels im Sinne einer Endothelitis oder Endotheliopathie mit konsekutiver Beteiligung der mikro- und makrovaskulären Strukturen zu spielen [8, 26]. Im Liquor von COVID-19-Patienten mit neurologischen Symptomen konnten eine hohe Konzentration an proinflammatorischen Zytokinen (Interleukin 6, 8, 15 und „macrophage inflammatory protein-1b“), Autoantikörper für eine Reihe ZNS(Zentralnervensystem)-spezifischer Antigene, eine deutliche Aktivierung extrafollikulärer B‑Zellen sowie eine klonale Expansion von CD4+-Zellen nachgewiesen werden [4]. Eine T‑Zellen-Invasion wurde eher in perivaskulären Räumen als im Parenchym gezeigt. Einige Studien beschreiben eine Aktivierung der Mikroglia und Astrozyten während der Infektion, die möglicherweise als Auswirkung einer Sepsis oder Hypoxie interpretiert werden kann. Zudem korreliert diese Aktivierung nicht mit dem Nachweis von Virus-RNA in Hirngewebe [27]. Diese Ergebnisse konnten auch in PET(Positronenemissionstomographie)-Studien von COVID-19-Patienten mit Enzephalopathie (teilweise kombiniert mit Autopsiedaten) bestätigt werden, die einen Hypometabolismus frontoparietal als Auswirkung einer Mikrogliaaktivierung zeigten [28]. Prognose und Outcome Obwohl die Mehrzahl der NM nach Ende der Infektion rückläufig sind, können Symptome wie Abgeschlagenheit, Anosmie, Kopfschmerzen und kognitive Einschränkungen lange persistieren. Für stationäre Patienten mit NM, insbesondere in den ersten Wellen der Pandemie, zeigt sich eine prolongierte Hospitalisierung, ein schlechteres funktionales Ergebnis bei Entlassung sowie eine höhere Mortalität [10, 13, 14, 39]. In einer kürzlich publizierten Metaanalyse hatten 50 % dieser Patienten ein schlechtes funktionelles Ergebnis mit einem modified Ranking Scale (mRS) Score von 3–6 (7 % mRS 0 = keine Symptome). Das Auftreten eines Komas, das mit einem schlechteren Outcome korrelierte, war deutlich wahrscheinlicher, je intensiver und länger ein SIRS angehalten hat [6]. Die Wahrscheinlichkeit eines schlechten Ergebnisses war bei Patienten mit zerebrovaskulären Ereignissen signifikant höher als bei anderen NM [39]. Sechs Monate nach Entlassung war die Hälfte der Patienten einer prospektiven Studie von Frontera et al. mit einem Anteil von 22 % Intensivpatienten kognitiv beeinträchtigt und nur 53 % konnten ihre Arbeit wieder aufnehmen [14]. In der oben erwähnten PANDEMIC Studie zeigte sich das Auftreten einer zerebrovaskulären Erkrankung als der relevanteste Prädiktor für Tod während des stationären Aufenthaltes (Odds Ratio [OR] 8,2, 95 %-Konfidenzintervall[CI] 3,8–17,3). Insbesondere ICB und AIS erhöhten die Wahrscheinlichkeit zu versterben, auch nach Adjustierung für andere Parameter (ICB: OR 6.1, 95 % CI 2,5–14,9; AIS: OR 3.9, 95 % CI 1,9–8,2) [10]. Die Gesamtmortalität dieser Studie betrug 36 % und ist somit vergleichbar mit anderen Studien mit ähnlichen Patientencharakteristika [13, 30]. Impfungen Seit Ausbruch der Pandemie wurden in Rekordzeit Impfstoffe entwickelt und große Teile der Bevölkerung geimpft. Neben einer beeindruckenden Effektivität und Sicherheit der Impfstoffe wurden mitunter auch neurologische Begleiterscheinungen berichtet. Als schwerwiegende und teils intensivpflichtige NM wurden GBS, zerebrovaskuläre Ereignisse (AIS und zerebrale Sinus- und Venenthrombose [SVT]), epileptische Anfälle, demyelinisierende Erkrankungen und Myelitis beschrieben [21]. Am häufigsten wurden zerebrovaskuläre Erkrankungen beschrieben. Gleichzeitig zeigte eine neuere Studie ein geringeres Risiko für AIS und Myokardinfarkte von COVID-19-Patienten, wenn diese geimpft waren [19]. Insgesamt kann ein Zusammenhang zwischen AIS, GBS oder sonstigen selten aufgetretenen Erkrankungen wie Multiple Sklerose (MS), akute disseminierte Enzephalomyelitis (ADEM), Myelitis oder Hirnnervenparesen nicht sicher hergestellt werden [4, 40]. Hingegen wird nach Gabe eines Vektorimpfstoffs mit „vaccine-induced immune thrombotic thrombocytopenia“ (VITT) und SVT ein kausaler Zusammenhang stark vermutet. Hier ist ein Heparin-induced-thrombocytopenia(HIT)-ähnlicher Mechanismus, basierend auf Platelet-factor 4-Antikörper (PF4-AK), für die Aktivierung von Thrombozyten mit konsekutiver Thrombose und Thrombopenie verantwortlich. Eine frühe Behandlung mit Immunglobulinen und eine Antikoagulation mit nichtheparinbasierten Antikoagulationsregimen können einen positiven Einfluss auf den Krankheitsverlauf nehmen. Salih et al. konnten in einer Fallsammlung zeigen, dass starke Kopfschmerzen und Thrombopenie (mit positivem Nachweis von PF4-AK) einer SVT oder sonstigen Thrombose vorausgehen können und ein frühzeitiges Erkennen und Initiierung der Therapie möglich machen [37]. Therapie neurologischer Manifestationen beim Intensivpatienten Therapeutisch steht in den meisten Fällen die COVID-19-Erkrankung mit SIRS und ggf. Multiorganversagen im Vordergrund. Jedoch sollten spezifische Therapien beim Auftreten von NM nicht vernachlässigt werden, weswegen eine Früherkennung bzw. Ausschluss solcher Differenzialdiagnosen essenziell sind. So sollten z. B. eine systemische Lysetherapie oder mechanische Thrombektomie COVID-19-Patienten mit AIS nicht vorenthalten werden, die Anlage einer externen Ventrikeldrainage (EVD) bei entsprechender Indikation bei ICB mit Ventrikelbeteiligung unverzüglich durchgeführt werden, ein Status epilepticus mittels Antiepileptika oder einer Narkose rasch durchbrochen werden und akute autoimmunentzündliche Erkrankungen wie z. B. ein GBS mit Immunglobulinen oder Plasmapharese behandelt werden. Konkrete Empfehlungen können der entsprechenden Leitlinie der Deutschen Gesellschaft für Neurologie (DGN) entnommen werden [22]. Zudem wurden kürzlich von der Global COVID-19 Neuro Research Coalition Empfehlungen zum Management von Enzephalopathie und Delir veröffentlicht [29]. Managementaspekte (Triage, Umorganisation, Ressourcen, Ausbildung von Neurointensivmedizinern) Neben den oben diskutierten möglichen direkten und indirekten Auswirkungen auf die Gesundheit sind im Rahmen der Pandemie eine Reihe von „Kollateralschäden“ entstanden. Hierunter fallen unter anderem eine mangelhafte Betreuung chronisch Kranker, eine verzögerte Vorstellung akut kranker Patienten sowie die Einschränkungen in Weiterbildung und Forschung [5, 36]. Ein weiterer wichtiger Effekt für die Neurointensivmedizin war die Umwidmung der spezifischen Neurointensivstationen zu COVID-19-Stationen. Obwohl Neurointensivmediziner COVID-19-Patienten vergleichbar gut zu anderen Intensivmediziner behandelten, hatten Neurointensivpatienten durch Fehlbelegungen möglicherweise ein schlechteres Ergebnis [35]. Die Wahrnehmung des Neurointensiv-Personals in einer Umfrage in 47 Ländern bestätigt die Sorgen einer mangelnden Behandlung während der Pandemie. Zudem haben Teilnehmer eine Reduktion der neurologischen Aufnahmen, einen Mangel an wichtigen Medikamenten oder Materialien, fehlende Verfügbarkeit zeitgerechter Diagnostik sowie den Ausfall von Fortbildungsveranstaltungen bemängelt [23]. Der Mangel an Intensivbetten hat eine Diskussion hinsichtlich der Triage von Patienten ausgelöst. Neurointensivmediziner in Deutschland haben Patientenwünsche, Vorzustand, Sequential Organ Failure Assessment Score (SOFA) und Alter als die wichtigsten Einflussfaktoren identifiziert. Zudem wurde dem Konzept „first-come, first-serve“ Vorrang gegenüber einem Losverfahren eingeräumt [15]. Zuletzt birgt die Erfahrung der Pandemie die Gefahr, dass etablierte Strukturen zur Versorgung kritisch kranker neurologischer Patienten infrage gestellt werden. In den oben genannten Umfragen scheint ein erheblicher Teil der Neurointensivstationen, insbesondere in ärmeren Ländern, nicht zurück zu ihrer spezialisierten Rolle gefunden zu haben [23]. Fazit für die Praxis Im Rahmen von COVID-19 (coronavirus disease 2019) sind neurologische Manifestationen mit hoher Prävalenz beschrieben worden. Die Mehrheit stellt unspezifische Symptome dar. Bei schwer kranken Intensivpatienten werden Enzephalopathien, zerebrovaskuläre Erkrankungen und ICUAW (intensive care unit-acquired weakness) am häufigsten berichtet. Obwohl ein direkter neuronal schädigender Effekt des Virus nicht etabliert werden konnte, sind sekundär ausgelöste Begleiterkrankungen oft mit einem schlechteren Ergebnis verbunden. Somit ergibt sich in diesem Kontext eine hohe Relevanz für das Screening und die Behandlung durch Neurologen. Obwohl Neurointensivstationen mit gutem Ergebnis schwer kranke COVID-19-Patienten behandeln konnten, gibt es einen dringenden Bedarf zur Rückkehr in die fachspezifische Versorgung und zum Schließen der durch die Pandemie entstandenen Lücke in Forschung, Fort- und Weiterbildung im Bereich der Neurointensivmedizin. Einhaltung ethischer Richtlinien Interessenkonflikt K. Dimitriadis, M. Schmidbauer und J. Bösel geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. QR-Code scannen & Beitrag online lesen ==== Refs Literatur 1. Agarwal S Jain R Dogra S Cerebral Microbleeds and Leukoencephalopathy in Critically Ill Patients With COVID-19 Stroke 2020 51 2649 2655 10.1161/STROKEAHA.120.030940 32755456 2. Ahmad SJ Feigen CM Vazquez JP Neurological sequelae of COVID-19 J Integr Neurosci 2022 21 77 10.31083/j.jin2103077 35633158 3. Alcantara M Katzberg HD GBS and COVID-19: untangling the knots Can J Neurol Sci 2022 49 1 2 10.1017/cjn.2021.128 34121644 4. Aschman T Mothes R Heppner FL What SARS-CoV-2 does to our brains Immunity 2022 55 1159 1172 10.1016/j.immuni.2022.06.013 35777361 5. 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Desforges M Le Coupanec A Brison E Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans Adv Exp Med Biol 2014 807 75 96 10.1007/978-81-322-1777-0_6 24619619 10. Dimitriadis K Meis J Neugebauer H Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC Crit Care 2022 26 217 10.1186/s13054-022-04080-3 35842675 11. Dziewas R Hufelschulte LM Lepper J Dysphagia in patients with severe coronavirus disease 2019-potential neurologic etiologies Crit Care Explor 2021 3 e0332 10.1097/CCE.0000000000000332 33521647 12. Dziewas R Warnecke T Zurcher P Dysphagia in COVID-19 -multilevel damage to the swallowing network? Eur J Neurol 2020 27 e46 e47 10.1111/ene.14367 32460415 13. Frontera JA Sabadia S Lalchan R A prospective study of neurologic disorders in hospitalized patients with COVID-19 in New York city Neurology 2021 96 e575 e586 10.1212/WNL.0000000000010979 33020166 14. 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DGN Leitlinie D. https://dgn.org/wp-content/uploads/2020/08/030144_LL_Neurologische_Manifestationen_bei_COVID-19_V3.1.pdf;. Zugegriffen: 31. Juli 2022 23. Lele AV Wahlster S Alunpipachathai B Perceptions regarding the SARS-coV-2 pandemic’s impact on neurocritical care delivery: results from a global survey J Neurosurg Anesthesiol 2022 34 209 220 10.1097/ANA.0000000000000825 34882104 24. Leven Y Bosel J Neurological manifestations of COVID-19—an approach to categories of pathology Neurol Res Pract 2021 3 39 10.1186/s42466-021-00138-9 34311778 25. Mao L Jin H Wang M Neurologic manifestations of hospitalized patients with Coronavirus disease 2019 in Wuhan, China JAMA Neurol 2020 77 683 690 10.1001/jamaneurol.2020.1127 32275288 26. Martinez-Salazar B Holwerda M Studle C COVID-19 and the vasculature: current aspects and long-term consequences Front Cell Dev Biol 2022 10 824851 10.3389/fcell.2022.824851 35242762 27. Matschke J Lutgehetmann M Hagel C Neuropathology of patients with COVID-19 in Germany: a post-mortem case series Lancet Neurol 2020 19 919 929 10.1016/S1474-4422(20)30308-2 33031735 28. Meyer PT Hellwig S Blazhenets G Molecular imaging findings on acute and long-term effects of COVID-19 on the brain: a systematic review J Nucl Med 2022 63 971 980 10.2967/jnumed.121.263085 35177424 29. Michael BD Walton D Westenberg E Consensus clinical guidance for diagnosis and management of adult COVID-19 encephalopathy patients. J Neuropsychiatry Clin Neurosci 2022 10.1176/appi.neuropsych.22010002 30. Misra S Kolappa K Prasad M Frequency of neurologic manifestations in COVID-19: a systematic review and meta-analysis Neurology 2021 10.1212/WNL.0000000000012930 31. Naik-Tolani S Oropello JM Benjamin E Neurologic complications in the intensive care unit Clin Chest Med 1999 20 423 434 10.1016/S0272-5231(05)70150-7 10386265 32. Nannoni S De Groot R Bell S Stroke in COVID-19: a systematic review and meta-analysis Int J Stroke 2021 16 137 149 10.1177/1747493020972922 33103610 33. Napolitano A Arrigoni A Caroli A Cerebral microbleeds assessment and quantification in COVID-19 patients with neurological manifestations Front Neurol 2022 13 884449 10.3389/fneur.2022.884449 35677326 34. Neumann B Schmidbauer ML Dimitriadis K Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms J Neurol Sci 2020 418 117090 10.1016/j.jns.2020.117090 32805440 35. Philips S Shi Y Coopersmith CM Surge capacity in the COVID-19 era: a natural experiment of neurocritical care in general critical care Neurocrit Care 2022 10.1007/s12028-022-01559-3 36. Richter D Eyding J Weber R A full year of the COVID-19 pandemic with two infection waves and its impact on ischemic stroke patient care in Germany Eur J Neurol 2022 29 105 113 10.1111/ene.15057 34370900 37. Salih F Schonborn L Kohler S Vaccine-induced thrombocytopenia with severe headache N Engl J Med 2021 385 2103 2105 10.1056/NEJMc2112974 34525282 38. Schmidbauer ML Ferse C Salih F COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis. J Clin Med 2022 10.3390/jcm11030605 39. Singh B Lant S Cividini S Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis PLoS ONE 2022 17 e0263595 10.1371/journal.pone.0263595 35653330 40. Taga A Lauria G COVID-19 and the peripheral nervous system. A 2-year review from the pandemic to the vaccine era J Peripher Nerv Syst 2022 27 4 30 10.1111/jns.12482 35137496 41. Taquet M Geddes JR Husain M 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records Lancet Psychiatry 2021 8 416 427 10.1016/S2215-0366(21)00084-5 33836148

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==== Front Eur Arch Otorhinolaryngol Eur Arch Otorhinolaryngol European Archives of Oto-Rhino-Laryngology 0937-4477 1434-4726 Springer Berlin Heidelberg Berlin/Heidelberg 7788 10.1007/s00405-022-07788-8 Rhinology Platelet-rich plasma injection in the olfactory clefts of COVID-19 patients with long-term olfactory dysfunction http://orcid.org/0000-0002-0845-0845 Lechien Jerome R. Jerome.Lechien@umons.ac.be 12345 Le Bon Serge D. 4 Saussez Sven 234 1 Department of Otolaryngology, Polyclinic of Poitiers, Elsan, Poitiers, France 2 grid.8364.9 0000 0001 2184 581X Department of Human Anatomy and Experimental Oncology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMons), Mons, Belgium 3 grid.8364.9 0000 0001 2184 581X Division of Laryngology, Department of Otolaryngology-Head and Neck Surgery, EpiCURA Hospital, University of Mons, Mons, Belgium 4 grid.50545.31 0000000406089296 Department of Otorhinolaryngology and Head and Neck Surgery, CHU Saint-Pierre, Brussels, Belgium 5 grid.12832.3a 0000 0001 2323 0229 Department of Otorhinolaryngology and Head and Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Paris, France 15 12 2022 18 23 10 2022 8 12 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Objective To investigate safety, feasibility, and effectiveness of platelet-rich plasma (PRP) injection into the olfactory clefts of COVID-19 patients with persistent olfactory dysfunction (OD). Methods From March 2022 to July 2022, COVID-19 patients with persistent OD were consecutively recruited to benefit from PRP injection into the olfactory clefts. Patient pain, annoyance, time of procedure, and adverse events were evaluated. Olfactory function was evaluated at baseline and 2-month post-injection with the olfactory disorder questionnaire (ODQ) and threshold, discrimination, and identification (TDI) test. Results Eighty-seven patients with anosmia (N = 30), hyposmia (N = 40), or parosmia (N = 17) with a mean OD duration of 15.7 months completed the evaluations. The PRP injection was successfully performed in all patients with a mean procedure time of 18.4 ± 3.4 min. The adverse events included transient epistaxis (N = 31), parosmia related to xylocaine spray (N = 10), and vasovagal episode (N = 2). The injection procedure was evaluated as somewhat or moderately painful by 41 (47%) and 22 (25%) patients, respectively. Thirty-seven patients were assessed after 2 months post-injection. The mean ODQ and TDI scores significantly improved from baseline to 2-month post-injection (p < 0.01). The olfactory improvement occurred after a mean of 3.6 ± 1.9 weeks. Conclusion The injection of PRP into the olfactory clefts is safe and associated with adequate patient-reported outcomes. The findings of this preliminary study suggest possible efficacy on subjective and psychophysical evaluations, but future randomized controlled studies are needed to determine the superiority of PRP injection over placebo. Keywords COVID-19 Otolaryngology Rhinology Coronavirus SARS-CoV-2 Anosmia Hyposmia Olfactory Smell Recovery Platelet-rich plasma ==== Body pmcIntroduction The pandemic of coronavirus disease 2019 (COVID-19) led to an increase of the prevalence of olfactory dysfunction (OD) in the population [1]. The OD is one of the most common symptoms of the infection, reaching 30% to 86% of patients according to variants [2–4]. Most patients recover smell sense over the post-infection weeks, but some individuals report mid- to long-term OD, including anosmia, hyposmia, phantosmia, or parosmia [5]. Thus, the 12-month persistence of OD according to psychophysical olfactory evaluations may reach 46% of cases [6]. Others reported that the prevalence of patient-reported OD ranged from 15 to 70% 1 year after the infection [7, 8]. To date, there is no treatment for the long-term OD. Patients are recommended to adhere to an olfactory training protocol [8, 9], while some dietary supplements (e.g., omega 3, zinc, and B12 vitamin) may be advised [10]. In 2019, Yan et al. [11] published a preliminary paper describing the injection of platelet-rich plasma (PRP) into the olfactory cleft of seven individuals with post-viral OD as a new potential approach to improve the smell recovery. To date, there is no study assessing feasibility, safety, and tolerance of this procedure in large cohort of patients. In the present study, we investigated the feasibility, safety, and tolerance of the injection of PRP into the olfactory clefts of patients with COVID-19-related OD. Methods Setting and patients From March 2022 to July 2022, patients with post-COVID-19 persistent OD were consecutively recruited from two medical centers [Ear Nose and Throat Dour Medical Center (Dour) and CHU Saint-Pierre University Hospital (Brussels, Belgium)]. The OD occurred after the COVID-19, which was diagnosed with RT-PCR. The persistent OD was defined as smell sense disorder lasting more than 6 months and consisted of anosmia, hyposmia, phantosmia, or parosmia. Anosmia and hyposmia were defined with the threshold, discrimination, and identification testing (TDI) [12]. Anosmia consisted of a TDI score ≤ 16 points, while hyposmia was established as a TDI score of less than 30.75. TDI > 30.75 was considered as normal [12]. Patients benefited from tomodensitometry or magnetic resonance imaging, which did not report sinus or olfactory region abnormalities (e.g., rhinosinusitis, olfactory, or nasal tumor). Patients with the following conditions were excluded: OD before the pandemic (e.g., post-viral, post-traumatic, neurological, and idiopathic); chronic rhinosinusitis with or without nasal polyposis; nasal obstruction related to rhinitis; history of nasal radiation or functional endoscopic sinus surgery. The study protocol was approved by the ethics committee of the University hospital CHU Saint-Pierre (CHUSP2102028). The electronic informed consent was obtained for all patients. Epidemiological, clinical, and olfactory data The following epidemiological and clinical outcomes were collected with a standardized online questionnaire at the first evaluation: age; gender; comorbidities; allergy and tobacco consumption. The nasal symptoms were assessed with the French version of the sinonasal outcome tool-22 (SNOT-22) [13]. The olfactory and gustatory questions were based on the smell and taste component of the National Health and Nutrition Examination Survey [14]. The impact of OD on quality of life was assessed with the French version of the Olfactory Disorder Questionnaire, which includes parosmia (/12), quality of life (/57), and sincerity (/18) outcome scores [15]. The ODQ total score ranges from 0 (no OD) to 87 (important impact of OD on quality of life). Patients benefited from psychophysical evaluations with the TDI (Medisense, Groningen, The Netherlands) [12]. The olfactory cleft endoscopy scale [16] was scored at the first consultation and at the time of the PRP injection. This scale is a validated scale reporting the findings of discharge, polyps, edema, scarring, or crusting on a scale of 0, 1, or 2 on each side, giving a total score ranging from 0 to 20. Patients were evaluated for TDI and ODQ at the time of inclusion and 2 months after the PRP injection. Injection procedure and outcomes The PRP injections were performed by the same otolaryngologist (J.R.L.). The procedure was briefly described in Fig. 1. The blood extraction was performed into a 20 mL tube with sodium citrate anticoagulant and the isolation of PRP was made through a 10-min centrifugation at 4200 rpm. The supernatant was drawn up into a 10 mL syringe. The PRP was transferred into a 1 mL syringe. The injection was performed with a 27-G needle (10 cm). The local (nasal) anesthesia was performed in patients with Xylocain 10% spray, while otolaryngologist used xylometazoline chlorhydrate drops to have a better access to the nose and the olfactory cleft. The injection was performed through a 0° rigid optic to guide the needle direction. In some cases (septal deviation), the needle was bent to have a better access to the olfactory cleft. Several points of 0.2–0.5 mL were performed in the middle turbinate and in the nasal septum in regard of the head of the middle turbinate. The procedure was similarly performed in the contralateral nasal fossae. Note that common precautions were taken to ensure no injection into intravascularly, while patients were awake during the procedure about any visual changes occurring during the procedure. Patient was observed for 15 min after the procedure for potential adverse events and was discharged.Fig. 1 Procedure. The figure shows: blood extraction (A); centrifugation (B); 27-G needle syringe preparation (C, E); local anesthesia (D), injection of PRP through a 0° rigid optic in the middle turbinate/nasal septum in regard of the head of the middle turbine (F–I) At the end of the procedure, patient was invited to fulfill an online questionnaire assessing pain and annoyance with a 4-point visual analog scale ranging from totally disagree (= 0) to totally agree (= 3) for the following steps: blood extraction, local anesthesia, and procedure. The physician assessed the following outcomes: time of PRP preparation (e.g., blood extraction and centrifugation); time of local anesthesia; time of injection; quantity of injected PRP and immediate and delayed adverse events. Statistical analyses Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (SPSS, v23,0; IBM Corp, Armonk, NY, USA). The evolution of subjective and objective olfactory evaluations was studied with the Wilcoxon Rank test. A p value < 0.05 was considered as significant. The relationship between epidemiological, clinical, olfactory, and procedure outcomes was analyzed with Spearman coefficient (rs < 0.30 = low correlation; 0.30–0.60 = moderate correlation; > 0.60 = strong correlation). Results Eighty-seven patients benefited from PRP injections (Table 1). There were 62 females and 25 males, respectively. The mean age was 41.6 ± 14.6 years. The most common comorbidities included thyroid disorders (16%), hypertension (9%), arthrosis (9%), and diabetes (9%; Table 1). Sixty patients (69%) received at least one dose of vaccine.Table 1 Epidemiological and clinical characteristics of patients Outcomes Patients (N = 87) Age (mean, SD—years) 41.6 ± 14.6 Sex (N (%))  Male 25 (28.7)  Female 62 (71.3) Comorbidities [N (%)]  Thyroid disorder 14 (16.1)  Hypertension 8 (9.2)  Arthrosis 8 (9.2)  Diabetes 8 (9.2)  Hypercholesterolemia 7 (8.0)  Depression 5 (5.7)  Psoriasis 5 (5.7)  Asthma 4 (4.6)  Reflux 4 (4.6)  Renal insufficiency 2 (2.3)  Rheumatoid polyarthritis 2 (2.3)  Cancer history 1 (1.1)  Hepatic insufficiency 1 (1.1)  Cardiologic affections 1 (1.1)  Allergy 5 (5.7)  Tobacco consumption 4 (4.6) Vaccine [N (%)]  No response 13 (14.9)  No vaccine 14 (16.1)  One-dose vaccine 5 (5.7)  Two-dose vaccine 20 (23.0)  Three-dose vaccine 35 (40.2) N number, SD standard deviation Olfactory features The olfactory features are reported in Table 2. The included patients reported a mean duration of OD of 15.7 ± 7.5 months. Fifty-eight patients (67%) recognized to have adhered to a 12-week olfactory training at the onset of the OD, while 39 (45%) and 37 (42%) received nasal or oral corticosteroids in the first days after the onset of the OD. Some dietary supplements were prescribed in some patients in the first weeks of the OD (Table 2). At the time of the inclusion, the mean SNOT-22 and ODQ were 32.5 ± 18.1 and 51.0 ± 18.0, respectively. According to psychophysical evaluations, 30 (34%) and 40 (46%) patients reported anosmia and hyposmia, respectively (Table 2). Seventeen patients (19%) had normal TDI score but severe parosmia.Table 2 Olfactory dysfunction features of patients Olfactory dysfunction outcomes Duration of OD (mean ± SD (range); mo) 15.7 ± 7.5 (14.1–17.3) Intervention pre-injection (N (%))  Olfactory training (12 weeks) 58 (66.7)  Alpha lipoic acid 16 (18.4)  Nasal corticosteroids 39 (44.8)  Oral corticosteroids 37 (42.5)  Vitamin B 26 (29.9)  Vitamin A 14 (16.1)  Omega 3 12 (13.8)  Zinc 37 (42.5) SNOT-22 (mean, SD) 32.5 ± 18.1 ODQ outcomes (mean, SD)  Parosmia statement 7.8 ± 3.8  Life quality statement 34.1 ± 13.8  Sincerity statement 9.1 ± 4.4  ODQ total score 51.0 ± 18.0 Psychophysical evaluations (mean, SD)  Threshold 4.3 ± 3.8  Discrimination 8.5 ± 4.5  Identification 8.2 ± 4.6  TDI total score 20.3 ± 10.5 OD types (TDI; N (%))  Anosmia 30 (34.5)  Hyposmia 40 (46.0)  Normosmia with parosmia 17 (19.5) The results consisted of mean standard ± deviation or number (%) mo months, OD olfactory dysfunction, ODQ olfactory disorder questionnaire, SNOT-22 sinonasal outcome 22, TDI threshold discrimination identification Procedure outcomes The injection of PRP was successfully performed in all patients. Thirty-five patients reported unilateral nasal deviation, limiting the injection of PRP into the olfactory cleft of the deviation side. In case of deviation, the injection was performed closest to the olfactory cleft region. The mean times of PRP preparation (i.e., blood collection, centrifugation, and syringe preparation), local anesthesia, and PRP injection were reported in Table 3. The mean procedure time was 18.4 ± 3.4 min. Thirty-one patients (36%) had post-injection transient epistaxis, which was the primary acute adverse event. The local anesthesia with the xylocaine spray led to transient parosmia in ten patients (11%). Note that the two coagulations of PRP into the syringe occurred in patients who had vasovagal episode. Postnasal drip sensation (N = 5) and nausea (N = 2) were the only two adverse events occurring in the post-injection days.Table 3 Procedure outcomes Procedure outcomes Mean (SD) PRP preparation time (min) 12.8 ± 2.6 Local anesthesia time (min) 1.1 ± 0.3 Right olfactory cleft score 0.6 ± 1.9 Right olfactory cleft injection time (min) 2.3 ± 1.0 Right olfactory cleft amount (mL) 1.2 ± 0.4 Left olfactory cleft score 0.1 ± 0.4 Left olfactory cleft injection time (min) 2.4 ± 1.0 Left olfactory cleft amount (mL) 1.2 ± 0.3 Total duration (min) 18.4 ± 3.4 N (%) Acute adverse events  Transient epistaxis 31 (35.6)  Parosmia during local anesthesia (spray) 10 (11.5)  Vasovagal episode 4 (4.6)  Panic attack 2 (2.3)  PRP coagulation 2 (2.3) Delayed adverse events  Postnasal drip sensation 5 (5.7)  Nausea 2 (2.3) The data of this table concerned the entire cohort (n = 87) SD standard deviation The patient outcomes are reported in Table 4. Among the procedure steps, the injection was judged as the most painful and annoying step compared with other steps. Seventeen patients (19%) reported severe pain during the injection, while 41 (47%) and 22 (25%) evaluated the pain as moderate or low, respectively. According to the visual analog scale ranging from 0 (ineffective) to 3 (fully effective), the mean score of the local anesthesia effectiveness was 2.1 ± 0.9. The local anesthesia was evaluated as optimal, adequate, moderately adequate, and ineffective in 33 (38%), 33 (38%), 18 (21%), and 3 (3%) patients, respectively.Table 4 Patient-reported outcomes about procedure Patient-reported outcomes Mean (SD) Range 0 (no p/a) 1 (mild p/a) 2 (mod. p/a) 3 (full p/a) Injection pain 1.8 ± 0.9 7 (8.0) 22 (25.3) 41 (47.1) 17 (19.5) Blood collection pain 0.3 ± 0.6 65 (74.7) 21 (24.1) 0 (0.0) 1 (1.1) Blood collection annoyance 0.3 ± 0.5 67 (77.0) 17 (19.5) 3 (3.4) 0 (0.0) Local anesthesia pain 1.1 ± 1.0 30 (34.5) 26 (29.9) 25 (28.7) 6 (6.9) Local anesthesia annoyance 1.1 ± 0.9 26 (29.9) 29 (33.3) 29 (33.3) 3 (3.4) Injection annoyance 1.5 ± 0.9 16 (18.4) 19 (21.8) 45 (51.7) 7 (8.0) The data of this table concerned the entire cohort (n = 87) p/a pain/annoyance, SD standard deviation Evolution of olfactory outcomes and predictors Thirty-seven patients were re-evaluated 2 months after the PRP injection. There were no synechia, mucosal disturbances, or inflammation at the nasofibroscopic examination. Among them, 8 patients (22%) did not report subjective improvement of OD, while 20 (54%) and 9 individuals (24%) reported substantial improvement of anosmia/hyposmia or parosmia, respectively. Thirty-three patients (89%) adhered to the olfactory training, which was performed 2.3 ± 1.5 times daily for 8 weeks. According to the patient experience, the significant improvement of olfaction occurred after a mean of 3.6 ± 1.9 weeks. The pre- to post-injection changes in ODQ and TDI scores are reported in Table 5. Both ODQ and TDI scores significantly improved from baseline to 2-month post-injection.Table 5 Evolution of olfactory outcomes after PRP injection Outcomes Baseline 2 mo p value Parosmia score 7.8 ± 3.8 7.5 ± 3.1 0.047 Life quality statement score 34.1 ± 13.8 24.4 ± 8.0 0.001 Sincerity statement score 9.1 ± 4.4 8.9 ± 3.3 NS Fr-ODQ total score 51.0 ± 18.0 40.7 ± 10.9 0.001 Threshold 3.5 ± 4.0 5.8 ± 4.5 0.024 Discrimination 8.5 ± 4.5 11.2 ± 3.9 0.007 Identification 8.3 ± 4.6 10.4 ± 3.5 0.002 TDI total score 20.3 ± 10.5 26.0 ± 11.2 0.009 The data of this table concerned 37 patients who were assessed at 2-month post-injection mo month, NS non-significant, ODQ olfactory disorder questionnaire, PRP platelet-rich plasma, TDI threshold discrimination identification There were negative significant associations between age and the following baseline outcomes: ODQ-Life quality score (rs = − 0.309; p = 0.007), sincerity score (rs = − 0.237; p = 0.041), and ODQ total score (rs = − 0.323; p = 0.005); meaning that young patients reported stronger impact of OD on the quality of life. Discussion The injection of platelet-rich plasma into injured tissues is an old approach used in orthopedic, plastic surgery, dermatology, or rehabilitation [17]. In otolaryngology, PRP was used in the management of neck fistula [18], vocal fold scars [19], or tympanic membrane perforation [20], reporting encouraging results. The primary finding of this pilot study was the demonstration of the safety, feasibility, and tolerance of PRP injection into the olfactory cleft. The injection-related pain was judged as tolerable by 81% of patients, who assessed the local anesthesia as effective. The occurrence of transient epistaxis was related to the realization of several mucosa injection points and was the main adverse event. Both injection pain and risk of transient epistaxis were, however, not reported in the study of Yan et al., which limits the comparison of our data with the current literature [11]. The mean time of the procedure was 18.4 min, which makes the PRP olfactory cleft injection a rapid procedure. The mean time of PRP extraction and injection found in the present study corroborated those of studies in which PRP procedure was performed for other otolaryngological indications [19, 21]. The mean injected PRP amount was 1.2 mL/side, which was consistent with the data of Yan et al. [11]. The main advantage of this approach is the safety and the easiness of the technique. Because PRP is an autologous biological product derived from the patient blood, there is no risk of reject, disease transmission, or blood adverse event. However, from a practical standpoint, the injections need to be performed in the minutes following the end of the centrifugation, because there is a risk of coagulation of the supernatant. In the present study, two patients had vasovagal event, delaying the injection of few minutes, which led to the coagulation of plasma. A proportion of patients (n = 37) were re-evaluated 2 months after the PRP injection, reporting significant improvements of ODQ and TDI scores. These data supported those of the preliminary study of Yan et al., who reported a substantial improvement of TDI scores in five out of seven patients [11]. The usefulness of PRP injection into the olfactory cleft was recently supported by Steffens et al. [22] who observed that patients treated by PRP injection for a persistent (> 1 year) OD reported higher increase of TDI score improvements 1 month after the PRP injection compared with patients who did not benefit from injection. The study of Steffens et al. [22] may support our observations. In the present study, patients recovered subjectively smell sense 3.6 weeks after the injection, which may corroborate the current knowledge about the physiological effect of PRP [23]. From a physiological standpoint, the PRP pockets in the mucosa will progressively release anti-inflammatory and pro-regenerative factors of the platelets, leading to the upregulation of some factors by the cells of nasal and olfactory tissues, e.g., growth and transforming factors, vascular endothelial growth molecules, epidermal growth factor, and insulin-like growth factor [17, 23]. It was moreover suggested that PRP may promote axon regeneration and neuroregeneration [17]. The anti-inflammatory effects of PRP are particularly relevant in patients with COVID-19 OD, because a recent multicenter study supported that OD patients may have persistent virus in the olfactory region and associated inflammation in the neuroepithelium, which may account for prolonged or relapsing loss of smell [24]. Theoretically, the potential anti-inflammatory effect of PRP may reduce the chronic inflammation and the cell-related injuries, promoting the regeneration of the olfactory tissues. However, the effectiveness of PRP injection on persistent OD cannot be formally established without the conduction of randomized controlled study. Because the injection of a ‘therapeutic material’ into the olfactory cleft may have a placebo effect [11], the design of future studies may include the injection of saline solution in the olfactory cleft of patients of the control group. The lack of control group and the low number of patients who completed the 2-month follow-up evaluations are the primary limitations of the present study. However, the main objective of this preliminary study was the evaluation of the safety, feasibility, and tolerance of the technique. The publication of our preliminary results about the potential effectiveness of PRP was motivated by the potential impact of this approach in COVID-19 patients with a persistent OD. The uses of ODQ and TDI scores are the main strengths of the present study, because they are both validated approaches providing different but complementary olfactory findings. Conclusion The injection of PRP into the olfactory cleft of patients with OD related to COVID-19 is a safe approach associated with adequate patient-reported outcomes. The findings of this preliminary study suggest possible efficacy on subjective and psychophysical evaluations, but future randomized controlled studies are needed to determine the superiority of PRP injection over placebo. Acknowledgements B. Johnson for the proofreading. Funding None. Data availability Data are available on request to the first author according the rights of University (data protection/copyright). Declarations Conflict of interest Authors have no conflict of interest. Sponsorships None. Research involving human participants and/or animals IRB was not required for this study. Informed consent Experts agreed to participate. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Karamali K Elliott M Hopkins C COVID-19 related olfactory dysfunction Curr Opin Otolaryngol Head Neck Surg 2022 30 1 19 25 10.1097/MOO.0000000000000783 34889850 2. Lechien JR Chiesa-Estomba CM Hans S Barillari MR Jouffe L Saussez S Loss of smell and taste in 2,013 European Mild-to-moderation COVID-19 patients Ann Int Med 2020 173 8 672 675 10.7326/M20-2428 32449883 3. Tong JY Wong A Zhu D Fastenberg JH Tham T The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: a systematic review and meta-analysis Otolaryngol Head Neck Surg 2020 163 1 3 11 10.1177/0194599820926473 32369429 4. Boscolo-Rizzo P Tirelli G Meloni P Hopkins C Madeddu G De Vito A Gardenal N Valentinotti R Tofanelli M Borsetto D Lechien JR Polesel J De Riu G Vaira LA Coronavirus disease 2019 (COVID-19)-related smell and taste impairment with widespread diffusion of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Omicron variant Int Forum Allergy Rhinol 2022 10.1002/alr.22995.10.1002/alr.22995 5. D'Ascanio L Pandolfini M Cingolani C Latini G Gradoni P Capalbo M Frausini G Maranzano M Brenner MJ Di Stadio A Olfactory dysfunction in COVID-19 patients: prevalence and prognosis for recovering sense of smell Otolaryngol Head Neck Surg 2021 164 1 82 86 10.1177/0194599820943530 32662745 6. Boscolo-Rizzo P Hummel T Hopkins C Dibattista M Menini A Spinato G Fabbris C Emanuelli E D'Alessandro A Marzolino R Zanelli E Cancellieri E Cargnelutti K Fadda S Borsetto D Vaira LA Gardenal N Polesel J Tirelli G High prevalence of long-term olfactory, gustatory, and chemesthesis dysfunction in post-COVID-19 patients: a matched case-control study with one-year follow-up using a comprehensive psychophysical evaluation Rhinology 2021 59 6 517 527 10.4193/Rhin21.249 34553706 7. Ferreli F Gaino F Russo E Long-term olfactory dysfunction in COVID-19 patients: 18-month follow-up study Int Forum Allergy Rhinol. 2022 10.1002/alr.22990 8. Fortunato F Martinelli D Iannelli G Milazzo M Farina U Di Matteo G De Nittis R Ascatigno L Cassano M Lopalco PL Prato R Self-reported olfactory and gustatory dysfunctions in COVID-19 patients: a 1-year follow-up study in Foggia district, Italy BMC Infect Dis 2022 22 1 77 10.1186/s12879-022-07052-8 35065619 9. Kattar N Do TM Unis GD Migneron MR Thomas AJ McCoul ED Olfactory training for postviral olfactory dysfunction: systematic reviewand meta-analysis Otolaryngol Head Neck Surg 2021 164 2 244 254 10.1177/0194599820943550 32660334 10. Oleszkiewicz A Bottesi L Pieniak M Fujita S Krasteva N Nelles G Hummel T Olfactory training with Aromastics: olfactory and cognitive effects Eur Arch Otorhinolaryngol 2022 279 1 225 232 10.1007/s00405-021-06810-9 33864109 11. Helman SN Adler J Jafari A Bennett S Vuncannon JR Cozart AC Wise SK Kuruvilla ME Levy JM Treatment strategies for postviral olfactory dysfunction: a systematic review Allergy Asthma Proc 2022 43 2 96 105 10.2500/aap.2022.43.210107 35317886 12. Yan CH Mundy DC Patel ZM The use of platelet-rich plasma in treatment of olfactory dysfunction: a pilot study Laryngoscope Investig Otolaryngol 2020 5 2 187 193 10.1002/lio2.357 13. Oleszkiewicz A Schriever VA Croy I Hähner A Hummel T Updated Sniffin' Sticks normative data based on an extended sample of 9139 subjects Eur Arch Otorhinolaryngol 2019 276 3 719 728 10.1007/s00405-018-5248-1 30554358 14. de Dorlodot C Horoi M Lefebvre P Collet S Bertrand B Eloy P Poirrier AL French adaptation and validation of the sino-nasal outcome test-22: a prospective cohort study on quality of life among 422 subjects Clin Otolaryngol 2015 40 1 29 35 10.1111/coa.12315 25269784 15. Bhattacharyya N Kepnes LJ Contemporary assessment of the prevalence of smell and taste problems in adults Laryngoscope 2015 125 1102 1106 10.1002/lary.24999 25369790 16. Lechien JR, Vaira LA, Le Bon SD, Geerts R, Boscolo-Rizzo P, Saussez S (2022) Validity and reliability of a French version of the olfactory disorders questionnaire. J Otolaryngol Head Neck Surg (Submitted to) 17. Soler ZM Hyer JM Karnezis TT Schlosser RJ The Olfactory Cleft Endoscopy Scale correlates with olfactory metrics in patients with chronic rhinosinusitis Int Forum Allergy Rhinol 2016 6 3 293 298 10.1002/alr.21655 26718315 18. Sariguney Y Yavuzer R Elmas C Yenicesu I Bolay H Atabay K Effect of platelet-rich plasma on peripheral nerve regeneration J Reconstr Microsurg 2008 24 3 159 167 10.1055/s-2008-1076752 18452111 19. Eryılmaz A Demirci B Gunel C Kacar Doger F Yukselen O Kurt Omurlu I Basal Y Agdas F Basak S Can tissue adhesives and platelet-rich plasma prevent pharyngocutaneous fistula formation? Auris Nasus Larynx 2016 43 1 62 67 10.1016/j.anl.2015.06.012 26229017 20. Suresh A Balouch B Martha VV Sataloff RT Laryngeal applications of platelet rich plasma and platelet poor plasma: a systematic review J Voice 2021 10.1016/j.jvoice.2021.07.007 21. Mandour MF Elsheikh MN Khalil MF Platelet-rich plasma fat graft versus cartilage perichondrium for repair of medium-size tympanic membrane perforations Otolaryngol Head Neck Surg 2019 160 1 116 121 10.1177/0194599818789146 30037309 22. Bhatt NK Gao WZ Timmons Sund L Castro ME O'Dell K Johns MM 3rd Platelet-rich plasma for vocal fold scar: a preliminary report of concept J Voice 2021 10.1016/j.jvoice.2020.12.040 23. Steffens Y Lebon SD Prunier L Rodíguez A Lechien JR Saussez S Horoi M Effectiveness and safety of PRP on persistent olfactory dysfunction related to COVID-19: towards a new therapeutic hope Eur Arch Oto-Rhino-Larynol 2022 10.1101/2022.02.14.22270109 24. Wang C Fan H Li Y Yun Z Zhang Z Zhu Q Effectiveness of platelet-rich plasma injections for the treatment of acute Achilles tendon rupture: a systematic review and meta-analysis Medicine (Baltimore) 2021 100 41 e27526 10.1097/MD.0000000000027526 34731144 25. de Melo GD Lazarini F Levallois S Hautefort C Michel V Larrous F Verillaud B Aparicio C Wagner S Gheusi G Kergoat L Kornobis E Donati F Cokelaer T Hervochon R Madec Y Roze E Salmon D Bourhy H Lecuit M Lledo PM COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters Sci Transl Med. 2021 13 596 eabf8396 10.1126/scitranslmed.abf8396 33941622

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==== Front Pediatr Clin North Am Pediatr Clin North Am Pediatric Clinics of North America 0031-3955 1557-8240 W.B. Saunders S0031-3955(21)00101-2 10.1016/S0031-3955(21)00101-2 Article Forthcoming Issues 9 7 2021 8 2021 9 7 2021 68 4 xiiixiii 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcForthcoming Issues October 2021 Covid-19 in Children Elizabeth Secord and Eric John McGrath, Editors December 2021 Pediatric Gastroenterology Harpreet Hall, Editor February 2022 International Aspects of Pediatric Infectious Diseases Chokechai Rongkavilit and Fouzia Naeem, Editors Recent Issues June 2021 Integrated Behavioral Health in Pediatric Practice Roger Apple, Cheryl Adele Dickson, Maria Demma I. Cabral, Editors April 2021 Ending the War Against Children: The Rights of Children to Live Free of Violence Danielle Laraque-Arena, Bonita F. Stanton, Editors February 2021 Pulmonary Manifestations of Pediatric Diseases Nelson L. Turcios, Editor Series of Related Interest Clinics in Perinatology http://www.perinatology.theclinics.com/ Advances in Pediatrics http://www.advancesinpediatrics.com/

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==== Front Med Oncol Med Oncol Medical Oncology (Northwood, London, England) 1357-0560 1559-131X Springer US New York 1922 10.1007/s12032-022-01922-6 Review Article Contracting triple-negative breast cancer with immunotherapeutic armamentarium: recent advances and clinical prospects http://orcid.org/0000-0001-9914-8539 Khadela Avinash avinashkhadela@gmail.com 1 Soni Shruti sonishruti200@gmail.com 1 Megha Kaivalya kaivumegha@gmail.com 1 Shah Aayushi C. aayushah2613@gmail.com 1 Pandya Aanshi J. aanshijp01@gmail.com 1 Kothari Nirjari nirjarikothari@gmail.com 1 Shah Ishika ivshah2002@gmail.com 1 Avinash C. B. dravinash@gmail.com 2 1 grid.419037.8 0000 0004 1765 7930 Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat 380009 India 2 ClearMedi Radiant Hospital, Mysore, 570017 India 15 12 2022 2023 40 1 483 11 2022 6 12 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Triple negative breast cancer (TNBC) portraying deficient expression of estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) is known to be the most aggressive subtype associated with poor prognosis and interventional strategies limited to chemotherapy and breast conserving surgery. Some TNBC incidences have also been reported with positive circ-HER2 expression thus rendering circ-HER2 a potential immunotherapy target to direct drug development. Resistance and recurrence reported with traditional approaches has led us towards the application of immunotherapeutic interventions owing to their anti-tumor efficacy. This review provides an elaborative insight on potential molecular biomarkers to be targeted by immunotherapy. Additionally, clinical trials proposing the application of immunotherapy in neoadjuvant, adjuvant and metastatic TNBC setting have also been included. The gathered evidence indicates a positive application of immunotherapy in TNBC with therapeutic limitation available only owing to the possibility of adverse events which can be dealt considering risk-to-benefit ratio. Furthermore, potential targets to aim for therapeutic vaccines along with evidence from clinical trials have also been mentioned. Keywords Triple-negative breast cancer Immunotherapy Cancer vaccine Immune checkpoint inhibitors Neoadjuvant Adjuvant Metastasis issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2023 ==== Body pmcIntroduction Breast cancer (BC) forms one of the most common culprits of invasive cancers in women. BC had the highest frequency of diagnosis in women worldwide with case counts rising to 2.26 million, compared to 0.41 million in uterine, 0.6 million in cervical and 0.3 million in ovarian cancers in the year 2020 [1]. The incidence of BC has been higher in developed countries and this finding is contributed by the fact that women in developed countries give fewer births and breastfeed for shorter durations, as compared to the developing ones [2]. Though the developed countries stood foremost in incidence rates, countries located in Asia and Africa shared 63% of the total death count in 2020 [3]. Survival was better in high-income and developed countries as compared to low income and many middle-income countries [4]. Over the last three decades incidence and death rates have remarkably increased, for which population structure, environment, genetic particulars and quality of life could be few of the responsible factors [5, 6]. BC encompasses wide phenotypical heterogeneity due to which the clinical profile of each of its subtype varies as they possess distinct demeanors towards the therapy [7]. Several molecular biomarkers are defined under the pathology of this cancer such as estrogen receptor alpha-positive (ERα+), progesterone receptor-positive (PR+), human epidermal growth factor receptor-2 (HER-2/ERBB2), epidermal growth factor receptor (EGFR), Cytokeratin 5/6 (CK5/6), vascular endothelial growth factor (VEGF) and Antigen KI67 [8]. Identification of subtypes with distinguishing prognosis and therapy targets of BC stems from gene expression studies [9]. Differing immunohistochemical properties aid classification of this carcinoma into five namely Luminal A, Luminal B, HER2, Triple negative and normal-like breast cancer. The prognosis profile ranges from best for Luminal A type to worst for triple negative breast cancer (TNBC). The prevalence rates are hereby given in a descending order with the highest seen in Luminal A(70%) followed by Triple negative (15–20%), Luminal B (10–20%), HER2 (5–15%) with least rate observed in normal-like breast cancer [10]. The above statements lead us to the fact that TNBC has the worst prognostication accompanying its higher occurrence. Ergo, embarking upon TNBC, it gained its substantiality in the mid-2000s. The poor prognosis of TNBC is owed to the lack of estrogen and progesterone receptors and under-expression of HER-2 which impedes achievement of successful treatment outcomes [11]. There exists four subtypes of TNBC based on the cellular particulars that include basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M) and luminal androgen receptor (LAR). These four TNBC subtypes are associated with distinct expression patterns with immune-modulatory infiltrates varying within each of these subtypes [12]. For further advancements in the development of successful treatment strategies, confirmatory prognostic and predictive biomarkers are desired [13]. The Traditional therapy aiming to mitigate TNBC includes Neoadjuvant therapy, Adjuvant therapy, Surgery and Radiotherapy. Contraction of TNBC using the conventional approach faced a major shortcoming of resistance accompanied by numerous side effects and this demanded the advent of a newer perspective to treat this carcinoma. Aiming to develop even more precise intervention and eradicate the limitations mentioned formerly, immunotherapy was introduced to deal with the carcinogenesis with a novel vision [14]. Immunotherapy strengthens the resident immune machinery and prepares it to recognize and destroy cancerous cells with enhanced efficiency [15]. The immunological profile of TNBC portrays a tumor microenvironment (TME) with abundant lymphocyte infiltration and overexpression of Programmed Death-Ligand 1 (PD-L1) as compared to other subtypes [16]. In addition, TNBC presents with a higher number of somatic mutations resulting from genomic instability which escalates the frequency of neoantigen availability [17]. This depicts a higher responding capability of TNBC to immunotherapy in contrast to traditional approaches. Classes that are conventionally established on the foundation of immunotherapy include monoclonal antibodies, checkpoint inhibitors, cytokines, vaccines and Chimeric Antigen Receptor-T (CAR-T) cell therapy. Monoclonal antibodies offer target specificity with low toxicity profiles. They work in one or multiple ways depending on the antigen its targeting. Checkpoint inhibitors on the other hand target specific immune checkpoint proteins that regulate the functioning of immune system [18]. Cytokine inhibitors target cytokines which are highly inducible secretory proteins that mediate the communication between the immune cells [19]. Onco-vaccines can be preventive or therapeutic that mainly use tumor associated antigens (TAAs) and tumor specific antigens (TSAs). CAR-T cell therapy uses techniques to modify T-cells to produce chimeric antigen receptors. These receptors allow T-cells to get attached to the desired antigens [20]. This review focuses on revealing additional information regarding immunotherapy and to define the targets along with the target-specific interventions for TNBC. Molecular targets of immunotherapy for breast cancer The pathogenesis of BC unveils contribution of numerous molecular targets in uncontrolled proliferation and promotion of survival of the tumor. Identification of these molecular targets present a lead towards development of potential drugs that rectify the overexpression of such biomarkers and help eradicate the disease [21]. The potency of these molecular targets and the drugs aimed for achieving anti-tumor activity in TNBC are presented in Fig. 1. This list of molecular targets extends from mesothelin, CD133, CTLA4, PD-1/PD-L1, LAG-3, STAT-3, IDO to CD3 and HER2 and is summarized in Table 1.Fig.1 Molecular targets holding clinical potential to aim immunotherapy interventions for their immunomodulatory effect. (Tumor-infiltrating lymphocyte (TIL), antigen-presenting cell (APC), programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), regulatory T- cells (Treg cells), indoleamine 2,3-dioxygenase (IDO), tryptophan (Trp), kynurenine (Kyn), T-cell receptor (TCR), L-tryptophan (L-TRP)) Table 1 Molecular biomarkers qualifying as a potential immunotherapy target for TNBC Target Function Target inhibitor drug 1. Mesothelin It is a cell surface glycoprotein and promotes the survival and proliferation of cancer cells. It also elicits a T-cell response in various cancers Anetumab, ravtansine (BAY 94–9343) 2. CD133 or Prominin 1 It is a five-membered trans-membrane surface glycoprotein that causes malignancy. CD133 progenitor cells are capable of regeneration, differentiation, and maintenance A CD133 inhibitor CMab-43 is under investigation for its use in breast cancer. No particular trials for TNBC have been initiated yet 3. CTLA 4 CTLA4 is a protein found on T-cells and it halts the function of T-cells and keeps them away from killing other cells including cancerous ones Tremelimumab Ipilimumab 4. PD-1/PD-L1 This is a receptor-ligand system that maintains immune tolerance in the tumor microenvironment and hence blocks the anti-tumor response Pemrolizumab Nivolumab Atezolizumab Avelumab 5. LAG-3 It is a member of the immunoglobulin superfamily that inhibits the proliferation and maturation of dendritic cells by getting engaged with MHC-II protein IMP321 6. STAT-3 It is a protein and when signaled, it regulates the oncogenic pathway leading to tumor progression Ruxolitinib (JAK-STAT Pathway inhibitor) 7. IDO It is an enzyme that promotes immunosuppression by suppressing the immunostimulatory mechanism LY3381916, Epacadostat 8. Bispecific antibodies a.CD3 and HER2 HER2 is a membrane tyrosine kinase and oncogene. When activated provides the cell with anti-apoptotic signals and is crucial for the development and proliferation of breast cancer Ertumaxomab 9. A2A/A2B A2A is a G-protein coupled receptor that plays important role in regulation of myocardial oxygen consumption, coronary blood flow, and CNS neurotransmitters INCB106385 CTLA-4 Cytotoxic T lymphocyte-associated antigen-4; PD-1/PD-L1 Programmed death-1 receptor-ligand-1; IDO Indoleamine-2,3-dioxygenase; LAG-3 Lymphocyte activation gene-3; STAT3 Signal transducer and activator of transcription 3; IDO Indoleamine-2,3-dioxygenase; HER2 Human-epidermal growth factor Mesothelin (MSLN), a 40 kDa glycosyl-phosphatidyl inositol-linked membrane glycoprotein is expressed on the mesothelial cells surfaced on peritoneum, pericardium and pleura. Overexpression of MSLN factors in progression of cancers presenting with aggressive phenotypical characteristics and poorer prognosis [22]. It is a key component in sustaining the course of progression, invasion and survival of tumor cells besides developing drug resistance. This overexpression has recently been demonstrated in TNBC thus making it a potential molecular site for targeting therapeutic interventions [23]. CD133 otherwise known as prominin-1 is a pentaspan transmembrane single chain glycoprotein residing in the protrusions present in the biological membrane with specific availability in cholesterol-based lipid domains [24]. Due to its availability on surface, it qualifies as a surface marker for the detection of cancer stem cells [25]. Mislocalization of CD133 from surface to nucleus disrupts transcriptional regulation by causing an interference in the molecular cascades directly in association with proliferation and differentiation of cancerous cells [26]. This deduces CD133 as a potential target to eradicate disease pathology. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a glycoprotein notably expressed on the cell surface of stimulated T cells, subset of Tregs and on non-lymphoid cells of different tissues alongside being expressed on the surface of some solid tumors [27]. CTLA-4 has a potential to down-regulate T-cell responses and fade peripheral tolerance which shrinks the efficacy of generated antitumor response ultimately leading to tumor immune tolerance [28]. Upregulation of CTLA-4 is one of the important underlying causes of immune evasion and this addresses the role of anti-CTLA-4 antibodies in acquiring CTLA-4 as a putative drug target to obtain optimal therapeutic action [29]. Tremelimumab and Ipilimumab drugs are both fully humanized monoclonal antibodies capable of inducing durable responses by blocking CTLA-4 antigen [30]. PD-1/PD-L1 is a programmed death-1 receptor-ligand system, also referred to as CD279 and B7-H1 is a 33-kDa type 1 transmembrane glycoprotein usually expressed on activated T cells, natural killer (NK) cells, B lymphocytes, macrophages, dendritic cells (DCs) and monocytes with higher level of expression on tumor specific T-cells [31]. PD-1 has a negative impact on adaptive and innate immune responses down-regulating antitumor responses. It inhibits proliferation of tumor-infiltrating lymphocytes, halts cytokine production and strengthens tumor to escape immune response generated by antibodies, ultimately favouring tumor survival [32]. This suggests that it is imperative to target drugs on PD-1/PD-L1 to reverse its detrimental effect. Pembrolizumab, Avelumab, Atezolizumab and Nivolumab are monoclonal antibodies with a proposed mechanism of preventing the interaction of PD-1 receptor with PD-L1 ligand to diminish the consequences of PD-1 pathway-mediated immune responses against tumor cells [33]. As this chain of mechanistic cascades also function in TNBC, the role of these drugs can be explored in diminishing the influence of this carcinoma. Lymphocyte activation gene-3 (LAG-3) alternatively addressed as CD223 is expressed on the surface of T cells, NK cells, NK T cells and regulatory T (Treg) cells [34]. Overexpression of LAG-3 translates into negative regulation of T cell stimulation and proliferation [35]. It further may also yield a synergistic effect with PD-1/PD-L1 to facilitate depletion of immunity [36]. This ultimately worsens the course of carcinogenesis and categorizes itself as one of the immune checkpoints to target by developing drugs to accomplish superiority over tumorigenesis. LAG-3, CTLA-4 and PD-1/PD-L1 inhibitory drugs are housed under the drug class of immune checkpoint inhibitors (ICIs). Signal transducer and activator of transcription 3 (STAT3) are designated to be an early tumor diagnostic biomarker localized in basal-like cells of breast cancer cells CD44+ CD24– [37]. Constitutive activation and overexpression of STAT3 upregulate cyclin D-1, c-myc, and bcl-2 and suppress the apoptosis of tumor cells promoting tumor survival and progression [38]. Thus, it is worthy to note STAT3 as one of the probable biomarkers to aim for during drug development process. Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme expressed by dendritic cells residing in tissues and draining lymph nodes of breast cancer patients. IDO catabolizes the breakdown of an essential amino acid L-tryptophan into kynurenines which causes L-tryptophan deficiency [39]. Such a deficient reserve of amino acid exhausts the cytotoxicity of T cells disabling their capability to withstand the negative influence of tumor progression [40]. Therefore, IDO enzyme inhibitors evolve as an approach to consider for immunotherapy development towards TNBC. HER2 is 180 kDa transmembrane glycoprotein present on the surface of diverse set of T cells whose overexpression is associated with promotion of malignancy of cancer by generating anti-apoptotic signals [41]. TNBC lack expression of HER2 but a part may express circ-HER2 generated from HER2. The generation of this plasmid is a result of chemical gene synthesis of the sequence of exon3-7 of HER2 alongside addition of circulation promoter sequences to 83 bp upstream and 53 bp downstream [42]. Trastuzumab-Deruxtecan has been found to be efficacious in diminishing HER2 positive TNBC. CD3 is another surface marker inhabiting T lymphocytes which has a role of prominence in extinguishing tumor environment [43]. Therefore, simultaneous targeting of both HER2 and CD3 may present remarkable efficacy in eliminating tumor cells. Bispecific antibody like Ertumaxomab addresses this co-targeting necessity by acting on an epitope of HER2 and CD3 by involving Fc fragment to yield active macrophages and antibody dependent cellular cytotoxicity (ADCC) [44]. This achievement demands further investigations and development of similar bispecific antibodies with anti-tumor properties. Recently, adenosine receptor antagonists are being explored for immunosuppressive myeloid cells in cancer. Two G-protein coupled receptors namely, A2B and predominantly A2A mediate the immunosuppressive action of extracellular adenosine and subsequent blocking of these adenosine receptors enhance anti-tumor immune responses. INCB106385 is a novel drug that has been entrenched as a dual antagonist which binds to both A2A and A2B receptors in the single-digit nanomolar range and antagonizes the production of cAMP in A2A and A2B expressing immune cells [45]. A diagrammatic perspective of this theoretical explanation is depicted in Fig. 2. Further discovery campaigns need to be established for evaluating the efficacy of adenosine receptor antagonists.Fig. 2 Immunosuppressive influence of adenosine binding with A2A and A2B receptors in the tumor micro environment and mechanism of enhancement of anti-tumor response through blocking of these receptors by adenosine receptor antagonists (INCB106385). (adenosine triphosphate (ATP), adenosine monophosphate (AMP), myeloid-derived suppressor cells (MDSC).) Roadmap of FDA approvals for TNBC On March 08, 2019, Atezolizumab qualified for an accelerated approval from FDA for its efficacy in unresectable locally advanced or metastatic TNBC with positive PD-L1 expression. Atezolizumab accompanied by nanoparticle albumin-bound (nab)-Paclitaxel received a joint-approval for the formerly mentioned indication based on its prolongation effect on progression-free survival (PFS). Combining nab-Paclitaxel with Atezolizumab improved the anticancer activity [46]. The recommended dose for Atezolizumab is 840 mg administered as an IV infusion over 60 min on days 1 and 15, followed by administration of 100 mg/m2 nab-paclitaxel on days 1, 8 and 15 for each 28-day cycle. This was to be continued until resolution of disease progression or occurrence of any unacceptable toxicity [47]. The FDA assessment of changes in the therapeutic landscape of metastatic TNBC concluded in voluntary withdrawal of accelerated approval of this drug combination by Genentech where drug safety and efficacy parameters were not responsible for withdrawal [48]. The voluntary withdrawal of this accelerated approval of Atezolizumab for this indication accompanied a disappointing phase but continuing extensive research in this field presents a hope of successfully finding an efficacious treatment of TNBC in the near future [49]. Another remarkable drug was added to the armamentarium of TNBC treatment on July 26, 2021, when FDA approved Pembrolizumab for high risk, early-stage TNBC in the capacity of neoadjuvant. Pembrolizumab combined with chemotherapy regimen was found to be efficacious as neoadjuvant chemotherapy and as a sole Pembrolizumab adjuvant after surgery [50]. Combination of Pembrolizumab with chemotherapy had a positive impact on pathological complete response rate (pCR) and event free survival (EFS). The recommended dose of Pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks as an IV infusion over 30 min with neoadjuvant therapy continuing for 24 weeks and adjuvant therapy for 27 weeks [51]. On April 7, 2021, FDA granted approval to Sacituzumab govitecan in patients previously exposed to two or more systemic therapies for unresectable locally advanced or metastatic TNBC [52]. This approval is rooted from its affirmative potential in prolonging PFS and overall survival (OS). Dosage recommendations for Sacituzumab govitecan are 10 mg/kg once a week on days 1 and 8 of 21-day cycle continued until resolution of disease progression or occurrence of any unacceptable toxicity [53]. This timeline of drug development and subsequent FDA approvals is presented diagrammatically in Fig. 3.Fig. 3 Timeline of FDA approvals in the successful application of immunotherapy in TNBC Emerging immunotherapies and ongoing investigations have led us to a possibility of more FDA drug approvals for this indication in near future. Evidence retrieved from clinical trials Immunotherapy has gained a valuable designation in the interventional sphere of metastatic TNBC and this prompted the investigation of its role in the neoadjuvant setting. Neoadjuvants are a part of an interventional strategy that aim to shrink down the tumor before administration of primary treatment thus improving the efficacy of primary treatment. One trial leaning towards the affirmative potential of Pembrolizumab- a humanized IgG4 monoclonal antibody in combination with chemotherapy as neoadjuvant in TNBC treatment was conducted by enrolling 60 participants and equally dividing the number into six cohorts of Pembrolizumab plus chemotherapy regimens (NCT02622074). Specified primary endpoints were safety and recommended phase II dose (RP2D) and secondary endpoints were pCR rate, objective response rate (ORR), EFS and OS. Endpoints to be explored included defining a relationship between outcome and molecular biomarkers such as PD-L1 expression and stromal tumor-infiltrating lymphocytes. Only two out of total six cohorts met RP2D threshold with 22 patients encountering dose-limited toxicity in the form of febrile neutropenia. The most common grade ≥ 3 treatment-related adverse event was noted as neutropenia (73%). Immune-mediated and infusion reactions were observed in 18 patients with grade ≥ 3 in 6 patients. Across all cohorts, the pCR rate was 60% and 12 month event-free and OS ranged between 80 and 100%. This deduced that administering combination of chemotherapy with Pembrolizumab as neoadjuvant in high-risk, early-stage TNBC showed manageable toxicity and promising antitumor potential [54]. This draws us towards the possibility of administering Pembrolizumab as adjuvant and neoadjuvant therapy in TNBC to potentiate tumor eradication. Another trial exemplifying role of Atezolizumab- a humanized IgG1 monoclonal antibody combined with Nab-paclitaxel in previously untreated metastatic TNBC was conducted by choosing placebo combined with Nab-paclitaxel as a comparator (NCT02425891) [55]. 902 participants were enrolled with primary end points selected as PFS and OS and secondary outcomes as Objective Response of Complete Response (CR) or Partial Response (PR), Duration of response (DOR), Time to Deterioration (TTD), Percentage of patients with at least one adverse event, percentage of participants with anti-therapeutic antibodies against Atezolizumab, maximum serum concentration of Atezolizumab, minimum serum concentration (Cmin) for Atezolizumab and plasma concentrations of total Paclitaxel. The median PFS was 7.4 months for Atezolizumab plus nab-paclitaxel as compared to 4.8 months for placebo plus nab-paclitaxel receiving patients. ORR and stratified hazard ratio also favoured the administration of combination under study over placebo [46]. This draws a deduction that Atezolizumab plus nab-paclitaxel has a potential to qualify as an interventional strategy in diluting metastatic TNBC. Although the trials support implication of ICIs in neoadjuvant, adjuvant and metastatic settings of TNBC, these cannot be solely relied upon as a complete cure for this indication as their applicability comes at a cost of incidences of immune-related adverse events (AEs). This demands further investigations to explicate the role of ICI in PD-1/PD-L1 positive TNBC. To summarize, both ongoing and completed clinical trials of immunotherapy are present in Tables 2, 3 and 4 respectively.Table 2 Ongoing clinical trials evaluating the safety and efficacy of immunotherapy in TNBC NCT no Phase Comparator arm 1 Comparator arm 2 Comparator arm 3 Treatment setting Primary outcomes Secondary outcomes Remarks References NCT03982173 II Durvalumab + tremelimumab – – – Objective tumor response rate – The basket trial aims to evaluate the efficacy of combination therapy with Durvalumab and Tremelimumab in patients with metastatic solid tumors [65] NCT03818685 II Nivolumab + ipilimumab Capecitabine – Post operative adjuvant DFS OS, local regional recurrence, distant metastasis, distant recurrence, adverse event, immune monitoring, cytokines, circulating growth factors, molecular subtyping, mutational profiles, circulating tumor DNA, copy no. alterations, and loss of heterozygosity The study aims at assessing the clinical benefits of post-operative combination of radiotherapy, nivolumab and ipilimumab in comparison to the alternative combination of radiotherapy and capecitabine for TNBC patients with residual disease [66] NCT03449108 II Nivolumab + ipilimumab + chemotherapy – – Neoadjuvant ORR DCR, DoR, PFS, OS, and incidence of adverse events of adoptive cell therapy with TILs across multiple tumor types The trial maily aims at evaluating the clinical profile of autologous tumor infiltrating lymphocytes, LN-145 and LN-145-S1 against several cancers, one of which being TNBC [67] NCT03487666 II Nivolumab Capecitabine Nivolumab + Capecitabine Adjuvant Immune activation measured by changes in PIS Immune activation, OS, DRFS, grade 3 and 4 toxicites, circulating tumor DNA, intracellular cytokine staining, CD8 + T-cell clonal expansion The trial aims to predict the benefit of immune checkpoint inhibition, alone or in combination with chemotherapy, for high risk TNBC patients having residual disease following effective neoadjuvant chemotherapy [68] NCT04159818 II Nivolumab Cisplatin + Nivolumab Doxorubicin + Nivolumab – PFS OS, CBR, ORR, toxicity, and PFS The trial aims to evaluate the efficiency of induction treatments including cisplatin or doxorubicin in the nivolumab-based therapeutic regimens, in patients with TNBC [69] NCT04148911 III Atezolizumab + nab-paclitaxel – – – percentage of participants with TEAEs (grade ≥ 3) and TEimAEs (grade ≥ 2) OS, PFS, TEAEs, and TESAEs The global trials aims at assessing the combination of Atezolizumab and Nab-paclitaxel in patients with unresectable, locally advanced or metastatic PD-L1 + TNBC [70] NCT03281954 III Placebo Atezolizumab – Neoadjuvant EFS OS, DDFS, DFS, pCR, cardiac safety lead-in, frequency of AEs and SAEs, The study is designed to evaluate the efficacy of Atezolizumab plus neoadjuvant therapy, compared to the combination of neoadjuvant chemotherapy and placebo [71] [72] NCT03164993 II Pegylated liposomal doxorubicin + cyclophosphamide + placebo pegylated liposomal doxorubicin + cyclophosphamide + Atezolizumab – PFS and assessment of toxicity OS, objective tumor response rate, DOR, DTRR, Patient reported outcome, CBR, The trial aims to investigate the efficacy of Atezolizumab in combination with the immunogenic chemotherapy in patients with mTNBC [73] NCT03498716 II Atezolizumab + paclitaxel + dose-dense doxorubicin or epirubicin + cyclophosphamide Paclitaxel + dose-dense doxorubicin or epirubicin + cyclophosphamide – Adjuvant chemotherapy iDFS DFS, OS, RFI, distant RFI, percentage of participants with adverse events, iDFS, ADAs, serum conc. of atezolizumab, mean changes form baseline The study aims to evaluate the efficacy and safety endpoints for the combination of Atezolizumab and adjuvant Anthracycline-based or Taxane-based chemotherapy, in patients with resectable TNBC [72] [74] NCT05498896 II Atezolizumab + chemotherapy Atezolizumab + chemotherapy + ipatasertib – Neoadjuvant pCR ORR The study aims to investigate the contributive efficacy of Ipatasertib to the combination of Neoadjuvant chemotherapy and Atezolizumab in TNBC [75] NCT04739670 II Atezolizumab, bevacizumab, gemcitabine and carboplatin – – – PFS AEs, ORR, DOR, and OS The trial aims to assess the efficacy and safety particulars of Bevacizumab, Carboplatin, Gemcitabine and Atezolizumab in early relapsing mTNBC [76] NCT03371017 III Atezolizumab + gemcitabine + capecitabine + carboplatin Placebo + gemcitabine + capecitabine + carboplatin – – OS Proportion of patients alive, PFS, ORR, DOR, CBR, C-ORR, C-DOR, TTD, OS, percentage of patients with AEs, Cmax, Cmin, ADAs, The purpose of the study is to evaluate the efficacy and safety of the combination of Atezolizumab and Chemotherapy in patients with unresectable and recurrent TNBC [77] NCT04770272 II Atezolizumab + CTX therapy Atezolizumab (window) + CTX therapy with atezolizumab – Neoadjuvant pCR pCR, near pCR, safety measures, TILs, CCCA, low cellularity, combined complete response, DFS, OS, EFS The trial aims to compare efficacy of a mono-Atezolizumab window followed by a Atezolizumab—CTX therapy, with that of Atezolizumab—CTX therapy alone [78] NCT03756298 II Atezolizumab + capecitabine Capecitabine – Adjuvant Therapy iDFS – The study aims at investigating the safety and efficacy of Atezolizumab in combination with Capecitabine for the therapy of patients with TNBC [79] NCT02530489 II Atezolizumab, nab-paclitaxel – – – pCR PFS and OS The trial aims at investigating the combination of Nab-Paclitaxel and Atezolizumab prior to the surgical intervention in TNBC [80] NCT04408118 II Atezolizumab + paclitaxel + bevacizumab – – – PFS TTR, ORR, CBR, DOR, OS, efficacy, safety AEs and SAEs, irORR, irPFS, molecular markers The objective of the study is to evaluate the efficacy and safety of Atezolizumab in combination with Paclitaxel and Bevacizumab, in patients with advanced or metastatic TNBC [81] NCT02883062 II Carboplatin, paclitaxel, mastectomy, lumpectomy Atezolizumab, carboplatin, paclitaxel, breast surgery – – Increase in TIL percentage pCR The study aims to assess the efficacy of carboplatin and paclitaxel in combination with atezolizumab, prior to the surgical intervention for the treatment of patients with newly diagnosed, stage II-III TNBC [82] NCT04434040 II Atezolizumab and SACITUZUMAB govitecan – – Rate of undetectable circulating tumor cfDNA Rate of undetectable circulating tumor cfDNA, no. of participants with TRAEs, iDFS, DMFS, OS The objective of the trial is to evaluate the combination of Atezolizumab and Sacituzumab in preventing the recurrence of TNBC [83] NCT05266937 II Atezolizumab + carboplatin + nab-paclitaxel – – – OS OS, ORR, TTF, incidence and severity of AEs and SAEs, and post-progression survival The aim of the study is to provide preliminary efficacy and safety evidences on the combination of Atezolizumab, Carboplatin and Nab-paclitaxel as first-line therapy in PD-L1 positive TNBC [84] NCT05001347 II TJ004309 and atezolizumab – – – ORR ORR, DOR, DCR, PFS, incidence of TEAE, no. of participants with laboratory value, physical examination result and vital sign abnormalities, OS, and PK parameters The clinical trial aims at assessing the safety and efficacy of TJ004309 With Atezolizumab (TECENTRIQ®) in patients with advanced or metastatic solid tumors, including TNBC [85] NCT02926196 III Avelumab – – Adjuvant DFS OS and safety profile The aim of the study is to access the the effect of avelumab as adjuvant and post-adjuvant in TNBC [86] NCT05582538 II Ceralasertib + durvalumab + nab-paclitaxel – – – PFS ORR, DCR, CBR, DOR, OS, no. of AEs The study aims to evaluate the efficacy and safety of Ceralasertib followed by the combination of Durvalumab and Nab-paclitaxel in treating patients with TNBC [87] NCT04837209 II Niraparib + dostarlimab + radiation therapy – – ORR ORR, OS, PFS, change in QOL, no. of participants with TRAEs, trial satisfaction, change in social activity level, change in PRO-CTCAE The purpose of the study is to assess the safety and efficacy of the combination of Dostarlimab and Niraparib plus Radiation Therapy (RT) in mTNBC [88] NCT05491226 II Pembrolizumab with radiation therapy and axatilimab – – – pCR Change in TILs, PFS, EFS, no. of AEs, OS, and node clearance The trial aim to reinvigorate the response of TNBC to Immunotherapy, when combined with myeloid inhibition and radiation [89] NCT05539365 II ST-alpha-DC1, pembrolizumab ORR, incidence of adverse events PFS, OS, ORR The objective of the trial is to investigate the safety and efficacy endpoints of Dendritic Cell-Based Treatment Plus Immunotherapy for the treatment of metastatic or unresectable TNBC [90] NCT05177796 II Panitumumab,pembrolizumab,neoajuvant chemotherapy – – – pCR The clinical trial aims at evaluating the efficacy of Panitumumab and Pembrolizumab in combination with Neoadjuvant chemotherapy, for the treatment of Stage III-IV TNBC [91] NCT05076682 II Choline + anti-PD-1 immunotherapy Sodium cromoglicate + anti-PD-1 immunotherapy Efavirenz + anti-PD-1 immunotherapy – ORR, immune changes in peripheral blood Biomarker analysis, DCR, PFS, and safety and TRAEs The study aims at evaluating the efficacy and safety of combined treatment of Sodium cromoglicate, Choline or Efavirenz with Immune checkpoint inhibitor in mTNBC patients who progressed on previous immune checkpoint inhibitors [92] NCT03639948 II Carboplatin & docetaxel + pembroluzimab – – Neoadjuvant pCR MRD and RFS The trial aims to assess the effectiveness of Pembrolizumab And Carboplatin in combination with Docetaxel in TNBC [93] NCT04443348 II No rt + pembrolizumab + doxorubicin + paclitexel + cyclophosphamide Low RT + pembrolizumab + doxorubicin + paclitexel + cyclophosphamide High RT + pembrolizumab + doxorubicin + paclitexel + cyclophosphamide Neoadjuvant and adjuvant TIL and rate of pathologic response RCB, change in TIL counts, no.of participants with TRAEs, iDFS, EFS, change in satisfaction and symptoms with treatment, trial satisfaction, financial burden, changes in patient-reported outcomes, pathologic response rate, and symptomatic improvement The study aims to investigate the efficacy parameters of Preoperative Chemotherapy, Pembrolizumab and varying doses of Radiation in TNBC [94] NCT02411656 II Pembrolizumab with radiation therapy and axatilimab – – – Rate of disease control Biomarker analysis, disease control survival, and OS The clinical study aims to evaluate the efficacy endpoints of Pembrolizumab in treating patients with TNBC [95] NCT04877821 II Sintilimab + anlotinib + chemotherapy – – – pCR EFS, OS, and percentage of participants with AEs The clinical study aims to assess the efficacy and safety of the Sintilimab plus Anlotinib combined with Chemotherapy as Neoadjuvant Therapy in treating patients with TNBC [96] NCT02957968 II Decitabine + pembrolixumab + doxorubicin + cyclophosphamide + carboplatin + paclitaxel Decitabine + pembrolixumab + doxorubicin + cyclophosphamide + carboplatin + paclitaxel + pembrolizumab – Neoadjuvant Increase in percent of tumor and stroma with infiltrating lymphocytes Aes, pCR, RCb, cCR, enumeration of T-cells and immune cells, PFS, MDSC, percentage of patients meeting criteria for LPBC, and no. of patients with no or minimal residual disease The main aim of this study is to determine if immunotherapy, when administered prior to initiation of standard neoadjuvant chemotherapy, increases the presence and percentage of tumor and/or stromal area of infiltrating lymphocytes [97] NCT04802876 II Spartalizumab – – – ORR CBR, PFS, DOR, TtR, OS, and incidence, seriousness, treatment-related, and intensity of TEAEs The study aims at evaluating the efficacy parameters of spartalizumab when used as monotherapy in treatment of TNBC [98] NCT02954874 III No treatment Pembrolizumab – – iDFS, severity of fatigue, and physical function OS, DRFS, incidence of AEs, severity and frequency of treatment-related symptoms, emotional function and disease-related symptoms, long-term QOL, SNPs, resolution of treatment-related symptoms, and role of proinflammatory cytokines This study aims at recording the efficacy parameters of pembrolizumab in patients with TNBC [99] NCT05144698 II RAPA-201 cell – – – Safety of RAPA-201 cell therapy ORR, PFS, and QOL [100] NCT03829501 I/II KY1044 monotherapy KY1044 and atezolizumab – – ORR ORR, PFS, incidence and severity of AEs and SAEs, and no. of dose interruptions, reductions, and dose intensity The study aims to assess the safety, tolerability and efficacy of KY1044, alone or in combination with atezolizumab in patients with advanced malignancies, including TNBC [101] TNBC triple negative breast cancer, mTNBC metastatic triple negative breast cancer, PFS progression-free survival, AEs adverse events, CBR clinical benefit rate, OS overall survival, DFS disease-free survival, ORR objective response rate, DCR disease control rate, DOR duration of response, TILs-tumor-infiltrating lymphocytes, PIS peripheral immunoscore, DRFS distant recurrence-free survival, TEAEs treatment-emergent adverse events, TESAEs treatment-emergent serious adverse events, EFS event-free survival, pCR pathological complete response, SAEs serious adverse events, DTRR durable tumor response rate, TTP time to progression, iDFS invasive disease-free survival, RFI recurrence-free survival, ADAs anti-drug antibodies, C-ORR confirmed objective response rate, C-DOR duration of response for confirmed responders, BRCA-1 breast cancer gene 1, BRCA-2 breast cancer gene 2, TTD time to deterioration, Cmax maximum plasma concentration, Cmin minimum plasma concentration, CCCA complete cell cycle arrest, irORR immune-related objective response rate, irPFS immune-related progression-free survival, TRAEs treatment-related adverse effects, DMFS distant metastasis-free survival, DDFS distant disease-free survival, PFR progression-free rate, PK pharmacokinetics, BORR best overall response rate, QOL quality of life, PRO-CTCAE Common terminology criteria for adverse events, MRD minimal residual disease, RFS recurrence-free survival, RCB residual cancer burden, iPFS invasive progression-free survival, ICER Incremental cost-effectiveness ratio, EQ-5D-5L questionnaire developed 5-level version of EQ-5D questionnaire, HADS Hospital anxiety and depression scale, cCR clinical complete response, MDSC myeloid-derived suppressor cells, LPBC lymphocyte-predominant breast cancer, SNPs Single nucleotide polymorphisms, PD-L1 programmed death ligand 1, MTD maximum tolerated dose, DLT dose-limiting toxicity, CR complete response, PR partial response. Table 3 Completed clinical trials presenting supportive evidence in application of immunotherapy in TNBC NCT No Phase Treatment regimen Arm 1 Arm 2 Treatment setting Result Remarks References NCT03742349 II Pembrolizumab + carboplatin + docetaxel – – Neoadjuvant PCR: 60%, RCB: 71% The given combination regimen was well tolerated. No new signs of toxicity were evident [102] NCT02489448 II MEDI4736 Concurrent with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy – – Neoadjuvant pCR: no significant change; 3-year OS: 87% (non-AA pt) v/s 81% (AA pt.); 3 yr EFS were 78.3% and 71.4% in non-AA and AA pts respectively pCR rates were similar in both type of patients, 3-year OS, EFS and irAEs were reported to be similar in both AA nad Non-AA patients [103] NCT02555657 III Pembrolizumab or single agent chemotherapy of physician's choice Pembrolizumab Chemotherapy: capecitabine, eribulin, gemcitabine, or vinorelbine – Median OS: 9.9 months for pembrolizumab and 10.8 months for chemotherapy In previously treated mTNBC patients, pembrolizumab failed to improve OS in patients compared to chemotherapy [104] NCT02981303 II Imprime PGG + pembrolizumab – – – OR: 15.9%, CR+PR+SD: 54.5%, CR+PR+SD≥24w: 25.0%, median OS: 16.4 This study provides a clinical proof for combination of imprime PGG and pembrolizumab [105] NCT02730130 II Pembrolizumab + radiotherapy – – – 3 partial responses represented 60%, 54%, and 34% decreases in tumor burden. Mild common toxicities were observed The combination of pembrolizumab with RT was observed to be well tolerated and can be used to improve response rate [106] NCT02447003 II Pembrolizumab – – – ORR: 5.3%, DCR: 7.6%, Median PFS: 2 months, median OS: 9 months, In previously treated mTNBC patients, pembrolizumab showed durable anti-tumor activity [107] NCT02657889 II Niraparib with pembrolizumab – – – ORR: 10 patients (21%; 90% CI, 12–33%) and DCR: 23 (49%; 90% CI, 36–62%). Median DOR was not reached The combination yield a promising anti-tumor effect with higher response rate in advanced or mTNBC [108] NCT02425891 III Atezolizumab, nab-paclitaxel and placebo Atezolizumab with nab-paclitaxel Placebo Plus Nab-Paclitaxel – median PFS: 7.2 v/s 5.5 months, median OS: 21.3 v/s 17.6 monts, Atezolizumab plus nab-paclitaxel prolonged PFS in both intention to treat population and the PD-L1 positive subgroup [55] [46] NCT03197935 III Atezolizumab, chemotherapy and placebo Atezolizumab and chemotherapy Placebo and Chemotherapy Neoadjuvant median follow-up: 20.6 v/s 19.8 months, pCR: 58 v/s 41% the combination with atezolizumab improved pCR rates and is well tolerated in early-stage TNBC [109] NCT03098550 II Nivolumab and daratumumab – – – ORR:4.9, PFS:1.22 In this trial not a single patient of TNBC has completed the study and mainly reported higher SAE with combination [110] NCT03316586 II Nivolumab and cabozantinib – – – ORR: 5.6, PFS: 1.97 months, CBR: 16.7% This study has evaluated the safety and effectiveness of nivolumab and cabozantinib in TNBC patients [111] NCT02178722 II Pembrolizumab and INCB024360 – – – ORR:11.1, PFS: 3.6 months, DDC: 11.47 months Atezolizumab in combination with INCB024360 given to the patients of TNBC to evaluate the safety profile [112] mTNBC metastatic triple-negative breast cancer, PCR pathologic complete response, RCB residual cancer burden, OS overall survival, AA african-American, EFS event-free survival, irAEs immune-related adverse events, OR overall response, CR complete response, PR partial response, SD stable disease, RT radiotherapy, ORR objective response rate, DCR disease control rate, PFS progression free survival, DOR duration of response, DDC duration of disease control Table 4 Completed clinical trials presenting a supportive evidence in application of immunotherapy in TNBC Sr. No.: NCT Phase Regimen Primary outcome Secondary outcome Remarks References 1 NCT03719326 I Drug: Etrumadenant Drug: IPI-549 Drug: Pegylated liposomal doxorubicin (PLD) Drug: nanoparticle albumin-bound paclitaxel (NP) AEs incidents, DLTs during dose escalation Plasma concentrations, clinical activity of combination therapy, AB928 receptor occupancy, immunophenotyping, gene expressions, cytokines Early results demonstrated favorable safety profile of etrumadenant combination therapy [113] 2 NCT03544125 I Durvalumab and olaparib Proportion of completion of CLIA analytics on pre-treatment biopsy before the planned for 4-week biopsy Incidence of >=grade 3 AEs, ORR, CBR, DOR, PFS, OS The pilot study confirmed feasibility of analysis to inform treatment decision [114] 3 NCT03256344 I Talimogene Laherparepve+atezolizumab Incidence of DLTs, incidence of AEs, clinically relevant laboratory abnormalities ORR, BOR, DOR, DRR, DCR, PFS, OS, Lesion Level Response in uninjected tumor Lesions: L-CRR. L-PRR, L-ORR – [115] 4 NCT03098550 I/II Nivolumab+daratumumab Incidence of AEs, SAEs, and grade of laboratory abnormalities ORR, PFS, ADA positivity, AUC, Cmin – [110] 5 NCT02447003 II a.Pembrolizumab ORR, no. of participants experiencing at least one adverse event and discontinuing study drug due to AEs – In previously treated mTNBC patients, pembrolizumab showed durable anti-tumor activity [107] NCT02555657 III b.Pembrolizumab PFS and OS ORR and DCR In previously treated mTNBC patients, pembrolizumab failed to improve OS in patients compared to chemotherapy [104] NCT02622074 I c.Pembrolizumab in combination with chemotherapy No. of participants with DLT, no. of participants who experienced an adverse event, and no. of participants who discontinued study treatment due to an adverse event pCR, ORR for first and second combination regimen, the EFS rate at 6,12 and 24th month, and OS rate at 6,12 and 24th month Combination neoadjuvant chemotherapy and pembrolizumab showed manageable toxicity and promising anti-tumor activity in high-risk, early-stage TNBC patients [116] NCT02425891 III d.Atezolizumab with nab-paclitaxel versus placebo with nab-paclitaxel PFS and OS in all randomized patients OS, DOR, ORR, and TTD, incidence, nature, and severity of AEs Atezolizumab plus nab-paclitaxel prolonged PFS in both intention to treat population and the PD-L1 positive subgroup [46] 6 NCT02125344 III a.ETC (epirubicin, taxel, cyclo-phosphamide) and paclitaxel/non-pegylated liposomal doxorubicin or carboplatin (PM(Cb)) pCR Clinical and imaging response, breast conservation time, OS in both arms, correlation of response, pharmacogenetic sub-study, examination of PIK3CA sub-mutation, GeparPET sub-study A significant benefit from iddEPC was observed in HR+ /HER2− BC patients [117] Cmin minimum blood plasma concentration, AE adverse event, DLT dose-limiting toxicity, ORR objective response rate, CBR clinical benefit rate, DOR duration of response, PFS progression-free survival, OS overall survival, CLIA Clinical Laboratory Improvement Act, BOR best overall response, DRR durable tumor response rate, DCR disease control rate, pCR pathological complete response, BC breast cancer, HER2 human epidermal growth factor receptor 2, iddEPC intense dose-dense epirubicin, paclitaxel, and cyclophosphamide, PD-L1 programmed death ligand 1, TTD time to deterioration, EFS event-free survival, TNBC triple negative breast cancer, mTNBC metastatic triple negative breast cancer, AUC area under curve, SAEs serious adverse events, L-CRR lesion complete response rate, L-PRR lesion partial response rate, L-ORR lesion objective response rate, ADA anti-drug positivity, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, HR + hormone receptor positive Tackling TNBC with vaccines Under the multitude of immunotherapies, cancer vaccines have been envisioned as a core focus since a long time. Cancer vaccines (CVs) are designed to mount an immune response by recognizing TAAs and destroy cancer cells that residents them [56]. CVs can be categorized into two based on their purpose of usage namely prophylactic and therapeutic CVs. Prophylactic vaccines aim at reducing future incidences while therapeutic CVs are developed to contract existing malignancy [57]. This strategy has also been practiced for development of CVs directed towards breast cancer. The most common targets and TAAs aimed for successful vaccination in BC include E75 peptide, glycoprotein 2 (GP2) peptide, CD4 + lymphocytes, mucin short variant S1 (MUC1) antigen, melanoma associated antigen-3 (MAGE-A3), New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1), Carcinoembryogenic antigen (CEA), human telomerase reverse transcriptase (hTERT), Wilms’ tumor antigen (WT-1), NY-BR-1, Mammaglobin-A (Mam-A) and TRICOM. Targets to develop vaccination are summarized in Table 5.Table 5 Possible targets for development of TNBC directed vaccines Type of vaccine Name of vaccine Targets/antigens Peptide based vaccine PVX, OncoPep X-box–binding protein 1 with two splice varieants, CD-138, CD-319 P10s-PADRE Mimotope TPIV200 FRα multi-epitope Tumour-specific mutant antigens (TSMA)–based synthetic long peptide vaccine – Galinpepimut-S WT-1, WT-A1 Adagloxad simolenin TAA Globo-H, keyhole limpet haemocyanin Viral vector based vaccine P53MVA P53 specific CD8 + cells GENE based vaccines Neoantigen vaccine with durvalumab – IVAC_W_bre1_uID Tumor associated antigens IVAC_M_uID Multiple target neo-antigens STEMVAC TAAs associated to breast cancer stem cells Pan-HLA-DR–binding epitope (PADRE), folate–receptor alpha (FRα), Wilms' tumour gene 1 (WT-1) protein, WT1-derived peptide (WT-A1), Tumor associated antigen (TAA) With emerging number of antigens specifically expressed in TNBC, huge scope of vaccine development against this carcinoma is presented. To date, numerous CVs right from peptide-based to DNA, cytokines and lymphocyte-based vaccines are paving their way to qualifying for TNBC treatment [58]. Their progress is hindered by immunologically inadequate clinical settings (large tumor burden in metastatic disease), predominance of TAAs as targets, choice of vaccine delivery platform, concomitant administration of therapies with CV and existence of influential unrestrained mechanisms favouring immune escape including antigen modification, absence of Human Leukocyte Ag class-1 (HLA-1) expression and down-regulation of TAAs which cannot be recognised as a target [59], 60, 61. Numerous clinical trials are advancing towards the search for a safe and effective vaccine. An open-label, phase 2 study was designed to assess the enhancement in tumor-specific immune response and determine efficacy of Biological AE37 Peptide vaccine combined with Pembrolizumab in metastatic triple-negative breast cancer (mTNBC) patients (NCT04024800). The study progressed with Simon two-step design and from 29 eligible patients, 13 patients were grouped as safety cohort in Stage 1 and were subjected to the combination therapy of AE37 vaccine with Pembrolizumab. The primary outcome measures to be assessed were recommended dose within 72 h of vaccination in first 13 patients and ORR determined by RECIST 1.1. The secondary outcomes selected were PFS, OS, Clinical benefit rate (CBR) and Overall toxicity. The study aims to establish the recommended biologic dose of combined AE37 vaccine with Pembrolizumab and the results of the same are expected soon [62]. Another trial presenting a noteworthy evidence is a phase 1b/2 study that evaluated safety and efficacy of metronomic combination therapy in TNBC patients who progressed on or after standard of care (SoC) chemotherapy (NCT03387085) [63]. Treatment was administered by choosing a 3 week cycle routine in a lower dose (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), Stereotactic Body Radiation Therapy (SBRT), engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, Avelumab. Selected primary endpoints for phase 1b was incidence of treatment-related adverse effect (TRAE) and serious adverse events (SAE). Secondary endpoints assessed were ORR, PFS, OS and Disease control rate (DCR). 8 subjects received 3 treatment cycles in an outpatient setting with all having atleast 1 grade ≥ 3 TRAE being chemotherapy-induced neutropenia. 2 subjects were observed to have grade ≥ 3 haNK- related effects while 2 subjects experienced SAEs. 7 subjects remained alive, 6 subjects continued to receive ongoing treatment while 1 CR and 2 PRs were noted. This trial proved that low dose chemo-radiation combined with innate and adaptive immunotherapy has a good safety profile to be administered in outpatient setting [64]. Clinical trials both ongoing and completed evaluating safety and efficacy of cancer vaccines in TNBC are summarized in Table 6.Table 6 Completed and ongoing clinical trials of vaccines targeting TNBC Sr No NCT No Phase and status Regimen Primary outcome Secondary outcome Remark References 1. NCT02018458 I/II Completed Chemotherapy with DC vaccine Safety of DC vaccine when combined with chemotherapy pCR rate and DFS Safety and clinical efficacy were demonstrated when autologous DC vaccines were administered intratumoral and SC during preop chemotherapy in TNBC patients [118] 2. NCT04879888 I Completed Peptide pulsed Dendritic cell Number of AEs – – [119] 3. NCT04105582 I Completed Neo-antigen pulsed Dendritic cell AEs and safety Neoantigen Immunogenicity – [120] 4. NCT03387085 I/II Active, not recruiting NANT Triple Negative Breast Cancer (TNBC) Vaccine Incidence of treatment-emergent AEs and ORR ORR, PFS, OS, DOR, DCR, patient-reported outcomes, and incidence of TEAEs – [63] 5. NCT03362060 Ib, Active, not recruiting PVX-410 vaccine Plus pembrolizumab The immune response following treatment PFS, OS, response rate, DCR, CBR, DOR, late immune response after treatment, and incidence of TEAEs – [121] 6. NCT02826434 Ib Active, not recruiting Adjuvant PVX-410 vaccine and durvalumab DLTs Immune response rate, DFS, and AEs – [122] 7. NCT03606967 II Recruiting Individualized vaccine to Nab-paclitaxel, durvalumab, and tremelimumab and chemotherapy PFS CBR, OS, clinical response rate, and incidence of AEs – [123] 8. NCT05269381 I Recruiting Combination of Cyclophosphamide, Neoantigen Peptide Vaccine, Pembrolizumab, Sargramostim Incidence of AEs Immunogenicity responders, ORR – [124] DC dendritic cell, SC subcutaneous, pCR pathological complete response, DFS disease free survival, TNBC triple negative breast cancer, ORR overall response rate, OS overall survival, DCR disease control rate, DOR duration of response, TEAEs treatment emergent adverse events, CBR clinical benefit rate, AEs adverse effects, DLTs dose limiting toxicities Achievable prospects The edges embodying immunotherapeutic applications in the neoadjuvant, adjuvant and metastatic stages in TNBC have been widened by the preclinical and clinical evidences. Adding to this, cumulative facts obtained from other solid tumors suggest early biopsy to hold a promising potential in revealing the extent of immunotherapeutic benefits reaching to the patient. Unveiling the entire spectrum of clinical benefits of immunotherapy is possible by development of specific biomarkers to precisely predict the response and possible resistance to given immunotherapy. A rational clinical trial design assisted with strong sample collection approach could provide more reliability and accuracy to the efficacy of immunotherapy in diminishing TME. A comprehensive understanding of the fundamentals of TNBC heterogeneity, molecular biomarkers, immunotherapy mechanism cascades and development of resistance could facilitate development of better immunotherapeutic regimens with maximized benefits. Novel approaches to overcome the obstacle of narrow therapeutic index of these drugs should be developed. Identification of clearly defined indications of these drugs as monotherapy and in combination is necessary to achieve increment in drug prescription rationality. Conclusion Extending the therapeutic strategies to include immunotherapy in eradication of TNBC has become a necessity due to the shortcomings of conventional approaches and poor prognosis of this subtype of BC. Clinical trials included lean towards the successful use of immunotherapy in neoadjuvant, adjuvant and metastatic TNBC but this is accompanied with occurrences of alarming AEs which can be perceived as a major setback of immunotherapy. Despite the possibility of unfavourable AEs, immunotherapy still can be envisioned as a potential strategy to target tumor cells as benefits outweigh the risks. Clinical trials contribute encouraging results in favour of applicability of vaccines and concrete evidence regarding the same may be expected soon. With ongoing investigations, newly established immunotherapies may prove to qualify as first line therapies for primary TNBC diagnoses. It may also enhance survival parameters in patients presenting with metastasis or recurrence. Abbreviations ADCC Antibody-dependent cellular cytotoxicity BC Breast Cancer BL1/BL2 Basal-like 1/Basal-like 2 CAR-T Chimeric antigen receptor T-cell therapy CBR Clinical benefit rate CEA Carcinoembryogenic antigen circ-HER2 Circular human-epidermal growth factor CR Complete response CTLA-4 Cytotoxic T lymphocyte-associated antigen-4 CVs Cancer vaccines DC Dendritic cells DCR Disease control rate DOR Duration of response EFS Event-free survival EGFR Epidermal growth factor receptor ER Estrogen receptor ERα+ Estrogen receptor a-positive GP2 Glycoprotein 2 HER2 Human-epidermal growth factor hTERT Human telomerase reverse transcriptase ICIs Immune checkpoint inhibitors IDO Indoleamine-2, 3-dioxygenase LAG-3 Lymphocyte activation gene-3 LAR Luminal androgen receptor MAGE-A3 Melanoma associated antigen-3 Mam-A Mammaglobin-A MSLN Mesothelin mTNBC Metastatic triple-negative breast cancer MUC1 Mucin short variant S1 NY-ESO-1 New York Esophageal Squamous Cell Carcinoma-1 ORR Objective response rate OS Overall survival pCR Pathological complete response PD-1/PD-L1 Programmed death-1 receptor-ligand-1 PD-L1 Programmed death ligand 1 PFS Progression-free survival PK Pharmacokinetics PR Partial Response PR Progesterone receptor PR+ Progesterone receptor-positive RP2D Recommended phase II dose SAE Serious adverse events STAT3 Signal transducer and activator of transcription 3 TAAs Tumor-associated antigens TME Tumor microenvironment TNBC Triple-negative breast cancer TRAE Treatment-related adverse effect TSAs Tumor specific antigens TTD Time to Deterioration VEGF Vascular endothelial growth factor WT-1 Wilms’ tumor antigen Author contributions Study conception, design, manuscript draft review and editing were performed by AK, SS and ACB. The first draft of the manuscript was written by ACS, AJP, and KM. The data curation was performed by NRK and IS. All authors read and approved the final manuscript. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Declarations Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Ethical approval Not applicable. Consent to participate Not applicable. Consent to publish Not applicable. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. 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Accessed 30 Nov 2022 67. “LN-145 or LN-145-S1 in treating patients with relapsed or refractory ovarian cancer, triple negative breast cancer (TNBC), anaplastic thyroid cancer, osteosarcoma, or other bone and soft tissue sarcomas—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03449108. Accessed 30 Nov 2022 68. “OXEL: immune checkpoint or capecitabine or combination therapy as adjuvant therapy for tnbc with residual disease—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03487666. Accessed 30 Nov 2022 69. “Immune induction strategies to improve response to immune checkpoint blockade in triple negative breast cancer (TNBC) patients—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04159818. Accessed 30 Nov 2022 70. “A study of atezolizumab plus nab-paclitaxel in the treatment of unresectable locally advanced or metastatic PD-L1-positive triple-negative breast cancer—Full Text View—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04148911. Accessed 30 Nov 2022 71. “Clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo in patients with triple-negative breast cancer followed after surgery by atezolizumab or placebo—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03281954. Accessed 30 Nov 2022 72. Pérez-García J Soberino J Racca F Gion M Stradella A Cortés J Atezolizumab in the treatment of metastatic triple-negative breast cancer Expert Opin Biol Ther 2020 20 9 981 989 10.1080/14712598.2020.1769063 32450725 73. “Atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT03164993?term=PD1%2FPDL1%2C+Atezolizumab&cond=Breast+Cancer&draw=2&rank=2. Accessed 03 Oct 2022 74. “A study comparing atezolizumab (anti PD-L1 antibody) in combination with adjuvant anthracycline/taxane-based chemotherapy versus chemotherapy alone in patients with operable triple-negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03498716. Accessed 30 Nov 2022 75. “Investigate the contribution of ipatasertib to neoadjuvant chemotherapy plus atezolizumab in TNBC—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05498896. Accessed 30 Nov 2022 76. “Evaluating the efficacy and safety of bevacizumab, carboplatin, gemcitabine and atezolizumab in breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04739670. Accessed 30 Nov 2022 77. “A study of the efficacy and safety of atezolizumab plus chemotherapy for patients with early relapsing recurrent triple-negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03371017. Accessed 30 Nov 2022 78. “Study to compare a mono atezolizumab window followed by a atezolizumab - ctx therapy with atezolizumab—ctx therapy—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04770272?term=NCT04770272&draw=2&rank=1. Accessed 03 Oct 2022 79. “Efficacy and safety of atezolizumab plus capecitabine adjuvant therapy for triple receptor-negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03756298. Accessed 30 Nov 2022 80. “Nab-paclitaxel and atezolizumab before surgery in treating patients with triple negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT02530489?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=30. Accessed 03 Oct 2022 81. “First Line atezolizumab, paclitaxel, and bevacizumab (Avastin®) in mTNBC—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04408118. Accessed 30 Nov 2022 82. “Carboplatin and paclitaxel with or without atezolizumab before surgery in treating patients with newly diagnosed, stage ii–iii triple-negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT02883062?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2. Accessed 03 Oct 2022 83. “Atezolizumab + sacituzumab govitecan to prevent recurrence in tnbc (aspria)—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04434040. Accessed 11 Oct 2022 84. “Atezolizumab plus carboplatin plus nab-paclitaxel—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05266937. Accessed 30 Nov 2022 85. “A clinical study of TJ004309 with Atezolizumab (TECENTRIQ®) in patients with ovarian cancer and selected solid tumors—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05001347. Accessed 30 Nov 2022 86. “Adjuvant treatment for high-risk triple negative breast cancer patients with the anti-PD-l1 antibody avelumab—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02926196. Accessed 30 Nov 2022 87. “Restoring sensitivity to immunotherapy in advanced triple negative breast cancer exploiting ceralasertib priming followed by combined durvalumab/nab-paclitaxel—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05582538. Accessed 30 Nov 2022 88. “Radiation, immunotherapy and parp inhibitor in triple negative breast cancer - tabular view - clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT04837209?term=immunotherapy&recrs=abdf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=5. Accessed 03 Oct 2022 89. “Reinvigorating TNBC response to immunotherapy with combination myeloid inhibition and radiation—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05491226. Accessed 30 Nov 2022 90. “Dendritic cell-based treatment plus immunotherapy for the treatment of metastatic or unresectable triple negative breast cancer—full text view— clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05539365. Accessed 30 Nov 2022 91. “Panitumumab and pembrolizumab in combination with neoadjuvant chemotherapy for the treatment of stage III–IV triple negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05177796?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=15. Accessed 03 Oct 2022 92. “Reverse triple negative immune resistant breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT05076682?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2. Accessed 03 Oct 2022 93. “Neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT03639948?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=20. Accessed 03 Oct 2022 94. “Pre-op pembro + radiation therapy in breast cancer (P-RAD)—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT04443348?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=23. Accessed 03 Oct 2022 95. “Pembrolizumab in treating patients with stage iv metastatic or recurrent inflammatory breast cancer or triple-negative breast cancer who have achieved clinical response or stable disease to prior chemotherapy—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT02411656?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=35. Accessed 03 Oct 2022 96. “The efficacy and safety of sintilimab plus anlotinib combined with chemotherapy as neoadjuvant therapy in TNBC—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT04877821?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=38. Accessed 03 Oct 2022 97. “Neoadjuvant Pembrolizumab + decitabine followed by std neoadj chemo for locally advanced HER2- breast Ca—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/study/NCT02957968?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=4&rank=50. Accessed 03 Oct 2022 98. “Efficacy of spartalizumab across multiple cancer-types in patients with PD1-high mRNA expressing tumors—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04802876?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=54. Accessed 03 Oct 2022 99. “Testing MK-3475 (Pembrolizumab) as adjuvant therapy for triple receptor-negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02954874?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=55. Accessed 03 Oct 2022 100. “RAPA-201 therapy of solid tumors—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05144698?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=62. Accessed 03 Oct 2022 101. “Safety and efficacy of KY1044 and atezolizumab in advanced cancer—full text view–clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03829501. Accessed 30 Nov 2022 102. “Study of safety and efficacy of novel immunotherapy combinations in patients with triple negative breast cancer (TNBC). - Tabular View - ClinicalTrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT03742349?term=immunotherapy&recrs=abdf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=2. Accessed 03 Oct 2022 103. “Neoadjuvant MEDI4736 concomitant with weekly nab-paclitaxel and dose-dense AC for stage I–III triple negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02489448. Accessed 30 Nov 2022 104. Winer EP Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial Lancet Oncol 2021 22 4 499 511 10.1016/S1470-2045(20)30754-3 33676601 105. “Study of imprime PGG and pembrolizumab in advanced melanoma and triple negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02981303. Accessed 30 Nov 2022 106. “Study to assess the efficacy of pembrolizumab plus radiotherapy in metastatic triple negative breast cancer patients—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02730130. Accessed 30 Nov 2022 107. Adams S Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study Ann Oncol Off J Eur Soc Med Oncol 2019 30 3 397 404 10.1093/ANNONC/MDY517 108. “Niraparib in combination with pembrolizumab in patients with triple-negative breast cancer or ovarian cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02657889. Accessed 30 Nov 2022 109. “A study to investigate atezolizumab and chemotherapy compared with placebo and chemotherapy in the neoadjuvant setting in participants with early stage triple negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03197935. Accessed 30 Nov 2022 110. “A study to test the safety and effectiveness of nivolumab combined with daratumumab in patients with pancreatic, non-small cell lung or triple negative breast cancers, that have advanced or have spread—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03098550?term=NCT03098550&draw=2&rank=1. Accessed 03 Oct 2022 111. “A phase II study of nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03316586. Accessed 30 Nov2022 112. “Study to explore the safety, tolerability and efficacy of mk-3475 in combination with INCB024360 in participants with selected cancers—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT02178722. Accessed 30 Nov 2022 113. Powderly J Phase I evaluation of AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced malignancies Ann Oncol 2019 30 v493 10.1093/annonc/mdz253.032 114. Labrie M Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies NPJ Precis Oncol 2021 5 1 10.1038/S41698-021-00232-W 33479506 115. “Study of talimogene laherparepvec with atezolizumab for triple negative breast cancer and colorectal cancer with liver metastases—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT03256344?term=NCT03256344&draw=2&rank=1. Accessed 03 Oct 2022 116. Schmid P Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study Ann Oncol Off J Eur Soc Med Oncol 2020 31 5 569 81 10.1016/J.ANNONC.2020.01.072 117. Schneeweiss A Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): a randomised phase III trial Eur J Cancer 2019 106 181 92 10.1016/J.EJCA.2018.10.015 30528802 118. O’Shaughnessy J Roberts LK Smith JL Levin MK Timis R Finholt JP Safety and initial clinical efficacy of a dendritic cell (DC) vaccine in locally advanced, triple-negative breast cancer (TNBC) patients (pts) J Clin Oncol 2016 34 1086 10.1200/JCO.2016.34.15_SUPPL.1086 119. Bernal-Estévez D Sánchez R Tejada RE Parra-López C Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient BMC Cancer 2016 16 1 10.1186/S12885-016-2625-2 120. “Breast cancer neoantigen vaccination with autologous dendritic cells—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT04105582?term=immunotherapy&recrs=e&cond=Triple+Negative+Breast+Cancer&draw=1&rank=2. Accessed 03 Oct 2022 121. “PVX-410 vaccine plus pembrolizumab in HLA-A2+ metastatic triple negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT03362060?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=12. Accessed 03 Oct 2022 122. “Adjuvant PVX-410 vaccine and durvalumab in stage II/III triple negative breast cancer—tabular view—clinicalTrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT02826434?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=18. Accessed 03 Oct 2022 123. “Testing the addition of an individualized vaccine to nab-paclitaxel, durvalumab and tremelimumab and chemotherapy in patients with metastatic triple negative breast cancer—tabular view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/record/NCT03606967?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=29. Accessed 03 2022 124. “Personalized neoantigen peptide-based vaccine in combination with pembrolizumab for the treatment of advanced solid tumors, the pneovca study—full text view—clinicaltrials.gov.” https://clinicaltrials.gov/ct2/show/NCT05269381?term=immunotherapy&recrs=adf&cond=Triple+Negative+Breast+Cancer&draw=2&rank=65. Accessed 03 Oct 2022

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Med Oncol. 2023 Dec 15; 40(1):48

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Med Oncol

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==== Front Reinforced Plastics 0034-3617 0034-3617 S0034-3617(20)30465-3 10.1016/j.repl.2020.12.056 Article Boeing suggests aerospace will face ‘significant challenges’ 8 2 2021 January-February 2021 8 2 2021 65 1 1919 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcBoeing’s 2020 Market Outlook predicts that the commercial aviation and services markets will continue to face significant challenges due to the Covid-19 pandemic, while global defense and government services markets could remain more stable. The report forecasts a total market value of US$8.5 trillion over the next decade including demand for aerospace products and services, down from US$8.7 trillion a year ago. While airlines globally have begun to recover from a greater than 90% decline in passenger traffic and revenue early this year, a full recovery will take years, according to the Boeing. According to the company, there will be demand for 18,350 commercial airplanes in the next decade, 11% lower than the comparable 2019 forecast, valued at about US$2.9 trillion. In the longer term, if key industry drivers remain stable, the commercial fleet could return to its growth trend, generating demand for more than 43,000 new airplanes in the 20-year forecast time period. Boeing also predicts a US$2.6 trillion market opportunity for defense and space during the next decade, due to the ongoing importance of military aircraft, autonomous systems, satellites and spacecraft. ‘Commercial aviation is facing historic challenges this year, significantly affecting near and medium-term demand for airplanes and services,’ said Darren Hulst, vice president, commercial marketing. ‘Yet history has also proven air travel to be resilient time and again. The current disruption will inform airline fleet strategies long into the future, as airlines focus on building versatile fleets, networks and business model innovations that deliver the most capability and greatest efficiency at the lowest risk for sustainable growth.’. ‘While this year has been unprecedented in terms of its disruption to our industry, we believe that aerospace and defense will overcome these near-term challenges, return to stability and emerge with strength,’ added Boeing chief strategy officer Marc Allen. Boeing market forecasts can be found via the company website. Boeing; www.boeing.com

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2021 Feb 8 January-February; 65(1):19

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==== Front Surg Clin North Am Surg Clin North Am The Surgical Clinics of North America 0039-6109 1558-3171 Published by Elsevier Inc. S0039-6109(21)00153-5 10.1016/j.suc.2021.11.001 Foreword Critical Care Martin Ronald F. MD, FACS Colonel (retired), United States Army, Department of General Surgery, Pullman Surgical Associates, Pullman Regional Hospital and Clinic Network, 825 SE Bishop Blvd, Suite 130, Pullman WA 99163, United States 18 11 2021 2 2022 18 11 2021 102 1 xiiixv © 2021 Published by Elsevier Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcRonald F. Martin, MD, FACS, Consulting Editor One of the issues that has been plaguing me of late is, how do we best distribute and apportion limited medical resources. As I type this foreword, we are approaching the 2-year mark into the global SARS-CoV-2 COVID-19 pandemic. I vividly remember when this pandemic began that I felt like it would take us a good long while to sort ourselves out and get back to something resembling normal living—but I did not imagine that 2 years in we would be struggling this hard with no clear path to normalcy in sight. I rack my brain trying to understand how the United States of America—with all its resources and capabilities—can be one of the most affected nations by this disease. On some levels, it makes sense. The United States is a country with unfettered travel within its borders and historically high volumes of people traversing its borders for myriad reasons. This country has had historical insulation from many world problems given its bicoastal geography, which may have lulled us into a false sense of security. We are used to solving problems and getting the results (more or less) that we want. On the other hand, globalization is real, and oceans aren’t as protective as they used to be. Our domestic investment in infrastructure and reserves has dwindled in service to short-term economic indicators favored by many “leaders.” While all those shortcomings have played their parts, perhaps the reason that concerns me most is that we have simply crossed over to a society that shuns collectivism in favor of a notion of individualism—which more accurately would be described as tribalism, in my opinion. In fact, if it were only individualists that failed to be part of the solution to our larger problems, this discussion would not be necessary. It takes a group or a tribe to successfully thwart a collective effort. Tribalism exists across all sectors of the economy, all socioeconomic classes, and among and between all political ideologies—and always has. While most groups are quick to point out that the “other” should change their ways, I don’t see a lot of introspection for groups to look inward at how they could change. The unfortunate net result of large sections of the population pulling in a diametrically opposed fashion is a compromised ability to plan for and deal with the consequences of our choices. As of the writing of this foreword, the COVID-19 infection has been listed as the cause of death for over 5 million people worldwide and over 750,000 persons in the United States alone. I repeat, 750,000 persons dead—well over 200 iterations of the 9/11 attacks. And still, we can’t come to uniformity of purpose on how to respond. And while the mortality has been horrible, the resource utilization required to treat the sick has not only taxed or exceeded the capacity to treat those ill from COVID but has reduced our capacity to treat and manage other diseases as well. It may be decades before we can accurately assess the excess mortality related to this pandemic. Of course, not all these deaths were preventable, though some fraction was. Furthermore, thanks to the dedication and brilliance of countless people and organizations, many people survived infection and many more were prevented from becoming ill thanks to a previously inconceivable vaccine development and implementation program. We all owe these people an enormous debt of gratitude. On the treatment side of the equation, those in the intensive care unit (ICU) setting truly standout. I mean no disrespect to our colleagues in the emergency departments, or general medical care teams, or our first responders—they have all done so much and received so little recognition for their efforts. Yet, the ICU world has had to learn to fix the airplane while still in flight. So much had to be learned so quickly, and much of what was learned was somewhat counterintuitive. In the past, I have written that in the ICU one must always remember these principles: air goes in and out; blood goes around and around; and oxygen is good. For the most part, all that is still true. What has changed is the complex bits of how we view each of those simple aphorisms have expanded to new levels. This issue of the Surgical Clinics on critical care as put together by Dr Brett Waibel and his colleagues is designed to help us revisit and reimagine what we need to know about critical care and how we can use its principles to benefit not just patients with COVID-19 but also patients with any severe physiologic derangement. We have asked much of them for this issue, and they have delivered. The reader of this issue will benefit from facts and analysis that will help to make a huge difference for someone in perhaps their most perilous moments. We are deeply indebted for their efforts and for their sharing of their wisdom. This pandemic has taught us (hopefully) many things: we can do what we can to prevent people from becoming ill; we can do what we can to mitigate illness once it occurs; and we can try to improve the survival of those most greatly afflicted with disease. It has also taught us that our resources are limited. We cannot simply absorb an unlimited quantity of ill persons and provide all of them with the care they need at all times. Our system of health care in the United States is not designed to effectively transfer patients all over the country when bed shortages occur. At that level of population health, collective engagement of the communities, the states, the regions, and the nation is required to mitigate the burdens. Decisions made at the collective level have real impacts on individuals. Conversely, individual decisions can have significant impact on the collective society. In order for civilization to function, we must find a mechanism to balance these competing desires and needs. The current wave of this pandemic is slightly on the downturn at this instant. I would be hesitant to assume another wave is not in the offing at some time. Even if we were to significantly turn the corner on this disease, I would hold off on declaring victory just yet. The fractious state of our health care apparatus, the lack of strategic and operational reserve we hold, and the lack of ability we have shown to unify have all been undeniably demonstrated. At present, we are not as prepared as we need to be for the next challenge, COVID related or otherwise. We must be thinking about the future events as we continue to manage this crisis. In my opinion, the best way to prepare is to become educated. This issue of the Surgical Clinics should greatly help in that regard. Once we have become educated, we must find a way to educate others. Perhaps most importantly, we, as subject matter experts, need to find a way to instill trust in our communities and regain our ability to be helpful as an institution. As difficult as this may be, the alternatives are likely to be far worse.

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Surg Clin North Am. 2022 Feb 18; 102(1):xiii-xv

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10.1016/j.suc.2021.11.001

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==== Front Socioecon Plann Sci Socioecon Plann Sci Socio-Economic Planning Sciences 0038-0121 0038-0121 Elsevier Ltd. S0038-0121(22)00130-6 10.1016/j.seps.2022.101340 101340 Article Synthesis of strategies in post-COVID-19 public sector supply chains under an intuitionistic fuzzy environment Ocampo Lanndon abc∗ Aro Joerabell Lourdes b Evangelista Samantha Shane b Maturan Fatima b Atibing Nadine May b Yamagishi Kafferine bd Selerio Egberto Jr. b a Department of Industrial Engineering, Cebu Technological University, Corner M. J. Cuenco Ave. & R. Palma St., Cebu City, 6000, Philippines b Center for Applied Mathematics and Operations Research, Cebu Technological University, Corner M. J. Cuenco Ave. & R. Palma St., Cebu City, 6000, Philippines c Graduate School, Cebu Technological University, Corner M. J. Cuenco Ave. & R. Palma St., Cebu City, 6000, Philippines d Department of Tourism Management, Cebu Technological University, Corner M. J. Cuenco Ave. & R. Palma St., Cebu City, 6000, Philippines ∗ Corresponding author. Center for Applied Mathematics and Operations Research, Cebu Technological University, Corner M. J. Cuenco Ave. & R. Palma St., Cebu City, 6000, Philippines. 20 5 2022 20 5 2022 1013402 9 2021 2 3 2022 11 5 2022 © 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Entities in public sector supply chains (SCs) often operate independently despite having interdependent objectives. Such a fragmented operational design poses several problems magnified by the presence of necessary public health measures fueled by COVID-19. This work contributes to the domain literature by introducing an overarching framework for synthesizing strategies in public sector SCs. The underlying component is the translation of information from the upstream to the downstream entities of the SCs, which is carried out by a Kano-enhanced quality function deployment. The proposed framework introduces intuitionistic fuzzy (IF) decision maps with the aid of the full consistency method to incorporate inherent interrelationships among strategies in the translation agenda. Under an IF environment that better captures judgment uncertainties, an actual case study of a multi-level public sector SC motivated by a government-funded project under the COVID-19 pandemic is demonstrated in this work. Findings of the case suggest that the government prioritizes meeting all project objectives. This requirement is reflected in the downstream SC. The project planning entity focuses on creating an overarching plan of operations, material request entity on complying with government procurement protocols, and maintaining public health and safety in operations for the procurement entity. Results show the effective synthesis of strategies across the SC, ensuring SC integration and collaboration. The case study demonstrates that maintaining public health and safety is a significant component of post-COVID-19 public sector SCs. Several practical insights on the synthesis of public sector SC strategies are also provided in this work. Keywords Kano model Quality function deployment Full consistency method Fuzzy decision maps Intuitionistic fuzzy set theory COVID-19 Public sector supply chain ==== Body pmc1 Introduction The management of existing supply chains (SCs) has become a prevalent topic due to its strategic importance for organizations in gaining competitive advantage [1]. One driving force of its prominence is disruptive events that disrupt the material and resource flow. Most of these disruptions are caused by a natural disaster, supplier bankruptcy, war, and terrorism [2,3]. The disruption of the SC may have a cascading effect on relevant sectors, which may result in severe and devastating impacts [4]. Due to the adverse effects of SC disruption, mitigation actions become crucial. For instance Ref. [5], take on big data analytics to build an institutional response to SC disruptive events and establish IT infrastructure capabilities. Furthermore [6,7], developed a mathematical model to help address arising concerns for sustainable SC. The model involves several aspects of the production-distribution-inventory-allocation-location domain. On the other hand, Sawik [8] presented an integrated portfolio approach on supplier selection that efficiently considers the decisions made before and after the SC disruption. It is demonstrated in the literature that mitigating the impact of inevitable SC disruptions is possible with the comprehensive knowledge of the factors that affect the propagation of these disruptions [9]. This approach, however, may fall short when dealing with disruptions of multiple SCs, such as a global pandemic [10]. emphasized that disruption of an upstream SC may lead to ripple effects downstream, which may cause the entire SC to shut down. This is accurately depicted in the recent disruption on the global SC caused by the COVID-19 pandemic [11], and multiple intelligent actors (e.g., government, organizations), each is satisfying their utilities, must be involved in the analysis (e.g., Ref. [12]. When China decided to impose movement restrictions towards people and resources and cross-border restrictions to contain the spread of the coronavirus in January 2020, the global 10.13039/100006132 SC suffered a significant delay in material movement, which has been associated with the failure of raw material acquisition to support operations of several manufacturers worldwide that are dependent on the factories in China [13]. As a result, the global SC failed to promptly distribute the necessary goods to the public (i.e., toilet paper, cotton swab, wheat, and flour) [14]. In addition, the general population contributed to enormous variability in demand for specific goods when they resorted to panic buying and stockpiling in fear of resource shortage [13]. However [14], emphasized that the COVID-19 pandemic was not an aberration. Businesses are not entirely blindsided since the global SC has already been disrupted by major natural calamities, such as the 2003 SARS crisis and the Fukushima Daichi nuclear disaster [15]. Due to effective mitigation efforts, several businesses have successfully recovered their operations amid the pandemic. For instance, a pharmaceutical company presented in the study of [14] has been contracting with fourth-party logistics to find multiple available logistics options instead of a single-source logistics provider to develop an agile and resilient SC. Also, some companies voluntarily decided to pivot their normal operations into the procurement and manufacturing of essential supplies (i.e., personal protective equipment and ventilators) during the pandemic [16,17]. Since SC risks are multifaceted and unique to each case [18], businesses are still challenged to adapt existing mitigations for specific disruptions. Thus, despite the popularity of SC mitigation strategies for natural calamities, the scope of COVID-19 pandemic impact (i.e., number of affected people, geographical impact, and longevity of the situation) is inevitable to cause downstream interruption and closure of production in many SCs. Business operations for Apple, for instance, has been widely interrupted because their assembler, Foxconn, is working below capacity [19] due to the delay in material flow from Apple's suppliers in China, Malaysia, South Korea, and Europe caused by the imposed lockdowns and a paucity of parts supplies from their sub-suppliers [20]. Evidently, there are constraints under the new normal conditions experienced by industries that adversely affect normal operations. Several companies were forced to adopt new ways of remotely working, utilizing new communication systems, altering work practices to meet social distancing protocols, and modifying work patterns to continue business operations [21]. On the other hand, Kodamo [22] also observed that public service organizations and governments are adapting through the utilization and deployment of technology applications and cloud-based infrastructure to provide services to their stakeholders. In the public sector, supply chain management (SCM) may be interpreted as the acquisition of commodities and services by the government or public entities (e.g., through buying or purchasing) [23]. Public sector SCM is part of various economic activities that support government service delivery, social and political roles, ranging from simple goods to extensive construction and development projects [24]. To ensure transparency and accountability for all government activities, an organization assigned to control material acquisition (e.g., Bids and Awards Committee) is tasked to engage in the 10.13039/100006132 SC for the public sector, thus adding to the public sector SC's complexity. Public sector SCM is deemed to have an essential role in the development of society due to its contribution to both micro-and macro-economic development [25]. Public procurement represents an average of 13%–20% of the GDP, and managing such activities boosts economic growth and shared prosperity [26]. However, the domain of public SC remains largely underexplored [27]. Nevertheless, ineffective public sector SCM can have adverse consequences for any economy [28]. Mismanaged public SC may result in excessive prices charged by suppliers, unreliable and substandard quality of goods and services, corruption, and waste [29]. The COVID-19 pandemic disrupted the usual face-to-face communication among entities of the public sector SC. This disruption adversely impacts the flow of information across the SC, which leads to misalignment of objectives, operational asynchrony, and dissatisfaction [30]; resulting in distortion, dilution, and diversion of sector financing, resources, and capacity [31]. These communication challenges are more pronounced in technologically deficient third-world countries. For instance, in the Philippines, the expiration of at least Php 9 billion (i.e., governmental departments) in addressing the COVID-19 pandemic became a highlight. This has amplified the health crisis in the country, especially since the wages of several contractual health workers are sourced from expired funds [31]. emphasized that promoting an integrated plan would forge opportunities for greater sectoral integration. Such an agenda becomes relevant as decision-makers in the public sector face procedural, legal, and political constraints that might hamper integration efforts. In addition, many internal and external stakeholders, both in upstream and downstream SC, have conflicting goals, given the presence of public and private entities. Such integration of factors (initiatives and requirements) and actors (internal and external stakeholders) are crucial in public sector SCM. Thus, a framework to facilitate the synthesis of SC initiatives in the public sector amid the COVID-19 pandemic can be a useful tool to synchronize SC entities, promote proactive policy and plan development, and address the problems highlighted here. Despite such an important agenda, limited attention is offered in the current literature. This work overcomes this gap by offering an integrated framework that synthesizes the strategies of SC entities in the delivery of public goods operating under response measures due to the pandemic. Such a synthesis requires that downstream entities of the public sector SC satisfy the requirements of those in the upstream. These links are initialized by a set of requirements identified by the government (i.e., as the implementing entity of public services) for a given project. In this work, the translation of requirements from the government to downstream entities of the public sector SC is facilitated with the use of the quality function deployment (QFD). QFD was initially designed as a product development tool for maximizing customer satisfaction by translating customer requirements into design decisions throughout the product or service development stages [32]. The core of the QFD is the house of quality (HoQ) that guides the design teams at every stage of product development to ensure that the product or service closely matches customer requirements [33]. However, analogous to analyzing markets, satisfying the requirements of each SC entity (i.e., government, downstream entities) is not linear, and to address this non-linear relationship, different customer satisfaction models (e.g., quadrilateral, Kano, analytic, American customer satisfaction indices) have been developed. Among these models, the Kano model is widely popular. It poses that the relation between the degree of satisfaction of the specific product or service features is dependent on the attribute under consideration and is not necessarily linear [34]. Since its development in 1984, its application has gained prominence in various domains of the literature, such as in healthcare (e.g. Ref. [35], smart manufacturing systems [36], logistics [37], education [38,39], among others. The role of the Kano is generally to elucidate the underlying feature of a given requirement that is used to initialize the QFD. Analogous to the systematic transfer of quality from the product planning to production and assembly stage [40], the integration of the Kano model and the QFD (i.e., popularly coined as the Kano-QFD model) augments the translation of requirements of the entities from upstream to downstream public sector SC. However, these requirements have intertwined relationships not addressed in most Kano-QFD integration. These interrelationships, through dependence and feedback, would potentially alter the decisions. In addition, the evaluation of these requirements at every level of the SC is associated with ambiguity and uncertainty brought about by the insufficient knowledge of the SC entities or the conditions of the decision-making environment. Thus, this work offers a systematic approach that extends the Kano-QFD model in handling dependence and feedback of the translation of the requirements of the SC entities. This approach resembles the fuzzy decision-making trial and evaluation laboratory (DEMATEL), analytic hierarchy process (AHP), and the analytic network process (ANP) integration of [41,42]. However, methodologically, we introduce innovations of the previous approach to advance some crucial drawbacks of its computational structure. First, the limitations of the fuzzy set theory of [43] in better handling uncertainty are addressed using the intuitionistic fuzzy set (IFS) theory (Atanassov, 1986). Secondly, the use of the full consistency method (FUCOM) [44] overcomes the burden necessary in eliciting judgments within the AHP. Finally, Yu and Tzeng [45] demonstrated the drawbacks of the DEMATEL-ANP, and fuzzy decision maps (FDM) are deemed beneficial to advance these drawbacks. Thus, this work contributes to the domain literature by exploring the integration of IFS theory within the framework of FUCOM-FDM in augmenting the Kano-QFD model for synthesizing the translation of strategies across the public sector SC in the delivery of public goods amidst a disruption. As the current literature has not explored such integration, this work is the first attempt to develop such a computational procedure. To demonstrate the proposed novel approach, a case study of the SC of a research institute established in a state university is carried out in this work. This paper is outlined as follows: Section 2 illustrates the preliminaries of the IFS, Kano-QFD integration, FUCOM, and the FDM. Section 3 presents the proposed framework, while Section 4 presents the case application. It proceeds with a discussion of findings in Section 5 and managerial insights in Section 6. It ends with a conclusion and discussion of future works in Section 7. 2 Preliminaries 2.1 Intuitionistic fuzzy set (IFS) theory [43] proposed the fuzzy set theory (FST) in handling vagueness and uncertainty in computing information. An extension of the FST is the intuitionistic fuzzy set (IFS) theory introduced by Atanassov (1986). IFS is characterized by a membership function, a non-membership function, and a hesitancy degree that respectively express support, opposition, and neutrality in eliciting information (Atanassov, 1986). This is an advantage over the FST as it can better handle the uncertainty of information, particularly within the framework of decision-making [46]. detailed three main advantages of the IFS theory under a decision-making environment. First, it offers the ability to model unknown information via the degree of hesitation. In the practical application (e.g., COVID-19 pandemic), where decision-makers are unsure about their preferences, the IFS theory is more suitable in extracting opinion than the FST. Secondly, it is characterized by three grades of information that can better capture uncertainty comprehensively. Finally, the traditional FST only handles the degree of “agreement” but fails to represent the degree of “disagreement”, often depicted in eliciting opinion. The following provides some fundamental concepts of the IFS relevant in this work.Definition 1 (Atanassov, 1986): Suppose X is a finite, non-empty set. Then an IFS A in X is defined as(1) A={x,μA(x),νA(x):x∈X} where μA(x):X→[0,1] and νA(x):X→[0,1] such that 0≤μA(x)+νA(x)≤1,x∈X (i.e., the intuitionistic condition). μA(x) and νA(x) represent the membership function and the non-membership function, respectively, of x∈X to A. πA(x) expresses the degree of lack of knowledge of every x∈X to A, and 0≤πA(x)≤1. μA(x), νA(x), and πA(x) follow Equation (10) (2) πA(x)=1−μA(x)−νA(x),x∈X πA(x) is also referred to as the intuitionistic index of x in A, which is associated with the degree of indeterminacy membership of x in A. Definition 2 [47]: For any two intuitionistic fuzzy sets (IFSs) A={x,μA(x),νA(x):x∈X} and B={x,μB(x),νB(x):x∈X}, the following operations hold,(3) A≤Bifandonlyif,∀x∈X,μA(x)≤μB(x),andνA(x)≥νB(x) (4) A=BifandonlyifA≤BandB≤A (5) A∪B={x,max(μA(x),μB(x)),min(νA(x),νB(x)):x∈X} (6) A∩B={x,min(μA(x),μB(x)),max(νA(x),νB(x)):x∈X} Early works on IFS theory demonstrated its use within the agenda of multi-criteria (or attribute) decision-making (e.g., Refs. [[48], [49], [50], [51]]. A widely engaged research stream in IFS theory since its inception until lately is the notion of distance between two IFSs [[52], [53], [54], [55]]. Some widely regarded distances include Hamming distance, normalized Hamming distance, Euclidean distance, normalized Euclidean distance, and Minkowski distance [52,54]. Here, we present the definition of the Euclidean distance offered by Ref. [56]. For convenience, we write an IFS A={x,μA(x),νA(x):x∈X} as A=(μA,νA), with μA, νA∈[0,1] and 0≤μA+νA≤1. Definition 3 [56]: Let A=(μA,νA) and B=(μB,νB) be any two IFSs. The Euclidean distance between the IFS A and B, denoted by dE(A,B), is defined as:(7) dE(A,B)=(μA−μB)2+(νA−νB)22 When used in decision-making, a ranking of IFS becomes a crucial aspect. In this regard, significant interests from domain scholars are observable, and various approaches have been offered, where most of them were based on specific distance measures. The earliest and widely known approach, which is based on vague sets, was the score function of [57]. Due to its limitations [50], proposed an algorithm that combines the score function and the accuracy function of [58] in ranking IFS. Since then, several formulations have been put forward (e.g., Refs. [52,54,59]. Here, we present the notion of [54] on the ideal positive degree, which is based on Euclidean distance. The ideal positive degree intends to address some problems of inadmissibility, non-robustness problem, and indifference. Definition 4 [54]: Let A=(μA,νA) be an IFS. The ideal positive degree I(A) of IFS A is described as follows:(8) I(A)=1−(1−μA)2+(νA)22 Theorem 1 [54]: Let A=(μA,νA) and B=(μB,νB) be any two IFSs. It follows that A≥B if and only if I(A)≥I(B). Definition 5 [47]: Let A=(μA,νA) and B=(μB,νB) be any two IFSs and a real number r>0. Some operations are defined as follows:(9) (i)ThecomplementofAdenotedbyAC=(νA,μA) (10) (ii)A⊕B=(1−(1−μA)(1−μB),νAνB) (11) (iii)A⊗B=(μAμB,1−(1−νA)(1−νB)) (12) (iv)rA=(1−(1−μA)r,(νA)r) (13) (v)Ar=((μA)r,1−(1−νA)r) Another flourishing area of IFS theory lies in the aggregation operators of IFSs. Early works highlight some arithmetic aggregation operators [60] and geometric aggregation operators [61]. Based on these methods [62], offered the notion of generalized aggregation operators [63]. discussed some aspects and areas of IFSs and offered a mechanism to defuzzify an IFS. Definition 6 [60]: Let Aj=(μAj,νAj) (j=1,2,…,n) be a collection of IFSs. Then the intuitionistic fuzzy weighted averaging (IFWA) operator of Aj is defined as follows(14) IFWA(A1,A2,…,An)=w1A1⊕w2A2⊕…⊕wnAn=(1−∏j=1n(1−μAj)wj,∏j=1nνAjwj) where wj (j=1,…,n) is the weight vector of Aj=(μAj,νAj), with wj∈[0,1] and ∑j=1nwj=1. For wj=1n (j=1,…,n), the IFWA operator is reduced to an intuitionistic fuzzy averaging (IFA) operator of n dimension, defined as:(15) IFWA(A1,A2,…,An)=1n(A1⊕A2⊕…⊕An) The notion of an intuitionistic fuzzy number (IFN), as a special type of IFS, was put forward by Ref. [64] while drawing an analogy from vague sets. Some notes on IFNs were offered by Refs. [65,66]. Definition 7 [64]: An intuitionistic fuzzy number (IFN) A˜ is characterized by the following properties:(i) an intuitionistic fuzzy subset on the real number line (ii) normal, i.e., there exists x0∈R such that μA˜(x0)=1, which implies that νA˜(x0)=0. (iii) convex for the membership function μA˜, i.e., μA˜(λx1+(1−λ)x2)≥min{μA˜(x1),μA˜(x2)},∀x1,x2∈R,λ∈[0,1] (iv) concave for the non-membership function vA˜, i.e., νA˜(λx1+(1−λ)x2)≤max{νA˜(x1),νA˜(x2)},∀x1,x2∈R,λ∈[0,1] A “generalized” notion of the IFN was proposed by Ref. [67]. As a special type of IFN, the triangular intuitionistic fuzzy number (TIFN) is defined as follows:Definition 8 [56]: A TIFN a˜=(a1,a2,a3);wa˜,ua˜ is a special IFS on R, whose membership function μa˜ and the non-membership function νA˜ are defined as follows:(16) μa˜(x)={(x−a1)wa˜/(a2−a1)ifa1≤x<a2wa˜ifx=a2(a3−x)wa˜/(a3−a2)ifa2<x≤a30otherwise (17) νa˜(x)={[a2−x+ua˜(x−a1)]/(a2−a1)ifa1≤x<a2uaifx=a2[x−a2+ua˜(a3−x)]/(a3−a2)ifa2<x≤a30otherwise where wa˜ and ua˜ represent the maximum membership degree and the minimum non-membership degree, respectively, such that wa˜, ua˜∈[0,1], and 0≤wa˜+ua˜≤1. A TIFN a˜ expresses an ill-known “approximate a2”, which denotes a quantity approximately equal to a2 [68]. Accordingly, the “approximate a2” is expressed by way of any value in between a1 and a3 with varying degrees of membership and non-membership. It further implies that the most possible value is a2 with a membership degree and non-membership degree of wa˜ and ua˜, respectively. On the other hand, both a1 and a3 have a membership degree of 0 and a non-membership degree of 1. Any x∈(0,1) has a membership degree of μa˜(x) and a non-membership degree of νa˜(x). If wa˜=1 and ua˜=0, then μa˜(x)+νa˜(x)=1 (∀xR). Consequently, the TIFN a˜=(a1,a2,a3);wa,ua becomes a˜=(a1,a2,a3);1,0, which essentially represents the triangular fuzzy number (TFN) in FST [69], making the TIFN a generalization of the TFN. The parameters wa˜ and ua˜ reflect the confidence and non-confidence level of the TIFN a˜, which expresses more uncertainty than the triangular fuzzy number [68]. 2.2 The Kano model, its intuitionistic fuzzy set extension, and the quality function deployment [34] have developed a two-dimensional model to understand customer requirements (CRs) or attributes and their impact on customer satisfaction (CS). The Kano model divides CRs into six categories, each affecting CS differently. In Fig. 1 , Kano categories are briefly explained as follows [[70], [71], [72]]:⁃ Attractive (A): The functional presence of these attributes will result in a high level of CS, while their absence will not affect CS. ⁃ One-dimensional (O): The functional presence of these attributes will generate CS, while their absence will result in non-satisfaction. ⁃ Must-be (M): Customers take the presence of these attributes for granted. Insufficiency of these attributes will result in extreme non-satisfaction, but the sufficiency will not increase satisfaction level. ⁃ Indifferent (I): The attributes in this category, whether present or not, do not affect CS. ⁃ Reverse (R): The presence of these attributes will generate non-satisfaction and vice versa. ⁃ Questionable (Q): This outcome indicates that either the responses do not make any logical sense or the question was phrased incorrectly. Fig. 1 The Kano model. Fig. 1 As shown in Table 1 , the Kano model assigns two questions for each attribute, representing its functional and dysfunctional aspects, and a five-by-five evaluation table is generated to evaluate which category such an attribute belongs to Ref. [34].Table 1 The Kano evaluation table. Table 1Functional Dysfunctional Like Must-be Neutral Live-with Dislike Like Q A A A O Must-be R I I I M Neutral R I I I M Live-with R I I I M Dislike R R R R Q The Kano model is widely used in analyzing CRs [73]. However, the traditional Kano model is a qualitative method that provides limited decision support for designers [[74], [75], [76]]. [70] initialized the quantitative analysis of the Kano model with two quantitative CS coefficients, namely, the satisfaction index and the dissatisfaction index, to reflect the average impact of a CR on customer satisfaction or dissatisfaction. Then, the CS coefficients have been modified and utilized as adjustment factors for re-prioritizing CRs to achieve maximum CS [77,78]. Recently, an IFS extension of the Kano model was introduced by Ref. [79]. The extension addresses the uncertainty and vagueness associated with how people express their preferences in the evaluation process. In their extension, they used TIFNs to represent the evaluation scores of decision-makers answering the functional and dysfunctional questions, i.e., Enjoy =(7,9,9), Expect =(5,7,9), Neutral =(3,5,7), Live with =(1,3,5), and Dislike =(1,1,3), with membership and non-membership functions defined in Equation (16) and Equation (17), respectively. Then with an evaluation elicited by the decision-maker, membership function degrees are obtained. They devised a membership degree denoted by computing for(18) μηijκ=m(Fiκ)η×m(Djκ)η where m(Fi)η and m(Dj)η represent the membership and non-membership degrees of the to i th standard answer to the functional question (i.e., Fi) and j th standard answer to the dysfunctional question (i.e., Dj), elicited by the η th participant on the κ th CR. Then, using a revised Kano evaluation table as shown in Equation (19), the adjustment factor/coefficient for the κ th CR as evaluated by the η th participant is shown in Equation (20) [79].(19) V=[vij]5×5=[00.2000.2500.3000.500−0.10000.0500.0750.900−0.125−0.02500.1001.000−0.150−0.038−0.05000.800−0.250−0.450−0.500−0.4000] (20) AFkn=∑i=15∑j=15vijμηijκ The Kano model has long been integrated with QFD (see Refs. [77,78]. QFD has long been the primary framework for product development. It is a technique used to translate the “voice of customers” into engineering design specifications while providing quality assurance throughout the production phase [80]. The majority of works on QFD-based product design focus on the first phase of QFD, highlighting the linking of customer requirements to product design needs, as illustrated in the HoQ in Fig. 2 .Fig. 2 The house of quality. Fig. 2 Customer needs and demands are found in Section A, usually based on market research. The computations for prioritizing Section A are found in Section B. The product they seek to design and develop is described in Section C. It is usually launched from Section A. The strength of the relationship between each element of Sections A and C is judged in Section D. Section E contains the Section C correlations. Finally, Section F prioritizes the design targets from Section C. 2.3 Full consistency method (FUCOM) Like the well-known AHP [81] and the best-worst method (BWM) [82], the FUCOM was developed by Ref. [44] as comparison-based multi-attribute decision-making (MADM) method that combines some of the features of the AHP and the BWM in generating the priority weights of a set of pre-defined attributes (or criteria). Closely linked to the BWM, where the attribute weights are obtained via an optimization model constructed from two comparison systems based on best and worst attributes, FUCOM diverges from such construction by introducing two familiar groups of constraints: (1) consistency between the relations of attribute weights and the comparative priorities of these attributes, and (2) mathematical transitivity. The optimization model determines the allocation of priority weights of the attributes by minimizing the deviation from full consistency (DFC) metric, denoted by χ, associated with these two constraint groups. Such a metric measures the reliability of the resulting attribute weights. Compared to AHP and BWM, the major strength of the FUCOM is the minimal pairwise comparisons that decision-makers need to perform, thereby minimizing their mental workload in the judgment elicitation process. When FUCOM is used to derive weights of the attributes (or criteria) as well as the priority weights of the alternatives for each attribute, then FUCOM can be used to solve a classic MADM problem under a goal-criteria-alternative hierarchical structure. Usually integrated with other methods, the efficacy of the FUCOM has been demonstrated in decision-making problems related to supply chain management [83,84], sustainable supplier selection [85], human resource evaluation [86], service quality improvement [87], and business process management [88], among others. Here, the computational steps of the FUCOM are introduced following [44]. The term “criteria” is used here for representation. In general, they can be referred to as any set of homogeneous elements (e.g., attributes, factors).Step 1: From the set of evaluation criteria C={c1,c2,…,cn}, the criteria are ranked according to their degree of significance. According to the expected weights of the criteria, then the criteria set can be ranked as follows: (21) cj(1)>cj(2)>…>cj(k) where k indicates the rank of the observed criterion. If two criteria are perceived to have equal weights, then “>” can be replaced by “=”.Step 2: The ranked criteria are compared, and the comparative priority (φk/(k+1),k=1,2,…,n), where k represents the rank of the criterion in the set of evaluation criteria is determined. The vector of the comparative priorities of the criteria is represented as: (22) Φ=(φ1/2,φ2/3,…,φk/(k+1)) where φk/(k+1) represents the priority that the criterion rank cj(k) has compared to the criterion cj(k+1) rank.Step 3: The final weights (wj:j=1,…,n)T of the evaluation criteria are computed. These weight values should satisfy the following two conditions: (1) the ratio of the weight values is equal to the comparative priority among the observed criteria (φk/(k+1)) defined in Step 2, i.e., the following condition is met: (23) wkwk+1=φk/(k+1) (2) in addition, the final weight values should satisfy the transitivity requirement, i.e., φk/(k+1)⊗φ(k+1)/(k+2)=φk/(k+2). Since φk/(k+1)=wkwk+1 and φ(k+1)/(k+2)=wk+1wk+2, that wkwk+1⊗wk+1wk+2=wkwk+2. Thus, the following condition is required: (24) wkwk+2=φk/(k+1)⊗φ(k+1)/(k+2) To attain full consistency, these two conditions must be met. In meeting these conditions, the weight assignments (wj:j=1,…,n)T must satisfy |wkwk+1−φk/(k+1)|≤χ and |wkwk+2−φk/(k+1)⊗φ(k+1)/(k+2)|≤χ, where χ represents the DFC. Thus, obtaining the weight vector (wj:j=1,…,n)T requires solving the following optimization problem: (25) minχ subject to:|wkwk+1−φk/(k+1)|≤χ,∀k |wkwk+2−φk/(k+1)⊗φ(k+1)/(k+2)|≤χ,∀k ∑j=1nwj=1 wj>0,∀j 2.4 Fuzzy decision maps The framework of fuzzy decision maps (FDMs) was first proposed by Ref. [45] to deal with a decision-making problem that assigns priority weights to elements with dependence and feedback. FDMs overcome the limitations of the AHP and the ANP in determining the overall priorities of decision elements that constitute a network. It combines the eigenvalue method of the AHP and the fuzzy graph-theoretic approach of fuzzy cognitive mapping (FCM). The AHP, developed by Ref. [81]; provides a process in determining the weights of elements within the same level of a decision hierarchy. On the other hand, the FCM originally introduced by Ref. [89] is an extension of cognitive maps [90] that incorporates fuzzy sets to depict fuzzy relationships among objects in a complex system. The basic notion of the FCM is as follows: Given a 4-tuple (N,E,C,F) where N={1,2,…,n} denotes a set of n elements or concepts, E=(eij)n×n is an n×n matrix where eij∈[−1,1] represents the fuzzy causal relationship of an element i to element j (i.e., eij>0, eij<0, and eij=0 denote positive, inverse, and no relationship, respectively), C is a state matrix where C(0) represents the initial state and C(t) signifies the state after t iterations, and f is the threshold function. The threshold function keeps the value of the concept in C(t) within [0,1]. Some popular threshold functions include the hard limit, hyperbolic tangent, and logistic functions. The influence of a specific element on another element at any given iteration is calculated using the updating equation as follows:(26) C(t+1)=f(C(t)⋅E),C(0)=In×n The methodology of the fuzzy decision map can be outlined as follows:Step 1: Compare the importance of the elements to determine their local priority vector z using the eigenvalue approach of the AHP. Step 2: Determine the fuzzy cognitive map to reflect the fuzzy relationships among elements. Step 3: Use Equation (26) to obtain the steady-state matrix C∗. Step 4: Normalize the local priority weight vector and the steady-state matrix using Equation (27) and Equation (28). (27) znorm=1λz where znorm is the normalized local priority vector and λ is the largest element in z.(28) Cnorm∗=1γC∗ where Cnorm∗ is the normalized steady-state matrix and γ is the largest row sum of C∗.Step 4: Calculate the global priority weights of the elements using Equation (29). (29) w=znorm+Cnorm∗znorm where w is the global priority vector of the elements. [91] was able to demonstrate that if f(x)=x (i.e., a linear function), the DEMATEL is a special case of the FDMs [92]. extends the FDMs by assigning TFNs on eij. On the other hand, Fajardo et al. [93] elucidated the application of FDMs in territorial planning. Despite its elegance, applications of the FDMs in MADM are scarce in the literature. 3 The proposed quantitative modelling framework In contrast to private sector SCs, particularly relevant in developing economies [94], provides some underlying features of SCs in the public sector. In public sector SCM, the goal is to deliver quality service to the public, and SCM is viewed as a procurement tool, while taxes and fees are sources of revenues in contrast to sales in the private sector. In terms of governance, public sector SCM is guided by legislative bodies with laws and regulations, less skilled actors, and emphasis is placed on transparency and accountability. Organizational structures are highly complex with various tasks. In addition, they have low competencies, confidentiality, collaboration, integration, partnership, implementation, and technological application [94]. These features are susceptible to the adverse effects of disruptions, especially during the unprecedented COVID-19 pandemic, with a massive impact on downstream entities of the SC. While maintaining public health measures of social distancing, work-from-home arrangements, and limited mobility, public sector SCs are compelled to deliver goods and services to the public, subject to strict transparency and accountability measures. Thus, strategic initiatives must be implemented by SC entities. Additionally, these strategies must be synthesized at the network level to promote collaboration and integration across the SC in the efficient and effective delivery of public goods. To model this public sector SC, we assume that the government as the head of the executive branch manages and accomplishes some desired social services. In this regard, the public sector SC serves as the strategic planner [95]. Public sector SC members may be composed of both private and public entities. Once a government-funded project emerges along with stipulated requirements, SC entities must develop strategies to satisfy these requirements. To translate these requirements throughout the supply chain, downstream entities must align their strategies with those upstream. Thus, synthesizing these strategies across the public sector SCM is a crucial initiative in achieving effective and efficient delivery of public goods. Fig. 3 shows such a synthesis. It shows a series of modified HoQs representing the public sector SC entities 1,…,n. The government (i.e., as the champion) identifies its requirements, with varying degrees of importance and priorities, which will be input to Section B. The priorities (i.e., in terms of priority weights) of these requirements are inputs to Section C. Once these requirements are identified, the upstream entity (e.g., SC entity 1) of public sector SC develops its response strategies (see Section E) along with some inputs associated with the pandemic. Such an entity provides priorities to its response strategies, which are inputs to Section F. Due to the varying characteristics of the requirements and upstream entity strategies, adjustment factors of the requirements and the strategies are inputs to Section D and Section G, respectively. Following the inherent interrelationships among government requirements and among upstream entity strategies, the proposed model integrates them into the analysis. They are reflected in Section A and Section H, respectively. The causal relationships of requirements on strategies are reflected in Section I. The final priority weights of the upstream entity strategies are shown in Section J, which considers all information from Section A to Section I.Fig. 3 The conceptual framework. Fig. 3 The modelling framework integrates the information (i.e., strategies, priorities) of the government and the initial information (i.e., strategies, priorities) of the upstream entity into a holistic approach in a way that an output reflects a synthesis represented by an “aggregate” priority of the upstream entity, under an environment that captures uncertainty in the decision-making process. The entity in the second level (e.g., SC entity 2) of the public sector SC realizes the information of the upstream entity (i.e., strategies, priorities) and takes this set of information in developing and prioritizing strategies. The same holistic platform is adopted to generate the “aggregate” information (i.e., final priority weights in Section J) for use in the downstream member. Such a process is repeated to all entities of the public sector SC represented in the system boundary of Fig. 3, except that the “government requirements” are replaced by previous SC entity strategies. The strategies of the previous SC entity (i.e., represented as a modified HoQ) in Section E become inputs to Section B of the next modified HoQ. Also, the final priority weights in Section J of the previous HoQ are inputs to Section C of the next HoQ. Through transitions among modified HoQs, this modelling framework assures integration and synthesis of information across the public sector SC. The proposed algorithm that computes the final priority weights of SC entity strategies in Section J of each modified HoQ in Fig. 3 is as follows:Step 1: As the project champion, the government identifies the requirements for a project that intends to deliver public goods [Section B]. Step 2: The government elicits judgments on the priorities of these requirements. Due to the uncertainty associated with the judgment elicitation process, the IFS theory is integrated into the framework of FUCOM in generating priority weights of the requirements. It is noteworthy that this work offers the first attempt to incorporate IFS into FUCOM. After arranging these requirements in decreasing order of importance, the government elicits evaluation φ˜k/(k+1)=(μφ˜k/(k+1),νφ˜k/(k+1)) which represents the intuitionistic fuzzy (IF) importance of the requirement with rank k over the requirement with rank k+1.Step 3: Obtain the priority weights of the requirements [Section C]. In obtaining these weights, the IFS is integrated into the computational platform of FUCOM. This process requires solving two optimization problems in Equation (30) and Equation (31).(30) minξ subject to:|μwkμwk+1−μφ˜k/(k+1)|≤ξ,∀k |μwkμwk+2−μφ˜k/(k+1)⊗μφ˜(k+1)/(k+2)|≤ξ,∀k μw(k)≥μw(k+1)≥…≥μw(k≤n) ∑j=1nμwj=1 μwi>0,∀i (31) minζ subject to:|νwkνwk+1−νφ˜k/(k+1)|≤ζ,∀k |νwkνwk+2−νφ˜k/(k+1)⊗νφ˜(k+1)/(k+2)|≤ζ,∀k νw(k)≥νw(k+1)≥…≥νw(k≤n) ∑j=1nνwj=1 νwi>0,∀i These optimization problems are analogous to the problems proposed by Ref. [96] in solving the IF extension of the BWM. Their approach suggests two optimization models corresponding to the membership and non-membership degrees of φ˜k/(k+1). Since Equation (25) is closely matched to the required optimization problem of the BWM in solving for the weights of the elements, then the IF-FUCOM integration can be developed accordingly. The proposed problems in Equation (30) and Equation (31) generate w˜i=(μwi,νwi) which represents the IF priority weights of the government requirements defined by a membership degree μwi and non-membership degree νwi.Step 4: The government elicits satisfaction degree of the functional and dysfunctional form of the requirements [Section D]. We modify the IFS-Kano integration of [79]. This process generates a 1–9 rating for each form of the requirement (1,…,n1). Such an evaluation is mapped to the TIFNs a˜Like=(7,9,9), a˜Must−be=(5,7,9), a˜Neutral=(3,5,7), a˜Live with=(1,3,5), and a˜Dislike=(1,1,3), a slight variation of the linguistic terms in Ref. [79]. This mapping may produce one or more ρ and σ combinations, where ρ,σ∈{Like,Must−be,Neutral,Live with,Dislike}. Each ρ,σ combination is represented by an IFS A˜ρσi=(μA˜ρσi,νA˜ρσi) where μA˜ρσi and νA˜ρσi are computed using Equation (16) and Equation (17), respectively. With the Kano evaluation table proposed by Ref. [79] in Equation (19), the adjustment factor AFi is as follows:(32) AFi=(μAFi,νAFi)=∑i=1n∑j=1nvijA˜ρσi=∑i=1n∑j=1nvij(μA˜ρσi,νA˜ρσi) The operations in Equation (32) are defined in Equation (10) and Equation (12) of Definition 4. The aggregation in Equation (32) includes both membership and non-membership degrees of the TIFNs, as opposed to Ref. [79]; which merely uses the membership degrees. The inclusion of both membership and non-membership degrees of the TIFNs better captures the uncertainty of the evaluation process.Step 5: Aggregate the IF priority weight and the adjustment factor for each requirement. The adjustment factors AFi obtained in Equation (32) are integrated into w˜i (1,…,n1) obtained in Step 3. The resulting product is adjusted IF priority weights w¨i which are computed as follows:(33) w¨i=(μw¨i,νw¨i)=AFi⊗w˜i=(μAFi,νAFi)⊗(μwi,νwi) Step 6: The upstream entity identifies response strategies [Section E]. Given the list of requirements set by the government, the upstream entity (SC entity 1) identifies a set of specific strategies as a response to the requirements. These strategies are known via a consensus of the relevant stakeholders of the SC entity. They would take into account the current environmental conditions (e.g., public health crisis due to COVID-19)Step 7: Perform Step 3 to Step 5 to generate the adjusted IF priority weights w¨i (1,…,n2) of the upstream entity strategies. This step generates [Section F] and [Section G] of Fig. 3. The remaining steps intend to implement the IF extension of the FDM. It is again noteworthy that this work offers the first attempt to explore such an extension. The extension, referred here as the intuitionistic fuzzy decision map (IFDM), is structured analogously with the extension proposed by Ref. [92] by assigning TFNs on eij∈E. Rather than obtaining the weights of the elements (i.e., stored in z) through the eigenvalue method of the AHP as in the original FDM formulation, the adjusted IF priority weights generated by Step 4 to Step 7 are used in the computation of the global priority weights.Step 8: Build the IF decision map [Section A], [Section H], [Section I]. The elements in the IFDM consist of both the government requirements (i=1,…,n1) and the upstream entity strategies (i=1,…,n2). The upstream entity provides the IF weights of the fuzzy relationships among elements. The IF causal relationships of the elements are described in E˜=(e˜ij)n×n=((μe˜ij,νe˜ij))n×n. For better illustration, E˜ is depicted in Fig. 4 as a partitioned matrix of IF causal relationships. Each partition of E˜ describes a corresponding section of an HoQ in Fig. 3.Step 9: Obtain the steady-state matrix. Fig. 4 depicted as a partitioned matrix of IF causal relationships. Fig. 4 The steady-state matrix C˜∗=((μcij∗,νcij∗))n×n is obtained using the updating Equation (34) and Equation (35). Note that each iteration t (t=1,…) generates a matrix C˜(t)=((μcij(t),νcij(t))). Then we can obtain two matrices from C˜(t) by introducing [μC˜(t)](t)=[μcij](t) and [νC˜(t)](t)=[νcij](t).(34) [μcij](t+1)=f([μcij](t)[μe˜ij]) (35) [νcij](t+1)=f([νcij](t)[νe˜ij]) where f represents the threshold function. This process is analogous to the TFN extension of the FDM proposed by Ref. [92].Step 10: Normalize the steady-state matrix. With the steady-state matrix C˜∗=((μcij∗,νcij∗))n×n, we can write [μC˜∗]=[μcij∗] and [νC˜∗]=[νcij∗]. The normalized matrices C˜∗′=((μcij∗′,νcij∗′))n×n can be represented as [μC˜∗]′=[μcij∗′] and [νC˜∗]′=[νcij∗′], where(36) μcij∗′=1γμμcij∗ (37) νcij∗′=1γννcij∗ where γμ=maxi∑j=1n1+n2μcij∗ and γν=maxi∑j=1n1+n2νcij∗.Step 11: Normalize the adjusted IF weights. Let N={1,…,n}={1,…,n1,1,…,n2} where n=n1+n2, and {1,…,n1} represents and the set of government requirements and {1,…,n2} is the list of upstream entity strategies. Thus, the adjusted IF weights of n elements can be written as w¨i=(μw¨i,νw¨i) (1,…,n). Analogous to Step 10, the vector w¨i can be represented as [μw¨i] and [νw¨i]. The normalized IF weight for each i, denoted as w¨i′=(μw¨i′,νw¨i′), is computed as(38) μw¨i′=1λμμw¨i (39) νw¨i′=1λννw¨i where λμ=maxiμw¨i and λν=maxiνw¨i.Step 12: Obtain the global priority weights [Section J]. With the normalized IF weight w¨i′ in Equation (38) and Equation (39) and the normalized steady-state matrix C˜∗′, the global priority weights w˜∗=(μw˜∗,νw˜∗) are obtained as follows:(40) [μw˜∗]=[μw¨i′]+[μC˜∗]′[μw¨i′] (41) [νw˜∗]=[νw¨i′]+[νC˜∗]′[νw¨i′] Step 13: Integrate this set of information (i.e., strategies, global priority weights w˜∗) into the next SC entity. Step 14: Perform Step 1 to Step 13 for the succeeding SC entities. A graphical summary of the integrated methodology proposed in this work is presented in Fig. 5 . Here, as in the case of any public sector SC, the demanding entity is the government.Fig. 5 Methodological framework. Fig. 5 Fig. 6 The case public sector SC with the required information for each entity. Fig. 6 4 An application in a government-funded research project 4.1 Case study information Increasing the number of institutions performing research and development activities in the Philippines is the response of the higher education institutions (HEIs) to the mandate of the Commission on Higher Education (CHED) in building up the country's research capabilities [97]. CHED is the Philippine government arm tasked to handle all relevant concerns related to higher education. This agenda set by CHED intends to improve the quality of higher education by establishing policy directives and a grant and incentive structure that prioritizes academic excellence [98]. Furthermore, a need to provide capacity-building programs to significantly improve the performance of HEIs in responding to pressing needs, particularly associated with the fourth industrial revolution, is identified by CHED [99]. Hence, they offered the Institutional Development and Innovation Grants (IDIG) program that will financially support institutions capable of delivering capability-building initiatives. Cebu Technological University (CTU) is one of the HEIs financially supported by the IDIG program under the project “Creation of an Interdisciplinary Graduate Program and Courses for Applied Mathematics and Operations Research: As Tools for Innovation Studies”. The project aims to address the underlying problem of the current inadequacy of academic programs in the local region, specifically in applied mathematics and operations research (AM&OR). Meanwhile, the Center for Applied Mathematics and Operations Research (CAMOR), based at CTU, is established to act as the research hub in spearheading high-impact research for stakeholders and HEIs in addressing pressing problems that can be modelled with tools in AM&OR. CAMOR also serves as one of the implementing arms of the IDIG program, carrying out the objectives and coordinating with various stakeholders for achieving those objectives. Since CAMOR is established within a state university, it must adhere to the procurement process guidelines in government transactions. Particularly, material acquisition associated with the project (i.e., setting up a laboratory) needs alignment with the Bids and Awards Committee (BAC). To ensure better outcomes in any project, competence in the procurement process becomes imperative [100]. Moreover [101], adds that stakeholders’ trust boosts selecting a suitably competent supplier since it increases the likelihood of helping meet project objectives. In addition, (a) cost, (b) delivery time, (c) quality, (d) innovation, (e) reputation, (f) response to customers, and (g) location are some of the criteria that should be evaluated [102]. However, by the time HEIs reached mid-March in 2020, COVID-19 had ravaged normal business operations as it spread globally. A nationwide lockdown was imposed, and HEIs were forced to conduct operations primarily via work-from-home (WFH) arrangements. As a response, HEIs in the country have established new normal conditions aligned with the national government, especially related to social distancing measures, WFH scheme, minimum public health standards, among others, to continue operations. Aside from teaching and learning activities, business transactions (i.e., material procurement, payroll distribution) inside HEIs are also affected by the imposition of new normal conditions. As such, risk mitigation efforts in ensuring the health and safety of the university stakeholders (i.e., social distancing guidelines, online transactions, the digitalizing network of information) are strictly adhered to across the university. Since all project leaders under the IDIG program instigated by CHED need to satisfy their objectives on schedule (i.e., two years), CAMOR is compelled to continue its operations under the new normal conditions through initiating effective communication channels (i.e., phone calls, text messages or via emails) with the necessary stakeholders involved in implementing the project. These conditions in CTU brought ripple effects to the entire public sector SC, not just to CAMOR and BAC operating inside the university. With the set of requirements identified by CHED, the entire SC (i.e., CAMOR, BAC, and the supplier) must design strategies for the efficient and effective delivery of public goods stipulated in the IDIG project. Fig. 5 illustrates the case public sector SC, with CAMOR, BAC, and the supplier as the entities. A set of requirements by CHED initializes the SC. The set of required information from each entity is also shown in Fig. 6. 4.2 The proposed procedure The application of the proposed framework in the case study is discussed in the following. Note that the required dataset of the case study is supplied as Supplementary Material.Step 1: Obtain the requirements of CHED and the response strategies of CAMOR, BAC, and the supplier. These elements (i.e., requirements, strategies), shown in Table 2 , are ideally generated through a focus group discussion of the public sector SC entities. The requirements of CHED are explicitly reflected in the project memorandum. The Director identified the response strategies of CAMOR in consultation with the rest of the staff of the research center. These requirements also capture the current COVID-19 related guidelines. Upon identifying these strategies, the BAC determines its response strategies along with the procurement protocols imposed by the government. Finally, the identified supplier develops its own strategies in response to the strategies set by the BAC.Table 2 The model elements of the case public sector SC. Table 2Codes Model elements CHED (grant funding institution) requirements A11 All project objectives are achieved. A12 Project timelines are met. A13 Project objectives are implemented within the specified budget. A14 The framework of the graduate program is effectively developed. A15 Courses in applied mathematics and operations research are enhanced to respond to pressing needs. A16 Quality equipment is purchased. CAMOR (implementing institution) strategies A21 Maintaining public health and safety in project implementation A22 Creating an overarching plan of operations within timelines and budget A23 Synchronizing workforce with the overarching plan A24 Implementing “lean” operations A25 Carrying out coordination efforts with the needed stakeholders A26 Initiating effective communication channels among stakeholders A27 Setting quality product and service specifications BAC (purchasing department) strategies A31 Maintaining public health and safety in transactions A32 Complying with government procurement protocols A33 Implementing coordination activities with the requesting unit and the supplier A34 Implementing “lean” office A35 Maintaining a portfolio of quality suppliers of products and services A36 Establishing a list of supplier evaluation criteria A37 Procuring products and services within specifications A38 Creating progress reports of purchased products Supplier strategies A41 Maintaining public health and safety in operations A42 Implementing an agile business model A43 Implementing responsive customer relationship management A44 Implementing “lean” service concepts A45 Implementing strict quality control measures A46 Implementing a competitive pricing policy A47 Implementing effective communication strategies to ensure accurate transactions A48 Meeting deadlines set for procurement requirements Step 2: Obtain the priorities of CHED requirements. According to CHED, the priority ranking of the requirements is as follows: A11≥A14≥A15≥A13≥A12≥A16. Then, CHED elicits judgments on the relative importance of the requirements via the evaluation scale presented in Table 3 . Using Equation (30) and Equation (31), two optimization models in Equation (42) and Equation (43) are constructed to generate the initial IF priority weights. Equation (42) yields μwA11=0.7343, μwA12=0.0175, μwA13=0.0350, μwA14=0.1049, μwA15=0.1049, μwA16=0.0035, with ξ=0.0001. On the other hand, Equation (43) produces νwA11=0.0290, νwA12=0.2045, νwA13=0.1534, νwA14=0.0966, νwA15=0.1074, νwA16=0.4091, with ζ=0.0000.Table 3 The evaluation scale for the IF-FUCOM. Table 3Rate Linguistic scale Corresponding IFS 1 Equal importance (1,0.9) 2 Weak importance (2,0.75) 3 Moderate importance (3,0.7) 4 Moderate plus importance (4,0.55) 5 Strong importance (5,0.5) 6 Strong plus importance (6,0.35) 7 Very strong or demonstrated importance (7,0.3) 8 Very, very strong importance (8,0.15) 9 Extreme importance (9,0.1) (42) minξ subject to:|μwA11μwA14−7|≤ξ;|μwA14μwA15−1|≤ξ;|μwA15μwA13−3|≤ξ;|μwA13μwA12−2|≤ξ;|μwA12μwA16−5|≤ξ |μwA11μwA15−7∗1|≤ξ;|μwA14μwA13−1∗3|≤ξ;|μwA15μwA12−3∗2|≤ξ;|μwA13μwA16−2∗5|≤ξ μwA11≥μwA14≥μwA15≥μwA13≥μwA12≥μwA16 ∑j=16μwA1j=1 μwA1i>0,∀i=1,…,6 (43) minζ subject to:|νwA11νwA14−7|≤ζ;|νwA14νwA15−1|≤ζ;|νwA15νwA13−3|≤ζ;|νwA13νwA12−2|≤ζ;|νwA12νwA16−5|≤ζ |νwA11νwA15−7∗1|≤ζ;|νwA14νwA13−1∗3|≤ζ;|νwA15νwA12−3∗2|≤ζ;|νwA13νwA16−2∗5|≤ζ νwA11≤νwA14≤νwA15≤νwA13≤νwA12≤νwA16 ∑j=16νwA1j=1 νwA1i>0,∀i=1,…,6 The IF priority weights of the CHED requirements are shown in Table 4 .Table 4 The IF priority weights of CHED requirements. Table 4CHED requirements IF priority weights (w˜i) A11 (0.7343,0.0290) A12 (0.0175,0.2045) A13 (0.0350,0.1534) A14 (0.1049,0.0966) A15 (0.1049,0.1074) A16 (0.0035,0.4091) Step 3: Implement the IF-Kano for each CHED requirement. As discussed in Step 4 of Section 3, CHED elicits the satisfaction level for each requirement. With the 1–9 satisfaction rating, Table 5 displays the initial evaluation.Table 5 The Kano evaluation and mapping to standard scale. Table 5Codes Satisfaction level rating Function form (mapping of TIFNS) Dysfunction form (mapping of TIFNS) functional form dysfunctional form Like Must-be Neutral Live with Dislike Like Must-be Neutral Live with Dislike A11 9 1 ✓ ✓ ✓ ✓ A12 7 3 ✓ ✓ ✓ ✓ ✓ ✓ A13 7 5 ✓ ✓ ✓ ✓ ✓ ✓ A14 8 2 ✓ ✓ ✓ ✓ A15 8 2 ✓ ✓ ✓ ✓ A16 6 6 ✓ ✓ ✓ ✓ Following Step 4 of Section 3, the AFi values are computed using Equation (32). These adjustment factors are shown in Table 6 . For brevity, the computations are not presented here. Nevertheless, for tractability, they are provided in the Supplementary Material.Table 6 Adjustment factors of CHED requirements. Table 6CHED requirements Adjustment factors (AFi) A11 (0.6838,0.0000) A12 (0.1586,0.0000) A13 (0.1087,0.0000) A14 (0.6539,0.2922) A15 (0.6539,0.2922) A16 (0.0148,0.9828) Step 4: Aggregate the w˜i and the AFi for each requirement i. Equation (33) provides the adjusted IF priority weights (w¨i). Also, to allow us to rank the priorities of the requirements expressed in IFS, the ideal positive degree I(⋅) of Definition 4 is used. Table 7 shows the w¨i, the I(w¨i) which maps w¨i to R, and the corresponding rank of a given CHED requirement. It shows that A11≥A14≥A15≥A13≥A12≥A16. While it maintains the initial ranking of CHED requirements during the IF-FUCOM, it effectively assigns the appropriate priority weights for each requirement.Table 7 The adjusted IF priority weights of CHED requirements. Table 7CHED requirements Adjusted IF priority weights (w¨i) I(w¨i) Rank A11 (0.5021,0.0290) 0.7506 1 A12 (0.0028,0.2045) 0.4910 5 A13 (0.0038,0.1534) 0.4960 4 A14 (0.0686,0.3606) 0.5006 2 A15 (0.0686,0.3682) 0.4992 3 A16 (0.0001,0.9898) 0.2965 6 Step 5: Perform Step 2 to Step 4 to calculate the adjusted IF priority weights of CAMOR strategies. For brevity, the w˜i, AFi, and w¨i are shown in Table 8 .Table 8 The adjusted IF priority weights of CAMOR strategies. Table 8CAMOR strategies w˜i AFi w¨i A21 (0.0968,0.0781) (0.3801,0.5743) (0.0368,0.6076) A22 (0.5806,0.0410) (0.1586,0.0000) (0.0921,0.0410) A23 (0.1935,0.0586) (0.2597,0.7073) (0.0503,0.7245) A24 (0.0032,0.3306) (0.1259,0.8556) (0.0004,0.9033) A25 (0.0968,0.0868) (0.0720,0.9170) (0.0070,0.9242) A26 (0.0097,0.2314) (0.2057,0.0000) (0.0020,0.2314) A27 (0.0194,0.1736) (0.2597,0.7073) (0.0050,0.7581) Step 6: Build the IFDM of the CHED requirements and CAMOR strategies. The IF causal relationships among requirements were elicited by CHED. On the other hand, CAMOR provides the IF causal relationships among identified strategies. Using the IF scale in Table 9 , modified from Ref. [103]; the IFDM is developed and is shown in Table 10.Table 9 The evaluation scale for the intuitionistic fuzzy decision map. Table 9Linguistic scale Corresponding IFS scale No influence (0,1) Low influence (0.25,0.7) Medium influence (0.5,0.45) High influence (0.75,0.2) Very high influence (0.9,0.1) To attain the normalized steady-state matrix C˜∗′, it is necessary to carry out the computations in Equation (34) up to Equation (37). The resulting C˜∗′ is presented in Table 11 . The Supplementary Material provides the required computations of the IFDM.Table 10 The IFDM for CHED requirements and CAMOR strategies. Table 10 A11 A12 A13 A14 A15 A16 A21 A22 A23 A24 A25 A26 A27 A11 (0,1) (0.75,0.2) (0.75,0.2) (1,0.1) (1,0.1) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A12 (0.5,0.45) (0,1) (0,1) (0.5,0.45) (0.25,0.7) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A13 (0.5,0.45) (0,1) (0,1) (0.25,0.7) (0.25,0.7) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A14 (0.5,0.45) (0.25,0.7) (0.25,0.7) (0,1) (0.75,0.2) (0.5,0.45) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A15 (0.5,0.45) (0.25,0.7) (0,1) (1,0.1) (0,1) (0.5,0.45) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A16 (0.5,0.45) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A21 (0.75,0.2) (1,0.1) (0.5,0.45) (0,1) (0,1) (0,1) (0,1) (0.5,0.45) (0.75,0.2) (0.5,0.45) (0.75,0.2) (0.25,0.7) (0,1) A22 (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.5,0.45) (0,1) (1,0.1) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.75,0.2) A23 (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.75,0.2) (0.25,0.7) (0,1) (0.5,0.45) (1,0.1) (0.75,0.2) (0,1) A24 (0.5,0.45) (0.5,0.45) (0.5,0.45) (0.25,0.7) (0.25,0.7) (0.5,0.45) (0.5,0.45) (0.5,0.45) (0.75,0.2) (0,1) (0.5,0.45) (0.25,0.7) (0.75,0.2) A25 (1,0.1) (0.75,0.2) (0.25,0.7) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.75,0.2) (0.5,0.45) (0,1) (1,0.1) (0.75,0.2) A26 (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.5,0.45) (0.75,0.2) (0.75,0.2) (0.25,0.7) (0.5,0.45) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) A27 (0.5,0.45) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (0,1) (0.5,0.45) (0,1) (0.75,0.2) (0.75,0.2) (0.25,0.7) (0,1) Table 11 The normalized steady-state matrix C˜∗′ for CHED requirements and CAMOR strategies. Table 11 A11 A12 A13 A14 A15 A16 A21 A22 A23 A24 A25 A26 A27 A11 (0,0.0035) (0,0.0051) (0,0.0047) (0,0.0043) (0,0.0046) (0,0.0048) (0,0.007) (0,0.0077) (0,0.0066) (0,0.0063) (0,0.0057) (0,0.0074) (0,0.0072) A12 (0,0.0055) (0,0.0081) (0,0.0075) (0,0.0068) (0,0.0072) (0,0.0075) (0,0.011) (0,0.0121) (0,0.0104) (0,0.01) (0,0.009) (0,0.0116) (0,0.0114) A13 (0,0.0052) (0,0.0076) (0,0.007) (0,0.0064) (0,0.0068) (0,0.0071) (0,0.0104) (0,0.0114) (0,0.0098) (0,0.0094) (0,0.0085) (0,0.0109) (0,0.0108) A14 (0,0.0048) (0,0.007) (0,0.0065) (0,0.0059) (0,0.0063) (0,0.0065) (0,0.0095) (0,0.0104) (0,0.009) (0,0.0086) (0,0.0078) (0,0.01) (0,0.0099) A15 (0,0.0049) (0,0.0072) (0,0.0067) (0,0.0061) (0,0.0065) (0,0.0067) (0,0.0099) (0,0.0108) (0,0.0093) (0,0.0089) (0,0.0081) (0,0.0104) (0,0.0102) A16 (0,0.0044) (0,0.0065) (0,0.006) (0,0.0055) (0,0.0059) (0,0.0061) (0,0.0089) (0,0.0097) (0,0.0084) (0,0.008) (0,0.0073) (0,0.0094) (0,0.0092) A21 (0.1022,0.004) (0.0675,0.0059) (0.0781,0.0054) (0.1228,0.0049) (0.112,0.0052) (0.0984,0.0054) (0.0206,0.008) (0.0159,0.0087) (0.0226,0.0076) (0.022,0.0072) (0.0262,0.0065) (0.0194,0.0084) (0.0184,0.0082) A22 (0.1408,0.0017) (0.0929,0.0025) (0.1075,0.0023) (0.1692,0.0021) (0.1543,0.0023) (0.1355,0.0024) (0.0283,0.0035) (0.0218,0.0038) (0.0312,0.0033) (0.0303,0.0031) (0.0361,0.0028) (0.0268,0.0036) (0.0253,0.0036) A23 (0.117,0.0022) (0.0772,0.0032) (0.0893,0.003) (0.1406,0.0027) (0.1282,0.0029) (0.1126,0.003) (0.0235,0.0044) (0.0181,0.0048) (0.0259,0.0042) (0.0251,0.004) (0.03,0.0036) (0.0222,0.0046) (0.021,0.0046) A24 (0.1095,0.0033) (0.0723,0.0049) (0.0836,0.0045) (0.1316,0.0041) (0.12,0.0044) (0.1054,0.0045) (0.022,0.0066) (0.017,0.0072) (0.0242,0.0063) (0.0235,0.006) (0.028,0.0054) (0.0208,0.007) (0.0197,0.0069) A25 (0.1397,0.0019) (0.0922,0.0028) (0.1067,0.0026) (0.1679,0.0024) (0.1531,0.0025) (0.1345,0.0026) (0.0281,0.0038) (0.0217,0.0042) (0.0309,0.0036) (0.03,0.0035) (0.0358,0.0031) (0.0266,0.004) (0.0251,0.004) A26 (0.1234,0.002) (0.0814,0.0029) (0.0942,0.0027) (0.1482,0.0025) (0.1352,0.0026) (0.1187,0.0027) (0.0248,0.004) (0.0191,0.0044) (0.0273,0.0038) (0.0265,0.0036) (0.0316,0.0033) (0.0235,0.0042) (0.0222,0.0042) A27 (0.0845,0.0031) (0.0558,0.0046) (0.0645,0.0042) (0.1015,0.0039) (0.0926,0.0041) (0.0813,0.0043) (0.017,0.0063) (0.0131,0.0068) (0.0187,0.0059) (0.0182,0.0057) (0.0216,0.0051) (0.0161,0.0066) (0.0152,0.0065) Step 7: Obtain the global priority vector. Following the normalization of w¨i in Table 8 using Equation (38) and Equation (39) and the normalized steady-state matrix C˜∗′ in Table 11, Equation (40) and Equation (41) generate the global priority vector w˜∗ (i.e., shown in Table 12 ). The w˜∗ vector then becomes inputs in the computation of the global priority vector of the next SC entity strategies (i.e., BAC). The main interest of Table 12 is to generate the priority weights of CAMOR strategies and identify those priority strategies as inputs to response efforts necessary for CAMOR in its participation in the public sector SC. The results, as depicted in Fig. 7 , shows the following: A22≥A23≥A21≥A26≥A25≥A24≥A27. This ranking incorporates salient information on uncertainty, complexity, and synthesis of priorities among CHED requirements and CAMOR strategies.Table 12 The global priority vector of CAMOR strategies. Table 12Elements Global priority vector (w˜∗) I(w˜∗) Rank A11 (0.5981,0.0106) A12 (0.0033,0.0419) A13 (0.0045,0.0332) A14 (0.0817,0.0654) A15 (0.0817,0.0669) A16 (0.0001,0.1648) A21 (0.1291,0.1033) 0.5644 3 A22 (0.2272,0.0095) 0.6245 1 A23 (0.1575,0.1188) 0.5776 2 A24 (0.0919,0.1491) 0.5378 6 A25 (0.1249,0.1501) 0.5552 5 A26 (0.1053,0.0402) 0.5568 4 A27 (0.0765,0.1257) 0.5331 7 Fig. 7 Distribution of the global priority vector of CAMOR strategies. Fig. 7 Step 8: Repeat Step 2 to Step 7 to identify the priority strategies of BAC and the supplier. For brevity, we skip the detailed discussion of the steps in generating the priority strategies of the remaining SC entities. We present Table 13 for the w˜i, AFi, and w¨i values of the response strategies of BAC and the supplier.Table 13 The w˜i, AFi, and w¨i values of the response strategies of BAC and the supplier. Table 13Response strategies w˜i AFi w¨i A31 (0.0988,0.0001) (0.6838,0.0000) (0.0675,0.0001) A32 (0.8889,0.0000) (0.6838,0.0000) (0.6078,0.0000) A33 (0.0110,0.0003) (0.6838,0.0000) (0.0075,0.0003) A34 (0.0001,0.0063) (0.4377,0.0000) (0.0001,0.0063) A35 (0.0000,0.1596) (0.4377,0.0000) (0.0000,0.1596) A36 (0.0000,0.0318) (0.6838,0.0000) (0.0000,0.0318) A37 (0.0012,0.0013) (0.6838,0.0000) (0.0008,0.0013) A38 (0.0000,0.8007) (0.6838,0.0000) (0.0000,0.8007) A41 (0.8047,0.0015) A42 (0.0002,0.3086) A43 (0.0894,0.0146) A44 (0.0026,0.1080) A45 (0.0009,0.1543) A46 (0.0128,0.0540) A47 (0.0894,0.0162) A48 (0.0002,0.3429) It must be pointed out that IF-Kano analysis was not performed in the supplier strategies as the supplier becomes the last entity in the case public sector SC. The IFDM of CAMOR and BAC strategies are presented in Table 14 , while Table 15 shows the IFDM of BAC and supplier strategies.Table 14 The IFDM for CAMOR strategies and BAC strategies. Table 14 A21 A22 A23 A24 A25 A26 A27 A31 A32 A33 A34 A35 A36 A37 A38 A21 (0,1) (0.5,0.45) (0.75,0.2) (0.5,0.45) (0.75,0.2) (0.25,0.7) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A22 (0.5,0.45) (0,1) (1,0.1) (0.75,0.2) (0.75,0.2) (0.5,0.45) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A23 (0.75,0.2) (0.25,0.7) (0,1) (0.5,0.45) (1,0.1) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A24 (0.5,0.45) (0.5,0.45) (0.75,0.2) (0,1) (0.5,0.45) (0.25,0.7) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A25 (0.75,0.2) (0.5,0.45) (0.75,0.2) (0.5,0.45) (0,1) (1,0.1) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A26 (0.75,0.2) (0.25,0.7) (0.5,0.45) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A27 (0,1) (0.5,0.45) (0,1) (0.75,0.2) (0.75,0.2) (0.25,0.7) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A31 (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (0.5,0.45) (0.5,0.45) (0.5,0.45) (0.5,0.45) A32 (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) A33 (1,0.1) (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (0.5,0.45) A34 (0,1) (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) A35 (0,1) (0,1) (0.75,0.2) (1,0.1) (1,0.1) (0.25,0.7) (0.25,0.7) (0,1) (1,0.1) (0,1) (1,0.1) (0,1) (0.75,0.2) (0.5,0.45) (1,0.1) A36 (0,1) (0,1) (0.5,0.45) (1,0.1) (1,0.1) (0.25,0.7) (0.25,0.7) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) A37 (0,1) (0,1) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) A38 (0,1) (0,1) (0.75,0.2) (1,0.1) (1,0.1) (0,1) (1,0.1) (0,1) (1,0.1) (0,1) (1,0.1) (1,0.1) (0,1) (0,1) (0,1) Table 15 The IFDM for CAMOR strategies and BAC strategies. Table 15 A31 A32 A33 A34 A35 A36 A37 A38 A41 A42 A43 A44 A45 A46 A47 A48 A31 (0,1) (1,0.1) (1,0.1) (1,0.1) (0.5,0.45) (0.5,0.45) (0.5,0.45) (0.5,0.45) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A32 (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A33 (1,0.1) (1,0.1) (0,1) (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (0.5,0.45) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A34 (0.75,0.2) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A35 (0,1) (1,0.1) (0,1) (1,0.1) (0,1) (0.75,0.2) (0.5,0.45) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A36 (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A37 (0,1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A38 (0,1) (1,0.1) (0,1) (1,0.1) (1,0.1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) (0,1) A41 (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) A42 (1,0.1) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (0.75,0.2) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) A43 (1,0.1) (0.75,0.2) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (1,0.1) (0.75,0.2) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) A44 (0.75,0.2) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) A45 (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) (0.75,0.2) (0.75,0.2) A46 (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) (0.75,0.2) A47 (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) (0.75,0.2) A48 (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (1,0.1) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0.75,0.2) (0,1) The information in Table 13 and the information in Table 14, Table 15 are integrated following Step 7 in obtaining the global priority vectors for BAC and supplier strategies. The priority strategies for BAC are highlighted in Table 16 , while the supplier priority strategies are presented in Table 17 . Furthermore, a graphical presentation of the global priority vectors for BAC and supplier strategies are shown in Fig. 8 and Fig. 9 , respectively.Table 16 The global priority vector of BAC strategies. Table 16Elements Global priority vector (w˜∗) I(w˜∗) Rank A21 (0.0841,0.0810) A22 (0.1479,0.0136) A23 (0.1025,0.1079) A24 (0.0598,0.1334) A25 (0.0813,0.1334) A26 (0.0686,0.0400) A27 (0.0498,0.1146) A31 (0.049,0.00210) 0.5510 2 A32 (0.3724,0.0014) 0.8873 1 A33 (0.0152,0.0017) 0.5158 3 A34 (0.0111,0.0059) 0.5115 4 A35 (0.0072,0.0996) 0.5010 7 A36 (0.0100,0.0235) 0.5101 6 A37 (0.0105,0.0039) 0.5109 5 A38 (0.0053,0.4808) 0.3712 8 Table 17 The global priority vector of the supplier strategies. Table 17Elements Global priority vector (w˜∗) I(w˜∗) Rank A31 (0.0512,0.0077) A32 (0.3875,0.0053) A33 (0.0160,0.0063) A34 (0.0118,0.0091) A35 (0.0077,0.0872) A36 (0.0106,0.0244) A37 (0.0112,0.0085) A38 (0.0057,0.3966) A41 (0.4108,0.0023) 0.7054 1 A42 (0.0085,0.1561) 0.4981 7 A43 (0.0535,0.0089) 0.5267 2 A44 (0.0096,0.0563) 0.5040 5 A45 (0.0091,0.0794) 0.5030 6 A46 (0.0151,0.0293) 0.5073 4 A47 (0.0534,0.0104) 0.5267 3 A48 (0.0088,0.1737) 0.4968 8 Fig. 8 Distribution of the global priority vector of BAC strategies. Fig. 8 Fig. 9 Distribution of the global priority vector of supplier strategies. Fig. 9 Table 16 shows the following priority ranking of BAC strategies: A32≥A31≥A33≥A34≥A37≥A36≥A35≥A38. On the other hand, the supplier strategies generate the following priority ranking in Table 17: A41≥A43≥A47≥A46≥A44≥A45≥A42≥A48. 5 Discussion This study aims to provide a systematic approach in positioning the strategies of each entity in the SC of the public sector within the premise of the COVID-19 pandemic integrating the Kano-QFD with FUCOM-based decision maps under an intuitionistic fuzzy environment. Three processes are identified in the SC in the case study: (1) project planning, (2) material request, and (3) procurement. These processes involved four stakeholders: the funding institution (i.e., 10.13039/501100006733 CHED ), research institution (i.e., CAMOR), BAC, and the supplier. Unlike previous models, the proposed approach considers the individual capacity of each entity to conduct its tasks by utilizing the information (i.e., strategies, priorities) of the previous entity. In addition, the level of satisfaction of each strategy (or requirements), along with the notion of uncertainty in eliciting decisions, is integrated into the allocation of priority weights for each strategy. Identifying priority strategies by holistically taking into consideration the complexity and uncertainty of the decision problem ensures strong integration of interests along with the SC, which is pivotal for the public sector in resource allocation decisions, policy design, and strategy development. Collectively, the proposed approach provides a synthesis of complex and uncertain information across the public sector SC for the delivery of public goods. In the case study, the strategy with the highest priority weight in the project planning process is creating an overarching plan of operations within timelines and budget (A22). This result is highly relevant considering that in carrying out a large and complex operation, a systematic plan acceptable for all stakeholders involved (i.e., funding institution and research center) must establish first to accomplish predetermined targets. Moreover, a fundamental feature to project implementation within limited resources (e.g., time, budget) is creating a roadmap of operations necessary to ensure that all project objectives are achieved. Accordingly, decision-makers in the research center must balance the project scope against the constraints of schedule, budget, staff resources, and quality objectives. Consequently, this involves the second-ranked strategy, synchronizing the workforce with the overarching plans (A23). This is then followed by maintaining public health and safety in project implementation (A24), initiating effective communication channels among stakeholders (A26), carrying out coordination efforts with the needed stakeholders (A25), implementing lean operations (A24), and setting quality product and service specifications (A27), respectively. It is evident that maintaining public health emerges with a higher priority, which implies that achieving target requirements set by the government (i.e., CHED) requires a deliberate and careful effort in ensuring that public health is maintained. On the other hand, complying with government procurement protocols (A32) is the priority for the material request process. Since the BAC is tasked to execute the necessary procedures for government compliance, this strategy, as the priority, seems to be a straightforward implication. Furthermore, since the BAC links CAMOR and the supplier, face-to-face interaction is inevitable for their operations. Thus, maintaining public health and safety in transactions (A31) as the second-ranked priority is crucial. The rest of the strategies are arranged as follows: implementing coordination activities with the requesting unit and the supplier (A33), implementing lean office (A34), procuring products and services within specifications (A37), establishing a list of supplier evaluation criteria (A36), maintaining a portfolio of quality suppliers of products and services (A35), and creating progress reports of purchased products (A38). Maintaining public health and safety (A41) for the procurement process is the strategy with the highest priority weight. Since most activities carried out by the suppliers include face-to-face interaction with the stakeholders (i.e., delivery), implementing extra precautions are necessary measures for the safety of all stakeholders involved under the new normal conditions. This is followed by implementing responsive customer relationship management (A43), which implies that having an effective communication channel with the customer from the requested material specifications until after-procurement services is critical for ensuring the reliability of outcomes and accuracy in every transaction. Studies conducted by Refs. [104,105] revealed that collaborations and consistent communications among supply chain stakeholders have a crucial role in obtaining sustainable future support from SC partners and enhancing SC performance and customer satisfaction. Thus, suppliers must ensure that their facilities and capabilities are excellent, and there is an emphasis on customer orientation and open communication as well as inter-agency communication. The remaining strategies are sequenced as follows: implementing effective communication strategies to ensure accurate transaction (A47), implementing a competitive pricing policy (A46), implementing lean service concepts (A44), implementing strict quality control policies (A45), implementing an agile business model (A42), and meeting deadlines set for procurement requirements (A48). 6 Managerial insights The disruptions of the COVID-19 pandemic foster the need for integration among entities in the public sector SCs and establishing shared value for all stakeholders. The public sector SCs have been affected by degraded demand, facilities that were shut down, fiscal restrictions, and public health measures resulting in more complex processes. The integrated approach and the case strategies in this study provide a spectrum of benefits to decision-makers of the public sector SCs. Priority strategies in the upstream are tightly integrated downstream, forcing close coordination among members of the SC. These strategies accelerate efforts by creating an enabling environment, strengthening SCs, and encouraging product and service innovation in the public sector. In effect, it better augments the socio-economic conditions of the public as the receiver of goods and the human resources supporting the SC. The study insights contribute to the efficacy of public sector SCs in responding and adapting to disruptions fueled by the pandemic. The conceptual SC design and its demonstration via a case study emphasize the significance of cooperation among entities in translating government requirements into tangible goods that would uplift socio-economic conditions of the public while maintaining cost-efficiency, public welfare, enhanced customer service, and upholding public health standards. In particular, the proposed framework captures a synthesis of strategies necessary for the public sector SC entities. In the case study, note that the priority requirement from a government entity (i.e., CHED) is meeting all project objectives. This requirement is well reflected in the priority strategies of CAMOR (i.e., the upstream entity) by highlighting the significance of creating an overarching plan of operations, synchronizing workforce, and maintaining public health and safety in project implementation strategies. The first two are almost straightforward; however, it is surprising that maintaining public health and safety becomes equally important in achieving priority CHED requirements. While still under the COVID-19 pandemic, disruptions caused by lockdowns, infections, and hospitalizations triggered by deliberately ignoring public health protocols may hamper operations on a certain scale, affecting the overall project timelines and incurring some overhead costs. This agenda is well-represented in the downstream entity (i.e., BAC), which underlines the importance of complying with government procurement protocols and public health in achieving the priority strategies of the upstream SC entity (i.e., CAMOR). Compliance with procurement guidelines ensures prompt implementation of project activities, as failure to abide by these guidelines would force the government to stop the implementation for possible fraud. In addition, the downstream entity emphasizes maintaining public health to avoid delays due to viral spread. These agenda of the BAC are also reflected in the agenda of the downstream entity (i.e., the supplier). In the priority strategies of the supplier, maintaining public health and safety in operations emerges on top of the priority list, followed by responsive customer relations and effective communication. These strategies adequately address the strategies of the upstream entity (i.e., BAC). Responsive customer relations coupled with effective communication would ensure compliance with government procurement protocols. In addition, maintaining public health safeguards against disruption in operations and meeting the requirements of the upstream entities. With the proposed method, each entity maintains and reflects the transition of information across the SC. Finally, although the case study demonstrated in this work contains idiosyncrasies, it is evident that a crucial mitigation effort in cushioning the impact of the pandemic is maintaining public health and safety in operations of the entire public sector SC. 7 Conclusion and future work In summary, this study introduces a framework for synthesizing strategies in otherwise isolated entities in public sector supply chains. The proposed framework intends to integrate the operations of entities in public sector SCs. The integration of information yields three primary benefits: (1) alignment of objectives of the entities, (2) synchronization of processes in otherwise independently operating entities, and (3) maximization of product and service quality. These benefits lead to the maximization of the satisfaction level of each public sector SC entity. The framework introduced in this work is developed based on an intuitionistic fuzzy environment. This platform addresses uncertainty in decisions involved in public sector SCs. Accounting for such uncertainties allows the proposed framework to systematically process subjective judgments and hesitations of decision-makers, which are prevalent in judgment elicitations. It is important to account for such uncertainties to obtain more robust estimations of parameters (i.e., priorities of strategies), which minimizes the risk of counterintuitive decisions that can be costly in public sector SCs. The use of IFS is also advantageous compared to stochastic approaches, which rely heavily on a manifold of data. Unlike private sector enterprises, data can be challenging to obtain in public sector SCs. Its use makes it possible to estimate the value of quality parameters (e.g., customer requirements) based on a few expert judgments. Conventional deterministic and stochastic approaches fail to account for the important factors highlighted above, which warrants the framework proposed in this work. In addition, the integration of an analytic framework that systematically incorporates the crucial information on uncertainty, complexity, and priority into the Kano-QFD model effectively translates the priorities from upstream to downstream entities of the public sector SC. The integrative modelling framework is novel in this analysis, and some components are reported only in this work. Although rigorous comparisons of performance may be necessary, this work offers a starting point of discussion for future research in this work. For instance, the integration of IFS within the computational framework of the FUCOM has not been reported yet. Incorporating uncertainty through the IFS is a natural extension of eliciting judgments expressed in words. Likewise, the IFS extension of the FDMs is first demonstrated in this work. These components augment a robust model that effectively translates information from one entity to another entity in the SC. In this work, the proposed framework is illustrated through a case study of a multi-level public sector SC in the Philippines. The case study highlights the applicability of the proposed framework not only in the case environment but also in other public sector SCs. For instance, the framework proposed here can be used in SCs involving the procurement of COVID-19 vaccines. In many countries, especially in the developing world, the chaos brought by the COVID-19 pandemic has made it difficult to synchronize processes, align objectives, and assure procurement and delivery of high-quality healthcare products and services to customers in the public sector SCs. The proposed framework can be employed in such environments as a decision support tool to address these problems. However, certain limitations exist with the proposed framework. First, this study only uses a straightforward approach to the decision strategies of each SC entity. Given the complexity of public sector SCs, the multifaceted interaction among the strategies of each SC entity should be considered. Furthermore, the required computations of the proposed methodological framework may not be easily handled by stakeholders of the public sector SC. In this regard, analysts must design such a computational platform to facilitate the necessary computations. For instance, a manageable decision support system with a user-friendly interface may be developed for the proposed framework to enable decision-makers to effectively carry out the judgment elicitations after thoroughly identifying the relevant strategies in response to the conditions of the SC. Future works may explore other fuzzy environments (e.g., Pythagorean fuzzy sets, rough sets, Fermatean fuzzy sets, Picture fuzzy sets, neutrosophic sets) in handling the uncertainty associated with the decision-making platform. The integration of the decision support framework proposed here into enterprise resource planning systems is an avenue for work in the domains of decision support systems. Lastly, case-specific studies may employ the proposed framework in planning the implementation of measures for post-pandemic socioeconomic development, which may require the synchronization of multi-level public sector SCs. Author statement Lanndon Ocampo - Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Supervision; Validation; Roles/Writing - original draft; Writing - review & editing. Joerabell Lourdes Aro - Conceptualization; Data curation; Formal analysis; Methodology; Software; Validation; Visualization; Roles/Writing - original draft; Writing - review & editing. Samantha Shane Evangelista - Conceptualization; Data curation; Formal analysis; Methodology; Software; Validation; Visualization; Roles/Writing - original draft; Writing - review & editing. Fatima Maturan - Conceptualization; Data curation; Formal analysis; Methodology; Software; Validation; Visualization; Roles/Writing - original draft; Writing - review & editing. Nadine May Atibing - Conceptualization; Data curation; Formal analysis; Roles/Writing - original draft; Writing - review & editing. Kafferine Yamagishi - Conceptualization; Formal analysis; Roles/Writing - original draft; Writing - review & editing. Egberto Selerio, Jr. - Conceptualization; Data curation; Formal analysis; Methodology; Software; Validation; Visualization; Roles/Writing - original draft; Writing - review & editing. Lanndon Ocampo is an Associate Professor in the Department of Industrial Engineering and currently the Director of the Center for Applied Mathematics and Operations Research at Cebu Technological University (Philippines). He received his Ph.D. in Industrial Engineering from De La Salle University (Philippines) and his MEng and BSc (cum laude) degrees in Industrial Engineering, as well as an MSc in Mathematics from the University of San Carlos (Philippines). He has authored over 130 international peer-reviewed journal papers and has presented papers at over 30 research conferences. His research interests include multi-attribute decision-making, problem structuring, and decision science. He is on the Editorial Board of Advances in Production Engineering and Management, Engineering Management in Production and Services, International Journal of Management and Decision Making, International Journal of Business and Systems Research, and Education Research International. He is a 2017 Outstanding Young Scientist awardee by the National Academy of Science and Technology, Philippines (NAST PH), and a 2018 Outstanding Cebuano awardee in the field of Science and Technology. He is named one of 2018 THE ASIAN SCIENTIST 100 – an annual listing of the region's top researchers, academics, and innovators. Most recently, he is conferred as the 2019 Achievement Awardee of the National Research Council of the Philippines (NRCP) under the Division of Engineering and Industrial Research. Joerabell Lourdes Aro is a graduate of BS in Industrial Engineering at the University of San Jose-Recoletos. She is currently a Science Research Analyst of the Center for Applied Mathematics and Operations Research at Cebu Technological University. Samantha Shane Evangelista is a Science Research Analyst of the Center for Applied Mathematics and Operations Research at Cebu Technological University. She received her BS in Industrial Engineering from the University of San Jose-Recoletos. Fatima Maturan received her BS in Industrial Engineering at the University of San Jose-Recoletos. She is currently a Science Research Analyst of the Center for Applied Mathematics and Operations Research at Cebu Technological University. Nadine May S. Atibing is a licensed professional teacher currently working as an admin staff in the Center for Applied Mathematics and Operations Research at Cebu Technological University. She received her bachelor's degree in Elementary Education at Cebu Technological University and currently taking up MAEd major in Educational Management at Cebu Normal University. Kafferine Yamagishi is an Assistant Professor and currently the Chair of the Department of Tourism Management, College of Management and Entrepreneurship at Cebu Technological University, Philippines. She attained her Master of Management major in Tourism Management at the University of San Carlos (Philippines), where she is currently taking up her Doctor of Philosophy degree in Business Administration. She received her Certification in Professional Education and attained her Master of Arts in Education major in Administration and Supervision at Cebu Technological University. She graduated Bachelor of Science in Tourism (cum laude) from the University of San Jose-Recoletos, Philippines. Before joining academia, she worked both in the hospitality and tourism industry. She currently has 22 published articles indexed in Scopus. Also, she has presented papers to research conferences throughout her academic career. Her research interests include tourism management, destination planning, tourism marketing, and events management. Egberto F. Selerio Jr., MSIE obtained his Bachelor of Science in Industrial Engineering from the University of San Jose-Recoletos (Philippines) with cum laude honors and Master of Science in Industrial Engineering from the University of San Carlos (Philippines) under the scholarship grant of the Department of Science and Technology – Engineering Research and Development for Technology. He specializes in applied operations research and has published his works in several WoS/Scopus-indexed journals such as Applied Soft Computing (Elsevier), Structural Change and Economic Dynamics (Elsevier), Socio-economic Planning Sciences (Elsevier), Urban Water Journal (TandF), and Environment, Development, & Sustainability (Springer) Appendix A Supplementary data The following are the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Multimedia component 2 Multimedia component 2 Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.seps.2022.101340. ==== Refs References 1 Shen W. Hu D. Günay E.E. Kremer G.E.O. Evolution of supply chain management: a sustainability focused review Int J Sustain Manuf 4 2/3/4 2020 319 335 2 Khojasteh-Ghamari Z. Irohara T. Supply chain risk management: a comprehensive review Khojasteh Y. Supply chain risk management 2018 Springer Singapore 3 Snoeck A. Udenio M. Fransoo J.C. 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==== Front Pattern Recognit Pattern Recognit Pattern Recognition 0031-3203 0031-3203 Elsevier Ltd. S0031-3203(21)00352-6 10.1016/j.patcog.2021.108189 108189 Article A multi-task fully deep convolutional neural network for contactless fingerprint minutiae extraction Zhang Zhao a Liu Shuxin c Liu Manhua ⁎b a Department of Instrument Science and Engineering, School of EIEE, Shanghai Jiao Tong University, China b The MoE Key Lab of Artificial Intelligence, Artificial Intelligence Institute, Shanghai Jiao Tong University, 200240, China c College of Electrical Engineering, Shanghai DianJi University, China ⁎ Corresponding author 21 7 2021 12 2021 21 7 2021 120 108189108189 29 11 2020 13 6 2021 4 7 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. With the outbreak and wide spread of novel coronavirus (COVID-19), contactless fingerprint recognition has attracted more attention for personal recognition because it can provide significantly higher user convenience and hygiene than the traditional contact-based fingerprint recognition. However, it is still challenging to achieve a highly accurate recognition due to the low ridge-valley contrast and pose variances of contactless fingerprints. Minutiae points are a kind of ridge flow discontinuities, and robust and accurate extraction is an important step for most automatic fingerprint recognition algorithms. Most of existing methods are based on two stages which locate the minutiae points first and then compute their directions. The two-stage method cannot make full use of location and direction information. In this paper, we propose a multi-task fully deep convolutional neural network for jointly learning the minutiae location detection and its corresponding direction computation which operates directly on the whole gray scale contactless fingerprints. The proposed method consists of offline training and online testing stages. In the training stage, a fully deep convolutional neural network is built for the tasks of minutiae detection and its direction regression, with an attention mechanism to make the direction regression branch concentrate on the minutiae points. A new loss function is proposed to jointly learn the tasks of minutiae detection and its direction regression from the whole fingerprints. In the testing stage, the trained network is applied on the whole contactless fingerprint to generate the minutiae location and direction maps. The proposed multi-task leaning method performs better than the individual single task and it operates directly on the raw gray-scale contactless fingerprints without preprocessing. The results on three contactless fingerprint datasets show the proposed algorithm performs better than other minutiae extraction algorithms and the commercial software. Keywords Contactless fingerprint Minutiae extraction Deep convolutional neural network Multi-task learning MSC 00-01 99-00 ==== Body pmc1 Introduction Fingerprint is a widely used biometrics characterized as the ridge friction patterns on finger tips. After more than forty years of research, automatic fingerprint identification system (AFIS) has achieved a great success for wide applications [1], [2], [3]. Traditional AFIS is usually based on contact fingerprints captured by pressing a finger on the scanner surface. With the outbreak and wide spread of novel coronavirus 2019 (COVID-19), World Health Organization (WHO) recommends to avoid contact with objects in public places to reduce the transmission of virus. Contactless fingerprints captured without any contact between a finger and sensor have become an important and highly promising prospect for personal recognition because of its significantly higher user convenience and hygiene than the traditional contact-based fingerprints. With the rapid advances of digital cameras, contactless fingerprints can be captured with the high-resolution and high-speed camera to provide higher-quality images. However, the acquisition of contactless fingerprints is significantly different from that of contacted fingerprint. Existing methods for contact-based fingerprint recognition cannot be directly used for contactless fingerprints. There are some difficulties in contactless fingerprint recognition. First, since the fingerprint acquisition with camera is affected by lighting sources, the contactless fingerprints are usually low-contrast between ridge and valleys which may cause poor performance in extraction of feature points. Second, the presentation of fingers against sensors is often uncontrollable in acquisition, which results in the perspective distortion and pose variances of images. Fig. 1 shows some contactless fingerprints with poor qualities. Thus, it is still challenging to achieve a highly accurate contactless fingerprint recognition. In recent years, there are many efforts made to address these problems and improve the performance of contactless fingerprint recognition [4], [5], [6], [7].Fig. 1 Samples of contactless fingerprints with poor qualities: (a) low contrast caused by over exposing, (b) uneven lighting and (c) pose variation. Fig. 1 Minutiae points are defined as the discontinuities of fingerprint ridge flows. There are several types of minutia points such as ridge ending and bifurcation. Minutiae location and direction are often used for fingerprint representation so that automatic recognition problem can be converted to comparison of minutiae sets between two fingerprints. Since most of existing fingerprint recognition algorithms rely on minutiae matching, minutiae points are considered as highly significant features for automatic fingerprint recognition. There are a lot of minutiae extraction methods proposed for contact-based fingerprints in the literature [2], [8], [9], [10], [11]. These methods can be broadly classified into two categories: traditional handcrafted methods and deep learning based methods. The traditional handcrafted methods usually use the domain knowledge or heuristics to detect the minutiae points [2], [8]. In these methods, fingerprint segmentation, enhancement, thinning and binarization are often performed before searching the minutiae-like patterns of localized pixels for minutiae detection. Bansal, et al. [8] proposed a mathematical morphology method for minutiae extraction, which use the morphological Hit or Miss transform (HMT) on binary image to detect minutiae points. Farina, et al. [2] proposed to extract minutiae points on the skeleton binary fingerprint images. To overcome information lost caused by binarization and thinning processes, some methods were proposed to detect minutiae points from the gray-scale images obtained by fingerprint enhancement [12]. Although these traditional handcrafted methods can achieve good performance for minutiae detection on good quality fingerprints, they require strong prior knowledge to define the patterns of minutiae points and thus are sensitive to noises. In recent years, deep learning networks such as Convolutional Neural Networks (CNNs) have successfully been investigated for fingerprint minutiae extraction [9], [10], [11], [13]. Sankaran, et al. [9] proposed a minutiae extraction method for latent fingerprints by using the stacked sparse autoencoder to learn features for classification of image patches as minutia or non-minutia. Jiang, et al. [10] proposed a minutiae extraction approach based on two deep networks with a JudgeNet to select candidate patches followed by a LocateNet to determine the minutiae locations. This method can make use of representation ability of deep network and directly detect minutiae points from raw fingerprint images, but it cannot compute minutiae directions. Darlow, et al. [13] processed each pixel of input fingerprint by convolutional neural network to predict minutiae locations, and then minutiae directions were calculated by the principal axis of image gradients. Tang, et al. [11] proposed a FingerNet to combine the domain knowledge with deep learning. They first integrated some convolution kernels converted from traditional methods to form a shallow network with fixed weights, which is expanded to a full network for minutiae extraction. Nguyen, et al. [3] proposed to built a CoarseNet to generate a minutiae score map and estimate minutiae directions, followed by a FineNet to refine the candidate minutiae locations based on score map. The above minutiae extraction methods can achieve good performance on the contact-based fingerprints with a clear distinction of ridges and valleys. However, they cannot work well on contactless fingerprints due to the low ridge-valley contrast. Earlier works on contactless fingerprint recognition tend to enhance the images and then extract minutiae features by using the contact-based methods. Lin, et al. [14] enhanced fingerprints with Gabor filtering and adaptive histogram equalization, followed by minutiae extraction with the algorithm in [1]. In [4], a ridge enhancement model was built to enhance the unwrapped contactless fingerprint images and the minutiae points were extracted with NIST mindtct software [15] and Verifinger SDK [16]. Yin, et al. [5] proposed a contactless fingerprint matching algorithm based on minutiae features extracted with Verifinger SDK on the fingerprints pre-enhanced by intrinsic image decomposition and guided image filtering in [6]. More recently, Tan, et al. [7] proposed a deep network for minutiae extraction from raw contactless fingerprints. But the network was trained with the cropped patches, which cannot make use of the global information. In addition, the network detected minutiae and computed directions in two stages, which needed post-processing to refine and remove spurious minutiae. In this paper, we proposes a multi-task fully deep convolutional neural network for minutiae extraction from the whole gray scale contactless fingerprints, which can jointly learn the detection of minutiae locations and the computation of minutiae directions. An attention mechanism is used to make the network concentrate on the direction regression of minutiae points. A new loss function is proposed to jointly combine the tasks of minutia detection and its direction regression, which can help each other in the learning. Different from the patch based method, both the training and testing of the network operate on the whole fingerprints, which can make full use of global information for minutiae extraction. The proposed multi-task leaning method can simultaneously detect the locations of minutiae and compute their directions from the raw contactless fingerprints without preprocessing. The proposed method is tested on three publicly available datasets including direct evaluation versus ground truths, contactless fingerprint matching and contact-based to contactless fingerprint matching. The main contributions of this paper are summarized as follows.• A multi-task fully deep convolutional neural network is proposed for minutiae extraction in contactless fingerprints. This is an end-to-end method by jointly learning detection of minutiae points and computation of minutiae direction, which is different from the two-stage methods with the minutiae detection followed by direction computation. • Instead of cropping fingerprint into local patches, the proposed method operates directly on whole fingerprints in both training and testing stages, which can make full use of global fingerprint features for minutiae extraction in one shot. • An attention mechanism is applied on the direction computation branch, which makes the network pay attention to the minutia points for more reliable direction computation. In addition, the minutia direction is represented with the cosine and sine values, which makes the loss function of direction regression optimized smoothly. The rest of this paper is organized as follows: Section 2 present the proposed minutiae extraction method for contactless fingerprints in detail; Experimental results are presented in Section 3; Conclusion is given in Section 4. 2 Proposed method In this section, we present the proposed minutiae extraction algorithm based on deep network for contactless fingerprints. First, we give an overview of the proposed algorithm. Next, the architecture of our deep network are presented with details. Finally, we present implementation details and minutiae extraction for test fingerprints. 2.1 Overview of the proposed algorithm Minutiae are special patterns of the interleaved ridge and valley flows which are widely used as important features for fingerprint recognition. There are several types of minutiae points such as ridge ending and bifurcation. In this work, we will not discriminate the types of minutiae and all minutiae are considered as interest points. Minutiae extraction includes two tasks: detection of minutia location and computation of minutia direction. Thus, a minutia i can be represented as a triplet (xi,yi,θi), where (xi,yi) denotes its location and θi∈[0,2π) denotes its direction. There are dozens of minutiae points in a fingerprint image. Minutiae extraction is often considered as a kind of object detection where each minutia is an object to be detected. Over the past few years, deep CNNs have been widely investigated for object detection. Accordingly, minutiae extraction based on deep CNNs is usually divided into two steps: detection of minutiae points followed by computation of minutiae directions. The two-step methods train two deep networks separately, which is not only time-consuming but also unable to make use of the features from the tasks of location detection and direction computation. To address the above problems, a novel minutiae extraction method is proposed based on multi-task fully deep convolutional neural network for contactless fingerprints, as shown in Fig. 2 . Since the minutiae location detection and direction computation are two related tasks, we propose a multi-task deep network to jointly learn these two tasks and share their computations and representations. Different from the two-stage method on image patches, the proposed algorithm operates on the full-sized fingerprint image to locate the pixel-level minutiae points and compute their corresponding directions simultaneously. It consists of offline training and online testing stages.Fig. 2 Overview of the proposed minutiae extraction algorithm for contactless fingerprints based on multi-task fully deep convolutional neural network. Fig. 2 In the offline stage, we train the multi-task fully deep convolutional neural network with the training data, which consists of the full sized contactless fingerprints and their corresponding minutia ground truths used as inputs and outputs of network, respectively. Since there are no publicly available contactless fingerprint database with the labelled minutiae coordinates and directions and labelling minutiae from scratch is very time-consuming and labor-sensitive, we use the commercial fingerprint recognition software to extract candidate minutiae followed by manual checking to generate the ground truths of minutiae. First, the COTS Verifinger SDK [16] is used to extract the minutiae locations and directions. Then, we develop a GUI tool to correct the minutiae points and directions in three ways: (a) add the new minutiae which are missed by Verifinger; (b) delete the spurious minutiae; (c) modify coordinates and directions which are not correctly labelled. Finally, the manually checked locations and directions are used as the ground truths of training images. In the online stage, we simply feed the raw full-sized fingerprint into our trained network to generate two heatmaps: one for detecting the minutiae locations and the other for computing their directions. The local peaks on the location map are detected as minutiae points, and the values of direction map on detected points are used as the minutiae direction. The architecture of the multi-task network is presented in the following subsection. 2.2 The multi-task fully deep convolutional neural network We design the architecture of the multi-task fully deep convolutional neural network called as ContactlessMinuNet with the Hourglass-shaped encoder-decoder network structure, as shown in Fig. 3 . The deep network consists of three parts: the shared subnetwork to learn the common representation and two branches for minutiae location detection and direction computation. First, a single shared encoder subnetwork is built to hierarchically process the input fingerprint images and learn the feature representation. After the encoder subnetwork, a shared decoder subnetwork is used to expand the representations back to higher resolution by upsampling. Finally, the network is split into two branches to learn the task-related weights with one for minutiae point detection and the other for minutiae direction computation. Thus, most of the network’s parameters are shared between two tasks to learn the relevant features.Fig. 3 The architecture of the proposed multi-task fully deep convolutional neural network. Fig. 3 2.2.1 The shared subnetwork To learn image features, the shared subnetwork employs the Hourglass-shaped structure which can capture multi-level features and bring them together to generate pixel-wise predictions. Firstly, the input contactless fingerprint image of size W×H×1 is processed by 2 ResBlocks with each one followed by a 2×2 convolutional layer with stride=2 for downsampling. The ResBlock consists of two 3×3 convolutional layers with stride=1, and padding is used to keep the width and height of feature maps constant during convolution. The input of ResBlock is added to the output of the second convolutional layer by element-wise summation as skip connection. The feature maps of W/4×H/4×C are generated for representation where C is the number of channels. Then, an hourglass network [17] is added to the feature maps, which includes encoding and decoding paths. The encoding path consists of the repeated application of ResBlock and a 2×2 convolutional layer with stride=2 for downsampling the feature maps by half, while the number of feature channels is doubled. In each step of decoding path, a sub-pixel module [18] is applied to double the widths and heights of feature maps while the feature channels are reduced to half. The feature maps of encoding path is concatenated into those of decoding patch in the same level, which can make full use of multi-level features for minutiae extraction. All the convolutional layers in ResBlock are followed by a batch normalization layer and ReLU activation. The hourglass network preserves spatial information at each resolution since the deep network maps the low-level image to high-level feature space. After learning the rich features of fingerprint images, the network is split into two branches to learn task specific weights one for minutiae point detection and the other for minutiae direction computation. 2.2.2 The minutiae point detection branch This network branch focuses on detection of minutiae points and the output of each pixel represents the probability of minutiae point. For minutiae point detection with the shared feature maps, one common method is to design an upsampling decoder back to full resolution via deconvolution operations. Unfortunately, upsampling layers tend to add a high amount of computation and can introduce the checkerboard artifacts. To reduce the computation, the minutiae point detection branch simply consists of a 1×1 convolutional layer, a batch normalization layer and a sigmoid layer. The sigmoid function is used as activation to generate minutiae location map of size W/4×H/4×1. Each value of location map represents the probability of a minutia in a certain location, which stands for a cell of 4×4 pixels in the original fingerprint image. The points with local maximum probabilities are detected as minutiae points. 2.2.3 The minutiae direction regression branch The direction regression branch is designed to predict the directions of minutiae, which is a phase angle θi∈[0,2π). To facilitate the regression, the direction is represented as two components (cosθ,sinθ) to be jointly predicted in this work. The feature maps learned from the shared subnetwork are input to the minutiae direction regression branch. To predict the minutiae direction more accurately, an attention based subnetwork is built to consist of an attention mechanism followed by a 1×1 convolutional layer, a batch normalization layer and a tanh layer. First, the attention mechanism is composed of two repeated Conv-BN-ReLU layers, and another convolutional layer with sigmoid activation function to transform the input feature maps into attention weight map for each point. The input feature map is then multiplied with the attention weight map to output the weighted feature maps which is further added with the input feature maps by element-wise summation as in [19]. After that, a 1×1 convolutional layer and a batch normalization layer are followed and hyperbolic tangent is used as activation function to limit the output of network to range of [−1,1]. Finally, two-channel direction maps of size W/4×H/4×2 is generated from the direction regression branch with each element of the direction map representing the cosine and sine values of a direction. To make sure that the elements of direction map meet the mathematical requirement cos2θ+sin2θ=1, a normalization layer is added at the end of network by (cc2+s2,sc2+s2) where c and s are the predicted cosine and sine values of direction map, respectively. The final outputs of direction regression branch are two components cosθ and sinθ of minutiae directions θ. 2.2.4 Loss functions In this work, we apply multi-task learning strategy to jointly learn the detection of minutia points and computation of minutia directions by combining the losses of two network branches: one for minutia point detector Lp and another for minutia direction regressor Ld. Firstly, minutiae detection is a severe class-imbalance problem because the number of non-minutia points is significantly larger than that of minutia points. If a regular binary cross-entropy loss function is adopted, the network training is inefficient as most locations are non-minutia that contribute no useful information. To solve this problem, a modified focal loss [20] is used to force the network training focus on minutia points with large classification weights. Let P^ and P denote the predicted and ground truth minutia location maps, respectively, the minutia detection loss Lp is computed as:(1) Lp=−1N∑xy{(1−P^xy)αlog(P^xy)ifPxy=1(1−Pxy)β(P^xy)αlog(1−P^xy)otherwise where α and β are hyper-parameters in focal loss; N is the number of minutiae points in input fingerprint. We set α=2 and β=4 in our experiments. Secondly, for direction regression, we only consider the minutiae points and their 8 neighborhoods while other locations have no directions and do not involve in regression, which can eliminate noises and reduce the computation. Let θ^ and θ be the predicted and ground truth minutia directions, respectively. Since the phase angle θ (∈[0,2π)) is a circular value, minutia points with angles of 0 and 2π have the same direction. If direct subtraction is used to compute the difference between θ^ and θ, two phase angles with close directions would have a big difference. For computation of minutiae directions, some algorithms divide the range of direction into eight or more categories and classify the direction of minutiae into one category. But it may results in quantization error and the number of categories is large which make it challenging for classification. In the previous study for minutiae extraction  [21], the smaller one of θ^−θ and 2−(θ^−θ) is used to measure the distance between the predicted and ground truth directions, where the direction is normalized to [−1,1). This may result in the problem of gradient computation. In this work, instead of using the phase angle, the cosine and sine components (cosθ,sinθ) are used to represent the minutiae direction θ. To achieve more precise direction prediction, the MSE loss function with both cosine and sine values of minutiae direction is used as the objective function of the direction regression, which is computed as:(2) Ld=1N∑xy{(cosθ^xy−cosθxy)2+(sinθ^xy−sinθxy)2(x,y)∈(x,y)|Px,y=1its8neighbors}0otherwise where N is the number of available pixels for direction regression, which include all minutiae points and their 8 neighbors. With this loss function, the network predicts the cosine and sine components of the direction, which are further used to compute the phase angle. Finally, for jointly learning the minutiae location detection and direction regression, we combine the location probability prediction loss and direction regression loss as:(3) L=Lp+λLd where λ is a weight term to balance these two losses. 2.3 Implementation details and minutiae extraction The proposed algorithm is implemented with the PyTorch framework by Python programming. It consists of network training and minutia extraction for test images. Given the gray-scale contactless fingerprint image I∈RW×H×1, the proposed ContactlessMinuNet generates the minutia location and direction maps of size W4×H4, so we downsample the ground truth location and direction maps to P∈[0,1]W4×H4×1 and Θ∈[−1,1]W4×H4×2, respectively. This can reduce the computation costs without sacrificing accuracy since there hardly exist two minutiae points in a cell of 4×4 pixels for contactless fingerprints. To generate ground truth location map P∈[0,1]W4×H4×1, we produces a heatmap Hx,y∈[0,1]W4×H4×1 for each minutia (x,y) with a Gaussian kernel as:(4) Hx,y(i,j)=exp(−(i−x)2+(j−y)22σx,y2) where σx,y is a standard deviation and is set to 1.5 in this work. The ground truth location map P is generated by applying element-wise maximum on Hx,y over all ground truth minutiae points, as shown in Fig. 4 (a). To generate ground truth direction map Θ∈[−1,1]W4×H4×2, we compute cosine and sine values (cosθ,sinθ) for the direction of each minutia. The location of each minutia and its 8 neighborhoods are assigned with value (cosθ,sinθ), while other locations are assigned with (0,0), which indicates they do not have directions, as shown in Fig. 4 (b).Fig. 4 (a) Ground truth location map and (b) ground truth direction map, where the values of location map denote the minutia probability and the values of direction map denote the cosine or sine values of minutiae direction. Fig. 4 When training the proposed ContactlessMinuNet, the weights of convolutional layer and batch normalization layer are initialized by following the rules in [22]. The batch size is set to 4. Adam optimizer [23] is used by setting β1=0.9, β2=0.999 and ϵ=1×10−8. Warm-up training with learning rate 3×10−4 is applied for the first 5 epochs, and then the network is trained for 200 epochs with the learning rate 1×10−3. ReduceLrOnPlateau scheduler is adopted to reduce the learning rate with a factor until the loss does not drop. For a given test contactless fingerprint, the network generates a location map of size W4×H4×1 and a direction maps of size W4×H4×2. We choose the local peaks of location map as the locations of minutiae, and the phase angle of minutiae direction is computed as arctan(sinθ/cosθ) with the predicted direction components at the minutiae location. Since the output location and direction maps are downsampled by 4 comparing to the input contactless fingerprint image of size W×H, the detected minutiae locations are mapped to the coordinates of input image with stride 4 based on receptive field theory [24]. 3 Experimental results In this section, we conduct experiments to test the effectiveness of the proposed algorithm for contactless fingerprint minutiae extraction. Firstly, we introduce the datasets and the settings used in the experiments. Secondly, we perform the ablation studies on the proposed ContactlessMinuNet to test the effectiveness of the multi-task learning, attention mechanism and loss function for minutiae extraction. Thirdly, we perform direct evaluation on extracted minutiae against the ground truths. Next, we perform matching experiments for both contactless fingerprint recognition and contact-based to contactless fingerprint recognition on three datasets and compare the results with other methods. Finally, discussion is provided to further compare the results with the recent published ones and demonstrate the generalization ability of proposed network using open-set protocol. 3.1 Datasets and settings To evaluate the proposed method and compare with other methods, three contactless fingerprint datasets: PolyU Cross [25], Benchmark 2D/3D [26] and a dataset prepared by our laboratory are used for our experiments. The PolyU Cross dataset includes two sessions. The first session contains 2016 contactless fingerprint images acquired from 336 fingers with 6 impressions for every finger. The second session contains 960 fingerprint images from the corresponding 160 fingers with 6 impressions for each finger, which were captured from the same clients as the first session in about 2 to 24 months. For each contactless fingerprint image, PolyU Cross dataset provides the corresponding contact-based fingerprint image with also 6 impressions for each finger. Benchmark 2D/3D dataset consists of 9000 contactless fingerprint images acquired from 1500 fingers with three different views and 2 impressions for each view. We use 3000 unwrapped contactless fingerprint images for minutiae extraction with 2 impressions for each finger. Benchmark 2D/3D dataset also contains 6000 corresponding contact-based fingerprint images with 4 impressions for each finger. In addition, we have collected a dataset, which consists of 1320 contactless fingerprints and corresponding contact-based fingerprints. The dataset is acquired from 110 fingers with 12 impressions for each finger. All fingerprints are captured from the volunteers of our university. Fig. 5 shows some fingerprint samples of three datasets.Fig. 5 Samples of contactless fingerprints (top) and contact-based fingerprints (bottom) from: (a) PolyU Cross dataset, (b) Benchmark 2D/3D dataset and (c) our dataset. Fig. 5 To train the proposed ContactlessMinuNet, we select the contactless fingerprints from fingers numbered from 1 to 136 in the first and second sessions of PolyU Cross dataset as the training set. Since there are some missing fingerprints in the second session, we have 1440 ((136+104)×6) contactless fingerprints for training. The remaining 200 fingers with 1200 impressions in the first session of PolyU Cross dataset are used for testing the proposed method. For robust minutiae extraction with Benchmark 2D/3D dataset, a small set with 400 contactless fingerprints from 200 fingers are used for fine-tuning the pre-trained network based on PolyU Cross dataset, and the remaining 2600 contactless fingerprints from 1300 fingers are used for evaluation. For our dataset, 120 fingerprints from 10 fingers are used for fine-tuning the ContactlessMinuNet and the left 1200 fingerprints from 100 fingers are used for testing. The goal of fingerprint minutiae extraction is to achieve reliable fingerprint recognition. Thus, we conduct fingerprint verification and identification experiments. To implement a complete process of fingerprint recognition, minutiae extraction is integrated with minutiae matching, which is automatically conducted using the existing Minutia Cylinder-Code (MCC) matcher [27] with the minutiae coordinates and directions as inputs. For fingerprint verification experiments, we use FVC protocol to evaluate the performance. Each impression is compared against the remaining ones of the same finger to generate genuine pairs while the first impression of each finger is matched with the first impression of other fingers to generate imposter pairs. For contactless fingerprints from PolyU Cross dataset, we have 3000 (200×6×5/2) genuine pairs and 19900 (200×199/2) imposter pairs. For contactless fingerprints in Benchmark 2D/3D dataset, we have 1300 (1,300×1) genuine pairs and 844350 (1,300×1299/2) imposter pairs. For contactless fingerprints in our dataset, we have 6600 (100×12×11/2) genuine pairs and 4950 (100×99/2) imposter pairs. We combine the minutiae extraction with the MCC matcher to generate a matching score for each pair of contactless fingerprints. With the matching scores from all pairs of fingerprints, we calculate True Positive Rate (TPR) and False Positive Rate (FPR) and plot Receiver Operating Characteristic (ROC) curve as well as the area under the ROC curve (AUC) and Equal Error rate (EER) for each dataset to evaluate the fingerprint verification performance. Different from verification, fingerprint identification is a one-vs-many matching process. For identification experiments, we use the first impression of each finger as the template, and the remaining impressions of each finger as the test fingerprints to match all template fingerprint images. A matching score is generated between a test and a template fingerprints. All matching scores are sorted in descending order and the templates are ranked for each test fingerprint. The Cumulative Matching Characteristic (CMC) curve, which plots the rank−k identification rate with k=1,2,3,⋯,20,⋯, is used to evaluate the performance of fingerprint identification. Several state-of-the-art minutiae extraction methods including the COTS Verifinger SDK  [16], open source extraction software NIST mindtct [15] and deep learning based method MinutiaeNet [3] are used to compare our proposed method. The Verifinger and NIST mindtct are directly used for minutiae extraction on the contactless fingerprints of test datasets. Since the released MinutiaeNet was trained on contact-based latent fingerprints, we retrain the network using the same contactless fingerprint training data as ours to make it effective on contactless fingerprints. All experiments are conducted on a single NVIDIA TITAN Xp GPU with 12 GB memory powered by Ubuntu-16.04-x64 system. Table 1 compares the computation requirements of different minutiae extraction methods used in the experiments.Table 1 Computation requirements of different minutiae extraction methods. Table 1Method Least requirements Resources used in this paper ContactlessMinuNet GPU with at least 8 GB memory NVIDIA TITAN Xp GPU with 12 GB memory Verifinger CPU Intel Xeon CPU NIST mindtct CPU Intel Xeon CPU MinutiaeNet GPU with at least 11 GB memory NVIDIA TITAN Xp GPU with 12 GB memory 3.2 Network ablation studies This experiment is to test the effectiveness of the multi-task learning, attention mechanism and direction regression loss used in the proposed network through the ablation studies. In the first ablation study, we replace the multi-task learning with the traditional two-stage method which detects the minutiae points and compute the minutiae direction separately as in  [7]. First, we remove the direction computation branch from the ContactlessMinuNet and thus the network only outputs the locations of minutiae. Then, the local patches of size 64×64 are cropped to be centered on the minutiae locations and a deep network is built for computation of minutiae direction. The second ablation study is to test the effectiveness of attention mechanism on the direction computation. In this study, we remove the attention module from the direction computation branch of ContactlessMinuNet while the other components of the network are retained. In the third ablation study, we replace the loss function of direction regression with that based on the phase angle from a recently published paper [21]. The training strategy for the ablation studies are same as what described in Section 2.3. We conduct both contactless fingerprint verification and identification experiments on Benchmark 2D/3D dataset since this dataset is more challenging than others. The verification and identification protocols follow with those in the above subsection. The comparisons of ROC and CMC curves by the proposed ContactlessMinuNet and three network ablation studies are shown in Fig. 6 and Fig. 7 , respectively. In addition, we also compute the AUC and EER to evaluate the fingerprint verification performance as shown in Table 2 . From the results, we can see that the multi-task learning, the attention mechanism and the direction regression loss all contribute to improvement of contactless fingerprint recognition accuracy. From Table 2, we can see that the multi-task learning, the attention mechanism and the novel direction loss achieve 1.59%, 2.71% and 5.61% improvements of AUC, and 1.08%, 2.40% and 4.75% improvements of EER, respectively.Fig. 6 ROC curves of network ablation studies on contactless fingerprint verification in Benchmark 2D/3D dataset. Fig. 6 Fig. 7 CMC curves of network ablation studies on contactless fingerprint identification in Benchmark 2D/3D dataset. Fig. 7 Table 2 AUCs and EERs of network ablation studies on contactless fingerprint verification in Benchmark 2D/3D dataset. Table 2Method AUC(%) EER(%) ContactlessMinuNet 98.24 4.28 Two-stage learning 96.65 5.36 Without attention 95.53 6.68 Change direction loss 92.63 9.03 3.3 Results on minutiae extraction This experiment is to perform the direct evaluation of minutia extraction by comparing the minutiae points predicted by the proposed method with their ground truths. However, there are no ground truth minutiae points provided for the contactless fingerprint datasets. It is impractical to get a large number of fingerprints with minutiae information labeled by human experts. For direct evaluation of minutia extraction, we have manually labelled the minutiae points of 100 fingerprint images randomly selected from the test set of Benchmark 2D/3D dataset as ground truths. First, we show the extracted minutiae points by different methods as well as their ground truths on two sample contactless fingerprints in Fig. 8 . We can see that our proposed method can achieve more reliable minutiae extraction with less missing minutiae points than NIST mindtct and MinutiaeNet, and also less spurious minutiae points than Verifinger.Fig. 8 The extracted minutiae features of two sample fingerprints by different methods: (a) Proposed method, (b) Verifinger SDK [16], (c) NIST mindtct [15] and (d) MinutiaeNet [3]. The blue circle and arrow denote the ground truth location and direction, while red ones denote the extracted location and direction with different methods. The green rectangle labels the missing minutiae and green ellipse labels the spurious minutiae. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 8 Furthermore, we perform the direct evaluations as in the previous work [3]. We define the location error D in pixel and direction error O in degree between the predicted and ground truth minutia as:(5) {D=∥le−lg∥2O=min(∥oe−og∥1,360∘−∥oe−og∥1) where (le,oe) and (lg,og) are coordinate (x,y) and direction of extracted minutia and ground truth minutia, respectively. The predicted minutia is considered to be accurate if it satisfies D≤TD and O≤TO. In our experiments, we set TD=12 pixels and TO=20∘ as suggested in  [3]. We calculate the precision (positive predictive value), recall (true positive rate) and F1 score to directly evaluate the accuracy and compare the proposed method with other methods as shown in Table 3 . We have also provided more results on the number of correct minutiae, missed minutiae and falsely detected minutiae relative to ground truth as well as the running time of one fingerprint on average for extracting minutiae of different methods in Table 3. In addition, by adjusting the threshold of the network, the precision vs recall curves are compared for different methods in Fig. 9 . Our results show that the proposed ContactlessMinuNet achieves higher accuracy than other methods. For running time, our algorithm is faster than Verifinger and MinutiaeNet although it is slower than NIST mindtct.Table 3 Minutiae extraction accuracy of different methods on the Benchmark 2D/3D contactless fingerprint dataset. Table 3Method Precision Recall F1 score #Correct #Missed #False Time (s) ContactlessMinuNet 79.16% 80.94% 80.04% 3361 791 884 0.86 Verifinger 46.52% 76.75% 57.93% 3187 965 3663 1.10 NIST mindtct 40.65% 63.30% 49.51% 2628 1524 3837 0.32 MinutiaeNet 23.14% 17.23% 19.75% 715 3436 2376 1.20 Fig. 9 The precision-recall curves of different minutiae extraction methods on the Benchmark 2D/3D dataset. Fig. 9 3.4 Results on contactless fingerprint recognition In this section, we conduct experiments to test the proposed minutiae extraction method on the contactless fingerprints from the test sets of PolyU Cross dataset, Benchmark 2D/3D dataset and our dataset. Both the fingerprint verification and identification experiments are performed to evaluate the performance of the minutiae extraction method. For fingerprint verification, Fig. 10 compares the ROC curves of different minutiae extraction methods on three datasets. Table 4 compares their corresponding AUCs and EERs. From Fig. 10, we can see that the ROC curve of proposed ContactlessMinuNet is higher than other methods for all three datasets. From Table 4, we can see that our proposed ContactlessMinuNet achieves 1.05%, 4.74% and 3.19% decrease in EER for PolyU Cross dataset, Benchmark 2D/3D dataset and our dataset, respectively, when comparing to Verifinger. These results shows that our proposed method performs better than other methods on contactless fingerprint verification.Fig. 10 ROC curves of different minutiae extraction methods on contactless fingerprint verification with (a) PolyU Cross dataset, (b) Benchmark 2D/3D dataset and (c) our dataset. Fig. 10 Table 4 AUCs and EERs of different minutiae extraction methods on contactless fingerprint verification with three datasets. Table 4Dataset Method AUC(%) EER(%) PolyU Cross dataset ContactlessMinuNet 99.33 1.94 Verifinger 98.16 2.99 NIST mindtct 68.91 36.85 MinutiaeNet 93.03 13.35 Benchmark 2D/3D dataset ContactlessMinuNet 98.24 4.28 Verifinger 95.44 9.02 NIST mindtct 81.84 22.93 MinutiaeNet 79.74 26.34 Our dataset ContactlessMinuNet 97.47 5.15 Verifinger 94.36 8.34 NIST mindtct 61.69 46.56 MinutiaeNet 80.77 24.29 For fingerprint identification, Fig. 11 compares the CMC curves of different minutiae extraction methods with PolyU Cross dataset, Benchmark 2D/3D dataset and our dataset. We can see that the CMC curve of the commercial Verifinger is significantly higher than those of other two methods on all three datasets. Nevertheless, comparing to Verifinger, our proposed method achieves the obvious and consistent improvements of identification performance on the Benchmark 2D/3D dataset and our dataset, and small improvements of identification performance on the PolyU Cross dataset. The rank-one accuracies of our proposed method are 89.61% and 94.10% for Benchmark 2D/3D dataset and our dataset, which increase 7.79% and 2.04% comparing to Verifinger, respectively.Fig. 11 CMC curves of different minutiae extraction methods on contactless fingerprint identification with (a) PolyU Cross dataset, (b) Benchmark 2D/3D dataset and (c) our dataset. Fig. 11 From the results, we can see that the improvements of verification and identification performances by our proposed method for PolyU Cross dataset are less than those for other two datasets when compared with the Verifinger. This may be caused by the good fingerprint image quality of PolyU Cross dataset. The contactless fingerprint images of PolyU Cross dataset have less pose and contrast variances than other datasets. Verifinger can achieve very high performance with 98.16% of AUC and 95.51% of the rank-one accuracy for this dataset. Thus, our proposed method can achieve small improvements when compared to Verifinger on other two datasets. 3.5 Results on contactless to contact-based fingerprint recognition In addition to work well on the contactless fingerprint recognition, it is also important to test our proposed method on matching between the contactless and contact-based fingerprints since there are a number of contact-based fingerprint database developed to protect national borders and support e-governance programs. Both the verification and identification experiments are conducted to test the effectiveness of contactless to contact-based fingerprint recognition. To improve the adaptiveness of our proposed method on contact-based fingerprints, we fine-tune the ContactlessMinuNet with the FVC 2002 DB1A [28] and FVC 2004 DB1A [29] datasets as well as the minutiae ground truths publicly available from [30]. For contactless to contact-based fingerprint recognition, our proposed ContactlessMinuNet is used to extract the minutiae of contactless fingerprints while the fine-tuned ContactlessMinuNet is used to extract the minutiae of contact-based fingerprints. For contactless to contact-based fingerprint verification, we adopt the same protocol as [26] in the experiments. The matching between the first contact-based and the first contactless impressions for each finger is considered as genuine pairs, while the first contact-based impression of each finger is compared with the first contactless fingerprint of remaining fingers as imposter pairs. For PolyU Cross dataset, there are 200 genuine pairs and 39800 (200×199) imposter pairs. For Benchmark 2D/3D dataset, there are 1300 genuine pairs and 1,688,700 (1300×1299) imposter pairs. For our dataset, there are 100 genuine pairs and 9900 (100×99) imposter pairs. Fig. 12 compares the ROC curves of different minutiae extraction methods on three datasets. The comparisons of AUCs and EERs are shown in Table 5 . From the results, we can see that the accuracy of contactless to contact-based fingerprint verification is lower than contactless fingerprint verification, while the ROC curve of proposed ContactlessMinuNet is significantly higher than other methods. Table 5 illustrates that proposed ContactlessMinuNet achieves 7.72%, 8.68% and 7.24% decrease in EER for three datasets, respectively, comparing with Verifinger. The results prove the effectiveness for our proposed method.Fig. 12 ROC curves of different minutiae extraction methods on contactless to contact-based fingerprint verification with (a) PolyU Cross dataset, (b) Benchmark 2D/3D dataset and (c) our dataset. Fig. 12 Table 5 AUCs and EERs of different minutiae extraction methods on contactless to contact-based fingerprint verification with three datasets. Table 5Dataset Method AUC(%) EER(%) PolyU Cross dataset ContactlessMinuNet 90.91 14.60 Verifinger 84.78 22.32 NIST mindtct 57.58 43.62 MinutiaeNet 50.78 50.00 Benchmark 2D/3D dataset ContactlessMinuNet 93.90 11.64 Verifinger 86.43 20.32 NIST mindtct 77.69 28.26 MinutiaeNet 56.23 45.87 Our dataset ContactlessMinuNet 88.28 17.52 Verifinger 81.07 24.76 NIST mindtct 56.71 48.96 MinutiaeNet 62.80 39.53 For contactless to contact-based fingerprint identification, we set the first contact-based impression of each finger as the template fingerprint, while the first contactless impression of each finger as the query fingerprint. CMC curves of different minutiae extraction methods are compared with three datasets in Fig. 13 . From these results, we can see that our proposed method can achieve impressive and consistent improvements than other methods for all three datasets. The rank-one accuracies increase from 45.50%, 47.32%, 35.04% by Verifinger to 65.05%, 54.61%, 63.08% by our proposed method on PolyU Cross dataset, Benchmark 2D/3D dataset and our dataset, respectively.Fig. 13 CMC curves of different minutiae extraction methods on contactless to contact-based fingerprint identification with (a) PolyU Cross dataset, (b) Benchmark 2D/3D dataset and (c) our dataset. Fig. 13 3.6 Discussion In the above sections, we have made the comprehensive comparison of our proposed method with three state-of-the-art fingerprint minutiae extraction methods in terms of both minutiae extraction accuracy and fingerprint recognition performances. Our results for contactless fingerprint minutiae detection indicates that the proposed ContactlessMinuNet has achieved better performances than other methods. Recently, a deep neural network-based approach called as ContactlessNet [7] was proposed for contactless fingerprint minutiae extraction. Since their source codes or trained model are not released and it is not easy to implement the method, we directly use the results reported in the paper for comparison as shown in Table 6 . The ContactlessNet [7] was tested on the Benchmark 2D/3D dataset, PolyU Contactless Fingerprint dataset and another dataset acquired during their work for experiments. The Benchmark 2D/3D dataset is same as our test dataset, but the other two datasets are not released for download. Thus, we compare the results of precision, recall, F1 score, AUC, EER and rank-1 accuracy on the Benchmark 2D/3D dataset in Table 6. It is worthy to note that the criterion to calculate precision and recall in [7] is looser than that in our experiments. The predicted minutia is considered to be accurate if its distance error to ground truth minutia is less than 16 pixels in [7] while it is less than 12 pixels in our results. Nevertheless, our results are better than those in [7].Table 6 Comparison of our proposed ContactlessMinuNet with the ContactlessNet [7] on the Benchmark 2D/3D contactless fingerprint dataset. Table 6Method Precision (%) Recall (%) F1 score (%) AUC (%) EER (%) Rank-1 accuracy(%) Our Proposal 79.16 80.94 80.04 98.24 4.28 89.60 ContactlessNet 74.10 69.10 71.00 74.39 31.82 49.86 In addition to the accuracy, the generalization is also important for the deep network. To demonstrate the generalization ability of our proposed method, we perform the fingerprint verification experiments using open-set protocol. Specifically, we directly use the model trained with Benchmark 2D/3D dataset without fine-tuning to predict the minutiae on other two datasets, i.e., PolyU Cross dataset and our dataset. The training and testing datasets are not overlapped. Fig. 14 shows the ROC curves of different models trained with and without fine-tuning processes, and the corresponding AUCs and EERs are compared in Table 7 . From the results, we can see that the recognition performances are reduced about 2.5-4.5% with the open-set protocol because of the different data distribution between the training and test datasets. Nevertheless, the results still show the good matching performances, which proves the generalization ability of the proposed method. The performances could be further improved by fine-tuning.Fig. 14 Comparison of ROC curves by the proposed method with open-set protocol and fine-tuning on PolyU Cross dataset and our dataset. Fig. 14 Table 7 Comparison of AUCs and EERs by the proposed methods with open-set protocol and fine-tuning on PolyU Cross dataset and our dataset. Table 7Training dataset Test dataset AUC(%) EER(%) PolyU Cross dataset PolyU Cross dataset 99.33 1.94 Benchmark 2D/3D dataset PolyU Cross dataset 96.85 5.83 our dataset our dataset 97.47 5.15 Benchmark 2D/3D dataset our dataset 93.21 9.28 4 Conclusion In this paper, we have proposed a deep learning framework based on multi-task fully deep convolutional neural network for contactless fingerprint minutiae extraction. Different from the traditional two-stage minutiae extraction, the proposed method can jointly learn and predict the minutiae location and direction from the whole contactless fingerprints by multi-task learning. The proposed method can make use of features learned from the minutiae detection and direction computation tasks. In addition, attention mechanism and a new loss function are used to improve the prediction of minutiae direction. The proposed method operates directly on the gray scale contactless fingerprints without any image processing. We test the proposed method on three fingerprint datasets. Experimental results demonstrate that our proposed algorithm achieves better performances than other methods for minutiae extraction on both contactless and contact-based fingerprints. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Zhao Zhang is a master student in Department of Instrument Science and Engineering, School of EIEE, Shanghai Jiao Tong University, China. His research interests include fingerprint recognition, machine learning, and image processing. Shuxin Liu is an Associate Professor in College of Electrical Engineering, Shanghai DianJi University, China. He received Ph.D degree from East China Normal University, Shanghai, China in 2016. His research interests include fingerprint recognition, machine learning, and image processing. Manhua Liu is a Professor in the MoE Key Lab of Artificial Intelligence, Artificial Intelligence Institute, Shanghai Jiao Tong University, China. She received Ph.D degree from EEE, Nanyang Technological University, Singapore in 2008. Her research interests include fingerprint recognition, biometrics, pattern recognition, brain image analysis and machine learning and so forth. Acknowledgement This work was supported by National Natural Science Foundation of China (NSFC) under the grant (No.61773263,U19B2035), Natural Science Foundation of Shanghai (20ZR1426300), Shanghai Jiao Tong University Scientific and Technological Innovation Funds (2019QYB02), STCSM (No. 18DZ1112300), Shanghai Municipal Science and Technology Major Project（2021SHZDZX0102). ==== Refs References 1 Jain A. Hong L. Bolle R. On-line fingerprint verification IEEE Trans Pattern Anal Mach Intell 19 4 1997 302 314 2 Farina A. Kovacs-Vajna Z.M. Leone A. Fingerprint minutiae extraction from skeletonized binary images Pattern Recognit 32 5 1999 877 889 3 Nguyen D.-L. Cao K. Jain A.K. Robust minutiae extractor: integrating deep networks and fingerprint domain knowledge 2018 International Conference on Biometrics (ICB) 2018 IEEE 9 16 4 Dabouei A. Soleymani S. Dawson J. Nasrabadi N.M. Deep contactless fingerprint unwarping 2019 International Conference on Biometrics (ICB) 2019 IEEE 1 8 5 Yin X. Zhu Y. Hu J. Contactless fingerprint recognition based on global minutia topology and loose genetic algorithm IEEE Trans. Inf. Forensics Secur. 15 2019 28 41 6 Yin X. Hu J. Xu J. Contactless fingerprint enhancement via intrinsic Image Decomposition and Guided Image Filtering 2016 IEEE 11th Conference on Industrial Electronics and Applications (ICIEA) 2016 IEEE 144 149 7 Tan H. Kumar A. Towards more accurate contactless fingerprint minutiae extraction and pose-invariant matching IEEE Trans. Inf. Forensics Secur. 15 2020 3924 3937 8 Bansal R. Sehgal P. Bedi P. Effective morphological extraction of true fingerprint minutiae based on the hit or miss transform International Journal of Biometrics and Bioinformatics (IJBB) 4 2 2010 71 9 Sankaran A. Pandey P. Vatsa M. Singh R. On latent fingerprint minutiae extraction using stacked denoising sparse autoencoders IEEE International Joint Conference on Biometrics 2014 IEEE 1 7 10 Jiang L. Zhao T. Bai C. Yong A. Wu M. A Direct Fingerprint Minutiae Extraction Approach Based on Convolutional Neural Networks 2016 International Joint Conference on Neural Networks (IJCNN) 2016 IEEE 571 578 11 Tang Y. Gao F. Feng J. Liu Y. Fingernet: an unified deep network for fingerprint minutiae extraction 2017 IEEE International Joint Conference on Biometrics (IJCB) 2017 IEEE 108 116 12 Hong L. Wan Y. Jain A. Fingerprint image enhancement: algorithm and performance evaluation IEEE Trans Pattern Anal Mach Intell 20 8 1998 777 789 13 Darlow L.N. Rosman B. Fingerprint minutiae extraction using deep learning 2017 IEEE International Joint Conference on Biometrics (IJCB) 2017 IEEE 22 30 14 Lin C. Kumar A. A cnn-based framework for comparison of contactless to contact-based fingerprints IEEE Trans. Inf. Forensics Secur. 14 3 2018 662 676 15 C.I. Watson, M.D. Garris, E. Tabassi, C.L. Wilson, R.M. McCabe, S. Janet, K. Ko, User’s guide to nist biometric image software (nbis). 16 Neurotechnology verifinger sdk, https://www.neurotechnology.com/verifinger.html. 17 Newell A. Yang K. Deng J. Stacked hourglass networks for human pose estimation European conference on computer vision 2016 Springer 483 499 18 Shi W. Caballero J. Huszár F. Totz J. Aitken A.P. Bishop R. Rueckert D. Wang Z. Real-time single image and video super-resolution using an efficient sub-pixel convolutional Neural network Proceedings of the IEEE conference on computer vision and pattern recognition 2016 1874 1883 19 Fukui H. Hirakawa T. Yamashita T. Fujiyoshi H. Attention branch network: learning of attention mechanism for visual explanation Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition 2019 10705 10714 20 Lin T.-Y. Goyal P. Girshick R. He K. Dollár P. Focal loss for dense object detection Proceedings of the IEEE international conference on computer vision 2017 2980 2988 21 Zhou B. Han C. Liu Y. Guo T. Qin J. Fast minutiae extractor using neural network Pattern Recognit 103 2020 107273 22 He K. Zhang X. Ren S. Sun J. Delving deep into rectifiers: surpassing human-level performance on imagenet classification Proceedings of the IEEE international conference on computer vision 2015 1026 1034 23 D.P. Kingma, J. Ba, Adam: A method for stochastic optimization, ArXiv preprint arXiv:1412.6980. 24 V. Dumoulin, F. Visin, A guide to convolution arithmetic for deep learning, ArXiv preprint arXiv:1603.07285. 25 Lin C. Kumar A. Matching contactless and contact-based conventional fingerprint images for biometrics identification IEEE Trans. Image Process. 27 4 2018 2008 2021 29990285 26 Zhou W. Hu J. Petersen I. Wang S. Bennamoun M. A benchmark 3D fingerprint database 2014 11th International Conference on Fuzzy Systems and Knowledge Discovery (FSKD) 2014 IEEE 935 940 27 Cappelli R. Ferrara M. Maltoni D. Minutia cylinder-code: a new representation and matching technique for fingerprint recognition IEEE Trans Pattern Anal Mach Intell 32 12 2010 2128 2141 20975113 28 Maio D. Maltoni D. Cappelli R. Wayman J.L. Jain A.K. Fvc2002: Second Fingerprint Verification Competition Object recognition supported by user interaction for service robots, Vol. 3 2002 IEEE 811 814 29 Maio D. Maltoni D. Cappelli R. Wayman J.L. Jain A.K. Fvc2004: third fingerprint verification competition International conference on biometric authentication 2004 Springer 1 7 30 M. Kayaoglu, B. Topcu, U. Uludag, Standard fingerprint databases: Manual minutiae labeling and matcher performance analyses, ArXiv preprint arXiv:1305.1443.

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==== Front Am J Obstet Gynecol MFM Am J Obstet Gynecol MFM American Journal of Obstetrics & Gynecology Mfm 2589-9333 Elsevier Inc. S2589-9333(21)00073-2 10.1016/j.ajogmf.2021.100378 100378 Expert Review Pregnant and hungry: addressing food insecurity in pregnant women during the COVID-19 pandemic in the United States Dolin Cara D. MD, MPH 1⁎ Compher Charlene C. PhD, RD 2 Oh Jinhee K. MD 1 Durnwald Celeste P. MD 1 1 Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (Drs Dolin, Oh, and Durnwald) 2 Biobehavioral Health Sciences, University of Pennsylvania School of Nursing, Philadelphia, PA (Dr Compher) ⁎ Corresponding author: Cara D. Dolin, MD, MPH. 28 4 2021 7 2021 28 4 2021 3 4 100378100378 15 2 2021 7 4 2021 12 4 2021 © 2021 Elsevier Inc. All rights reserved. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Food insecurity is a major social determinant of health affecting more than 10% of Americans. Social determinants of health are increasingly recognized as a driving force of health inequities. It is well established that food insecurity leads to adverse health outcomes outside of pregnancy, such as obesity, hypertension, diabetes mellitus, and mental health problems. However, limited data exist about the impact of food insecurity during pregnancy on maternal and neonatal outcomes. Food insecurity and other social determinants of health are rarely addressed as part of routine obstetrical care. The COVID-19 pandemic has only exacerbated the crisis of food insecurity across the country, disproportionally affecting women and racial and ethnic minorities. Women's health providers should implement universal screening for maternal food insecurity and offer resources to women struggling to feed themselves and their families. Reducing maternal health inequities in the United States involves recognizing and addressing food insecurity, along with other social determinants of health, and advocating for public policies that support and protect all women's right to healthy food during pregnancy. Key words diet quality food security maternal nutrition pregnancy outcomes SARS-CoV-2 social determinants of health ==== Body pmcIntroduction Every 1 in 3 women seen for prenatal care this week could not afford to buy the food needed to support a healthy pregnancy.1 Food insecurity, a lack of consistent access to the nutritionally adequate and safe food needed for a healthy life, is a major public health problem in the United States.2 As an important social determinant of health, food insecurity is associated with poor health outcomes. However, it is often a neglected component of women's healthcare. Most obstetrical providers do not routinely screen for food insecurity, and because of social stigma, most women do not voluntarily disclose their struggles to feed themselves and their families. Over the past year, the COVID-19 pandemic has only exacerbated the crisis of food insecurity, bringing this public health issue front and center to medical professionals caring for women of reproductive age. Food insecurity in the United States In 2019, 10.5% of US households experienced food insecurity, with 4.1% reporting very low food security.1 This translates into over 35 million Americans living in a food-insecure household. Of those 35 million Americans, 9 million live with very low food security,1 meaning they had disrupted eating patterns and reduced food intake because of a lack of money or resources for food (Box 1). Women are disproportionately affected by food insecurity, with single mothers bearing the largest burden. In 2019, approximately one-third of single mothers surveyed reported food insecurity.1 This gender disparity is partially due to the fact that women are more likely to be poor, be employed in low-wage and part-time jobs, and take on unpaid labor, including caring for children, older family members, and housework.3 , 4 In addition, women are more likely to take on the role of feeding the family, which includes foregoing food themselves to prevent depriving their children of food.5 There exists a racial disparity in food security in the United States, with significantly higher rates of racial and ethnic minorities suffering from food insecurity.1 Black non-Hispanic households are 2.4 times more likely to report food insecurity than White households, whereas Hispanic households are twice as likely to report food insecurity.1 Women are vulnerable to food insecurity no matter where they live, with urban cities and rural communities alike affected.1 Women in rural parts of the country often have less education, fewer employment opportunities, and lower wages, putting them at risk of food insecurity.6 Although food insecurity varies geographically across the United States with higher rates in the South (11.2%) and lower rates in the Northeast (9.6%), women with food insecurity can be found in every town and city in America.1 These sobering statistics conceal the fact that most obstetrical providers are caring for women with food insecurity every day regardless of their clinical practice location, further emphasizing the need for universal screening. Food insecurity is a social determinant of health Food security is a key social determinant of health. There is increasing recognition of the impact that these environmental and social exposures have on health outcomes and their contribution to health inequities. It is estimated that 50% to 60% of health status is driven by social determinants.7 Providing equitable care to all women involves accessing affordable, quality food to promote a healthy pregnancy. However, food insecurity often does not exist in isolation. Many intersecting social determinants of health, such as the built environment, neighborhood safety, transportation options, literacy, and exposure to discrimination and racism, contribute to food insecurity. For example, living in a neighborhood with lower perceived safety is associated with food insecurity in women.8 Furthermore, there are often competing interests for limited financial resources; paying rent and household utilities may be prioritized over buying food. Intertwined with the problem of food insecurity is the problem of food access, meaning the accessibility and affordability of food. Considerations of food access include the distance and time required to travel to buy food, the availability of healthy and fresh foods, and the price of food. There is significant racial inequity in the distribution of food in the United States.9 Access to local supermarkets is associated with increased intake of fruit and vegetables.10 In predominantly Black neighborhoods, the availability of supermarkets is only half that of White neighborhoods, whereas in predominantly Hispanic neighborhoods, it is even lower (32%).11 For many, the cost of transportation to obtain food can be prohibitive. Living in a food desert, an area with limited access to nutritious food, is associated with higher rates of obesity, diabetes mellitus, and cardiovascular disease in adults.12, 13, 14, 15 In pregnancy, living in a food desert is associated with pregnancy morbidity.16 Food swamps, areas saturated with convenience stores selling junk food and fast-food restaurants, overlie food deserts, creating the perfect storm.17 These areas, with a lack of access to healthy food choices and an abundance of access to cheap, unhealthy food, disproportionately predominate the landscape of low-income and minority communities.18 , 19 Without access to healthy food, individuals are more likely to consume inexpensive calorie-dense, highly processed foods with low nutrient value found in food swamps.17 Overall, this leads to a lower-quality diet and decreased nutrient intake. Adults with food insecurity consume fewer vegetables, fruits, and dairy compared with adults with food security.20 On a nutrient level, food insecurity has been shown to be associated with lower intake of calcium, magnesium, zinc, and vitamins A and B6 and higher intake of saturated fat.20 Studies looking specifically at women have found that diet quality is diminished in the setting of food insecurity.8 The impact of low-quality diet on pregnancy outcomes has yet to be fully elucidated. Food insecurity and health risks Food insecurity is associated with negative health outcomes in adults, including obesity, hypertension, diabetes mellitus, and mental health problems.21, 22, 23, 24, 25, 26, 27 In fact, food insecurity is more strongly associated with chronic disease than income.25 The underlying mechanisms linking food insecurity and chronic disease are hypothesized to include constrained food options and cyclic eating patterns leading to visceral adiposity and insulin resistance, severe stress contributing to dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic disturbance, and inflammation.28 Food insecurity can be a barrier to treatment strategies that rely on specific diets or healthy food choices, such as the treatment of diabetes mellitus, hypertension, hyperlipidemia, and obesity. Despite the fact that food insecurity is a major social determinant of health, there is a paucity of literature investigating the associations between maternal food insecurity and pregnancy outcomes. Moreover, existing studies are small and have conflicting findings (Table ). In fact, a recent study found that food insecurity during pregnancy is associated with lower gestational weight gain.29 However, previous work has found higher rates of prepregnancy obesity and gestational weight gain in women with food insecurity.32 The association between food insecurity and gestational diabetes mellitus is unclear.32 , 34, 35, 36 Women with food insecurity have higher rates of iron deficiency during pregnancy (31% vs 22%), but this finding was driven by differences in iron supplementation.30 Table Selected studies evaluating the effect of food insecurity in high-income countries on pregnancy outcomes TableStudy (author, year) Population and sample Key findings Tipton et al, 202016 Loyola University Medical Center in Chicago, IL (n=1001) Residing within a food desert associated with pregnancy morbidity (aOR, 1.64; 95% CI, 1.18–2.29; P<.004) Cheu et al, 202029 Northwestern Memorial Hospital in Chicago, IL (n=299) Food insecurity associated with lower median GWG (9.2 kg [IQR, 7.5–14.1] vs 13.9 kg [IQR, 10.6–16.7]; P<.001) Park and Eicher-Miller, 201430 National Health and Nutrition Examination Survey 1999–2010 (n=1045) Food insecurity associated with high odds of iron deficiency during pregnancy (aOR, 2.90; 95% CI, 1.29–6.51; P<.05) Tarasuk et al, 202031 Ontario, Canada (n=1998) Food insecurity during pregnancy was associated with postpartum mental health disorders (aRR, 1.86; 95% CI, 1.40–2.46) Laraia et al, 201032 University of North Carolina Hospitals (n=810) Food insecurity associated with prepregnancy obesity and higher GWG Hromi-Fiedler et al, 201133 Hartford, CT (n=135) Food insecurity associated with depressive symptoms during pregnancy among Latina women (aOR, 2.59; 95% CI, 1.03–6.52) aOR, adjusted odds ratio; aRR, adjusted risk ratio; CI, confidence interval; GWG, gestational weight gain; IQR, interquartile range. Dolin. Food insecurity during pregnancy. Am J Obstet Gynecol MFM 2021. Box 1 Definition of food security Box 1Food security High food security: no reported indication of food access problems or limitations. Marginal food security: 1 or 2 reported indications, typically of anxiety over food sufficiency or shortage of food in the house. Little or no indication of changes in diets or food intake. Food insecurity Low food security: reports of reduced quality, variety, or desirability of diet. Little or no indication of reduced food intake. Very low food security: reports of multiple indications of disrupted eating patterns and reduced food intake. Adapted from the Economic Research Service, US Department of Agriculture.2 Dolin. Food insecurity during pregnancy. Am J Obstet Gynecol MFM 2021. Notwithstanding the lack of pregnancy-specific literature, the link between food insecurity and chronic disease is well established.21, 22, 23, 24, 25, 26, 27 Many women enter pregnancy with comorbidities, including obesity, diabetes mellitus, and hypertension, known to increase the risk of adverse pregnancy outcomes, such as preeclampsia, fetal growth disturbance, preterm delivery, and stillbirth.37, 38, 39 Food insecurity during pregnancy likely contributes to the pathophysiology of complications associated with these chronic diseases. In addition, food insecurity is a barrier to diet therapy and weight management, both shown to have beneficial effects in the reduction of pregnancy-specific complications associated with these preexisting conditions.38 , 40, 41, 42 The chronic stress and subsequent adverse impact on mental health caused by food insecurity cannot be overlooked.26 Food insecurity is associated with over 2.5 times greater odds of depressive symptoms during pregnancy.33 Furthermore, more than a quarter of women with food insecurity during pregnancy report mental health disorders during the first 6 months after delivery compared with 14% of women with food security.31 Major depression and general anxiety disorder are reported twice as often in mothers with food insecurity compared with mothers with food security.43 Food insecurity affects the feeding choices of the newborn and infant, with potential implications for future obesity and disease risk.44 Women with food insecurity have reported concerns about breastmilk quality and supply because of poor diet and stress, leading them to supplement with or switch completely to formula.45 Pregnancy, and ideally preconception, is a time to address food concerns to promote a healthier mother-infant dyad throughout pregnancy and into the postpartum period. Food insecurity during the COVID-19 pandemic Since the beginning of 2020, the SARS-CoV-2 has spread throughout the United States and worldwide. This unprecedented pandemic has had a huge impact on unemployment, poverty, and access to healthy food with sweeping implications on food security in the United States. During the spring of 2020, the COVID-19 pandemic more than doubled the prevalence of food insecurity from 10.5% to 23% of all US households.46 It is projected that the number of Americans with food insecurity increased by 17 million during 2020.47 In those households with children, the prevalence of food insecurity tripled to 30%.46 This significant increase in food insecurity has disproportionally affected people of color. In households with children, a staggering 41% of Black and 36% of Hispanic households reported food insecurity during the COVID-19 pandemic.46 With schools closed because of concern for transmission of COVID-19, many of the millions of low-income children who normally benefit from school feeding programs now need to be fed at home.48 , 49 Although the government authorized measures to attempt to ensure continued delivery of food to children early in the pandemic, a decentralized and fragmented system at the state and local level left many children without access to healthy food.48 , 49 Studies have shown that when food resources are scarce, women prioritize feeding their children over feeding themselves.5 , 20 Mitigation strategies against the spread of COVID-19, including social distancing, quarantine, and community lockdowns, led to limited access to healthy food, consumption of a low-quality diet, and decreased physical activity.50 Before the pandemic, food procurement by those with food insecurity required more planning and coordination, shopping at multiple stores to find the lowest prices, using coupons, and planning meals to make the budget stretch. The addition of these necessary COVID-19 mitigation strategies has only further exacerbated this disparity in food access. Furthermore, the pandemic disrupted the normal food supply chain, globally leading to a dramatic increase in food cost. In 2020, food prices in the United States increased 3.4%, much higher than in previous years.51 Food insecurity may increase a pregnant woman's risk of contracting COVID-19. Long waits at now crowded food pantries increase the risk of exposure to COVID-19. Those with food insecurity are often forced to obtain their food in person, potentially exposing themselves to COVID-19, whereas those who enjoy food security and a higher income can remain at home and obtain healthy food through contactless delivery. Although the US Department of Agriculture is piloting a Supplement Nutrition Assistance Program (SNAP) online purchasing program, it is not yet available in all states and restricts online purchasing to only a few retailers, limiting healthy food choices. Women are currently not able to use the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) benefits for online purchases and must shop in person, creating additional opportunities for exposure to COVID-19. A call to action Food insecurity does not occur in isolation from other social determinants of health, including housing security, economic stability, neighborhood environment, literacy, discrimination, and racism.52 We, as healthcare providers, need to have a better understanding not only of food insecurity but also of how all social determinants of health contribute to disparities in maternal and child outcomes so we can establish an equitable healthcare delivery system. We advocate for the implementation of universal food insecurity screening of pregnant women. This recommendation is in line with the American College of Obstetricians and Gynecologist's suggestion that women's health providers screen patients for social determinants of health, including food insecurity.52 Screening should occur at least once during pregnancy and again during the postpartum period. A brief, validated, 2-item food insecurity screening tool, the Hunger Vital Sign, can be used (Box 2 ).53 This 2-item screen for food insecurity has 97% sensitivity, allowing providers to quickly identify almost all individuals at risk of food insecurity.53 , 54 Box 2 The Hunger Vital Sign: Food security screening questions Box 21. Within the past 12 months, you worried that your food would run out before you got money to buy more? 2. Within the past 12 months, the food you bought just did not last and you did not have money to get more? Answer: Never true, sometimes true, often true, patient declined. A positive screen is an answer of “often true” or “sometimes true” (vs “never true”) to either or both statements. Adapted from Hager et al.53 Dolin. Food insecurity during pregnancy. Am J Obstet Gynecol MFM 2021. A universal approach should be taken because food insecurity is associated with social stigma and most individuals will not disclose food insecurity unless asked directly. That being said, patients appreciate it when providers screen for food insecurity.55 Screening can be completed through paper survey, touchscreen pads in the office, previsit electronic survey, or in-person interview. Many electronic medical records already have the ability to integrate the brief 2-item food insecurity screening tool into clinical practice. Some women may feel more comfortable answering questions privately through a self-administered survey rather than face to face. If screening questions are asked verbally, care should be taken to screen women privately and not in the presence of children or other support persons. Food insecurity can be a difficult topic for providers to discuss. When asking screening questions, providers may start with: “As part of caring for the whole person, we ask everyone questions about food availability.” If feasible, administration of the full 18-item (10-item if no children in the house) US Household Food Security Survey can be considered (Appendix). Although longer and requiring additional administrative effort to administer in the clinical setting, this survey allows for the assessment of the severity of food insecurity and addresses more in-depth aspects of food insecurity. Women who screen positive for food insecurity should be offered referrals and connected to community-based resources. We recommend identifying an office social worker or other designated individual that can review the women's specific needs and provide information about local resources, including food banks and pantries. Women who are eligible for SNAP and WIC should be enrolled, if not already. Furthermore, one-third of women covered by Medicaid and eligible for WIC do not receive benefits.56 Once food insecurity is identified, the International Classification of Diseases, Tenth Revision, Clinical Modification code Z59.4 (lack of adequate food and safe drinking water) can be applied. This allows information about food security to be collected systematically and tracked. Individual education about the components of a healthy diet during pregnancy may promote a higher-quality diet, even within constrained food resources.57 Unfortunately, many obstetricians are not equipped with the tools to effectively counsel women regarding diet. Despite the role of diet in the primary prevention of the most common diseases, only an average of 4 to 6 hours is devoted to nutrition education during the entire 4-year medical school curriculum.58 Most obstetrics and gynecology residency programs contain little to no formal nutrition education. Registered dietitians are highly qualified to provide this counseling to women; however, these services are often not covered by insurance or readily available to all clinical practices. For women with Internet access, online nutrition education resources can be recommended (Box 3 ).Box 3 Resources for pregnant women with food insecurity Box 3www.findhelp.org www.fns.usda.gov/wic www.wichealth.org www.wichealthblog.org www.myplate.gov/life-stages/pregnancy-and-breastfeeding Dolin. Food insecurity during pregnancy. Am J Obstet Gynecol MFM 2021. As women's health providers and authorities on pregnancy, we should advocate for the expansion of SNAP and WIC benefits to address the crisis of food insecurity, especially during the COVID-19 pandemic. Currently, the WIC benefits only provide $2.25 per week per person for fruits and vegetables, foods that are the cornerstone of a healthy and nutritious diet during pregnancy and lactation.59 During the COVID-19 pandemic, some local WIC centers have implemented remote visits, but many have not. Pandemic or not, we must advocate to limit barriers to obtaining benefits, such as multiple in-person visits to the WIC office to secure benefits. However, this is just the beginning to address the underlying social constructs that contribute to food insecurity. Access to healthy food is not a privilege but should be considered a basic human right.60, 61, 62 With this framework in mind, the problem of food insecurity in pregnancy can be addressed in terms of the need to respect, protect, and fulfill access to food as a human right.60 Respect a pregnant woman's right to acquire food, protect her right to access food, and fulfill her right to food through social and economic policy. Progressing a public health agenda to ensure food security in pregnancy requires government accountability, public participation and transparency, addressing inequity in food access, and using health outcomes research to create meaningful policy. Food security in pregnant women should not be about charity but rather creating an environment that allows all women to have the ability to nourish themselves with healthy food during pregnancy. Ensuring food security for women means addressing the larger underlying problems within our society, including ensuring coverage and access to healthcare, promoting economic security, and investing in infrastructure. Future research Despite the large-scale crisis of food insecurity in the United States, limited data exist about its prevalence in pregnant women and its impact on maternal and child health outcomes. There is a need to study the extent that pregnant women experience food insecurity in the United States and specifically how the COVID-19 pandemic has exacerbated this major public health challenge. By understanding the scope of the problem, we can begin to foster innovative approaches to help women have consistent access to healthy food during pregnancy. Conclusion The problem of food insecurity during pregnancy has been neglected by women's healthcare providers for far too long. The COVID-19 pandemic has brought this and other social determinants of health to the forefront. Reaching health equity for women in the United States begins with recognizing and addressing food insecurity, in addition to other social determinants that limit us as medical professionals from providing the best overall care to our patients. The increase in food insecurity for pregnant women during the COVID-19 pandemic has the potential to have long-standing downstream effects that will impact generations.63 We must take the time to fully understand the social constructs in which our patients live and the interplay of these factors on our ability to deliver effective and equitable healthcare. These are some of the first steps in the much-needed ongoing work to end health inequities in our communities. Our advocacy needs to be far reaching from the individual patient level to our healthcare systems and community resources and requires initiatives to improve public policy that protects individual's rights to basic needs, such as healthy food. Appendix Questions used in the U.S. Household Food Security Survey Module1. “We worried whether our food would run out before we got money to buy more.” Was that often, sometimes, or never true for you in the last 12 months? 2. “The food that we bought just did not last and we did not have money to get more.” Was that often, sometimes, or never true for you in the last 12 months? 3. “We couldn't afford to eat balanced meals.” Was that often, sometimes, or never true for you in the last 12 months? 4. In the last 12 months, did you or other adults in the household ever cut the size of your meals or skip meals because there wasn't enough money for food? (Yes/No) 5. (If yes to question 4) How often did this happen—almost every month, some months but not every month, or in only 1 or 2 months? 6. In the last 12 months, did you ever eat less than you felt you should because there wasn't enough money for food? (Yes/No) 7. In the last 12 months, were you ever hungry, but did not eat, because there wasn't enough money for food? (Yes/No) 8. In the last 12 months, did you lose weight because there wasn't enough money for food? (Yes/No) 9. In the last 12 months did you or other adults in your household ever not eat for a whole day because there wasn't enough money for food? (Yes/No) 10. (If yes to question 9) How often did this happen—almost every month, some months but not every month, or in only 1 or 2 months? (Questions 11-18 were asked only if the household included children age 0-17) 11. “We relied on only a few kinds of low-cost food to feed our children because we were running out of money to buy food.” Was that often, sometimes, or never true for you in the last 12 months? 12. “We couldn't feed our children a balanced meal, because we couldn't afford that.” Was that often, sometimes, or never true for you in the last 12 months? 13. “The children were not eating enough because we just couldn't afford enough food.” Was that often, sometimes, or never true for you in the last 12 months? 14. In the last 12 months, did you ever cut the size of any of the children's meals because there wasn't enough money for food? (Yes/No) 15. In the last 12 months, were the children ever hungry but you just couldn't afford more food? (Yes/No) 16. In the last 12 months, did any of the children ever skip a meal because there wasn't enough money for food? (Yes/No) 17. (If yes to question 16) How often did this happen—almost every month, some months but not every month, or in only 1 or 2 months? 18. In the last 12 months did any of the children ever not eat for a whole day because there wasn't enough money for food? (Yes/No) Appendix B Supplementary materials Image, application 1 The authors report no conflict of interest. Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajogmf.2021.100378. ==== Refs References 1 Coleman-Jensen A Rabbitt MP Gregory CA Singh A Household food security in the United States in 2019 2020 Economic Research Service, US Department of Agriculture Available at: https://www.ers.usda.gov/publications/pub-details/?pubid=99281 Accessed November 16, 2020 2 Economic Research Service, US Department of Agriculture Definitions of food security 2020 US Department of Agriculture Available at: https://www.ers.usda.gov/topics/food-nutrition-assistance/food-security-in-the-u-s/definitions-of-food-security/ Accessed November 16, 2020 3 Cukrowska-Torzewska E Matysiak A The motherhood wage penalty: a meta-analysis Soc Sci Res 88–9 2020 102416 4 Semega J Kollar M Creamer J Mohanty A Income and poverty in the United States: 2018 2020 US Census Bureau Available at: https://www.census.gov/content/dam/Census/library/publications/2019/demo/p60-266.pdf Accessed November 16, 2020 5 McIntyre L Glanville NT Raine KD Dayle JB Anderson B Battaglia N Do low-income lone mothers compromise their nutrition to feed their children? CMAJ 168 2003 686 691 12642423 6 Probst J Eberth JM Crouch E Structural urbanism contributes to poorer health outcomes for rural America Health Aff (Millwood) 38 2019 1976 1984 31794301 7 Marmot M Allen JJ Social determinants of health equity Am J Public Health 104 Suppl4 2014 S517 S519 25100411 8 Sanjeevi N Freeland-Graves J Hersh M Food insecurity, diet quality and body mass index of women participating in the Supplemental Nutrition Assistance Program: the role of intrapersonal, home environment, community and social factors Appetite 125 2018 109 117 29427689 9 Walker RE Keane CR Burke JG Disparities and access to healthy food in the United States: a review of food deserts literature Health Place 16 2010 876 884 20462784 10 Morland K Wing S Diez Roux A The contextual effect of the local food environment on residents’ diets: the atherosclerosis risk in communities study Am J Public Health 92 2002 1761 1767 12406805 11 Powell LM Slater S Mirtcheva D Bao Y Chaloupka FJ Food store availability and neighborhood characteristics in the United States Prev Med 44 2007 189 195 16997358 12 Kelli HM Kim JH Samman Tahhan A Living in food deserts and adverse cardiovascular outcomes in patients with cardiovascular disease J Am Heart Assoc 8 2019 e010694 13 Ahern M Brown C Dukas S A national study of the association between food environments and county-level health outcomes J Rural Health 27 2011 367 379 21967380 14 Testa A Jackson DB Food insecurity, food deserts, and waist-to-height ratio: variation by sex and race/ethnicity J Community Health 44 2019 444 450 30560310 15 Spence JC Cutumisu N Edwards J Raine KD Smoyer-Tomic K Relation between local food environments and obesity among adults BMC Public Health 9 2009 192 19538709 16 Tipton MJ Wagner SA Dixon A Westbay L Darji H Graziano S Association of living in a food desert with pregnancy morbidity Obstet Gynecol 136 2020 140 145 32541293 17 Cooksey-Stowers K Schwartz MB Brownell KD Food swamps predict obesity rates better than food deserts in the United States Int J Environ Res Public Health 14 2017 1366 29135909 18 Block JP Scribner RA DeSalvo KB Fast food, race/ethnicity, and income: a geographic analysis Am J Prev Med 27 2004 211 217 15450633 19 Powell LM Chaloupka FJ Bao Y The availability of fast-food and full-service restaurants in the United States: associations with neighborhood characteristics Am J Prev Med 33 Suppl4 2007 S240 S245 17884571 20 Hanson KL Connor LM Food insecurity and dietary quality in US adults and children: a systematic review Am J Clin Nutr 100 2014 684 692 24944059 21 Adams EJ Grummer-Strawn L Chavez G Food insecurity is associated with increased risk of obesity in California women J Nutr 133 2003 1070 1074 12672921 22 Hernandez DC Reesor LM Murillo R Food insecurity and adult overweight/obesity: gender and race/ethnic disparities Appetite 117 2017 373 378 28739148 23 Gundersen C Ziliak JP Food insecurity and health outcomes Health Aff (Millwood) 34 2015 1830 1839 26526240 24 Seligman HK Bindman AB Vittinghoff E Kanaya AM Kushel MB Food insecurity is associated with diabetes mellitus: results from the National Health Examination and Nutrition Examination Survey (NHANES) 1999-2002 J Gen Intern Med 22 2007 1018 1023 17436030 25 Gregory CA Coleman-Jensen A Food insecurity, chronic disease, and health among working-age adults US Department of Agriculture 2017 Available at: https://www.ers.usda.gov/webdocs/publications/84467/err-235.pdf Accessed November 16, 2020 26 Bruening M Dinour LM Chavez JBR Food insecurity and emotional health in the USA: a systematic narrative review of longitudinal research Public Health Nutr 20 2017 3200 3208 28903785 27 Seligman HK Laraia BA Kushel MB Food insecurity is associated with chronic disease among low-income NHANES participants J Nutr 140 2010 304 310 20032485 28 Laraia BA Food insecurity and chronic disease Adv Nutr 4 2013 203 212 23493536 29 Cheu LA Yee LM Kominiarek MA Food insecurity during pregnancy and gestational weight gain Am J Obstet Gynecol MFM 2 2020 100068 30 Park CY Eicher-Miller HA Iron deficiency is associated with food insecurity in pregnant females in the United States: National Health and Nutrition Examination Survey 1999-2010 J Acad Nutr Diet 114 2014 1967 1973 24953790 31 Tarasuk V Gundersen C Wang X Roth DE Urquia ML Maternal food insecurity is positively associated with postpartum mental disorders in Ontario, Canada J Nutr 150 2020 3033 3040 32856046 32 Laraia BA Siega-Riz AM Gundersen C Household food insecurity is associated with self-reported pregravid weight status, gestational weight gain, and pregnancy complications J Am Diet Assoc 110 2010 692 701 20430130 33 Hromi-Fiedler A Bermúdez-Millán A Segura-Pérez S Pérez-Escamilla R Household food insecurity is associated with depressive symptoms among low-income pregnant Latinas Matern Child Nutr 7 2011 421 430 20735732 34 Richards M Weigel M Li M Rosenberg M Ludema C Food insecurity, gestational weight gain and gestational diabetes in the National Children's Study, 2009-2014 J Public Health (Oxf) 2020 [Epub ahead of print] 35 Banner GC Weaver KN Rushovich T York SL Yee LM. Association between food deserts and gestational diabetes mellitus in a large metropolitan area Am J Perinatol 2020 [Epub ahead of print] 36 Fonge YN Jain VD Harrison C Brooks M Sciscione AC Examining the relationship between food environment and gestational diabetes Am J Obstet Gynecol MFM 2 2020 100204 37 ACOG Practice Bulletin no 156: obesity in pregnancy Obstet Gynecol 126 2015 e112 e126 26595582 38 American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics ACOG Practice Bulletin no. 201: pregestational diabetes mellitus Obstet Gynecol 132 2018 e228 e248 30461693 39 American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics ACOG Practice Bulletin no. 203: chronic hypertension in pregnancy Obstet Gynecol 133 2019 e26 e50 30575676 40 Hill-Briggs F Adler NE Berkowitz SA Social determinants of health and diabetes: a scientific review Diabetes Care 44 2020 258 279 33139407 41 Chia AR Chen LW Lai JS Maternal dietary patterns and birth outcomes: a systematic review and meta-analysis Adv Nutr 10 2019 685 695 31041446 42 Schoenaker DA Soedamah-Muthu SS Callaway LK Mishra GD Prepregnancy dietary patterns and risk of developing hypertensive disorders of pregnancy: results from the Australian Longitudinal Study on Women's Health Am J Clin Nutr 102 2015 94 101 26040639 43 Whitaker RC Phillips SM Orzol SM Food insecurity and the risks of depression and anxiety in mothers and behavior problems in their preschool-aged children Pediatrics 118 2006 e859 e868 16950971 44 Benjamin-Neelon SE Allen C Neelon B Household food security and infant adiposity Pediatrics 146 2020 e20193725 45 Gross RS Mendelsohn AL Gross MB Scheinmann R Messito MJ Randomized controlled trial of a primary care-based child obesity prevention intervention on infant feeding practices J Pediatr 174 2016 171–7.e2 46 Schanzenbach D Pitts A How much has food insecurity risen? Evidence from the Census Household Pulse Survey 2020 Institute for Policy Research Rapid Research Report Available at: https://www.ipr.northwestern.edu/documents/reports/ipr-rapid-research-reports-pulse-hh-data-10-june-2020.pdf Accessed November 16, 2020 47 Gundersen C Hake M Dewey A Engelhard E Food insecurity during COVID-19 Appl Econ Perspect Policy 2020 [Epub ahead of print] 48 Bauer KW Chriqui JF Andreyeva T A safety net unraveling: feeding young children during COVID-19 Am J Public Health 111 2021 116 120 33211589 49 Dunn CG Kenney E Fleischhacker SE Bleich SN Feeding low-income children during the Covid-19 pandemic N Engl J Med 382 2020 e40 32227759 50 Kluge HHP Wickramasinghe K Rippin HL Prevention and control of non-communicable diseases in the COVID-19 response Lancet 395 2020 1678 1680 32401713 51 Economic Research Service, US Department of Agriculture Food prices, expenditures & costs 2020 Available at: https://www.ers.usda.gov/topics/food-markets-prices/food-prices-expenditures-costs/ Accessed November 16, 2020 52 Committee on Health Care for Underserved Women ACOG Committee Opinion no. 729: importance of social determinants of health and cultural awareness in the delivery of reproductive health care Obstet Gynecol 131 2018 e43 e48 29266079 53 Hager ER Quigg AM Black MM Development and validity of a 2-item screen to identify families at risk for food insecurity Pediatrics 126 2010 e26 e32 20595453 54 Gundersen C Engelhard EE Crumbaugh AS Seligman HK Brief assessment of food insecurity accurately identifies high-risk US adults Public Health Nutr 20 2017 1367 1371 28215190 55 Kopparapu A Sketas G Swindle T Food insecurity in primary care: patient perception and preferences Fam Med 52 2020 202 205 32159831 56 Soneji S Beltrán-Sánchez H Association of Special Supplemental Nutrition Program for Women, Infants, and Children with preterm birth and infant mortality JAMA Netw Open 2 2019 e1916722 57 Holben DH Marshall MB Position of the Academy of Nutrition and Dietetics: food insecurity in the United States J Acad Nutr Diet 117 2017 1991 2002 29173349 58 Hark LA Deen D Position of the Academy of Nutrition and Dietetics: interprofessional education in nutrition as an essential component of medical education J Acad Nutr Diet 117 2017 1104 1113 28648264 59 Food and Nutrition Service, US Department of Agriculture. Special Supplemental Nutrition Program for Women, Infants, and Children (WIC): WIC benefits and services. 2013. Available at: https://www.fns.usda.gov/wic/wic-benefits-and-services. Accessed March 27, 2021. 60 Chilton M Rose D A rights-based approach to food insecurity in the United States Am J Public Health 99 2009 1203 1211 19443834 61 Barnidge EK Stenmark SH DeBor M Seligman HK The right to food: building upon “food is medicine Am J Prev Med 59 2020 611 614 32800425 62 Office of the High Commissioner for Human Rights, United Nations. Fact Sheet No. 34, the right to adequate food. 2010. Available at: www.ohchr.org/Documents/Publications/FactSheet34en.pdf. Accessed November 16, 2020. 63 Gluckman PD Hanson MA Cooper C Thornburg KL Effect of in utero and early-life conditions on adult health and disease N Engl J Med 359 2008 61 73 18596274

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==== Front Technol Forecast Soc Change Technol Forecast Soc Change Technological Forecasting and Social Change 0040-1625 0040-1625 Elsevier Inc. S0040-1625(21)00619-3 10.1016/j.techfore.2021.121186 121186 Article Introduction to the special issue on universities and social innovation Göransson Bo Senior research fellow a⁎ Donati Letizia Post-doctoral research fellow b Wigren-Kristoferson Caroline Professor c a Department of Business Administration, Lund University, Sweden b Department of Economics and Management, University of Florence, Italy c Department of Urban Studies, Malmö University, Sweden ⁎ Corresponding author. 5 9 2021 12 2021 5 9 2021 173 121186121186 © 2021 Elsevier Inc. All rights reserved. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcEven before the Covid-19 pandemic, the world was faced with a number of severe challenges, including growing social inequality and exclusion, poverty, forced migration, and climate changes. These challenges have been described as ‘wicked problems’ since they exhibit multidimensional and multifaceted properties and are characterised by high levels of complexity. Recent academic and political discourses have primarily emphasised state-led and market-driven solutions, or technological fixes, to solve social challenges. However, neither the rules of the market nor the intervention of the State has successfully addressed the adverse effects of these challenges (Aoyama and Parthasarathy, 2018). Furthermore, the shock caused by the spread of Covid-19 is likely to exacerbate further the negative effects of these unsolved issues in both the global North and the global South. In this context, social innovation has emerged as a potential means to tackle complex social problems. Indeed, for more than a decade, policymakers, practitioners, and researchers have set their hope on social innovation to drive social transformations towards a more sustainable world (Haxeltine et al., 2017). The concept of ‘social innovation’ is not easily defined; several definitions and applications exist, each emerging from different research areas. However, it is possible to identify several core elements of the concept which are shared by the literature in the field of social innovation. These elements include (i) the process dimension, (ii) the inclusion of civil society and third sector actors, (iii) a focus on social change, (iv) the creation of social values, and (v) the aim of meeting unsatisfied social needs (Edwards-Schachter and Wallace, 2017). Following the transformative approach to social innovation developed by Haxeltine et al. (2017), we argue that social innovation can be defined as a response to social challenges that entails changing relations based on alternative ways of knowing, doing, framing, and organising, which contribute to a sustainable society. In this special issue, we focus on the potential role that academia can play in work with social innovation. During the last several decades, universities have come a long way in the institutionalization process of the so-called third mission—the growing expectation that universities should contribute to economic development through entrepreneurship and innovation. This process has been coupled with an increasing establishment of support organizations such as technology transfer offices, science parks, and ‘incubators’ which are aimed at helping students and researchers commercialise their research. This is achieved by starting a venture, licensing, or patenting. The concept of the ‘Entrepreneurial University’, in which the boundaries between university and industry are expanded upon so as to include strong linkages in the knowledge creation process (Etzkowitz, 2003), started to be implemented across different countries following a triple helix approach (Cai and Etzkowitz, 2020). The triple helix approach emphasises the importance of commercial innovation and its requirements in terms of organisation and incentive structures. Furthermore, this approach focuses on marketable products, thereby pushing higher education institutes to prioritise the commercialisation of research results over more socially inclusive goals. Gidlund and Frankelius (2003) have called this preoccupation with commercial innovations over social, regulative, and organisational innovations the “technology trap”. On the one hand, it allows universities to achieve excellence in providing commercial technology to industry but, on the other hand, it hampers their ability to deliver innovations that are aimed directly at alleviating complex social problems and promoting inclusive development. According to McKelvey and Zaring (2018, p. 596), the above scenario creates the risk that “universities are becoming knowledge businesses instead of social institutions”. A consequence of this is that social entrepreneurship and social innovation are largely overlooked in the modern university context. Simply put, there is a lack of attention toward the potential role of universities in supporting social innovation initiatives (Benneworth and Cunha, 2015; McKelvey and Zaring, 2018). Indeed, research on social innovation has focused mainly on the role of firms, the government, and NGOs (Westley et al., 2017), while the role of the university is seldom explicitly addressed, either in the transition to sustainability (Grin et al., 2010) or with regards to transformation (Westley et al., 2011; Olsson et al., 2014; Avelino et al., 2019). Noteworthy exceptions to this trend can be found in recent contributions in the field of sustainability science (Hart et al., 2015, 2016). One explanation for this omission is based on the observation that academic institutions lack the organisational structure and culture to become agents of change and thereby address the severe challenges mentioned above (Hart et al., 2016). The reason for this is because academic institutions are ‘bottom heavy’ (Clark, 1998) and consist of loosely coupled institutions (Benneworth et al., 2017). Universities are traditionally organised in faculties that are grouped around academic disciplines and contain power structures that tend to hamper, rather than support, interdisciplinary collaboration in research, education, or ‘third mission’ activities. Furthermore, universities are generally geared towards providing education and conducting research instead of focusing on the co-creation of knowledge in interaction with society as part of its third mission activities (Trencher et al., 2014). We now ask: What does the future hold for universities as social institutions? In this special issue, we explore their actual and potential role as change agents for social innovation. We do this by examining the role of universities from a strategic perspective and by emphasising new ways of how universities can work with third mission activities. The six contributions that are included in this special issue collectively address how change is taking place on a strategic level and with regards to third mission activities. For a university to take on the role as change agent entails a decision made by the management team of the university, i.e., a top-down decision, and the result of bottom-up initiatives, when faculty members decide to set out new research avenues, for example, by involving new actors like NGOs and civil society. Moreover, to confront the severe challenges that the world faces, there is a need for collaboration between different actors—collaboration at the local and national level and international collaboration. This special issue illustrates how much the global North and the global South have in common regarding how the narrative of the ‘entrepreneurial university’ can be nuanced and how much universities can learn from each other. In the rest of this introduction to the special issue, we present an overview of the individual contributions and their implications for future research. 1 Rethinking the third mission If we are to transform universities into change agents for social innovation, then we need to rethink the third mission that universities are responsible for and the university's role as a social actor. Generally, universities ascribe to the narrative of the ‘entrepreneurial university’ instead of expanding on the concept towards the notion of a ‘systemic Developmental University’,1 defined as a university that embraces the task of democratising knowledge so as to contribute to the sustainable development of society (Arocena et al., 2017). Developmental universities possess the potential to span the complex boundaries that are often encountered when multifaceted problems are addressed (Hart et al., 2015). Universities contain an extraordinary breadth of knowledge in a range of social sciences, natural sciences, medical sciences, and engineering that is relevant to addressing complex problems, they also can generate new knowledge, tools, and practices. Three contributions to this special issue offer new insights into this area, as they emphasise how the third mission needs to be re-conceptualised. The first do this by adopting a historical perspective on the role of universities in complex and adaptive systems (CAS), the second by developing a comprehensive literature review of the state-of-the-art research on the role of universities in social innovation, and the third by presenting new empirical findings on universities in the global South. Ola Tjörnbo and Katharine McGowan's contribution explores how transformative social innovation can trigger social changes within CAS. The authors reveal the specific contributions that research and academic institutions have brought to the development and consolidation of such transformative social innovation. Their in-depth analysis of historical social innovations, including the creation of National Parks in the US and the development of the Internet, reveals that academics and researchers were pivotal in providing the knowledge necessary to destabilize dominant system paradigms and trigger social changes. Tjörnbo and McGowan identify five channels through which academics have disrupted social innovations. Researchers can (i) provide the initial discovery; (ii) identify threats and challenge prevailing narratives; (iii) support niches conceived as protected spaces to experiment with social innovation; (iv) sustain shadow networks of social innovators; and (v) leverage vertical networks to allow social innovations to access influential supporters. Their results suggest that universities that currently aim to contribute to social innovation should reinforce their core mission of knowledge production and dissemination, thereby superseding traditional models of knowledge transfer since these models are ill-equipped to deal with transformative social innovation. Changes in the way that the third mission is perceived and implemented are further explored in the contribution by Blaise Bayuo, Cristina Chaminade, and Bo Göransson. Based on a bibliometric survey of the literature on factors that drive social innovation activities at universities (and the organizational and institutional changes that are made to accommodate such activities), Bayuo, Chaminade, and Göransson found that expectations for universities to integrate social innovation into their core mission as a response to social problems are increasing. The number of research publications on issues related to universities and sustainability, where the third mission is a central theme, has grown steadily during the last decade. Their bibliometric survey reveals that the literature on university engagement in socially-orientated activities that are part of the university's third mission is conceptually well-developed, albeit with considerable gaps in the knowledge base relevant to this project. Whereas the rationales used by universities and higher education actors to engage in social innovation are relatively well covered in the literature, there exist only a small number of studies that address issues related to institutional change and incentive structures that are relevant to the ability of a university to engage in social innovation. An area that is even less researched is the impact that university engagement has on social innovation activities in research and outreach programs. This point is all the more severe since commercial innovations have a visible and direct impact in funding, the awarding of patents, and university rankings, while the impact of social innovation is often indirect and overlooked. With their study on social innovation in Southern countries, Rodrigo Arocena and Judith Sutz focus on the potential contribution that universities make to social innovation. They argue that advanced technology should be harnessed to foster inclusive and ‘frugal’ innovations—a process in which universities should be the main actors. It is recognized that innovation work in the context of scarcity conditions is challenging. The authors suggest that universities introduce social innovation traits in canonical research, build research dialogues between universities and public enterprises, foster quality research in weak research sectors, and promote knowledge and innovation for social inclusion. A lack of resources is often the mother of invention, which implies that the lessons learned in Latin America are applicable in other contexts too. 2 Emphasising new ways of working and organising One way for universities to approach their work on social innovation is to rethink their third mission activities. Community engagement strategies (Vargiu, 2014) are increasingly entering in universities’ agendas to expand the set of actors to partner with and to better focus on less commercial knowledge transfer projects. By engaging with local communities and civil society organizations, universities of both the Global North and South are trying to find new ways of organising to meet social innovation challenges. The last three articles in this special issue are specifically devoted to shed lights on emerging patterns of collaborations with more social and non-traditional actors. In doing this, universities are reconfiguring triple helix arrangements by learning to collaborate with NGOs and actively engaging in quadruple helix partnerships with government, business and civil society (Carayannis et al., 2019) to meet complex social challenges, and eventually working with informal enterprises following socially responsive models of engagement. Balaji Parthasarathy, Supriya Dey, and Pranjali Gupta examine how a university partnered with NGOs so as to meet the needs of visually impaired children in India. As mentioned above, innovation capabilities are constrained by the weaknesses of the institutional context in the global South. While the global North can rely on dynamic national innovation systems where the triple helix relationship between government, industry, and university promotes the innovation process, the global South is characterised by high transactions costs and institutional thinness. In this context, the State has only a limited capacity to efficiently design market policies and provide public goods, thereby decreasing the possibility of private firms developing products and services that satisfy the needs of the poorest segments of the population. The presence of these ‘institutional voids’ that are neither occupied by the market nor the State is mitigated by the active role played by NGOs and civil society organizations. They act as intermediaries who possess unique knowledge regarding the unsatisfied social needs of disadvantaged social groups. Referring to their case study, the authors argue that if universities and research institutes are to benefit social innovation dynamics, then they have to learn how to partner with NGOs. In the global South, the role of NGOs must be reconsidered. Even though the context is different in the global North, the challenges are similar— many societies currently struggle with learning how to cooperate with NGOs and civil society organizations. According to Marco Bellandi, Letizia Donati, and Alessandra Cataneothe participation of universities in social innovation initiatives should be understood under the framework of university community engagement, where partnering with local communities’ actors is at the core of universities’ strategies grounded in collaborative and participatory practices. To explore how universities engage in these types of collaboration, the authors examine three quadruple helix partnerships in Italy. In particular, Bellandi, Donati and Cataneodevelop and apply a conceptual framework which illustrates the governance process of social innovation when this is led by a wide set of different actors pertaining to the quadruple helix’ sectors. This contribution gives valuable insights on how social innovation can be managed by new actors’ constellations. The results show on the one hand that social innovation can be effectively managed by quadruple helix partnerships, in which universities perform crucial roles, such as mediating conflicts between partners and providing research skills; on the other hand that social innovation can be achieved through a collective effort mediated by the presence of a common nexus between the involved partners. Il-haam Petersen and Glenda Kruss argue that universities should be more inclusive concerning the partners that they collaborate with. These authors have studied how universities can engage in social innovation and act as change agents by collaborating with non-traditional partners, for example, in informal enterprises. On the one hand, this collaboration implies that institutional borders are crossed over and, on the other hand, that researchers have to align themselves with locally embedded institutions and cooperate with new actors. Using empirical data from a South African township, they identify four types of engagement models, distinguishing between dominant, traditional knowledge transfer models and emergent, socially responsive models. This study sheds light on the importance of the institutional context by focusing on how collective agency affects systemic social change. Their study is also a practical contribution because the typology that they present can be used to assess current practices and inform future strategies. 3 Conclusion: a new way of viewing society The arguably limited effect that both the State and the market have in addressing grand social challenges has increasingly attracted the attention of policymakers, practitioners, and researchers to the role that social innovations may play in this area. A growing interest in social innovation suggests a new way of viewing society. It is also an indication that a market-driven innovation system, by itself, cannot necessarily address complex social problems and issues of sustainability. This new perspective challenges the assumption of the triple helix model that government, industry, and the university are the sole actors in the innovation system. Instead, broader engagement of universities with new actors and new constellations of partnerships to enhance processes of transformative social innovation are called for. Recent work on the evolution of transformative social innovations (Westley et al., 2017) shows that what is currently considered to be ‘transformative’ is actually the result of numerous small-scale social changes that culminate in system change. These small-scale changes are defined as shifts in “the defining routines, resource and authority flows, or beliefs of the broader social system in which it is introduced” (Westley et al., 2016:12). In this special issue, we explore how one might purposefully set in motion these transformations and, in particular, investigate how universities can serve as engines for sustainability transformation through engagement in social innovations in different countries and institutional settings. The six contributions that are included in this special issue provide valuable answers to these timely questions, not only by opening new avenues for future research on this topic but also by revealing the mechanisms through which significant societal changes can be achieved. Top-down and bottom-up initiatives are equally necessary if change is to occur. Furthermore, partnering with the local community (including informal enterprises, NGOs, and civil society organizations) is crucial to developing new solutions and enhancing inclusion and well-being in different institutional settings. In this sense, the global South and the global North face similar challenges, which demand that universities step forward and collaborate with socially excluded groups and design new institutional strategies for social goals. The contributions included in this special issue also reveal that universities can co-create knowledge, expand their capabilities beyond their boundaries, and move from disciplinary to interdisciplinary solutions. However, it is also apparent that a lack of trust in the collaboration process, the thinness of the institutional context, and the absence of adequate economic resources might hamper the involvement of a university in social innovation. Possible solutions to this problem may be found in establishing specific spaces, such as ‘Living Labs’ and ‘Science Shops’, which might facilitate interaction and the building of reciprocal knowledge between universities and local communities. In more fragile economic and social contexts, a lack of resources may well initiate socially innovative actions in the search for new solutions. In fact, the search for new approaches is reinforced by a growing understanding of the extended role that universities play in advancing economic growth and social development. However, given the rapidly changing conditions and complex challenges that lie ahead, research that is focused on socially engaged universities in diverse countries can be characterised as still being in its infancy. The contributions that are included in this special issue constitute a step forward in this direction and should guide future researchers as they explore how universities can enhance their capacity to act as change agents for social innovation. 1 The concept of a ‘Developmental University’ and the barriers that hinder its deployment are discussed in more detail by Rodrigo Arocena and Judith Stutz's contribution to this special issue. ==== Refs References Aoyama Y. Parthasarathy B. When both the state and market fail: inclusive development and social innovation in India Area Dev. Policy 3 3 2018 330 348 Arocena R. Göransson B. Sutz J. Developmental Universities in Inclusive Innovation systems: Alternatives for Knowledge Democratisation in the Global South 2017 Palgrave Publishing Cham Avelino F. Wittmayer J.M. Pel B. Weaver P. Dumitru A. Haxeltine A. Kemp R. Jørgensen M. Bauler T. Ruijsink S. O’Riordan T. Transformative social innovation and (dis)empowerment Technol. Forecast. Soc. Change 145 2019 195 206 Benneworth P. Cunha J. Universities’ contributions to social innovation: reflections in theory and practice Eur. J. Innov. Manag. 18 4 2015 508—527 Benneworth P. Pinheiro R. Karlsen J. Strategic agency and institutional change: investigating the role of universities in regional innovation systems (RISs) Reg. Stud. 51 2 2017 235 248 Cai Y. Etzkowitz H. Theorizing the triple helix model: past, present, and future Triple Helix, 1 aop 2020 1 38 Carayannis E.G. Grigoroudis E. Stamati D. Valvi T. Social business model innovation: a quadruple/quintuple helix-based social innovation ecosystem IEEE Trans. Eng. Manag 2019 Clark B.R. Creating Entrepreneurial Universities: Organisational Pathways of Transformation. Issues in Higher Education 1998 Elsevier Science Regional New York Edwards-Schachter M. Wallace M. Shaken, but not stirred: sixty years of defining social innovation Technol. Forecasting Soc. Change 119 2017 64—79 Etzkowitz H. Research groups as ‘quasi-firms’: the invention of the entrepreneurial university Res. Policy 32 1 2003 109—121 Gidlund J. Frankelius P. Innovative processes. (In Swedish) Swedish government official reports, SOU 2003:90 Stockholm 2003 Grin J. Rotmans J. Schot J. Transitions to Sustainable Development: New Directions in the Study of Long Term Transformative Change 2010 Routledge New York Hart D. Bell K.P. Lindenfeld L. Jain S. Johnson T. Ranco D. McGill B. Strengthening the role of universities in addressing sustainability challenges: the Mitchell center for sustainability solutions as an institutional experiment Ecol. Soc. 20 2 2015 4 Hart D.D. Buizer J.L. Foley J.A. Gilbert L.E. Graumlich L.J. Kapuscinski A.R. Kramer J.G. Palmer M.A. Peart D.R. Silka L. Mobilising the power of higher education to tackle the grand challenge of sustainability: lessons from novel initiatives Elementa Sci. Anthropocene 4 2016 Haxeltine A. Avelino F. Wittmayer J.M. Kunze I. Longhurst N. Dumitru A. O'Riordan T. Conceptualising the role of social innovation in sustainability transformations Backhouse J. Genus A. Lorek S. Vadovics E. Wittmayer J. Social Innovation and Sustainable Consumption 2017 Routledge London (12—25) McKelvey M. Zaring O. Co-delivery of social innovations: exploring the university’s role in academic engagement with society Industry Innov. 25 6 2018 594—611 Olsson P. Galaz V. Boonstra J. Sustainability transformations: a resilience perspective Ecol. Soc. 19 1 2014 Trencher G. Bai X. Evans J. McCormick K. Yarime M. University partnerships for co-designing and co-producing urban sustainability Global Environ. Change 28 2014 153—165 Westley F. Olsson P. Folke C. Homer-Dixon T. Vredenburg H. Loorbach D. Thompson J. Nilsson M. Lambin E. Sendzimir J. Banerjee B. Galaz V. Van der Leeuw S. Tipping toward sustainability: emerging pathways of transformation AMBIO: J. Human Environ. 40 2011 762 780 Westley F.R. McGowan K.A. Antadze N. Blacklock J. Tjornbo O. How game changers catalysed, disrupted, and incentivised social innovation: three historical cases of nature conservation, assimilation, and women’s rights Ecol. Soc. 21 4 2016 Westley F. McGowan K. Tjörnbo O. The Evolution of Social Innovation. Building resilience Through Transitions 2017 Edward Elgar Cheltenham Vargiu A. Indicators for the evaluation of public engagement of higher education institutions J. Knowl. Economy 5 3 2014 562 584

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Technol Forecast Soc Change. 2021 Dec 5; 173:121186

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Technol Forecast Soc Change

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==== Front Technol Forecast Soc Change Technol Forecast Soc Change Technological Forecasting and Social Change 0040-1625 0040-1625 Elsevier Inc. S0040-1625(21)00619-3 10.1016/j.techfore.2021.121186 121186 Article Introduction to the special issue on universities and social innovation Göransson Bo Senior research fellow a⁎ Donati Letizia Post-doctoral research fellow b Wigren-Kristoferson Caroline Professor c a Department of Business Administration, Lund University, Sweden b Department of Economics and Management, University of Florence, Italy c Department of Urban Studies, Malmö University, Sweden ⁎ Corresponding author. 5 9 2021 12 2021 5 9 2021 173 121186121186 © 2021 Elsevier Inc. All rights reserved. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcEven before the Covid-19 pandemic, the world was faced with a number of severe challenges, including growing social inequality and exclusion, poverty, forced migration, and climate changes. These challenges have been described as ‘wicked problems’ since they exhibit multidimensional and multifaceted properties and are characterised by high levels of complexity. Recent academic and political discourses have primarily emphasised state-led and market-driven solutions, or technological fixes, to solve social challenges. However, neither the rules of the market nor the intervention of the State has successfully addressed the adverse effects of these challenges (Aoyama and Parthasarathy, 2018). Furthermore, the shock caused by the spread of Covid-19 is likely to exacerbate further the negative effects of these unsolved issues in both the global North and the global South. In this context, social innovation has emerged as a potential means to tackle complex social problems. Indeed, for more than a decade, policymakers, practitioners, and researchers have set their hope on social innovation to drive social transformations towards a more sustainable world (Haxeltine et al., 2017). The concept of ‘social innovation’ is not easily defined; several definitions and applications exist, each emerging from different research areas. However, it is possible to identify several core elements of the concept which are shared by the literature in the field of social innovation. These elements include (i) the process dimension, (ii) the inclusion of civil society and third sector actors, (iii) a focus on social change, (iv) the creation of social values, and (v) the aim of meeting unsatisfied social needs (Edwards-Schachter and Wallace, 2017). Following the transformative approach to social innovation developed by Haxeltine et al. (2017), we argue that social innovation can be defined as a response to social challenges that entails changing relations based on alternative ways of knowing, doing, framing, and organising, which contribute to a sustainable society. In this special issue, we focus on the potential role that academia can play in work with social innovation. During the last several decades, universities have come a long way in the institutionalization process of the so-called third mission—the growing expectation that universities should contribute to economic development through entrepreneurship and innovation. This process has been coupled with an increasing establishment of support organizations such as technology transfer offices, science parks, and ‘incubators’ which are aimed at helping students and researchers commercialise their research. This is achieved by starting a venture, licensing, or patenting. The concept of the ‘Entrepreneurial University’, in which the boundaries between university and industry are expanded upon so as to include strong linkages in the knowledge creation process (Etzkowitz, 2003), started to be implemented across different countries following a triple helix approach (Cai and Etzkowitz, 2020). The triple helix approach emphasises the importance of commercial innovation and its requirements in terms of organisation and incentive structures. Furthermore, this approach focuses on marketable products, thereby pushing higher education institutes to prioritise the commercialisation of research results over more socially inclusive goals. Gidlund and Frankelius (2003) have called this preoccupation with commercial innovations over social, regulative, and organisational innovations the “technology trap”. On the one hand, it allows universities to achieve excellence in providing commercial technology to industry but, on the other hand, it hampers their ability to deliver innovations that are aimed directly at alleviating complex social problems and promoting inclusive development. According to McKelvey and Zaring (2018, p. 596), the above scenario creates the risk that “universities are becoming knowledge businesses instead of social institutions”. A consequence of this is that social entrepreneurship and social innovation are largely overlooked in the modern university context. Simply put, there is a lack of attention toward the potential role of universities in supporting social innovation initiatives (Benneworth and Cunha, 2015; McKelvey and Zaring, 2018). Indeed, research on social innovation has focused mainly on the role of firms, the government, and NGOs (Westley et al., 2017), while the role of the university is seldom explicitly addressed, either in the transition to sustainability (Grin et al., 2010) or with regards to transformation (Westley et al., 2011; Olsson et al., 2014; Avelino et al., 2019). Noteworthy exceptions to this trend can be found in recent contributions in the field of sustainability science (Hart et al., 2015, 2016). One explanation for this omission is based on the observation that academic institutions lack the organisational structure and culture to become agents of change and thereby address the severe challenges mentioned above (Hart et al., 2016). The reason for this is because academic institutions are ‘bottom heavy’ (Clark, 1998) and consist of loosely coupled institutions (Benneworth et al., 2017). Universities are traditionally organised in faculties that are grouped around academic disciplines and contain power structures that tend to hamper, rather than support, interdisciplinary collaboration in research, education, or ‘third mission’ activities. Furthermore, universities are generally geared towards providing education and conducting research instead of focusing on the co-creation of knowledge in interaction with society as part of its third mission activities (Trencher et al., 2014). We now ask: What does the future hold for universities as social institutions? In this special issue, we explore their actual and potential role as change agents for social innovation. We do this by examining the role of universities from a strategic perspective and by emphasising new ways of how universities can work with third mission activities. The six contributions that are included in this special issue collectively address how change is taking place on a strategic level and with regards to third mission activities. For a university to take on the role as change agent entails a decision made by the management team of the university, i.e., a top-down decision, and the result of bottom-up initiatives, when faculty members decide to set out new research avenues, for example, by involving new actors like NGOs and civil society. Moreover, to confront the severe challenges that the world faces, there is a need for collaboration between different actors—collaboration at the local and national level and international collaboration. This special issue illustrates how much the global North and the global South have in common regarding how the narrative of the ‘entrepreneurial university’ can be nuanced and how much universities can learn from each other. In the rest of this introduction to the special issue, we present an overview of the individual contributions and their implications for future research. 1 Rethinking the third mission If we are to transform universities into change agents for social innovation, then we need to rethink the third mission that universities are responsible for and the university's role as a social actor. Generally, universities ascribe to the narrative of the ‘entrepreneurial university’ instead of expanding on the concept towards the notion of a ‘systemic Developmental University’,1 defined as a university that embraces the task of democratising knowledge so as to contribute to the sustainable development of society (Arocena et al., 2017). Developmental universities possess the potential to span the complex boundaries that are often encountered when multifaceted problems are addressed (Hart et al., 2015). Universities contain an extraordinary breadth of knowledge in a range of social sciences, natural sciences, medical sciences, and engineering that is relevant to addressing complex problems, they also can generate new knowledge, tools, and practices. Three contributions to this special issue offer new insights into this area, as they emphasise how the third mission needs to be re-conceptualised. The first do this by adopting a historical perspective on the role of universities in complex and adaptive systems (CAS), the second by developing a comprehensive literature review of the state-of-the-art research on the role of universities in social innovation, and the third by presenting new empirical findings on universities in the global South. Ola Tjörnbo and Katharine McGowan's contribution explores how transformative social innovation can trigger social changes within CAS. The authors reveal the specific contributions that research and academic institutions have brought to the development and consolidation of such transformative social innovation. Their in-depth analysis of historical social innovations, including the creation of National Parks in the US and the development of the Internet, reveals that academics and researchers were pivotal in providing the knowledge necessary to destabilize dominant system paradigms and trigger social changes. Tjörnbo and McGowan identify five channels through which academics have disrupted social innovations. Researchers can (i) provide the initial discovery; (ii) identify threats and challenge prevailing narratives; (iii) support niches conceived as protected spaces to experiment with social innovation; (iv) sustain shadow networks of social innovators; and (v) leverage vertical networks to allow social innovations to access influential supporters. Their results suggest that universities that currently aim to contribute to social innovation should reinforce their core mission of knowledge production and dissemination, thereby superseding traditional models of knowledge transfer since these models are ill-equipped to deal with transformative social innovation. Changes in the way that the third mission is perceived and implemented are further explored in the contribution by Blaise Bayuo, Cristina Chaminade, and Bo Göransson. Based on a bibliometric survey of the literature on factors that drive social innovation activities at universities (and the organizational and institutional changes that are made to accommodate such activities), Bayuo, Chaminade, and Göransson found that expectations for universities to integrate social innovation into their core mission as a response to social problems are increasing. The number of research publications on issues related to universities and sustainability, where the third mission is a central theme, has grown steadily during the last decade. Their bibliometric survey reveals that the literature on university engagement in socially-orientated activities that are part of the university's third mission is conceptually well-developed, albeit with considerable gaps in the knowledge base relevant to this project. Whereas the rationales used by universities and higher education actors to engage in social innovation are relatively well covered in the literature, there exist only a small number of studies that address issues related to institutional change and incentive structures that are relevant to the ability of a university to engage in social innovation. An area that is even less researched is the impact that university engagement has on social innovation activities in research and outreach programs. This point is all the more severe since commercial innovations have a visible and direct impact in funding, the awarding of patents, and university rankings, while the impact of social innovation is often indirect and overlooked. With their study on social innovation in Southern countries, Rodrigo Arocena and Judith Sutz focus on the potential contribution that universities make to social innovation. They argue that advanced technology should be harnessed to foster inclusive and ‘frugal’ innovations—a process in which universities should be the main actors. It is recognized that innovation work in the context of scarcity conditions is challenging. The authors suggest that universities introduce social innovation traits in canonical research, build research dialogues between universities and public enterprises, foster quality research in weak research sectors, and promote knowledge and innovation for social inclusion. A lack of resources is often the mother of invention, which implies that the lessons learned in Latin America are applicable in other contexts too. 2 Emphasising new ways of working and organising One way for universities to approach their work on social innovation is to rethink their third mission activities. Community engagement strategies (Vargiu, 2014) are increasingly entering in universities’ agendas to expand the set of actors to partner with and to better focus on less commercial knowledge transfer projects. By engaging with local communities and civil society organizations, universities of both the Global North and South are trying to find new ways of organising to meet social innovation challenges. The last three articles in this special issue are specifically devoted to shed lights on emerging patterns of collaborations with more social and non-traditional actors. In doing this, universities are reconfiguring triple helix arrangements by learning to collaborate with NGOs and actively engaging in quadruple helix partnerships with government, business and civil society (Carayannis et al., 2019) to meet complex social challenges, and eventually working with informal enterprises following socially responsive models of engagement. Balaji Parthasarathy, Supriya Dey, and Pranjali Gupta examine how a university partnered with NGOs so as to meet the needs of visually impaired children in India. As mentioned above, innovation capabilities are constrained by the weaknesses of the institutional context in the global South. While the global North can rely on dynamic national innovation systems where the triple helix relationship between government, industry, and university promotes the innovation process, the global South is characterised by high transactions costs and institutional thinness. In this context, the State has only a limited capacity to efficiently design market policies and provide public goods, thereby decreasing the possibility of private firms developing products and services that satisfy the needs of the poorest segments of the population. The presence of these ‘institutional voids’ that are neither occupied by the market nor the State is mitigated by the active role played by NGOs and civil society organizations. They act as intermediaries who possess unique knowledge regarding the unsatisfied social needs of disadvantaged social groups. Referring to their case study, the authors argue that if universities and research institutes are to benefit social innovation dynamics, then they have to learn how to partner with NGOs. In the global South, the role of NGOs must be reconsidered. Even though the context is different in the global North, the challenges are similar— many societies currently struggle with learning how to cooperate with NGOs and civil society organizations. According to Marco Bellandi, Letizia Donati, and Alessandra Cataneothe participation of universities in social innovation initiatives should be understood under the framework of university community engagement, where partnering with local communities’ actors is at the core of universities’ strategies grounded in collaborative and participatory practices. To explore how universities engage in these types of collaboration, the authors examine three quadruple helix partnerships in Italy. In particular, Bellandi, Donati and Cataneodevelop and apply a conceptual framework which illustrates the governance process of social innovation when this is led by a wide set of different actors pertaining to the quadruple helix’ sectors. This contribution gives valuable insights on how social innovation can be managed by new actors’ constellations. The results show on the one hand that social innovation can be effectively managed by quadruple helix partnerships, in which universities perform crucial roles, such as mediating conflicts between partners and providing research skills; on the other hand that social innovation can be achieved through a collective effort mediated by the presence of a common nexus between the involved partners. Il-haam Petersen and Glenda Kruss argue that universities should be more inclusive concerning the partners that they collaborate with. These authors have studied how universities can engage in social innovation and act as change agents by collaborating with non-traditional partners, for example, in informal enterprises. On the one hand, this collaboration implies that institutional borders are crossed over and, on the other hand, that researchers have to align themselves with locally embedded institutions and cooperate with new actors. Using empirical data from a South African township, they identify four types of engagement models, distinguishing between dominant, traditional knowledge transfer models and emergent, socially responsive models. This study sheds light on the importance of the institutional context by focusing on how collective agency affects systemic social change. Their study is also a practical contribution because the typology that they present can be used to assess current practices and inform future strategies. 3 Conclusion: a new way of viewing society The arguably limited effect that both the State and the market have in addressing grand social challenges has increasingly attracted the attention of policymakers, practitioners, and researchers to the role that social innovations may play in this area. A growing interest in social innovation suggests a new way of viewing society. It is also an indication that a market-driven innovation system, by itself, cannot necessarily address complex social problems and issues of sustainability. This new perspective challenges the assumption of the triple helix model that government, industry, and the university are the sole actors in the innovation system. Instead, broader engagement of universities with new actors and new constellations of partnerships to enhance processes of transformative social innovation are called for. Recent work on the evolution of transformative social innovations (Westley et al., 2017) shows that what is currently considered to be ‘transformative’ is actually the result of numerous small-scale social changes that culminate in system change. These small-scale changes are defined as shifts in “the defining routines, resource and authority flows, or beliefs of the broader social system in which it is introduced” (Westley et al., 2016:12). In this special issue, we explore how one might purposefully set in motion these transformations and, in particular, investigate how universities can serve as engines for sustainability transformation through engagement in social innovations in different countries and institutional settings. The six contributions that are included in this special issue provide valuable answers to these timely questions, not only by opening new avenues for future research on this topic but also by revealing the mechanisms through which significant societal changes can be achieved. Top-down and bottom-up initiatives are equally necessary if change is to occur. Furthermore, partnering with the local community (including informal enterprises, NGOs, and civil society organizations) is crucial to developing new solutions and enhancing inclusion and well-being in different institutional settings. In this sense, the global South and the global North face similar challenges, which demand that universities step forward and collaborate with socially excluded groups and design new institutional strategies for social goals. The contributions included in this special issue also reveal that universities can co-create knowledge, expand their capabilities beyond their boundaries, and move from disciplinary to interdisciplinary solutions. However, it is also apparent that a lack of trust in the collaboration process, the thinness of the institutional context, and the absence of adequate economic resources might hamper the involvement of a university in social innovation. Possible solutions to this problem may be found in establishing specific spaces, such as ‘Living Labs’ and ‘Science Shops’, which might facilitate interaction and the building of reciprocal knowledge between universities and local communities. In more fragile economic and social contexts, a lack of resources may well initiate socially innovative actions in the search for new solutions. In fact, the search for new approaches is reinforced by a growing understanding of the extended role that universities play in advancing economic growth and social development. However, given the rapidly changing conditions and complex challenges that lie ahead, research that is focused on socially engaged universities in diverse countries can be characterised as still being in its infancy. The contributions that are included in this special issue constitute a step forward in this direction and should guide future researchers as they explore how universities can enhance their capacity to act as change agents for social innovation. 1 The concept of a ‘Developmental University’ and the barriers that hinder its deployment are discussed in more detail by Rodrigo Arocena and Judith Stutz's contribution to this special issue. ==== Refs References Aoyama Y. Parthasarathy B. When both the state and market fail: inclusive development and social innovation in India Area Dev. Policy 3 3 2018 330 348 Arocena R. Göransson B. Sutz J. Developmental Universities in Inclusive Innovation systems: Alternatives for Knowledge Democratisation in the Global South 2017 Palgrave Publishing Cham Avelino F. Wittmayer J.M. Pel B. Weaver P. Dumitru A. Haxeltine A. Kemp R. Jørgensen M. Bauler T. Ruijsink S. O’Riordan T. Transformative social innovation and (dis)empowerment Technol. Forecast. Soc. Change 145 2019 195 206 Benneworth P. Cunha J. Universities’ contributions to social innovation: reflections in theory and practice Eur. J. Innov. Manag. 18 4 2015 508—527 Benneworth P. Pinheiro R. Karlsen J. Strategic agency and institutional change: investigating the role of universities in regional innovation systems (RISs) Reg. Stud. 51 2 2017 235 248 Cai Y. Etzkowitz H. Theorizing the triple helix model: past, present, and future Triple Helix, 1 aop 2020 1 38 Carayannis E.G. Grigoroudis E. Stamati D. Valvi T. Social business model innovation: a quadruple/quintuple helix-based social innovation ecosystem IEEE Trans. Eng. Manag 2019 Clark B.R. Creating Entrepreneurial Universities: Organisational Pathways of Transformation. Issues in Higher Education 1998 Elsevier Science Regional New York Edwards-Schachter M. Wallace M. Shaken, but not stirred: sixty years of defining social innovation Technol. Forecasting Soc. Change 119 2017 64—79 Etzkowitz H. Research groups as ‘quasi-firms’: the invention of the entrepreneurial university Res. Policy 32 1 2003 109—121 Gidlund J. Frankelius P. Innovative processes. (In Swedish) Swedish government official reports, SOU 2003:90 Stockholm 2003 Grin J. Rotmans J. Schot J. Transitions to Sustainable Development: New Directions in the Study of Long Term Transformative Change 2010 Routledge New York Hart D. Bell K.P. Lindenfeld L. Jain S. Johnson T. Ranco D. McGill B. Strengthening the role of universities in addressing sustainability challenges: the Mitchell center for sustainability solutions as an institutional experiment Ecol. Soc. 20 2 2015 4 Hart D.D. Buizer J.L. Foley J.A. Gilbert L.E. Graumlich L.J. Kapuscinski A.R. Kramer J.G. Palmer M.A. Peart D.R. Silka L. Mobilising the power of higher education to tackle the grand challenge of sustainability: lessons from novel initiatives Elementa Sci. Anthropocene 4 2016 Haxeltine A. Avelino F. Wittmayer J.M. Kunze I. Longhurst N. Dumitru A. O'Riordan T. Conceptualising the role of social innovation in sustainability transformations Backhouse J. Genus A. Lorek S. Vadovics E. Wittmayer J. Social Innovation and Sustainable Consumption 2017 Routledge London (12—25) McKelvey M. Zaring O. Co-delivery of social innovations: exploring the university’s role in academic engagement with society Industry Innov. 25 6 2018 594—611 Olsson P. Galaz V. Boonstra J. Sustainability transformations: a resilience perspective Ecol. Soc. 19 1 2014 Trencher G. Bai X. Evans J. McCormick K. Yarime M. University partnerships for co-designing and co-producing urban sustainability Global Environ. Change 28 2014 153—165 Westley F. Olsson P. Folke C. Homer-Dixon T. Vredenburg H. Loorbach D. Thompson J. Nilsson M. Lambin E. Sendzimir J. Banerjee B. Galaz V. Van der Leeuw S. Tipping toward sustainability: emerging pathways of transformation AMBIO: J. Human Environ. 40 2011 762 780 Westley F.R. McGowan K.A. Antadze N. Blacklock J. Tjornbo O. How game changers catalysed, disrupted, and incentivised social innovation: three historical cases of nature conservation, assimilation, and women’s rights Ecol. Soc. 21 4 2016 Westley F. McGowan K. Tjörnbo O. The Evolution of Social Innovation. Building resilience Through Transitions 2017 Edward Elgar Cheltenham Vargiu A. Indicators for the evaluation of public engagement of higher education institutions J. Knowl. Economy 5 3 2014 562 584

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2022-12-16 23:25:06

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Thromb Res. 2021 Apr 20; 200:S35

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10.1016/S0049-3848(21)00208-5

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(22)01833-5 10.1016/S0140-6736(22)01833-5 Perspectives Biopower, racism, and yellow fever Mizelle Richard M Jr a Department of History, University of Houston, Houston, TX 77204-3003, USA 29 9 2022 1-7 October 2022 29 9 2022 400 10358 10961097 Olivarius Kathryn Necropolis: Disease, Power, and Capitalism in the Cotton Kingdom2022Belknap Press of Harvard University Press9780674241053 352US$35·00, £28·95© 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe COVID-19 pandemic has forced all of us to think anew about the power of disease and public health in our lives. The pandemic has influenced the world of politics and government, and reshaped regional built environments to accommodate the threat of disease. Historians of medicine are familiar with how the response to disease reveals a particular society's values and preferences—who it values and who can be disposed of. Achille Mbembe has called this “biopower”: who are considered worthy of protection and whose lives are considered expendable. Mbembe's theory of “necropolitics” illuminates how certain groups are deemed unworthy of protection or subject to sanctioned violence and elimination from society. Protection includes access to pharmacies and health-care services, information, resources, people, and goods that can shape one's life or lead to one's death. This framing of biopower can help us understand how some people are expected to die for the good and convenience of others. Disease is also, as environmental historian J R McNeill has written, about the power of non-human actors to shape our world, influencing wars, enslavement, and imperialism on a global scale. Although some historians argue McNeill's claims of yellow fever being the third actor in the Haitian Revolution (1791–1804) are overstated, armies have always had to fight both human enemies and the animals that transmit disease. Enter the Aedes aegypti mosquito, the insect vector that causes yellow fever and is the behind the scenes protagonist of Kathryn Olivarius's book, Necropolis: Disease, Power, and Capitalism in the Cotton Kingdom. This book is prescient for the questions it provokes about our experiences of COVID-19. As Olivarius points out: “Two centuries ago, humans took advantage of epidemics in ways that caused misery, enriched the few, and increased inequality. Today, we have sadly seen many similar patterns unfold.” Yellow Jack, as yellow fever was called, was intimately tied to the economic and political importance of cotton production in the American South and the rise of New Orleans as one of the most influential cities in the world by the 19th century. Yellow fever was known throughout the Atlantic World, with reoccurring epidemics in Charleston, Philadelphia, and other US port cities. Pinpointing the mosquito as the culprit of yellow fever did not occur until the late 19th century. Before this discovery, yellow fever was thought to stem from contagion of an unknown origin or miasma emanating from degraded spaces. The 1793 yellow fever epidemic in Philadelphia was thought by some, including physician and signer of the US Declaration of Independence, Benjamin Rush, to originate from rotten coffee grounds left in the port. Olivarius describes how understanding the cause of yellow fever was a contested process in this period. She also explores the impacts of the unique response to yellow fever in New Orleans: “Elites in New Orleans insisted that disease, like hurricanes or floods, was a problem with no solution. Profoundly uninterested in public health, politicians maintained that most tax revenue spent on quarantines, hospitals, garbage removal and sanitation was wasted…Instead, it was the individual's personal duty to get acclimated.” What separated New Orleans from other cities was the view that “acclimation” to yellow fever was necessary to become part of the ruling elite of the city—what Olivarius describes as “immunocapital”. Immunocapital is the “story of why so many unacclimated strangers died in nineteenth century New Orleans and how their collective deaths exacerbated inequality in an already violent and unequal slave society”, she writes. Long known as the “stranger's disease” due to misguided perceptions that only visitors and outsiders harboured yellow fever and brought it to New Orleans and other places, Olivarius takes a different approach in arguing that only the so-called acclimated were bestowed with vestiges of power in the form of local capital, networking opportunities, recognition from local credit houses and businesses, and status. In 19th-century New Orleans, only the acclimated were accepted by the power structure. To become acceptable, one had to stay in the city during the height of yellow fever season, become acclimated to prove your worth, or die trying. Yet, as Olivarius argues, the story created of the acclimated and unacclimated reified pre-existing ideas of biological difference and slavery that were foundational to an unequal slave society. Acclimated white people, particularly the ruling elite and those striving for power, argued their biological superiority over enslaved Black people, free people of colour, and poor white people. Leaning on the work of scholars of race and slavery, Olivarius describes how the enslaved and free Black people were considered immune to yellow fever—a racialised political argument specifically used to justify the continuation of slavery and subjugation of Black people. “Black people could possess immunity, but not immunocapital”, she writes. This view bolstered the inherent power structure of New Orleans that worked to keep Black slaves and free Black people in a position of perpetual forced labour and economic servitude. Olivarius highlights how Black people died from yellow fever yet the “system, simply, was already too entrenched to bend to the terrifying epidemiological reality”. Each chapter begins with a short vignette of a person confronted with the threat of yellow fever. Olivarius's style is novel-like in her ability to situate the reader along the notoriously stifling low-lying streets and damp levees precariously surrounding the city. The book takes you into the poor houses, hospitals, boarding houses, and homes of the elite and less privileged inhabitants as people stricken with yellow fever vomit, experience convulsions, and watch as their eyes and skin turn yellow. Others bled from the mouth and eyes, cursed out loud, and called out for living and deceased relatives before a painful death. But other inhabitants experienced few symptoms of yellow fever, and herein lies the conundrum of acclimation and non-acclimation that drives the book. People could never be completely sure they were truly acclimated to the disease; residents faced the difficult decision of whether they should risk staying in New Orleans during the fever season or flee. For white people, leaving the city meant risking their socioeconomic status and being branded a coward. Black enslaved people had no choice but to risk contracting yellow fever, and free people of colour's socioeconomic and political status would remain unchanged irrespective of their acclimation status. Olivarius vividly describes this 19th-century epidemiological roulette that some people won, and others did not. Necropolis shows how elite white people exploited disease in this uniquely unhealthy space for their own personal gain. The actions of New Orleans elites, and particularly their refusal to install quarantine protocols and formalise clean-up campaigns, had ramifications along the Mississippi River, and by consequence of their inaction, the broader Atlantic World through commerce. As people and goods moved in and out of New Orleans to other ports, the public health politics of allowing yellow fever to proliferate unchecked meant the disease could spread across borders. Olivarius could have done more to examine these events to explore a yellow fever diaspora emanating from New Orleans. Understandably, however, she keeps her focus close to New Orleans, and in doing so offers insights about disease capitalism. Necropolis plays out in ways that resonate with our current pandemic moment. One idea that stands out is what Olivarius calls climate gerrymandering. Local New Orleans elections were deliberately held during the height of fever season to bend results towards preferred candidates. Elections held in July, for instance, could help ensure that the non-acclimated, who might be predisposed to vote against the interests of the elite, were either too afraid to stay in the city, fearful of venturing into public to vote, or dead. Those who were acclimated and remained in the city were perhaps more likely to vote with the landed and powerful elite. “The system was exploitative, deadly, and self-perpetuating”, she writes. Olivarius's account of how yellow fever influenced local politics resonates for me with some aspects of 21st-century US elections. During the 2020 US election, COVID-19 was similarly on the ballot. While some public officials attempted to mitigate the potential impact of voting in the election by calling for increased access to mail-in ballots and more accessible and safer polling places, for instance, others hoped the impacts of COVID-19 might suppress “unwanted” voters from participating in the election. “COVID-19 pandemic amplifying voter disenfranchisement” was a headline of an October, 2020 ABC News piece. In that report Myrna Pérez, director of the voting rights and elections program at the Brennan Center for Justice, commented: “Disenfranchisement is baked in many ways into our system, but now COVID and the inequalities and dangers of COVID are hitting some communities harder.” And since 2020, some US states have proposed and passed laws to restrict voting hours, mail-in voting, and providing water for citizens waiting in long lines. Olivarius helps us to see that this is nothing new and has antecedents in 19th-century New Orleans. There has been much instructive scholarship about the history of yellow fever recently, notably Rana A Hogarth's Medicalizing Blackness: Making Racial Difference in the Atlantic World, 1780–1840 and Urmi Willoughby's Yellow Fever, Race, and Ecology in Nineteenth Century New Orleans. Hogarth describes how supposed ideas of innate immunity among Black people during yellow fever epidemics of the 18th and 19th centuries circulated in print throughout the Atlantic World and used a purported biological proof to further buttress slavery. Willoughby's work takes an environmental and ecological approach to yellow fever and the geographical place of New Orleans as a uniquely vulnerable landscape in the Atlantic World. Olivarius's new perspectives on yellow fever, immunocapitalism, and the politics of acclimation are a powerful addition to this important body of scholarship that will influence a generation of scholars to come on the intersections of racism, slavery, and public health. ==== Refs Further reading Croll L COVID-19 pandemic amplifying voter disenfranchisement. ABC News. Oct 7, 2020 https://abcnews.go.com/Health/covid-19-pandemic-amplifying-voter-disenfranchisement/story?id=73323400 (accessed Sept 20, 2022) Hogarth RA Medicalizing blackness: making racial difference in the Atlantic World, 1780–1840 2017 University of North Carolina Press Chapel Hill, NC Mbembe A Necropolitics 2019 Duke University Press Durham, NC McNeill JR Mosquito empires: ecology and war in the Greater Caribbean, 1620–1914 2010 Cambridge University Press Cambridge Willoughby U Yellow fever, race, and ecology in nineteenth century New Orleans 2017 Louisiana State University Press Baton Rouge, LA

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2022-12-16 23:25:06

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Lancet. 2022 Sep 29 1-7 October; 400(10358):1096-1097

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Lancet

10.1016/S0140-6736(22)01833-5

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==== Front Appl Geogr Appl Geogr Applied Geography (Sevenoaks, England) 0143-6228 0143-6228 Elsevier Ltd. S0143-6228(21)00176-4 10.1016/j.apgeog.2021.102560 102560 Article Promissory shock, broken future: COVID-19 and state-led speculations in biotechnology and pharmaceutical industries in South Korea Lim So Hyung Department of Geography, University of Wisconsin-Milwaukee, Milwaukee, WI, USA 15 10 2021 11 2021 15 10 2021 136 102560102560 13 12 2020 20 8 2021 4 9 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. This research examines institutional responses to shocking events, in this case, the COVID-19 pandemic and beyond. I argue that our analysis should consider state-led nationalism in finance and financialization especially when new modes of financial accumulation can be correlated with state projects of crisis management. Also, in dealing with shocking events, which are an inevitable aspect of capitalism, I claim nationalistic deregulations and speculation stimulated by institutional discourse can put ordinary people into permanently unpayable debt and reshape social exclusion. Drawing from interpretative policy analysis, I examine how early COVID-19 management by the Korean government took advantage of sloganeering of upper-K words, initiated by the Korean Wave, as discursive tools in invoking nationalistic sentiments. The instutional nationalism in the upper-case K as prefix is examined in promoting Korean biotechnology and pharmaceutical companies and their stocks. Further, I demonstrate how the accumulation strategies of this nationalistic COVID-19 management regarding bio and pharma industries were already practiced before COVID-19 in Korea, by the regulatory sandbox policy along with the Korean legitimation crisis. This set of practices has eventually accelerated the financialization of everyday life and Othering. I call for a critical lens to analyze the pressing agenda of discursive practices in institutional crisis responses. Keywords Crisis politics State financialization Nationalism Speculation COVID-19 Testing kits Stock market bubbles South Korea ==== Body pmc1 Introduction COVID-19 has stirred concerns about human rights and life and death over people, which are realms of the state (Agamben, 2021). However, statehood is framed by capitalism in which ‘shocking events’ tend to recur. Indeed, COVID-19 has shown that crisis management by the state can actually reveal several pre-existing crises. Exploring how shocking events accentuate or transmute pre-existing problems can be a way to understand what evolving COVID-19 measures and economies mean to us. When the state is leading financialization of a crisis, institutional actors can perform, mediate, and spectacular-ize security and emergency rhetoric both amid and beyond shocks. While being grounded on financial geographic discussions of the state, I claim that the discourse of financial capitalism has yet to be examined in the context of nationalistic financialization by the state. Here I introduce how the Korean government's surreptitious dealing with biotechnology and pharmaceutical firms during COVID-19 are aligned with ongoing operations and profits in those sectors, and how the Korean state's crisis management, which is allegedly creative and innovative, has been coupled with obscure opportunities offered to certain sections of finance capital. Based on the South Korean experience of financialization of pharmaceutical and biotech markets from 2017 to 2020 along with interpretative policy analysis from the early stages of the pandemic to mid-May 2020, I demonstrate how the South Korean state presented and legitimized itself as an competative and innovative civil service organization operating on behalf of the general public, while at the same time carrying out programs of deregulation and financialization for particular biotechnology and pharmaceutical companies. I consider the role of the South Korean state that promoted nationalism as well as financial deregulation and stock speculation. In doing so, I consider both the financialization of public institutions and financial regimes that are activated and supported by the state and their policies using nationalist language and discourses of vision and hype. I also show how this set of practices has eventually accelerated the financialization of everyday life and engendered individual bankruptcies and the exclusion of unfavorable social groups. By addressing the ethos of nationalism in financial regimes and its speculation effects, this research expands on the work of geographers who have shed light on the wider sociopolitical impacts and issues of statehood in finance and financialization. 2 State power in the making of nationalistic speculation Whereas the notion of financialization has a relatively longer trajectory in academia since the late 1980s, the term ‘state financialization,’ refers to the discourse, logics, instruments, and thereby accumulation in financial and monetary activities of the state (modified from Karwowski, 2019), has recently coined. At the beginning of financial geography as a school of a subdiscipline in the early 1980s (Knox-Hayes & Wójcik, 2020), the financialization of the state did not bring much attention or was pushed back on the priority list. Or, to put it more precisely, the state was ‘phantomized’ in the work of financial geographers who focused on monetary transformations at this time (Thrift & Leyshon, 1994). This is not surprising given that it was the era of heated debate of globalization and ‘the end of the nation state’, and money and finance were regarded as one of the most globalized forms of human activities. Up until the mid-2010s with a few exceptions, the tendency of geographical scholarship on financialization was divided into either firm and city levels with activity-centered approaches or international financial systems with the perspective of geographical political economy (Doucette, 2018). The role of the state in finance and financialization remained limited at best or was seen with taken-for-granted boundaries at worst. Yet, recently, the intellectual terrains of geography and the geopolitics of finance and money have been much widened to include the state. Market-friendly and expanding activities of the state led authorities and their policies to be increasingly dependent on financial indicators, services, and instruments. Particularly over the past five years or so, much light has been shed on the role of the state in financing housing, real estate, and urban built development (He et al., 2020; Feng et al., 2021; Lin et al., 2019), institutional products and services in banking, derivatives, and offshore (Lai & Daniels, 2015; Lagna, 2016), and social provisions and public services straightforwardly financed by the state (Dixon, 2020; Karwowski, 2019; Pan et al., 2021). In relation to contemporary international and/or global monetary systems, others have addressed how policy-making and other functions of the state can be situated in larger-scalar financial networks and flows (Töpfer, 2018, and related responses published in Dialogues in Human Geography; Hall, 2021; Johnson & Barnes, 2015). So the role of institutional agents in finance and financial geographies has been diversely explored, but how state institutions establish and stimulate financial rhetoric and regimes, as well as their operational and guiding logics, have not been directly examined and need to be further discussed (C·F., Dixon, 2020; Johnson & Barnes, 2015; Piroska, 2021). Additionally, bringing the matter of nationalistic speculation into financial discourse and practices has been overlooked, despite the fact that geographies of speculation have a long history since Harvey (1982) recognized speculation as a motive that finance capital is able to permeate through fictitious capitalism and create the spatio-temporal fix. By stimulating speculative markets, the state can identify new sources and support for businesses through investment money from a myriad of individual ‘Robinhoods.’ Unexplored, emerging modes of the speculation ethos should help shed light on the analysis of state-led financialization. Thus, I argue that we need more sensitivity to the state legitimization of financial accumulation projects and thereby speculations, including its decline and recurrence. Indeed, heterogeneous paths and mechanisms of institutional interests, motivations, and strategies beyond political agendas that organize populations in ways some flourish and others are left behind have been understudied in financialization studies (Van der Zwan, 2014). Financial knowledge, institutional interests, and policies as well as their inevitable financial outcomes—such as bankruptcies in real estate or stocks—are established and practiced through specific discursive projects. The creation and adoption of financialization logics by the state are not necessarily confined to the state's prioritization of profit maximization and shareholder value (Dixon, 2020). Instead, rhetoric and justification which does not directly seem to suggest finance, financialization, or investment exist in institutional stories and narratives in a mixture of language, texts, symbols, images along with channels such as advertisements and campaigns. Drawing this inquiry into analytical threads, I add the sociopolitical characteristics of nationalistic discourse and financial justification made by the state. First, following the intellectual capturing of nationalism from economic nationalism (Crane, 1998) to neoliberal nationalism (Harmes, 2012), including emerging research on financial nationalism (Johnson & Barnes, 2015; Piroska, 2021), a range of nationalistic discourse on financialization are able to be intertwined, be reformed and flow, and be sweeping in both theoretical conceptualization and empirical contextualization. Second, like logics in nation-building or economic development projects that sought nationalism as a significant indicator for economic growth and success, the advancement of economic wealth and property is regarded as the most crucial in the nationalistic discourse of financialization. Also, like other nationalistic or populist discourses, nationalistic discourse on finance and financialization can create and intensify social inclusion and exclusion, and inequality. Further, being guided by earlier findings on the crisis formulation of capitalist regimes that are “buying time (Streeck, 2014)”, nationalistic discourse on financialization can be a political device that delays, blurs, or suspends evaluation on—or opposition against—the government. Hence, this kind of institutional discourse can be functioned as ‘the state project of crisis management’ (He et al., 2020) in addition to a spatial fix of sociopolitical shocking events. Importantly, in this “buying” process and materialization under financialization, existing neoliberal policies and speculations can be (re)produced and mutated by the state authorities and its financial regimes. It is crucial to point out that the potential of this argument is by no means confined to rational designs and approaches on elites and financiers since institutional processes of financialization often lack coherence or uniformity even among policymakers in the same room at the same time as explained in Kripper (2011). Especially considering a lifetime of debt of ordinary people from speculation bubbles that eventually popped, examining how temporal discourse works as actual speculations and then as a perpetuator in the making of risk-taking investors and consumer interests is pivotal in exploring the discursive power of the state. Nationalistic representations and state-sponsored visions have a high possibility of cultivating sentiments of mass speculation and risk-taking. Hence, institutional narratives are able to normalize financial practices that turn individuals into investors and speculators, that become embedded in daily lives, and that intensify the inherently fragile nature of financialization of every day (Van der Zwan, 2014). By coinciding with state-led speculation with the focus on the government authorities that work as decision-makers and enforcers, regulators, and facilitators of financial rules and norms, this paper interrogates the permeation of financialization of everyday life. 3 Examining nationalistic visions and speculations by the South Korean state Financialization carried out by the South Korean state—that has been regarded as ‘developmental’ by many intellectuals—arises from the pertinacious demands of state accumulation projects in combination with exportism and neoliberalism (Jessop & Sum, 2006; Lim & Sziarto, 2020). Since independence, the Korean state has carried out many political-economic projects with family-owned conglomerates (chaebols) to gain rapid economic growth. Yet, since the 1997 Asian financial crisis and the global financial crisis in the 2000s, the South Korean economy has been transformed by finance-driven capitalism with an increasing proportion of leasing, real estate, and financial services such as stocks and credit (Jang, 2019). Also, the South Korean state has actively created bubbles in the stock and real estate markets by loosening consumer credit control (Choi, 2015). In looking for a link between state-led nationalism and speculation, I examine how the Korean state makes fictitious capital with promissory imaginaries of national interests and thereby personal prosperity on two interrelated economic projects: K-bio and the regulatory sandbox. First, this research looks at the Korean Wave as a resource and means for finance capitalism. The capital “K” has been traditionally placed in front of Korean products after the global recognition and success of K-pop, K-dramas, and K-movies (Joo, 2011). Under the circumstance of COVID-19, other groups of “K” words like “K-bio” and “K-quarantine” have been widely used in a variety of statements, handouts, and headlines by the Korean government, in order to further capitalize on the relative success of South Korea in containing the coronavirus and infection. Here, I define K-bio as South Korean biotechnology, bioengineering, pharmaceutical, and other industries that aim at exporting those bio- and pharma-related products and technologies. The term was not initiated by the pandemic. Korean bio and pharmaceutical firms had used words such as K-bio and K-pharma, but those words were not widely noticed among the Korean public, as K-bio showed little growth or clear decline in the stock market compared to other fields (Woo, 2019). Indeed, the bio and pharma industries by South Korean companies were not internationally recognized before the coronavirus pandemic. According to Scientific America, a well-known science magazine that has published worldwide rankings and statistics in biotechnology every year, the biotechnology sector in South Korea entered top 15 in world rankings in 2009 but had fallen to 26th among the top 54 countries examined during the period from 2009 to 2018 (Scientific American Custom Media, 2015, 2016, 2017, 2018). From the very beginning of the pandemic, however, the Korean government initiated and actively promoted use of the word K-bio with enormous public funding and exemptive, deregulatory favors. In this way, the sloganeering of the K-associated words has not just made South Koreans’ proud nor simply created another version of cultural nationalism; it has added speculation to biotech and pharmaceutical stock markets as I will show in the case study. Second, I address Korean nationalistic vision and consequential stock speculation by engaging with the process of financial deregulation in South Korea that has culminated via the ‘regulatory sandbox’. The regulatory sandbox, a financialization practice developed in the U.K. in 2016, is a ‘regulatory’ testing system that offers ‘innovative’ technology companies institutional aids in a controlled environment for up to five years. According to the U.K.’s Financial Conduct Authority, the goal of the regulatory sandbox is to offer businesses a “safe space” to test products and services with real consumers in a “safe environment” like a sandbox (Financial Conduct Authority, 2020a). It is not coincidental that this financial idea appeared at a time when the U.K. needed a spatio-temporal solution to the problems created by Brexit and European Union disinvestment in the U.K., given the importance of foreign direct investment from the EU to the U.K.’s financial service industries (Dhingra et al., 2016). Yet as the U.K.’s sandbox model transferred to the Moon Jae-in government in South Korea in 2019, this policy became an emerging opportunity of exception from governmental regulations with the sloganeering of “national economic growth to win global competition” by focusing on “scientific innovation” (from President Moon's speech, Moon, 2018, n.p.). Regardless of its rhetoric, what this mutated policy meant was nothing but relaxation; the Korean authorities—that are supposed to prevent and monitor fraudulent corporates via regulation—did not even conceal that the primary goal of the regulatory sandbox was overcoming regulatory restrictions by using campaign slogans such as “선허용후규제 (Licensing First, Regulation Later)” and “네거티브 규제 (Negative Regulation)” in advertising the regulatory sandbox (Ministry of Trade, Industry, and Energy, 2019). In this sense, the operational meaning in the Korean version of sandbox became contradictory to its title of ‘sandbox’, which is based on children's play space and implies ‘safety’ and ‘protections.’ Moreover, this policy has blurred the rules of regulation, and it has been actively involved with privatization and financialization. The regulatory sandbox initially implied the protection of both parties: companies and the wider public. Any testing in the regulatory sandbox had to be conducted on a small-scale basis. However, as it has functioned as a deregulation technique in Korea, its influences have been widened to every sphere of life as well as to the Korean and international political economies. Since the Moon administration started using this mechanism in 2019, the total number of authorized firms using it during the past three years is 7.5 times more than those being confirmed by the U.K. authorities where the regulatory sandbox was first employed (Regulation Information Portal, 2021; Financial Conduct Authority, 2019, Financial Conduct Authority, 2020b, Financial Conduct Authority, 2021). In South Korea, 476 companies have been authorized to use the regulatory sandbox from 2019 until May 2021, while there have been 64 authorized U.K. firms in the same period. Also, Korean bio and pharma companies, authorized and financialized by the regulatory sandbox, have caused speculations in bio and pharma stocks with the inevitable debts. To all outward appearances, K-bio and the regulatory sandbox imply positive ideas with a combination of ‘innovation’ and ‘creativity’. But both are heavily related to state-led financialization for crisis management. In terms of K-bio, nationalistic ideologies enabled the Moon government to maintain its legitimacy amid the urgent matter of COVID-19. Also, the exporting discourse that was explicitly promoted by the state was possible because other countries suddenly faced the COVID-19 crisis and had to absorb substantial amounts of pandemic products. The case of the regulatory sandbox can be understood within a crisis of and rationality legitimation in Korea in 2016. Neoliberal reform policies in public health in South Korea started since the 2000s (Lim & Sziarto, 2020), but it was in 2010 that the field of biotechnology emerged, when Samsung announced the bio industry as one of the most profitable areas (Song, 2014). Since then, every Korean government has implemented and intensified pro-business policies including deregulation, which particularly favored large bio and pharma companies including Samsung Biologics. However, the Moon administration was exceptional in offering preferential treatments for the Korean Big Pharma and Bio because the former President Park Geun-hye was outspoken in favoring Samsung and was jailed for bribery from Samsung along with corruption with other big enterprises (Constitutional Court of Korea, 2017). This led to a legitimacy crisis, so the Moon administration's official preference for deregulation had to proceed under the banner of fostering young and small-sized firms such as start-ups. As outlined in the sections below, the role of nationalism was stretched out from classic capitalistic regimes to a political tool to assuage nationwide struggle and opposition to the state by the shocks. Utilizing financialization methods, the Korean government has delayed not only institutional accountability to monitor financial markets but has also blurred people's reckoning and evaluation of the new office into an indefinite future. Further, this mode of nationalism has complicated a range of the capital accumulation projects by the state. Both were utilized by the state to evoke nationalistic support and speculations, and finally made political vulnerabilities such as Othering and bankruptcies. The interpretation into financialization behind the “K” theme and the regulatory sandbox in the realm of biomedical and pharmaceutical businesses in South Korea will be the center of two case sections. 4 Methods This paper critically examines the rapid pandemic response and emergency policy of the South Korean government, especially when many countries were suffering in the early stage of COVID-19. This response correlates with the 2016 legitimacy shock managed by the same Moon government through financialization of bio and pharma. For this, I employ an interpretative and contextual study design by demonstrating institutional processes and decision outcomes using assemblage thinking as the key methodology (Yanow, 2000; Baker & McGuirk, 2017) I examine an array of institutional documents and press outlets by multiple authorities of the Moon administration both right before and after COVID-19. Regarding Korean governmental documents, there have been two main health authorities to control the coronavirus outbreak in South Korea: The Korea Centers for Disease Control and Prevention (KCDC) and the Central Disease Control Headquarters (CDCH). I obtained all their documentation and records from January 20, 2020, to May 15, 2020, via official websites, where most of the data were publicly available. Documents included daily briefings, interviews, press conferences, urgent or short announcements, promotional posters, photographs, etc. (approximately 100 documents, adding up to about 400–500 pages). The first round of coding led me to identify the “K” themes as emerging in importance, such as K-bio, K-disinfection, and K-surveillance. I next filtered the data to include all texts and images including the nationalistic theme of K-bio. This selected data-set included 32 documents (still spanning all document types). Then, I examined texts and discourses to identify the meanings and their changes, by looking into multiple public figures and events related to the “K” discourse and bio and pharma stocks. In doing so, speeches of President Moon, press conferences, video clips, advertisements, and web posters and banners by other Korean institutions such as Cheongwadae (a.k.a., the Korean presidential residence), the Ministry of Foreign Affairs (MOFA), the Ministry of Health and Welfare (MOHW), the Ministry of Small and Medium-sized Enterprises and Startups (MSS), the Korea Customs Service, and the Korea Stock Exchange are used in interpreting the sloganeering of K-bio. Regarding the relationship between the regulatory sandbox and bio and pharma stocks in Korea before COVID-19, I used secondary data—both scholarly and popular—including statements from civil society groups for the interpretive analysis. Following this section, two empirical sections address the politics of COVID-19 shown in testing policies and advertisements in South Korea. The Korean government has advertised and celebrated certain aspects that it wanted to show, including the excellence and ingenuity of diagnostic kits developed by Korean firms. However, there have been several medical and political issues that the Korean government was hesitant to talk about or tried to hide from the public, which this paper aims to bring to light as the other side of nationalism. 5 “K-bio”: A state-sanctioned vision amid COVID-19 5.1 Corona reputations? One of the successful “K” stories in getting ahead of the COVID-19 curve was the Korean health authorities’ aggressive and early approach in developing working diagnostic kits and tests. From the very beginning, the Korea Centers for Disease Control and Prevention (KCDC) authorized the emergency use of four types of coronavirus testing kits from four companies, while many more kit firms were authorized later. KCDC ran about 15,000 to 25,000 tests per day (Ministry of Health and Welfare, 2020). In this way, KCDC offered the coronavirus test to over 520,000 people per million in about two months from the start of the coronavirus crisis. As of April 15, 2020, this represented the highest testing rate in the world (Ministry of Health and Welfare, 2020). It was around this time when the word “K-bio” dramatically emerged in Korea. The term K-bio became prominent in February especially through institutional outlets of public-private partnership (PPP) meetings related to coronavirus (Fig. 1 ). The fact that the government passed emergency use approval for the testing kit firms was known and represented as the main reason that South Korea mitigated the spread of COVID-19 in a relatively short period of time. These kinds of reports by both domestic and international news signified the very moment that the idea of a government-company partnership (i.e., PPP) was spurred in the middle of the crisis. On March 25, 2020, the Ministry of Small and Medium-sized Enterprises and Startups (MSS) announced that the government was thankful for K-bio developers and it would support and foster “K-testing kits” in terms of staffing, consulting, funding for R&D and exports, etc. (Ministry of Small and Medium-sized Enterprises and Startups, 2020b). According to its minister, Park Young-sun, this PPP was necessary “in order to utilize the K-decontamination image that is currently under the global spotlight” and “to add the image of the Korean Wave to Korean small and medium-sized firms in the present situation, considering that several Korean Waves such as BTS (South Korean band), Parasite (South Korean movie), etc. are setting the world on fire, so to speak (Ministry of Small and Medium-sized Enterprises and Startups, 2020a, n.p.).” She also highlighted that this partnership would contribute to making world-renowned diagnostic techniques and overcoming the COVID-19 crisis.Fig. 1 A meeting between President Moon Jae-in and test kit developers. Behind President Moon in the middle, the sign says “K-bio will be together with us for overcoming COVID-19”. (Source: Cho (2020), Copyright 2020 by SBS News). Fig. 1 What this series of episodes implies is that the South Korean government had emphasized blueprints and propaganda even at the very beginning stage of COVID-19, when these was still time to focus more on mitigating the pandemic and overcoming related crises. More importantly, the Korean state was keen to work with K-bio's exports (Fig. 2 ) and to circulate reports of profits from K-bio. Stocks of bio-related Korean companies started to skyrocket in the market from mid-February 2020, right after several international press outlets made reference to the Korean kits (Yang, 2020). At the same time, even far before the PPP announcement, the Korean government had aggressively advertised how Korean diagnostic kits were accurate and effective in detecting the COVID-19 virus and how South Korea got ahead of the rest of the world with these kits, referring to it as “corona diplomacy” (Cheongwadae, 2020). Up until May, progress reports and briefs on testing kit exports have regularly been released not by health authorities but by the Ministry of Foreign Affairs (MOFA) and the Korea Customs Service. It should be noted that these briefs were frequently released right before the stock market opens.Fig. 2 CEOs in a Korean testing kit company celebrating their kit exporting to the U.S. Federal Emergency Management Agency (FEMA) under the banner that appreciates the U.S. President Trump for allowing the export. (Photo source: Yonhap News Agency (2020), Copyright 2020 by Yonhap News Agency). Fig. 2 This debatable corona diplomacy conflicts with government claims to thoroughgoing ‘accuracy,’ ‘openness,’ and ‘transparency,’ which functioned as another set of logics to boost the national reputation. Government institutions have often covered how Korean test kits were being exported to other countries, which raises the profile of K-bio both domestically and overseas, shining up the image of both the Korean government and biotech firms. Further, several times media spectacles by the government came with ‘mistakes.’ As one example, a presidential spokesperson issued a brief in mid-March that MOFA exported K-diagnostic kits to the United Arab Emirates (UAE) with urgency, adding that the UAE expressed sincere appreciation to South Korea. From a bio firm, however, it turned out what was actually shipped was containers of cover kits, which are also known as collection kits, rather than the finished product (Park, 2020). The UAE already had its own reagents and testers and there was no need for them to import the full product. In another instance, MOFA on March 27 announced with fanfare that three out of the five types of Korean test kits had won approval for “emergency use” from the U.S. Food and Drug Administration (FDA) (Ministry of Foreign Affairs, 2020b), but it proved to be false. Once a few journalists exposed that the FDA did not approve any of the Korean kits, MOFA made a statement of correction (Ministry of Foreign Affairs, 2020c) that what was meant by the word emergency use was “provisional,” which counts as unofficial by the federal government of the U.S., not “preliminary.” Also, MOFA refused to reveal the names of the three companies that received the provisional use approval due to “the possible stock fluctuation of testing kit firms” (stated by a MOFA official who was interviewed by Yoon, 2020). But this nondisclosure made the five kits firms not only obscured but confused—none of them was informed of anything by the government. As of mid-April, the FDA had not authorized any of the made-in-Korea diagnostic kits, while thirty-three U.S. testing kits were granted emergency use authorization (Kim, 2020). There were many more occasions reported in which the government press was proven wrong, and the government glossed over the issues when the press or public health activists addressed non-transparency or identified incorrect facts, data, or quotes used in government announcements or press conferences (Kim, Y.-H., 2021). Methods to examine in what ways the misinformation by the government was produced are beyond the scope of this paper. The point here is that these gaffes and their pattern, and that of the information publicized, reveal a logic of nationalistic speculation. On a daily basis, the government authorities made announcements about the Korean state's transparency, openness, and speed, as well as its global reputation and competitiveness by stopping the spread of the coronavirus. But the information that the government has provided has been highly selective. Frequently missing from K-bio were the statistical accuracy of each testing kit made in Korea; names of the kit firms that have beenavailable; the amount of export and supply; and even the names of countries that received K-disinfection supplies. All of the non-transparency was justified with the excuse, “the diplomatic protocol” (Ministry of Foreign Affairs, 2020a; 2020c). Refusing to disclose the accuracy of the five testing kits hampers the enhancement and development of K-kits and the work of the medical industry. More importantly, for the majority of South Koreans who have suffered most from the pandemic—those most vulnerable to physical and mental illness, unemployment, domestic violence, to name a few—the promotion of “K-bio” and the ‘Moon-rocket’ in their stock rises might not be the most important issues. The government's domination over national media and efforts to make spectacles show how the COVID-19 spatulation can be employed and practiced by institutional efforts. 5.2 Doctors’ double-sacrifice for the nation During COVID-19, the world has seen heroic stories and images of medical workers, and so too has South Korea. Much appreciation was shown in hashtag campaigns, commentaries, images, and donations, and government officials including President Moon expressing gratitude to those doctors and nurses who work on the frontlines. But when the reputation of K-bio was challenged, the government slammed the hero (in)es as if they were to blame. On March 18, a 16-year-old teenager passed away with symptoms of the COVID-19 virus (headaches and pneumonia) after testing negative several times with one of the Korean kits. Right before his death, he was tested for COVID-19 eight times total, and the last DNA test on his body showed a possible positive test (Kwak, 2020), which implies the inaccuracy of the testing kit. This event led to a slugfest between the two major health authorities, i.e., KCDC and the Central Disease Control Headquarters (CDCH) versus the Yeungnam University Hospital where the patient had been hospitalized. The KCDC Director announced at a press briefing that “[w]e will not depend on the final outcome” and ordered the closure of the hospital raising the possibility of its contamination (Korea Centers for Disease Control and Prevention, 2020b). Further, KCDC ordered the hospital not to test the teenager's dead body or figure out if the cause of death was the coronavirus. The hospital and doctors nationwide expressed strong objection to using the word “contamination” for the hospital and condemned the health authorities' denial to know the truth. In many statements and press interviews, the health staff at the Yeungnam University Hospital objected that the government had denounced the sincere effort of hospital workers without any proof and that this would devastate the hospital and medical communities (Paik, 2020). As might have been expected, the hospital had to face many difficult phone calls from patients demanding refunds right after KCDC's announcement. There might be several reasons for the health authorities to deny an additional test, and to blame the death on sanitation conditions at the hospital. First, it was a month ahead of the April Parliamentary elections. The ruling party had seen popular support soar since the pandemic outbreak, so politicians might not have wanted to risk losing votes with the autopsy right before the election. Also, the high school student was out to purchase a mask, and started to have a headache, on the very same day; he died within seven days after showing symptoms. Revealed widely, this story of such a young person's rapid decline might add to the panic. But more importantly, if the testing kit was proven to be inaccurate, this would not only add to public panic but impact exports of K-testing kits and other COVID-19 tools. Also this death occurred just as news of the K-Bio's success stories raised awareness and stock prices of Korean bio industry and pharmaceutical companies were skyrocketing. In sum, the Korean government had to openly discuss the death, but wanted to control the narrative; blaming the hospital short-circuited wide public inquiry. This issue faded from public awareness without any clear-cut resolution. KCDC additionally announced that what was contaminated was the room where the patient was lodged, not the entire hospital (Korea Centers for Disease Control and Prevention, 2020c), but this announcement made the situation even more illogical and unsustainable. If this statement was correct, KCDC should have tested all of the hospital workers and closed the hospital for two weeks. But after this announcement, both KCDC and the hospital kept silent as if nothing had happened. As the April elections approached, the decrease in the daily number of newly confirmed cases enabled more self-promotion by the Korean government. At least, the number of new patients seemed to be dwindling, until several doctors posted comments on their social media regarding a change in the national guidelines for COVID-19 diagnostic testing. Until March 1, according to the 6th revised guidelines, “individuals with a medical opinion by a doctor” could receive the test for free (Korea Centers for Disease Control and Prevention, 2020b). This advisory was because a person can be asymptomatic but still carry the virus. However, as of March 2, under the 7th guidelines, KCDC changed the related clause to “individuals with a medical opinion by a doctor such as showing pneumonia for unknown reasons” (Korea Centers for Disease Control and Prevention, 2020a). Thus, if a person did not have pneumonia, but still wanted to get the COVID-19 test, s/he had to pay for it up front, which was approximately 130 dollars. What this change meant for doctors was a severe narrowing of the numbers of people eligible for free testing. In response, several doctors and physicians problematized the revision in their social media channels. The government then slammed the doctors as spreading “fake news” and dealt with them as conspiracy theorists. Several regulatory officers expressed strong discomfort with the doctors and warned penalties against invalid infodemics and allegations in the future (Korea Centers for Disease Control and Prevention, 2020d). Nonetheless, this statement revealed that the government can adjust a number of diagnostic tests and confirmed cases (i.e., confirmed cases dwindle in numbers if COVID-19 testing decreases), and that could be used to show the effectiveness of K-testing kits in selling them. 6 The regulatory sandbox: A state-sanctioned vision beyond COVID-19 6.1 Corona exceptions? The Korean state used “K-bio” propaganda, and this nationalistic promotion not only made the Korean bio and pharma products look good both hypothetically and in practice but also brought more profit. It is now easy to understand the extraordinary rise in prices of Korean testing tools during the first few months of the pandemic. According to the Korea Customs Service (2020), the estimated value of exportation for K-kits saw a large increase from about 3400 dollars as of January 2020 to 212 million dollars as of April 2020. This was “the highest gain in the shortest time in the history of K-Wave exports” (Koo Tae-min, an administrator in the Korea Customs Service, in an interview with a radio broadcast; TBS, 2020). Further, along with the promotions and advertisements, deregulation and other exceptions appeared in various ways. Prime Minister, Chung Sye-kyun, announced that it would initiate fund-raising activities for ‘K-bio New Development Funds VI’ and would grant bio industries 100 billion won (80 million US dollars) in order to facilitate K-bio's business abroad, as well as to make a “bio-economy” possible (Ministry of Health and Welfare, 2020, Office for Government Policy Coordination, 2020). The National Health Insurance Service (NHIS), which is a universal and mandatory health insurance in South Korea, announced it would invest in bio and pharma stocks using general insurance reserves (National Health Insurance Service, 2020a). Right after the COVID-19 outbreak, NHIS quickly deleted its regulation that the NHIS's assets must not be invested in high-risk instruments (ibid). In early April 2020, the NHIS made another announcement to select property and fund management companies that would help its investment in pharma and bio sectors (National Health Insurance Service, 2020a). In addition to making its own financial investments in K-bio, the government turned to deregulation in the form of privatization of regulation. The Moon administration authorized the Korea Chamber of Commerce and Industry (KCCI), the biggest private business organization in Korea, to run and monitor the regulatory sandbox (Shin, 2020). The government also used fast-track approval for related legislation amid the coronavirus outbreak and promoted this authority-sharing as ‘the world's first private sandbox’ (Ryu, 2020). The private sandbox system run by KCCI that is free from the supervision of state financial regulatory authorities was to focus on health care projects that have ‘innovative’ technologies and tech services. However, even after all of these efforts in merchandizing testing kits and developing COVID-19 vaccines ran by the government with taxes and public funding, there is no guarantee that the public will benefit from any of the profits made possible by these public properties. This is because bio and pharma companies will hold the patent licenses (Médecins Sans Frontières, 2020). Instead of transferring the patent profits into public property, what the Korean administration has done was vice versa: the government has been highly encouraging for applications for licensing. The Minister for Science, Technology and Innovation was transferring the technology and production of COVID-19 reagents that had been developed by governmental institutions into private bio firms ‘on a consignment basis’ (ibid). Speculative moments behind the South Korean government's aggressive protection and support of the bio and pharma industries are not easy to understand at a glance. The close-knit relationship between the state and businesses can be interpreted as being common interests of both the state and private sectors in enhancing their global positions or visibility. However, there must be a more specific state interest in the promotion of K-Bio and K-Pharma. In the next section, for a better understanding of nationalistic motivations and speculative effects from the government, I examine the recent relationship between the Korean state and bio industries that has centered on the stock market, as I find similar efforts and consequences by the government playing with bio industries even long before the COVID-19 pandemic. 6.2 Deregulations and stock bubbles before the COVID-19 shock From the beginning of his term, President Moon emphasized developing original and novel technology in bio industries, lowering barriers to entry of starting bio businesses, and the risk-return tradeoff (Moon, 2017). For the Moon administration “the future of biotechnology is the future of Korea,” as being hinted in its investment slogan of “D.N.A.+BIG3” (Data, Network, Artificial Intelligence, bio health, system semiconductors, and future cars) (Cheongwadae, 2019). This plan included pushing bio-related stocks on the Korea Securities Dealers Automated Quotation (KOSDAQ). By relaxing many rules and using deregulation such as the regulatory sandbox and its subclause that allowed firms to be named an ‘empirical regulatory exception’ (National IT Industry Promotion Agency, 2020), the Financial Services Commission, the government's financial regulator, granted ‘innovative’ bio and pharma firms an exception to be listed on KOSDAQ without governmental regulation or management. By taking advantage of the ‘deregulatory exception,’ seven of the top ten businesses became bio businesses by 2019. Bio and pharma stocks sharply rose as soon as Moon Jae-in started in office; his administration contributed to this rise through deregulatory policies under the banner of ‘innovativeness’ (사회진보연대, 2020). Whenever new or revised deregulatory policies were announced, not only bio stocks that would benefit from the policies but also bio-related subsidiaries of conglomerates like Samsung Biologics and Samsung Bioepis quickly soared (무상의료 운동본부, 2019). This bio bubble benefited at least those who purchased stocks and shares if blockbuster drugs were actually produced by these listed companies. However, the bio and pharma businesses that were included in the empirical regulatory exception policy made little progress in this effort. None of the companies listed in the stock market seemed to succeed in producing the promised ‘innovative’ technologies, as none of them has obtained authorization for their new medicine or technology production. Many of the emerging companies overstated their potential and future values to be enrolled in KOSDAQ, for none of them were selling actually existing treatments or products. Further, whenever clinical tests—especially human trials known as Phase III—failed to pass the final authorization by the FDA, the price of related Korean bio stocks and shares collapsed, and many firms were wiped out. As of January 2020, the companies listed on the Korea Stock Exchange (KRX) by the regulatory sandbox policy numbered 61; only six of them ran a surplus (Lee, 2020). From August 2019 to May 2020, only three of them succeeded in developing new medicines. More than six companies failed in Phase III either from the South Korea Ministry of Food and Drug Safety or the FDA, and announced they were giving up on clinical trials. The biggest issue of the bio and pharma stock boom was that it turned out to be a bubble and an enormous amount of money disappeared. More than 19 trillion won (i.e., 15.5 billion dollars) have been missing from investments to 73 bio and pharma firms authorized by the KRX during 2019 (사회진보연대, 2020).1 One would think such a loss would call for further investigation into the government and its financial regulation processes. There are several allegations that government Ministers and officials have been involved in wire fraud in bio and pharma stocks such as within the SillaJen scandal. SillaJen was a venture firm based on a few doctors developing a new cancer medicine. Once the company went public in KOSDAQ with help of the regulatory sandbox system, its stock skyrocketed and it ranked top in the KRX. Then its stock took a direct hit from the FDA's non-approval of the human trials, and the company's stock plunged; about 30,000 people took heavy losses (금융피해자연대, 2020). Four trillion won (3.2 billion dollars) vanished, and several individual investors committed suicide, but the governmental investigation has barely progressed. The Minister of Justice has dismantled the prosecution team looking for the missing money. According to victims and their lawyers, senior officials including former and current Ministers of Justice; a former Minister of Health and Welfare, members of the National Assembly; the Financial Supervisory Service and the Financial Services Commission; and even the President's doctor are under suspicion (금융피해자연대, 2020). The investigation by the prosecution recently resumed, but the truth and the missing money cannot be unearthed without cooperation by the Moon administration. The SillaJen scandal is only one of the multiple examples of biopharmaceutical wrongdoing and poor investigation under the current government. In the meantime, while the government's exceptional positions in the bio and pharma businesses made thousands of people broke, the government utilized the events of the COVID-19 outbreak as an ongoing chance to intensify speculation in bio and pharma stocks and shares. Unless the Korean state's favoring and deregulations of biopharma speculation took a fundamental rethinking and thorough investigation, approximately 37 billion dollars of public funding a year (금융피해자연대, 2020) would be solely benefitting certain bio and pharms firms, not the public. Thus K-bio and the Korean government's promotion of the biotech and pharmaceutical industries is benefiting some Koreans, especially corporations with story stock and some individuals within the state apparatus, but as is typical in the financialization of everyday life, many ordinary people are saddled with unpayable debt while being guided to becoming risk-taking subjects. 7 Conclusion: Post-corona or speculation-as-usual In this study, I explored the steadfast deregulation and financialization efforts by the Korean government amid the shocking event of COVID-19, along with the persistence of the state in financial capitalism beyond the shock. The South Korean state's well-promoted nationalistic images of utmost urgency, efficiency, and transparency combined with shock strategies have paved the way for both state and corporate financialization and super-profits beyond national scales. The institutional exceptions and nationalistic sentiment—as well as speculations—practiced by the Korean state in bio and pharm markets have not only simplified the effectiveness and durability of biotech products but have muted complex terrains of scientific debates regarding accountability of publicly funded vaccines, treatments, and other technologies. This study presents the sociopolitical significance of political-economic structures seeking financial paths and products, as well as the rise of state financialization that encourages nationalistic commodification. Altogether, they show a clear sign of needing further investigation. Heroic stories, self-deifying or flattering publicity, blaming, and growing melodramas during shocking events signal an urgent need to examine their nudging effect and untold intention. A more discursive, imaginary, legal, and somewhat subtle form of state-led financialization needs to be further explored in addition to the material realities of finance and money. It might be hard to interpret what financial motivations the state has and on what it is based, such as state-firm relations or lobbying. Nevertheless, what we clearly know is that the state has a different scalar and dimensional power—like diplomatic resources and legislation—and can have broad, deep impacts on political economy. If institutional agencies and policymakers obtain any outcomes that inadvertently turned into stimulating financialization processes and effects, their actions and regimes should be investigated. 8 Funding source declaration This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest None. Acknowledgments The author thanks Kristin Sziarto, reviewers, and Eun-Jung Kim for their valuable comments on the article, as well as the three organizers of the special issue, Giulia Urso, Luca Storti, and Neil Reid, for their kind support. The earlier draft of this articlehas benefitted greatly from participant comments at the Financial Geography Summer School's Roundtable and Writing Group. 1 This lost value is based on the comparison of aggregate market value of listed stocks between January and December in 2019. ==== Refs References Agamben G. Where are we now?: The epidemic as politics. Rowman & Littlefield 2021 Baker T. McGuirk P. 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Lee B.-C. Song W.-K. Lee C.-G. 위기의 삼성과 한국 사회의 선택 [Samsung in crisis and decision of Korean Society] 2014 Humanitas Seoul 561 606 [in Korean] Streeck W. Buying time: The delayed crisis of democratic capitalism 2014 Verso Books TBS 5/8 김어준의 뉴스공장 [May 8, Kim Eojun's News Factory] [YouTube] May 8 TBS. 2020 https://www.youtube.com/watch?v=F8K1q3TH2uc [in Korean] Thrift N. Leyshon A. A phantom state? The de-traditionalization of money, the international financial system and international financial centres Political Geography 13 4 1994 299 327 Töpfer L.M. China's integration into the global financial system: toward a state-led conception of global financial networks Dialogues in Human Geography 8 3 2018 251 271 Van der Zwan N. Making sense of financialization Socio-Economic Review 12 1 2014 99 129 Woo J.-Y. 장외서도 ‘K바이오 쇼크’ [‘K-Bio Shock’ even in off-board transactions] Maekyung Media. 2019 https://www.mk.co.kr/news/stock/view/2019/12/1081142/ [in Korean] Yang B.-H. '코로나 극복' 선봉엔 K바이오… [K-Bio is Spearheading the ‘Overcoming Coronavirus’…] The Korea Economic Daily 2020 https://www.hankyung.com/finance/article/202004165498i [in Korean] Yanow D. Conducting interpretive policy analysis 47 2000 Sage University Papers Series on Qualitative Research Methods Thousand Oaks: Sage Yonhap News Agency 미, 한국 코로나19 진단키트 제공에 "미국인 지원 감사" [U.S. thanks S. Korea for providing COVID-19 testing kits] Yonhap News Agency. 2020 https://www.yna.co.kr/view/AKR20200414053351071?section=safe/news [in Korean] Yoon K.-H. 진단용품 수출 홍보가 지금 급한가 [Is the promotion for kit exporting the rush] April 2 Seoul Economy 2020 https://www.sedaily.com/NewsVIew/1Z1BHVB0EH [in Korean] 금융피해자연대 [Solidarity for Finance Fraud Victims] 기자회견문: 금융사기 부실수사 검찰 규탄 [statement: Criticizing the prosecution's poor investigation into financial frauds]. [in Korean] 2020 무상의료 운동본부 [National Solidarity for Free Health Care] 기자회견문: 삼성에 의한, 삼성을 위한 의료민영화 즉각 중단하라 [statement: Stop privatizing health care by Samsung, for Samsung]. [in Korean] 2019 사회진보연대 [People's Solidarity for Social Progress] 2020년 보건의료 정세전망 [Situations and expectations of health care in 2020]. [in Korean] 2020

0

PMC9751681

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2022-12-16 23:25:09

no

Appl Geogr. 2021 Nov 15; 136:102560

utf-8

Appl Geogr

10.1016/j.apgeog.2021.102560

oa_other

==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00925-9 10.1016/S0140-6736(21)00925-9 Correspondence Refugee access to COVID-19 vaccines in Lebanon Jawad Nadine K a Taweeleh Lina Abu b Elharake Jad A cd Khamis Nicole e Alser Osaid f Karaki Fatima M g Aboukhater Layla a a Stanford School of Medicine, Stanford, CA 94305, USA b Stanford University, Stanford, CA, USA c Yale Institute for Global Health, New Haven, CT, USA d Yale School of Public Health, New Haven, CT, USA e Harvard Law School, Cambridge, MA, USA f Harvard Medical School, Cambridge, MA, USA g Refugee and Asylum Seeker Health Initiative, Department of Medicine, University of California San Francisco, San Francisco, CA, USA 21 5 2021 22-28 May 2021 21 5 2021 397 10288 18841884 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcLebanon is currently experiencing multiple unprecedented crises—political, infrastructural, and economic. The Beirut port explosion, in August, 2020, damaged 36% of health facilities.1 The Lebanese pound has lost 90% of its value, pushing more than half of the population into poverty.1 Complicating its desperate plight, Lebanon hosts the largest refugee population per capita in the world.2 The COVID-19 pandemic has exacerbated this situation, leaving an ill-equipped health-care system overwhelmed.1 Given that the country struggles to care for its own citizens, the individuals who are most vulnerable, such as refugees, are at a heightened risk, particularly given the historical neglect of refugee populations in Lebanon's routine vaccination efforts.3 Amid Lebanon's crises, the risk of failing to ensure equitable access to the COVID-19 vaccine for its 1·7 million refugees represents an impending public health crisis. In Lebanon, refugees make up approximately 30% of the population.2 Refugees live in high-density camps with scarce access to clean water, sanitation, and hygiene services, which leaves these individuals highly vulnerable during an infectious disease outbreak. According to the non-profit organisation Anera, public health interventions have been scarce across refugee camps since the beginning of the COVID-19 pandemic. Consequently, COVID-19 deaths were elevated among Syrian and Palestinian refugees in Lebanon, with a fatality rate that is four times and three times the national average, respectively.4 The Lebanese Ministry of Public Health prepared a National Deployment and Vaccination Plan (NDVP) for COVID-19 vaccines, which aims to vaccinate 80% of its total population, including non-citizens.2 However, the acquired number of doses thus far—including those from COVID-19 Vaccines Global Access (COVAX)—is only sufficient to vaccinate 2 million people.2 Although the NDVP commits to vaccinating refugees, routine immunisation rates among refugees in Lebanon have historically been alarmingly low compared with the native population. Only 12·5% of Syrian refugee children in Lebanon are fully immunised through routine vaccination services.3 Given that Lebanon does not have enough doses to vaccinate its own citizens, international support is needed to ensure that refugees in Lebanon receive the COVID-19 vaccine. Access to vaccinations by the most vulnerable is critical in curtailing the spread of COVID-19. While Lebanon struggles to address its economic and political crises, it is untenable for Lebanon to solely provide vaccinations for its refugee communities. Thus, international aid organisations must step in to ensure that those most at risk of COVID-19 are prioritised in vaccinations. Without international efforts to ensure equitable access, vaccine distribution in Lebanon risks becoming another crisis and a catastrophic moral failure. We declare no competing interests. ==== Refs References 1 International Medical Corps Beirut Explosion Situation Report #9 https://reliefweb.int/sites/reliefweb.int/files/resources/IntlMedCorps-BeirutExplosion_SitRep09.pdf 2021 2 Republic of Lebanon Ministry of Public Health Lebanon National Deployment and Vaccination Plan for COVID-19 Vaccines https://www.moph.gov.lb/userfiles/files/Prevention/COVID-19%20Vaccine/Lebanon%20NDVP-%20Feb%2016%202021.pdf 2021 3 Mansour Z Hamadeh R Rady A Vaccination coverage in Lebanon following the Syrian crisis: results from the district-based immunization coverage evaluation survey 2016 BMC Public Health 19 2019 58 30642314 4 Human Rights Watch Lebanon: refugees, migrants left behind in vaccine rollout https://www.hrw.org/news/2021/04/06/lebanon-refugees-migrants-left-behind-vaccine-rollout/ 2021

34022984

PMC9751700

NO-CC CODE

2022-12-16 23:25:09

no

Lancet. 2021 May 21 22-28 May; 397(10288):1884

utf-8

Lancet

10.1016/S0140-6736(21)00925-9

oa_other

==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01095-3 10.1016/S0140-6736(21)01095-3 Comment Report of the Independent Panel for Pandemic Preparedness and Response: making COVID-19 the last pandemic Sirleaf Ellen Johnson a Clark Helen b a Ellen Johnson Sirleaf Presidential Center for Women and Development, Monrovia, Liberia b The Helen Clark Foundation, Auckland, New Zealand 12 5 2021 10-16 July 2021 12 5 2021 398 10295 101103 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIn May, 2020, with COVID-19 affecting just about every country on the planet, the World Health Assembly requested the WHO Director-General to initiate an independent, impartial, and comprehensive review of the international health response to the pandemic. He asked us to convene an independent panel for this purpose. The members of the Independent Panel for Pandemic Preparedness and Response have spent the past 8 months examining the state of pandemic preparedness before COVID-19, the circumstances of the identification of SARS-CoV-2 and the disease it causes, and responses globally, regionally, and nationally, particularly in the early months of the pandemic. The panel has also analysed the wide-ranging impacts of the pandemic on health and health systems, and the social and economic crises that it has precipitated. The panel has produced a definitive account to date of what happened, why it happened, and how it could be prevented from happening again. This report1 was published on May 12, 2021, together with a companion report2 that describes 13 defining events which have been pivotal in shaping the course of the COVID-19 pandemic. In addition, the panel is publishing a series of background papers representing in-depth research, including an authoritative chronology of the early response. As the panel's Co-Chairs, we have been asked to present the report to the 74th World Health Assembly, to be held from May 24 to June 1, 2021. COVID-19 exposed the extent to which pandemic preparedness was limited and disjointed, leaving health systems overwhelmed when actually confronted by a fast-moving and exponentially spreading virus. The panel's conclusion is that closing the preparedness gap not only requires sustained investment, but also requires a new approach to measuring the leadership dimensions of preparedness and strengthened accountability in a system of universal periodic peer review of country preparedness. It is clear to the panel that the international alert system does not operate with sufficient speed when faced with a fast-moving respiratory pathogen, and that the legally binding International Health Regulations (IHR) (2005) are a conservative instrument that constrain rather than facilitate rapid action. The panel's chronology presented in the report and in the accompanying documents shows the time lost to IHR processes as SARS-CoV-2 spread internationally. The declaration of a Public Health Emergency of International Concern by the WHO Director-General on Jan 30, 2020, was not followed by forceful and immediate responses in most countries, despite the mounting evidence that a contagious new pathogen was spreading around the world. February, 2020, was a lost month in many countries, when steps could and should have been taken to curtail the epidemic and forestall the pandemic. On the basis of the panel's comparative analysis of 28 countries from across the spectrum of responses that is published alongside the report,1 it is clear that countries with successful responses had timely triage and referral of suspected COVID-19 cases to ensure swift case identification and contact tracing, and provided designated isolation facilities, either for all or for those unable to self-isolate. High-performing countries also developed partnerships on multiple levels across government sectors and with groups outside government, communicated consistently and transparently, and engaged with community health workers and community leaders as well as the private sector. Countries with poor results had uncoordinated approaches that devalued science, denied the potential impact of the pandemic, delayed comprehensive action, and allowed distrust to undermine efforts. Many had underfunded health systems beset by long-standing problems of fragmentation and undervaluing of health workers. They had insufficient capacity to mobilise rapidly and coordinate between national and subnational responses. The denial of scientific evidence was compounded by a failure of leadership to take responsibility or develop coherent strategies aimed at preventing community transmission. Importantly, COVID-19 has been a pandemic of inequality, exacerbated between and within countries, with the impact being particularly severe on people who are already marginalised and disadvantaged. Inequality has been a determining factor in explaining why the COVID-19 pandemic has had such differential impacts on peoples' lives and livelihoods.3, 4 The combination of poor strategic choices, unwillingness to tackle inequalities, and an uncoordinated response system allowed the pandemic to trigger a catastrophic human and socioeconomic crisis. The panel's report also highlights strengths on which to build. Open data and open science collaboration were central to alert and response. For example, sharing of the genome sequence of the novel coronavirus on an open platform quickly led to the most rapid creation of diagnostic tests in history. COVID-19 vaccines were developed at unprecedented speed. Doctors, nurses, midwives, long-term caregivers, community health workers, and other front-line workers, including at country borders, are still working tirelessly to protect people and save lives. The panel's recommendations flow from the diagnosis made of what went wrong at each stage of the pandemic in preparedness, surveillance and alert, and early and sustained response. These recommendations have two objectives: first, to end the pandemic, and, second, to prevent a future disease outbreak from becoming a pandemic. To end COVID-19 the panel recommends the following three immediate actions. First, high-income countries with a COVID-19 vaccine pipeline for adequate coverage should, alongside their scale-up, commit to provide at least 1 billion vaccine doses to the 92 low-income and middle-income countries of the Gavi COVAX Advance Market Commitment, no later than Sept 1, 2021, and more than 2 billion doses by mid-2022. Second, major vaccine-producing countries and manufacturers should convene, under the joint auspices of WHO and the World Trade Organization, to agree to voluntary licensing and technology transfer with intellectual property rights to be waived immediately if voluntary action, including action on the required technology transfer, does not occur within 3 months. Third, the G7 should immediately commit to 60% of the US$19 billion required for the Access to COVID-19 Tools (ACT) Accelerator in 2021 for vaccines, diagnostics, therapeutics, and strengthening of health systems, and a burden sharing formula should be adopted to fund such global public goods on a continual basis. To prepare the world for the future so that the next disease outbreak does not become a pandemic, the panel calls for a series of crucial reforms that will address gaps in high-level coordinated leadership globally and nationally, funding, access to what must become global goods, and WHO's independence, focus, and authority. Some of these reforms are shown in the panel .Panel Transformational change recommended by the Independent Panel for Pandemic Preparedness and Response • Establish a high-level Global Health Threats Council led by heads of state and government. Adopt a political declaration by heads of state and government at a Special Session of the UN General Assembly committing to transforming pandemic preparedness and response. Adopt a Pandemic Framework Convention within the next 6 months. • Establish the financial independence of WHO based on fully unearmarked resources and applying an increase in member states' fees to equate to two-thirds of the WHO base programme budget. Strengthen the authority and independence of the WHO Director-General, including by having a single term of office of 7 years with no option for re-election. The same rule should be adopted for WHO Regional Directors. • Focus WHO's mandate on normative, policy, and technical guidance; empower WHO to take a leading, convening, and coordinating role in operational aspects of an emergency response to a pandemic, without, in most circumstances, taking on responsibility for procurement and supplies. • All national governments to update their national preparedness plans against targets and benchmarks to be set by WHO within 6 months, ensuring that there are appropriate and relevant skills, logistics, and funding available to cope with future health crises. • WHO to formalise universal periodic peer reviews as a means of accountability. The International Monetary Fund needs to include routinely a pandemic preparedness assessment, including an evaluation of economic policy response plans, as part of the Article IV consultation with member countries. • WHO to establish a new global system for surveillance, based on full transparency by all parties, using digital tools. • The World Health Assembly to give WHO both the explicit authority to publish information about outbreaks with pandemic potential immediately without requiring the prior approval of national governments and the ability to dispatch experts to investigate pathogens with pandemic potential with rapid and guaranteed right of access. • Future declarations of a Public Health Emergency of International Concern should be based on the precautionary principle where warranted and on clear, objective, and published criteria. • Transform the present ACT Accelerator into a truly global end-to-end platform to deliver the global public goods of vaccines, therapeutics, diagnostics, and essential supplies. Secure technology transfer and commitment to voluntary licensing in all agreements where public funding has been invested in research and development. • Establish stronger regional capacities for manufacturing, regulation, and procurement of needed tools for equitable and effective access to vaccines, therapeutics, diagnostics, and essential supplies, as well as for clinical trials. • Create an International Pandemic Financing Facility to mobilise long-term (10–15 year) contributions of approximately US$5–10 billion per annum to finance preparedness. This facility should have the ability to disburse up to $50–100 billion at short notice in the event of a crisis. Use existing global and regional organisations, based on their functions, to manage and channel the funds. There should be an ability-to-pay formula adopted whereby larger and wealthier economies will pay the most, preferably from non-overseas development assistance budget lines and additional to established overseas development assistance budget levels. • The Global Health Threats Council will have the task of allocating and monitoring funding from this instrument to existing regional and global institutions, which can support development of pandemic preparedness and response capacities. • Heads of state and government should appoint national pandemic coordinators who are accountable to them, and who have a mandate to drive whole-of-government coordination for pandemic preparedness and response. The message for change is clear: COVID-19 should be the last pandemic. If the global community fails to take this goal seriously, we will condemn the world to successive catastrophes. EJS and HC are Co-Chairs of the Independent Panel for Pandemic Preparedness and Response. We declare no other competing interests. ==== Refs References 1 Independent Panel for Pandemic Preparedness and Response COVID-19: make it the last pandemic https://theindependentpanel.org/ 2021 2 Independent Panel for Pandemic Preparedness and Response How an outbreak became a pandemic. The defining moments of the COVID-19 pandemic https://theindependentpanel.org/ 2021 3 Pereznieto P Oehler I Social costs of the COVID-19 pandemic, background paper commissioned by the Independent Panel for Pandemic Preparedness and Response https://theindependentpanel.org/ 2021 4 Furceri D Loungani P Ostry JD Pizzuto P COVID-19 will raise inequality if past pandemics are a guide Vox May 8, 2020 https://voxeu.org/article/covid-19-will-raise-inequality-if-past-pandemics-are-guide

33991477

PMC9751704

NO-CC CODE

2022-12-16 23:25:09

no

Lancet. 2021 May 12 10-16 July; 398(10295):101-103

utf-8

Lancet

10.1016/S0140-6736(21)01095-3

oa_other

==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00899-0 10.1016/S0140-6736(21)00899-0 Correspondence Data discrepancies and substandard reporting of interim data of Sputnik V phase 3 trial Bucci Enrico M a Berkhof Johannes b Gillibert André c Gopalakrishna Gowri b Calogero Raffaele A d Bouter Lex M be Andreev Konstantin f Naudet Florian g Vlassov Vasiliy h a Sbarro Institute, Temple University Department of Biology, Philadelphia, 19122 PA, USA b Department of Epidemiology and Data Science, Amsterdam University Medical Centers, Amsterdam, Netherlands c Department of Biostatistics, CHU Rouen, Rouen, France d Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy e Department of Philosophy, Faculty of Humanities, Vrije Universiteit Amsterdam f Department of Molecular Biosciences, Howard Hughes Medical Institute, Northwestern University, Evanston, IL, USA g Centre Hospitalier Universitaire de Rennes, Université de Rennes, Rennes, France h Higher School of Economics University, Moscow, Russia 12 5 2021 22-28 May 2021 12 5 2021 397 10288 18811883 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcRestricted access to data hampers trust in research. Access to data underpinning study findings is imperative to check and confirm the findings claimed. It is even more serious if there are apparent errors and numerical inconsistencies in the statistics and results presented. Regrettably, this seems to be what is happening in the case of the Sputnik V phase 3 trial.1 Several experts3, 4 found problematic data in the published phase 1/2 results.2 We have made multiple independent requests for access to the raw dataset, but these were never answered. Despite publicly denying some problems, formal corrections were made to the Article,2 thus addressing some concerns.5 Notwithstanding the previous issues and lack of transparency, the interim results from the phase 3 trial of the Sputnik V vaccine1 again raise serious concerns. We have a serious concern regarding the availability of the data from which the investigators draw their conclusions. The investigators state that data will not be shared before the trial is completed, and then only by approval of stakeholders, including a so-called security department. Data sharing is one of the cornerstones of research integrity; it should not be conditional and should follow the FAIR principles. The second concern pertains to the trial protocol, as already described in an open letter by the Russian Society for Evidence-Based Medicine.3 The Sputnik V investigators mention that three interim analyses were added to the study on Nov 5, 2020,1 but this change was not recorded on ClinicalTrials.gov (NCT04530396). Unfortunately, the full study protocol has not been made publicly available, so the rationale behind this change or the type I error rate adjustment, if any, is not known. According to the ClinicalTrials.gov record NCT04530396, the primary outcome was changed on Sept 17, 2020. Initially, the primary outcome was to be assessed after the first dose, but the evaluation was postponed to after the second dose. The presented primary result (efficacy of 91·6%) is dependent on this change, but the reasons for the change have not been made public. Moreover, the latest ClinicalTrials.gov record (Jan 22, 2021) defines the primary outcome inconsistently: “Primary Outcome Measures: percentage of trial subjects…after the first dose…based on the percentage…after the second dose”. Besides these protocol amendments, the definition of the primary outcome is unclear in the Article,1 where it says that when COVID-19 was suspected, participants were assessed with “COVID-19 diagnostic protocols, including PCR testing”. Here, we lack some crucial information, such as the clinical parameters determining suspected COVID-19, what diagnostic protocols were used, when the PCR testing was done, what specific method was used, or how many amplification cycles were used. The way cases of suspected COVID-19 were defined could have led to bias in PCR testing used to assess the number of confirmed COVID-19 cases, which is crucial for the efficacy determination. A final point of concern about the study protocol relates to the enrolment and randomisation of patients. According to the trial profile in figure 1 of the Article,1 35 963 individuals were screened and 21 977 individuals were randomised. The ClinicalTrials.gov record for NCT04530396 (Jan 20, 2021) mentions that 33 758 patients were enrolled. We would expect that this last figure should be equal to either the number of participants screened or randomised. Moreover, there is no information about what caused the exclusion of 13 986 participants, as per the trial profile. The third concern relates to the data reported and numerical results. We found the following data inconsistencies: (1) in figure 2 of the Article,1 data for the vaccinated group on day 20 refer to more individuals than at day 10, as if there was either information missing for 100 participants at day 10, or participants were enrolled after day 10 (figure 2 was formally corrected on Feb 20, 2021, but the correction statement did not state the reasons leading to such correction); and (2) in table S1 of the appendix,1 the number of participants reported for the different vaccinated age cohorts do not add up to the reported total (n=338 vs n=342). With such inconsistencies, we question the accuracy of the reported data. A very peculiar result of the major subgroup analysis of the primary outcome caught our attention. The vaccine efficacy was said to be high for all age groups. The reported percentages were 91·9% in the 18–30-year age group, 90·0% in the31–40-year age group, 91·3% in the 41–50-year age group, 92·7% in the 51–60-year age group, and 91·8% in participants older than 60 years. We checked the homogeneity of vaccine efficacy across age groups (interaction tests): the p value of the Tarone-adjusted Breslow-Day test was 0·9963, and the p value of a non-asymptotic test was 0·9956,6 indicating a very low probability of observing a homogeneity this good if the actual homogeneity is perfect. By applying 18 other homogeneity tests (six in table 1, seven in table S6, six in table 2 of the Article1), we could not find other major abnormality in the overall distribution of p values (appendix). We also found some highly coincidental results reported in table S3 of the appendix. In particular, two upper confidence limit values for two different distributions (placebo group at baseline for unstimulated and antigen-stimulated measures) both equal 0·708. Of course, this is possible, but we call once more for access to the data from which the statistics originate for close scrutiny. In line with our earlier concerns with the phase 1/2 results4 and the substandard reporting of the phase 3 interim results,1 we invite the investigators once more to make publicly available the data on which their analyses rely. Access to the protocol, its amendments, and the individual patient records is paramount, as much for clarification as for open discussion of all the issues. We also invite the Editors of The Lancet to clarify the consequences of further denying access to the data needed for assessing the results presented, should the authors still deny it. EMB is the owner of Resis Srl. All other authors declare no competing interests. Code to test the homogeneity of vaccine efficacy across age groups is available on the Open Science Framework, https://osf.io/sudxe/ Supplementary Material Supplementary appendix ==== Refs References 1 Logunov DY Dolzhikova IV Shcheblyakov DV Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia Lancet 397 2021 671 681 33545094 2 Logunov DY Dolzhikova IV Zubkova OV Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomized phase 1/2 studies from Russia Lancet 396 2020 887 897 32896291 3 Vlassov V Rebrova O Aksenov V Commentary on the publication of preliminary results of the Sputnik-V vaccine phase 3 trial http://osdm.org/english/2021/02/06/a-commentary-on-the-publication-of-preliminary-results-of-the-sputnik-v-vaccine-phase-3-trial/ Feb 5, 2021 4 Bucci E Andreev K Björkman A Safety and efficacy of the Russian COVID-19 vaccine: more information needed Lancet 396 2020 e53 32971041 5 Logunov DY Dolzhikova IV Tukhvatullin AI Shcheblyakov DV Safety and efficacy of the Russian COVID-19 vaccine: more information needed—Authors' reply Lancet 396 2020 e54 e55 32971043 6 Sangnawakij P Böhning D Holling H On the exact null-distribution of a test for homogeneity of the risk ratio in meta-analysis of studies with rare events J Stat Comput Simul 91 2021 420 434

33991475

PMC9751705

NO-CC CODE

2022-12-16 23:25:10

no

Lancet. 2021 May 12 22-28 May; 397(10288):1881-1883

utf-8

Lancet

10.1016/S0140-6736(21)00899-0

oa_other

==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01056-4 10.1016/S0140-6736(21)01056-4 Editorial Lessons from the NHS for UHC and health security The Lancet 6 5 2021 22-28 May 2021 6 5 2021 397 10288 18591859 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIn 2018, to mark the 70th anniversary of the UK National Health Service (NHS), a new Commission was established by The Lancet and London School of Economics to independently evaluate the NHS and its role in health in the UK. After 3 years, much has changed. The Commission began with concerns about stalling life expectancy, rising inequality, and comparatively poor health outcomes, such as those for cancer and maternity care. Today, the Commission reports during a historic pandemic, in which the UK excess death rate has been very high. The pride and support that much of the public feel for the NHS remain high. With such a strong health-care system, how could the UK perform so badly relative to other countries during the COVID-19 pandemic? And what does this mean for the future of universal health coverage, and for the NHS? The Commission reports that the NHS has succeeded in providing universal services free at the point of delivery; it emphasises the position of the NHS at the heart of UK society, staffed by dedicated health workers. However, the Commission also highlights large staffing shortfalls and relative low funding (the UK spends over 1% less of its GDP on health compared with the G7 average). The Commission shows how previous deprioritisation of public health and social care led to poor national population health before the COVID-19 pandemic. Describing a high level of income inequality in the UK, and a gradient of life expectancy with economic deprivation both regionally and nationally, the Commission calls out glaring health inequalities, discrimination, and structural racism, evidenced by the worse health outcomes in many minority ethnic groups, including Black, Pakistani, and Bangladeshi people. The authors also emphasise that the NHS has not been able to respond adequately to the changing needs of the population. Despite a growing burden of non-communicable diseases and mental health problems, the NHS focuses on treatment, rather than shifting to prevention. The limitations of universal health coverage when imagined simply as the provision of services in response to illness echo ideas from a Lancet Health Policy paper, which discusses how misalignment between the concepts of universal health coverage and global health security has hampered responses to the COVID-19 pandemic. According to Arush Lal and colleagues, in countries that have traditionally focused on universal health coverage and provision of services, not enough attention has been given to public health and outbreak control, and in countries that focused on global health security, provision of universal health coverage has been relatively neglected. Before the pandemic, the UK was considered to have both strong universal health coverage and global health security systems. Discussing the UK, Lal and colleagues suggest that confidence in the health-care system contributed to complacency, delaying capacity building and leading to fragmented global health security responses. The UK's inability to protect its citizens from the COVID-19 pandemic must force re-examination of our understanding of successful universal health coverage and global health security. A true long-term response to the human devastation of the pandemic will only occur if we understand the crisis of the past year as a syndemic—a synthesis of epidemics—which has both biological and social interactions. The focus on universal health coverage must shift from providing the minimum finance required to deliver services, to the equitable provision of health, including public health security, healthy communities, and fully integrated health research. During the COVID-19 pandemic, the UK's research system has made critical contributions to saving lives, but must be further strengthened and better coordinated with clinical care. A health system envisaged through the traditional view of covering overheads for delivering certain services—eg, the NHS seen through the dimensions of workforce, products, money, and services—is not enough to deliver health to a population or to protect a population from health threats. There is a real danger that the success of the UK vaccination programme is obscuring the scale of the reforms necessary to protect and strengthen the health of the UK population. Broader concepts of health and wellbeing must be placed at the centre of government policy. Investment in public services that reduce inequality is necessary to maintain and improve population health and protect the UK population from future health threats. Lessons from the UK and the NHS show that universal health coverage is broader than health-care provision alone, and that a healthy population must be considered a prerequisite for health security and preparedness. © 2021 Caia Image/Science Photo Library 2021

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00230-0 10.1016/S0140-6736(21)00230-0 Health Policy What is the right level of spending needed for health and care in the UK? Charlesworth Anita Prof MSc ab Anderson Michael MSc c* Donaldson Cam Prof PhD d Johnson Paul Prof MSc e Knapp Martin Prof PhD c McGuire Alistair Prof PhD c McKee Martin Prof MD f Mossialos Elias Prof PhD c Smith Peter Prof MSc gh Street Andrew Prof PhD c Woods Michael MSc c† a The Health Foundation, London, UK b College of Social Sciences, Health Services Management Centre, University of Birmingham, Birmingham, UK c Department of Health Policy, London School of Economics and Political Science, London, UK d Yunus Centre for Social Business and Health, Glasgow Caledonian University, Glasgow, UK e Institute for Fiscal Studies, London, UK f Department of Health Services Research and Policy, London School of Hygiene & Tropical Medicine, London, UK g Centre for Health Economics and Policy Innovation, Imperial College London, London, UK h Centre for Health Economics, University of York, York, UK * Correspondence to: Dr Michael Anderson, Department of Health Policy, London School of Economics and Political Science, London WC2A 2AE, UK † Except for the first author, the remaining coauthors are listed alphabetically as they provided equal contributions to this paper 6 5 2021 22-28 May 2021 6 5 2021 397 10288 20122022 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The health and care sector plays a valuable role in improving population health and societal wellbeing, protecting people from the financial consequences of illness, reducing health and income inequalities, and supporting economic growth. However, there is much debate regarding the appropriate level of funding for health and care in the UK. In this Health Policy paper, we look at the economic impact of the COVID-19 pandemic and historical spending in the UK and comparable countries, assess the role of private spending, and review spending projections to estimate future needs. Public spending on health has increased by 3·7% a year on average since the National Health Service (NHS) was founded in 1948 and, since then, has continued to assume a larger share of both the economy and government expenditure. In the decade before the ongoing pandemic started, the rate of growth of government spending for the health and care sector slowed. We argue that without average growth in public spending on health of at least 4% per year in real terms, there is a real risk of degradation of the NHS, reductions in coverage of benefits, increased inequalities, and increased reliance on private financing. A similar, if not higher, level of growth in public spending on social care is needed to provide high standards of care and decent terms and conditions for social care staff, alongside an immediate uplift in public spending to implement long-overdue reforms recommended by the Dilnot Commission to improve financial protection. COVID-19 has highlighted major issues in the capacity and resilience of the health and care system. We recommend an independent review to examine the precise amount of additional funds that are required to better equip the UK to withstand further acute shocks and major threats to health. ==== Body pmcIntroduction Since the National Health Service (NHS) was founded in the UK in 1948, public spending on health has more than doubled from 3·5% of gross domestic product (GDP) then to 7·2% in 2018–19.1, 2 In real terms, spending is more than 10 times the amount it was 70 years ago.1 Despite the scale of growth in health and care spending, there have been repeated crises, as funding increases have not kept pace with rising demand, expectations, or technological needs.3 In the decade preceding the COVID-19 pandemic, measures to cope with the gap between demand and funding for health care in the UK have included raiding funds intended for capital investment to boost revenue spending and restricting growth in staff pay, alongside announcements to increase public funding, such as the 2018 pledge to increase funding for the NHS in England by £20·5 billion per year in real terms by 2023–24,4 and the 2019 pledge to increase capital investment in the NHS in England by £1·8 billion.5 We argue that instead of short-term and reactive funding measures, a longer-term solution for both NHS and social care funding is necessary for a sustainable health and care service, which we define as a service that provides, as a minimum, similar levels of quality and access as are currently enjoyed, taking into account future trends in demography, morbidity, and technology. Increased investment is also needed to improve the preparedness and resilience of the health and care system to withstand acute shocks and major threats to health. Survey data indicate that, if funding for the NHS were to increase, the majority of the public would support tax increases.6 Public views on who should pay for social care are more nuanced, but more than half of people surveyed believe the government should pay, although perhaps only for individuals on low incomes.7 However, there needs to be increased clarity about the level of funding necessary for a sustainable health and care service. This Health Policy paper attempts to provide such clarity, while also being conscious of the considerable economic uncertainty created by the COVID-19 pandemic. Consequently, we begin with a discussion on the state of the economy and the potential economic impact of the recent COVID-19 pandemic. We then discuss the contribution of the health and care sector to wider society, health spending in the UK in comparison to other countries, trends in spending over time and across the UK, and the role of private spending on health. Finally, we assess the level of spending that is needed for a sustainable health and care service. All these topics are linked to the fiscal sustainability challenges identified by the Office for Budget Responsibility,8 and the Organisation for Economic Co-operation and Development (OECD).9 The economy and the COVID-19 pandemic The social distancing measures implemented in response to the pandemic were necessary to slow the spread of SARS-CoV-2 and limit excess mortality, but they have also closed down business activity in many sectors and had a striking impact on the UK's economic output. The Office for Budget Responsibility estimates that GDP in the UK fell by 9·9% in 2020, the largest decline out of all G7 countries.10 While the UK's rapid roll-out of vaccination creates the potential for the its economy to rebound quicker than those of many other nations, future growth is still highly dependent upon the effectiveness of vaccination in preventing any further waves of infections and associated lockdowns. However, at the time of writing, there is consensus among projections from the Office for Budget Responsibility, the OECD, and the Institute for Fiscal Studies, that GDP is expected to recover to pre-pandemic levels at some point in 2022.10, 11, 12 Future economic growth is also uncertain because of the UK leaving the EU. Most projections indicate that the growth of the UK economy will be smaller after leaving the EU than it would have been with continuing membership.13 Key messages • According to estimates by the Office for Budget Responsibility, gross domestic product in the UK fell by 9·9% in 2020, the largest decline out of all G7 countries, while future growth is highly uncertain and dependent upon the effectiveness of vaccination in preventing any further waves of infections and associated lockdowns • Achieving increased health spending against this economic backdrop requires a combination of increased government borrowing in the short term and taxation in the medium-to-long term • There is a strong economic rationale to invest in the health and care sector, to improve health and societal wellbeing, and reduce health and income inequalities • In common with countries across the OECD, health spending in the UK has grown faster than the overall economy; however, growth in health and care spending has been highly volatile, with periods of relative plenty followed by periods of relative austerity • Spending volatility is not conducive to long-term planning and efficiency; to secure the long-term future of the National Health Service (NHS), there is a need for increased consensus regarding the right level of spending for health and care in the UK • Although responsibility for health and care delivery is devolved to the four nations, spending decisions in England affect Scotland, Wales, and Northern Ireland through proportional allocations set by the Barnett formula • Private spending on health plays a small role in the UK, and a major strength of the NHS is in providing protection against the financial consequences of ill health • For the NHS, to meet cost and demand pressures over the next 15 years, spending needs to grow on average by at least 3·3% per year in real terms; however, to improve the quality of services, reduce waiting times, increase staffing numbers, and invest in capital, spending will need to grow on average by at least 4% per year in real terms • For social care, to meet cost and demand pressures over the next 15 years, spending needs to grow on average by 3·9% per year in real terms; improving financial protection by introducing a means-tested threshold of £100 000 and a maximum contribution of £75 000 in England would require even more in social care spending • In the short term, a further uplift in public spending is needed to address the growing unmet need for health-care services caused by postponing or cancelling elective procedures and diagnostic tests during the pandemic • We also recommend an independent review to examine what additional funds are required to improve the preparedness and resilience of the health and care system to withstand further acute shocks and major threats to health Combined with the impact of a weaker economy, the Office for Budget Responsibility's estimates that government borrowing reached £355 billion in 202010 represent the highest deficit since World War 2. However, there is consensus among economists that immediate reductions in public spending or acute rises in taxation would make the long-term situation worse.14, 15 Increased public spending is needed to support individuals and businesses through, for example, furlough pay, grants, and loans, and to mitigate against potential long-term effects on the economy from otherwise viable businesses failing and high and sustained unemployment. Moreover, the period of austerity preceding the pandemic left the health and care system under-resourced and vulnerable to an acute shock and major threats to health. This state of affairs ultimately exacerbated the economic impact of the pandemic itself and has reinforced the economic case for developing a resilient health and care system. Such a system will require the UK Government to place improving health and societal wellbeing at the heart of policy making and commit to sustained increases in health and care spending. While we acknowledge it will be challenging to achieve this shift in the current economic climate, we argue that it could be achieved through a combination of increased government borrowing in the short term and taxation in the medium-to-long term. What is the contribution of the health and care sector to wider society? The health and care sector is valuable: it improves the health and wellbeing of the population, reduces inequalities, and improves societal welfare. The sector also improves productivity and output through the associated increases in population health, which is especially important as the retirement age is increasing. Furthermore, the health and care sector is a large part of the economy, accounting for 4·5 million jobs in 2018 (approximately one in eight jobs in the UK and nearly one in six jobs in Wales). Health spending and health outcomes The contribution that health spending makes towards improving health outcomes has been difficult to establish because outcomes are influenced by a range of environmental, social, and economic factors beyond the health and care system. Moreover, analysis of historical trends is not necessarily a predictor of future trends. Nevertheless, some studies attempt to quantify the link between health system spending and health outcomes.16 Research using the concept of amenable mortality,17 now incorporated in the Health Access and Quality Index, has shown that effective and timely health care makes a substantial contribution to population health.18 Several analyses of NHS programme budgeting data show a clear link between increased health spending and improved health outcomes in the NHS, with the cost of securing an extra quality-adjusted life year ranging between £5000 and £15 000.19, 20, 21 At the macro level, an analysis of OECD countries concluded that increased health and care expenditure was associated with better health outcomes.22 The return on expenditure varies across countries, being lowest in the USA, partly because high prices mean that expenditure buys a lower volume of health care.23, 24 Research by the OECD in 2017 found that, across 35 member countries between 1995 and 2015, a 10% increase in health spending was associated with a life expectancy gain of 3·5 months,25 although no measures of uncertainty were included in the analysis. Some of these macro-level analyses overlook the fact that the effect of health spending on health outcomes is also dependent on how resources are allocated throughout the system. For example, investments in prevention might increase life expectancy more than those in end-of-life care, and investments in front-line services might improve health outcomes more than those in expensive drugs or medical devices. Therefore, as health systems continue to manage resources in a climate of resource scarcity, optimising allocative efficiency will be an essential strategy to maximise the health gains from health spending. Health outcomes and economic growth There is a growing literature focusing on the effect of improving health outcomes on macroeconomic growth and the mechanisms through which this occurs, although this is a challenging area in which to find causal evidence. Nevertheless, better health has been shown to increase labour market participation and worker productivity, which can increase economic growth.26 There is also evidence that increased life expectancy increases incentives to invest in education,27, 28 which in turn can improve productivity. Poor health during childhood has also been shown to be a predictor of worsened health in later life.29, 30 Therefore, as improved health can increase overall labour force participation, especially near to and after retirement age,31, 32 childhood health can have long-lasting effects on economic growth. Furthermore, illness and disability increase the likelihood of being unemployed in the UK,33 and being unwell at work (so-called presenteeism) is responsible for a considerable cost to the UK economy.34 The International Monetary Fund has also found evidence that providing increased access to health services can reduce the decline in total factor productivity and thus enhance economic growth from an ageing workforce.35 The COVID-19 pandemic has also shown the extreme effect that a health crisis can have on the economy. Health spending, societal welfare, and inequality Beyond the potential benefits for macroeconomic growth, well directed health and care expenditure improves overall societal welfare. For example, improved health in old age can reduce isolation and facilitate greater participation in society. The reverse is also true: care expenditure to reduce social isolation has health benefits.36, 37 People also derive utility from the knowledge that other people can access health care—a so-called caring externality.38 A key founding motivation for the NHS was that the sick deserve care, irrespective of their financial circumstances or contributions to the economy.39 While the NHS has been largely successful in providing care on the basis of clinical need and not ability to pay, there remain substantial inequalities in health outcomes. There is estimated to be a 7·4-year difference in life expectancy and an 18·9-year difference in healthy life expectancy between people in the highest and lowest deprivation deciles (appendix p 1). Although the UK has seen considerable increases in life expectancy, the rate of increase has slowed markedly since 2010 and, at some ages, reversed,40 an issue discussed further within the Health Policy paper on changing health needs linked to the main LSE–Lancet Commission report.41 However, it is important to emphasise the restricted influence of the health and care sector on health and wellbeing inequalities, which are strongly driven by a range of social determinants.42, 43 Nevertheless, it has been argued that the NHS often compensates when other parts of the social safety net fail.44 The NHS is funded through general taxation, which is largely progressive. Resources are also distributed using a needs-based resource allocation formula that reflects deprivation.45 Broadly, people on higher incomes subsidise people on lower incomes, and employed people subsidise unemployed people; in addition, because of the positive association between health and income, healthier individuals subsidise less healthy individuals,46 further reducing inequality.47, 48 The redistributive effect also depends on the utilisation of health care. Evidence from the NHS in England49 suggests that lifetime hospital costs are substantially higher in more deprived populations, thereby increasing the redistributive effect. How does health spending in the UK compare with other countries? The UK spent 10·3% of GDP on health in 2019 (including both public and private spending), similar to the average of the EU15 group of countries (9·4% of GDP; figure 1 ). The highest-spending countries in the EU are Germany (11·7%), France (11·2%), and Sweden (10·9%). The UK spent less than the average of the G7 group of countries (11·5%), which includes the USA (17·0%). In 2018, 78% of health spending in the UK came from public funds—similar to the share in the EU15 (77%), but slightly above that in the G7 (73%). Public spending includes government spending or compulsory health insurance, whereas private spending includes any voluntary health insurance or out-of-pocket payments.50 The OECD definition of health spending includes aspects of long-term care that are conventionally understood as social care spending in the UK context.50 Figure 1 Spending on health in G7 and EU15 countries (2019) Source: Organisation for Economic Co-operation. GDP=gross domestic product. PPP=purchasing power parity. *Public–private split data for the USA is for 2013; although there are more recent data available, older data are used to provide comparable split with data from other countries. Although total spending on health as a proportion of GDP in the UK is above the EU15 average, it is around 6% lower than the EU15 average in terms of $US per person ($3620 vs $3837; figure 1). Furthermore, the UK generally has relatively little capital, such as the number of hospital beds and diagnostic equipment, and a small workforce (eg, nurses and physicians; appendix p 2). Possible explanations for the low number of resources but similar spending levels to other comparable high-income countries could be differences in input prices (eg, physician wages),23 differences in skill mix (eg, greater reliance on non-clinical staff),51 or an ongoing shift towards moving care delivery from hospitals to the community. International comparisons of health spending, capital, and workforce should be interpreted with caution. Data might not be comparable and contextual factors contribute to variations. For example, low numbers of hospital beds could reflect either a scarcity of capital investment or successful efforts to move care away from the hospital to community settings. Similarly, low numbers of physicians and nurses might reflect an understaffed workforce or different approaches to skill mix across health and care workers. It should be noted that, although the UK has comparatively lower numbers of clinical staff per person, such as nurses and physicians, the number of staff per person in the total health and care workforce is just above the average of EU15 and G7 countries (appendix p 2), which suggests that the UK makes greater use of skill mix (eg, non-clinical staff and allied health-care professionals). How has health and care spending changed over time? Public spending on health Since the NHS was founded, spending has increased by more than inflation and GDP, rising by an average of 3·7% a year in real terms (appendix p 3).1 Three major factors determine the path of health spending over the long term: demographic factors, income effects, and other cost pressures.52 Demographic factors include the age structure of the population, health status at given ages, and death-related costs. Income effects reflect the fact that people generally demand more health care as their income rises. Other cost pressures include the effect of technological advancements and the increasing relative cost of health care. Over time, these factors have led health spending in the UK to increase at a faster rate than national income, which is consistent with the pattern seen across OECD countries.53 On only three occasions have there been notable spending reductions: twice in the early 1950s and in 1977–78 when the International Monetary Fund was called upon to support the UK economy. However, year-on-year spending growth has been highly volatile, with periods of relative plenty followed by periods of relative austerity. Between 1948 and 1978, spending increased on average by 3·5% a year. During the Conservative Governments of 1979 to 1997, spending growth was slightly lower, at 3·3% a year. Spending growth increased substantially under the Labour Governments between 1997 and 2009, averaging an increase of 6% a year.54 Between 2010 and 2018, health spending has grown at a markedly slower rate of just 1·2% a year (figure 2 ).54 The UK population has been increasing in size, so per-capita spending has been increasing at a slower rate than NHS expenditure. Moreover, the composition of the population has been changing and becoming older, meaning growth in age-adjusted spending is lower than growth in per-capita spending because older people tend to make greater use of health care. However, it is important not to overemphasise the contribution of population ageing, as individuals generally still see most health expenditure in their last year of life even as the population ages. It has been estimated that, independent of population ageing, cost growth and technological advancements will be the main drivers of future growth in health spending.56 Figure 2 Index of real UK health spending after 2009–10 Total, per-capita, and age-adjusted per-capita spending in 2009–10 each take the value 100. Data are from the UK Government Public Expenditure Statistics Analyses,2 Office for Budget Responsibility,55 and Office for National Statistics. Public spending on social care The health and care sectors are linked, and many ill people require support from both. If health and care services are complementary, reduced spending on social care might put greater pressure on the health sector, and vice versa. While spending on adult social care has been reduced in real terms during the past decade, the reduction is significantly larger when adjusted for per-capita and age-adjusted per-capita spending (figure 3 ).Figure 3 Index of real UK adult social care spending after 2009–10 Total, per-capita, and age-adjusted per-capita spending in 2009–10 each take the value 100. Data are from the UK Government Public Expenditure Statistics Analyses,2 Office for Budget Responsibility,55 and Office for National Statistics. How does health and care spending vary across the UK? Public spending on health across the UK The funding systems in each of the four countries of the UK remain tax-based and free at the point of use, with divergence in the use of prescription charges (see the role of private spending below). Publicly funded health spending per person varies across the four UK countries (appendix p 4). Total funding allocations to each UK country for government spending are based on a combination of historical spending and the Barnett formula, which proportionally adjusts any uplift in government spending in England according to population size to Scotland, Wales, and Northern Ireland.57 Each UK nation then decides how to allocate its resources during annual spending reviews. Within England, around two-thirds of the NHS budget is allocated via weighted capitation payments (ie, predefined payments per head of the population calculated to reflect expected need for health care) to local commissioning bodies, taking account of population factors such as age, gender, and deprivation.45 Public spending on health per person is highest in Scotland and lowest in England (appendix p 4). However, there are regions in England, such as the northeast and London, with higher spending per person than that in Scotland. Differences across the UK in spending per person have narrowed, ranging from £1598–£2471 in 2010–11 to £1915–£2665 in 2017–18 (appendix p 4). This trend warrants further investigation, as it is not clear if demographic changes in relative need between regions are responsible or if other contributory factors exist. Once allocated to local commissioning bodies in England, an internal market exists whereby both the NHS and independent-sector hospitals are eligible to provide treatment for NHS patients. In 2017–18, independent-sector hospitals provided over 600 000 publicly funded elective procedures—6% of all NHS elective activity—growing from less than 2000 elective procedures in 2003–04.58 For some procedures such as hip replacements, independent-sector hospitals now provide 30% of all NHS-funded procedures.58 Analyses indicate that such reforms, despite less complex patients being treated in the independent care sector, might have improved access and outcomes.59, 60 However, concerns have been raised regarding a relative absence of transparency in independent-sector hospitals61 and the potential impact on the sustainability of NHS services.62 During the pandemic, independent-sector hospitals have been used to allow the continuation of NHS cancer treatment and elective procedures in facilities that have low exposure to COVID-19.63 Public spending on social care across the UK The constituent countries of the UK are responsible for social care within their jurisdictions, leading to variation in eligibility criteria and differences in patterns of both funding and delivery. For example, in Scotland, personal and nursing care are free, whereas, in England, all social care is means-tested (appendix p 5). Means-testing can lead to substantial costs incurred by older people needing social care support—the 2011 Dilnot Commission on social care in England found that one in ten people, at age 65, would face future lifetime care costs of £100 000.64 Social care spending per adult is 31% lower in England than in Scotland, where there is a system of free personal care for older people (appendix p 5). Although differences between the four UK nations might reflect differences in eligibility criteria and needs, they also reflect the larger cuts to social care in England since 2011 (appendix p 5). The Institute for Fiscal Studies estimated that between 2009–10 and 2017–18, councils in the most deprived areas made cuts to adult social care of 17% per person, compared with cuts of 3% per person in councils in the least deprived areas.65 These differences in social care eligibility and funding across the UK do not appear to have influenced preparedness against COVID-19, as all constituent countries experienced significantly increased excess mortality in care homes during the pandemic.66, 67, 68 What is the role of private spending on health in the UK? There is no developed country in which private spending is the predominant financing mechanism for health-care services (figure 1). Even in the USA, which has a more extensively privatised financing model, there is still a significant public system to provide coverage for low-income, older, and veteran populations. Indeed, despite substantial private financing, public spending in the USA still accounts for a higher percentage of GDP than it does in the UK (figure 1). Notably, countries with more privatised models have higher inequalities in access to health-care services,69 a lower redistributive effect between income groups,46 and a higher incidence of catastrophic health expenditure.70 In the UK, private spending on health is a little more than a fifth of all spending.54 However, most of the private spending on health is concentrated among individuals in the highest income quintile,71 with those in the lowest income quintile typically exempt from out-of-pocket payments to access NHS services.72, 73 Generally, a major strength of the NHS compared with health-care systems in other high-income countries is financial protection, evidenced by a comparatively low incidence of catastrophic health expenditure, which is defined as out-of-pocket payments for health-care services exceeding a certain proportion of household income (appendix p 3). Factors that influence the level of financial protection in any country include gaps in coverage, the frequency and size of out-of-pocket payments, and whether coverage policy is designed in a manner that minimises out-of-pocket payments for people on low-incomes and regular users of health-care services.74 Household health expenditure accounts for a little less than 70% of private spending in the UK and includes both direct purchases of medical goods and services by households and treatment funded through voluntary health insurance.75 Overall, payments for pharmaceuticals (copayments and over-the-counter payments) make up 34% of household health expenditure, followed by therapeutic appliances and equipment (20%), hospital services (18%), dental services (12%), and outpatient medical services (10%).75 Prescription charges apply only in England (although about 90% of prescriptions are exempt from charges), having been abolished in Wales in 2007, Northern Ireland in 2010, and Scotland in 2011.76 Inequality in unmet need follows income patterns and is greater for dental care than it is for medical care, with people in the lowest income quintile consistently more likely to report unmet need for dental care due to cost, distance, or waiting times than people in the highest income quintile.77 In addition to out-of-pocket expenditure, there is voluntary health insurance for both dental and general health plans. In 2016, 10·5% of the UK population had some form of voluntary health insurance; 8% through employer-paid schemes and 2·5% through individually paid schemes.78 The numbers insured fell slightly following the recession in 2008 but have now stabilised, although there has been a gradual decrease in the number of individually paid subscribers.78 The share of households with voluntary health insurance varies substantially by income quintile, with more than 20% of those in the highest income quintile and less than 5% of those in the lowest income quintile having voluntary health insurance.77 There is also considerable variation regionally, with nearly half of the share of UK spending on voluntary health insurance concentrated in London and the southeast (appendix p 6). What level of spending is needed in the future for a sustainable health and care service? Projections of health spending Projections of health spending are essential to understand the level of spending needed in the future for a sustainable health and care service. These projections need to take into account the goals of the health system, such as maintaining quality and access to a range of services in line with public expectations. Several bodies, such as the Office for Budget Responsibility and the OECD, produce top-down projections of health spending for the UK and other countries (table ). Such projections involve focusing on the three main drivers of health spending, categorised as demographic factors, income effects, and other cost pressures.80 The Institute for Fiscal Studies with the Health Foundation and the Institute for Public Policy Research both have produced bottom-up projections of health, which are populated with component-based data, such as drug costs, provider activity, and salaries (table). These projections were all made before the COVID-19 pandemic and thus do not factor in the consequences of the pandemic or additional funding required for preparedness to withstand further acute shocks and major threats to health. Arguably, the bottom-up projections better capture factors relevant to the UK than the top-down projections and consequently provide more robust forecasts. This approach does, however, require significantly more country-specific data than the top-down approach, making it less feasible if projecting expenditure for many different countries. However, synergies can be identified between the top-down and bottom-up approaches, and both approaches take account of long-term projections of GDP growth, produced by organisations such as the Office for Budget Responsibility81 and the OECD.82 Table Selected projections of public spending on health in the UK Baseline expenditure (% of GDP) Annual real growth Projected expenditure (% of GDP) Top-down projections OECD (cost-containment) 6·5% (2010) Not calculated 7·9% (2030; 1·4% increase) OECD (constant cost-pressure) 6·5% (2010) Not calculated 8·4% (2030; 1·9% increase) Office for Budget Responsibility 7·1% (2017–18) Not calculated 9·9% (2037–38; 2·8% increase) Bottom-up projections Health Foundation with the Institute for Fiscal Studies (status quo) 7·3% (2018–19) 3·3% (2033–34) 8·9% (2033–34; 1·6% increase) Health Foundation with the Institute for Fiscal Studies (modernised scenario) 7·3% (2018–19) 4·0% (2033–34) 9·9% (2033–34; 2·6% increase) Institute for Public Policy Research (England) Not calculated (2016–17) 3·8% (2029–30) Not calculated Data are from the Office for Budget Responsibility,56 OECD,53 Institute for Public Policy Research,79 and The Health Foundation with the Institute for Fiscal Studies.1 GDP=gross domestic product. OECD=Organisation for Economic Co-operation and Development. Alongside demographic and income effects, top-down projections are particularly affected by alternative cost pressure scenarios, which take account of assumptions related to input prices (ie, labour, goods and services, and fixed capital), technological advances, and policy changes. The Office for Budget Responsibility and OECD projections assume that health-care sector productivity is lower than that of the rest of the economy. This difference is partially due to the Baumol effect,83 which suggests that wages in labour-intensive industries such as the health-care sector must keep pace with wages in sectors with higher productivity potential. The significance of the Baumol effect is debated,84 although both the OECD and the Office for Budget Responsibility assume there is a Baumol effect for health care, with pay increasing faster than productivity growth. The Baumol effect is often cited as contributing to rising health spending, although Baumol himself reflected that such increased spending on health is neither necessarily unsustainable nor problematic as long as that spending is seen to be valued by society.85 The relationship between technological advances and health spending is also complex and often conflicting:86 in different cases, technology can increase costs, be cost-neutral, or even save costs. However, even if a technology is cost-saving, overall health expenditure might increase as the new technology allows expansion of treatment, increasing treatment volume, and therefore increasing overall expenditure. Therefore, there is considerable uncertainty regarding to what degree technology will increase costs in the future. The effect of cost pressures is challenging to forecast and, not surprisingly, results in large variability in projections.52 The OECD produces a cost-containment scenario, which assumes that changes in policy act more strongly than in the past to rein in some of the expenditure growth, and an alternative scenario (the cost-pressure scenario), which assumes that cost pressures continue at 1·7% a year, the average historical growth across all countries in the OECD. The cost-containment scenario projects spending for the UK to increase by 1·4% of GDP, whereas the cost-pressure scenario projects an increase of 1·9% of GDP by 2030. The Office for Budget Responsibility's projection draws upon a 2015–16 NHS England estimate of non-demographic cost pressures of 2·7% per year for primary care and 1·2% per year for secondary care.56 The projections assume these pressures will decline over time to 1% per year from 2036–37 onwards. The rationale for this assumption is that this decline might be expected as health spending takes up an even larger share of national income. This approach projects an increase of 2·6% of GDP in health spending by 2037–38. The Institute for Fiscal Studies and Health Foundation bottom-up projections use two alternative scenarios. The status-quo scenario takes account of core demand and cost pressures but does not provide sufficient funding to return waiting times to their target levels, support improvements to quality and outcomes, or modernise the physical infrastructure of the health service. This scenario projects an annual real growth rate of 3·3% for the UK and public spending of 8·9% of GDP by 2033–34. The alternative scenario by the Institute for Fiscal Studies and Health Foundation returns the NHS to previous levels of care quality and allows improvement in key priority areas of unmet need, including Accident and Emergency performance, waiting times for elective care, outpatient appointments, mental health, capital spending, and public health. This scenario projects an annual average real growth rate of 4% and public spending of 9·9% of GDP by 2033–34.1 Further areas of unmet need are identified in other accompanying LSE–Lancet Commission background papers, such as those on the health and care workforce51 and health information technology.87 The 4% growth rate is also broadly consistent with the other bottom-up projections from the Institute for Public Policy Research, which also uses a bottom-up methodology and projects a real annual growth rate of around 3·8%.82 When analysing these approaches together, some conclusions can be made. Top-down projections show that assumptions related to input prices, technological advances, and policy changes significantly affect future estimates of health spending. From bottom-up projections, there is a broad consensus that health spending needs to increase by 3·3–4% per year in real terms. However, if we are to seek improvements in the quality of NHS care rather than oversee gradual reductions in quality of care, increases need to average at least 4% per year in real terms. Further evidence to support such increases in health spending is contained in our background paper on the health and care workforce,51 which estimates that increases in health spending of 4% per year in real terms are necessary to sustain growth in the workforce at 2·3% per year. However, it is important to note that these top-down projections were done before the COVID-19 pandemic and assume that GDP growth will increase on average by 1·9% per year until 2033–34.1 Therefore, these projections give an indication of the level of spending required for a long-term funding settlement for the NHS, assuming GDP growth in the long term returns to pre-pandemic projections. In the short term, further increases in public spending will continue to be needed for the NHS to respond to the pandemic and address the growing unmet need for health-care services caused by postponing or cancelling elective procedures and diagnostic tests. We also recommend an independent review to examine what additional funds are required to improve the preparedness and resilience of the health and care system to withstand further acute shocks and major threats to health. Projections of social care spending With current eligibility criteria maintained, projections from the Personal Social Services Research Unit (now known as the Care Policy and Evaluation Centre), adapted by the Institute for Fiscal Studies and Health Foundation, conclude that public funding for social care needs to increase by 3·9% per year until at least 2033 to meet demand (figure 4 ). These projections estimate future demand for adult social care by including projections of population size, age, gender, prevalence of disability, and future expenditure by projecting the rising cost of providing social care services. Included in the expenditure projections is the assumption that health and social care costs rise in real terms in line with productivity, with an uplift to take account of the planned rises in the national living wage.88 Figure 4 UK social care spending projections Source: Institute for Fiscal Studies and Health Foundation,1 and the Personal Social Services Research Unit.1, 88 It is also important to note that reform of the social care model is long overdue. In England and Northern Ireland, current eligibility criteria and thresholds have remained unchanged since 2010–11, which has contributed to more than 400 000 fewer people accessing publicly funded social care in England in 2016−17 than in 2009−10, despite growing needs associated with population ageing.89 Future public social care spending will be dependent upon whether and how social care funding is reformed. Different options have been explored to reach a long-term funding settlement for social care. The Dilnot Commission on Fairer Care Funding suggested a lifetime cap of individual contributions of £35 000 and a means-tested threshold of £100 000.64 The government responded by initially suggesting the introduction of a lifetime cap for individual contributions of £75 000, although this cap has been postponed indefinitely.90 The 2017 Conservative election manifesto proposed implementing a means-tested threshold of £100 000, as suggested by the Dilnot Commission.91 The 2019 Conservative manifesto recommitted to the concept of improved financial protection,92 but no reform has taken place to date. No matter what reform is introduced for social care, a guiding principle should be to increase financial protection, so a substantial increase in public funding is likely to be required. For example, it has been estimated that implementing a means-tested threshold of £100 000 and a lifetime cap of £75 000 on individual contributions in England alone would cost an additional £3·2 billion, according to 2018–19 prices.93 Productivity and health spending Any claims made for increased spending on health or social care will need to come with the assurance that these funds will be put to good use. Such an assessment is most commonly established by measuring productivity, which compares the amount of output produced against the inputs used by any particular sector of the economy. In the health-care sector, outputs are measured by taking account of factors such as the number of hospital patients treated as elective cases, day cases, or emergency admissions, and the number of outpatient contacts in primary care, mental health, and community trusts.94 These outputs are cost-weighted and quality-adjusted using indicators such as patient-reported outcome measures, waiting times, survival in hospital settings, and the quality and outcomes framework in primary care.94 Health outcomes such as life expectancy are not considered as outputs, as these are not wholly attributable to the health-care sector. Health-care inputs include the number of doctors, nurses, and support staff providing care, the equipment and clinical supplies used, and the hospitals and other premises where care is provided.94 If growth in output exceeds growth in input, health-care productivity increases. However, productivity might increase if inputs are cut. The rate of productivity growth in the health-care sector since the early 2000s compares favourably with that achieved by other public sectors and the economy as a whole.95 However, the NHS, like the economy as a whole, faces challenges in continuing to make productivity gains.96 There are concerns that positive past productivity growth will not persist into the future. Past productivity gains might have been achieved by restricting growth in staffing levels, implying that existing staff have been working harder at a time when wage growth up to 2018–19 was limited to 1% per year—such a position is not sustainable. To retain staff and keep them motivated, especially in a situation of reduced immigration, wages will have to increase in line with economy-wide average earnings. For social care, reductions in productivity might be due to the high turnover of low-paid staff employed in a sector characterised by weak employment conditions, which itself reflects an increasing mismatch between funding and current demand. Low wages and reduced bed availability have negatively affected morale and left providers not capable of improving productivity. Staff also need the right equipment and technology to do their jobs. It has long been recognised that many of the more productive companies are those that have invested more heavily in capital and technology,97 a process termed capital deepening.98 But in recent years, the NHS has experienced the reverse; capital funds have been raided to fund hospital deficits, leading to a backlog in maintenance and poor investment in technology.99 Capital investment per NHS worker has fallen in real terms by 17% between 2010–11 and 2017–18.100 This decline will need to be rectified to secure future productivity growth. Looking forward, working existing inputs harder will not be enough. It will be essential that the NHS becomes better at reducing inefficiency and unwarranted variations in practice. Conclusion This Health Policy paper has covered a series of policy questions, and several conclusions can be drawn. The health and care sectors undeniably play a valuable role in improving population health and societal wellbeing, reducing health and income inequalities, and supporting economic growth. The UK has witnessed a large increase in health spending since the NHS was established, but growth in spending has slowed significantly in recent years. The UK spends around the average of the EU15, but still less than many other comparable high-income nations. Real-term funding for social care has decreased in recent years, which has implications for the NHS because the two sectors are inextricably linked. Within the UK, there is variation in health and care spending, with Scotland, Wales, and Northern Ireland all spending more per person than England does. The role of private spending also varies considerably and is concentrated in high-income groups, particularly in London and the southeast. We conclude that, for a sustainable health and care service, public spending on the NHS and social care will need to increase on average by at least 4% per year in real terms. An independent review is needed to estimate the additional funds required to improve the preparedness and resilience of the health and care system to withstand acute shocks and major threats to health. The pandemic will be responsible for a substantial recession that creates challenges to sustaining increases in health and care spending. It must be remembered that the NHS was established shortly after World War 2, during one of the most economically challenging times the UK has endured. The foundations for today's social care system were also laid at that time. As then, the NHS and social care will be integral to the recovery of the economy and society in general. Declaration of interests We declare no competing interests. Supplementary Material Supplementary appendix Acknowledgments Funding for the LSE–Lancet Commission on the future of the NHS was granted by the LSE Knowledge and Exchange Impact (KEI) fund, which was created using funds from the Higher Education Innovation Fund (HEIF). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Contributors AC led the working group that prepared the paper. AC, MA, and MW drafted the paper. MA and MW managed the processes of the working group, compiled the data and graphics, and contributed to editing. 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10.1016/S0140-6736(21)00230-0

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00230-0 10.1016/S0140-6736(21)00230-0 Health Policy What is the right level of spending needed for health and care in the UK? Charlesworth Anita Prof MSc ab Anderson Michael MSc c* Donaldson Cam Prof PhD d Johnson Paul Prof MSc e Knapp Martin Prof PhD c McGuire Alistair Prof PhD c McKee Martin Prof MD f Mossialos Elias Prof PhD c Smith Peter Prof MSc gh Street Andrew Prof PhD c Woods Michael MSc c† a The Health Foundation, London, UK b College of Social Sciences, Health Services Management Centre, University of Birmingham, Birmingham, UK c Department of Health Policy, London School of Economics and Political Science, London, UK d Yunus Centre for Social Business and Health, Glasgow Caledonian University, Glasgow, UK e Institute for Fiscal Studies, London, UK f Department of Health Services Research and Policy, London School of Hygiene & Tropical Medicine, London, UK g Centre for Health Economics and Policy Innovation, Imperial College London, London, UK h Centre for Health Economics, University of York, York, UK * Correspondence to: Dr Michael Anderson, Department of Health Policy, London School of Economics and Political Science, London WC2A 2AE, UK † Except for the first author, the remaining coauthors are listed alphabetically as they provided equal contributions to this paper 6 5 2021 22-28 May 2021 6 5 2021 397 10288 20122022 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The health and care sector plays a valuable role in improving population health and societal wellbeing, protecting people from the financial consequences of illness, reducing health and income inequalities, and supporting economic growth. However, there is much debate regarding the appropriate level of funding for health and care in the UK. In this Health Policy paper, we look at the economic impact of the COVID-19 pandemic and historical spending in the UK and comparable countries, assess the role of private spending, and review spending projections to estimate future needs. Public spending on health has increased by 3·7% a year on average since the National Health Service (NHS) was founded in 1948 and, since then, has continued to assume a larger share of both the economy and government expenditure. In the decade before the ongoing pandemic started, the rate of growth of government spending for the health and care sector slowed. We argue that without average growth in public spending on health of at least 4% per year in real terms, there is a real risk of degradation of the NHS, reductions in coverage of benefits, increased inequalities, and increased reliance on private financing. A similar, if not higher, level of growth in public spending on social care is needed to provide high standards of care and decent terms and conditions for social care staff, alongside an immediate uplift in public spending to implement long-overdue reforms recommended by the Dilnot Commission to improve financial protection. COVID-19 has highlighted major issues in the capacity and resilience of the health and care system. We recommend an independent review to examine the precise amount of additional funds that are required to better equip the UK to withstand further acute shocks and major threats to health. ==== Body pmcIntroduction Since the National Health Service (NHS) was founded in the UK in 1948, public spending on health has more than doubled from 3·5% of gross domestic product (GDP) then to 7·2% in 2018–19.1, 2 In real terms, spending is more than 10 times the amount it was 70 years ago.1 Despite the scale of growth in health and care spending, there have been repeated crises, as funding increases have not kept pace with rising demand, expectations, or technological needs.3 In the decade preceding the COVID-19 pandemic, measures to cope with the gap between demand and funding for health care in the UK have included raiding funds intended for capital investment to boost revenue spending and restricting growth in staff pay, alongside announcements to increase public funding, such as the 2018 pledge to increase funding for the NHS in England by £20·5 billion per year in real terms by 2023–24,4 and the 2019 pledge to increase capital investment in the NHS in England by £1·8 billion.5 We argue that instead of short-term and reactive funding measures, a longer-term solution for both NHS and social care funding is necessary for a sustainable health and care service, which we define as a service that provides, as a minimum, similar levels of quality and access as are currently enjoyed, taking into account future trends in demography, morbidity, and technology. Increased investment is also needed to improve the preparedness and resilience of the health and care system to withstand acute shocks and major threats to health. Survey data indicate that, if funding for the NHS were to increase, the majority of the public would support tax increases.6 Public views on who should pay for social care are more nuanced, but more than half of people surveyed believe the government should pay, although perhaps only for individuals on low incomes.7 However, there needs to be increased clarity about the level of funding necessary for a sustainable health and care service. This Health Policy paper attempts to provide such clarity, while also being conscious of the considerable economic uncertainty created by the COVID-19 pandemic. Consequently, we begin with a discussion on the state of the economy and the potential economic impact of the recent COVID-19 pandemic. We then discuss the contribution of the health and care sector to wider society, health spending in the UK in comparison to other countries, trends in spending over time and across the UK, and the role of private spending on health. Finally, we assess the level of spending that is needed for a sustainable health and care service. All these topics are linked to the fiscal sustainability challenges identified by the Office for Budget Responsibility,8 and the Organisation for Economic Co-operation and Development (OECD).9 The economy and the COVID-19 pandemic The social distancing measures implemented in response to the pandemic were necessary to slow the spread of SARS-CoV-2 and limit excess mortality, but they have also closed down business activity in many sectors and had a striking impact on the UK's economic output. The Office for Budget Responsibility estimates that GDP in the UK fell by 9·9% in 2020, the largest decline out of all G7 countries.10 While the UK's rapid roll-out of vaccination creates the potential for the its economy to rebound quicker than those of many other nations, future growth is still highly dependent upon the effectiveness of vaccination in preventing any further waves of infections and associated lockdowns. However, at the time of writing, there is consensus among projections from the Office for Budget Responsibility, the OECD, and the Institute for Fiscal Studies, that GDP is expected to recover to pre-pandemic levels at some point in 2022.10, 11, 12 Future economic growth is also uncertain because of the UK leaving the EU. Most projections indicate that the growth of the UK economy will be smaller after leaving the EU than it would have been with continuing membership.13 Key messages • According to estimates by the Office for Budget Responsibility, gross domestic product in the UK fell by 9·9% in 2020, the largest decline out of all G7 countries, while future growth is highly uncertain and dependent upon the effectiveness of vaccination in preventing any further waves of infections and associated lockdowns • Achieving increased health spending against this economic backdrop requires a combination of increased government borrowing in the short term and taxation in the medium-to-long term • There is a strong economic rationale to invest in the health and care sector, to improve health and societal wellbeing, and reduce health and income inequalities • In common with countries across the OECD, health spending in the UK has grown faster than the overall economy; however, growth in health and care spending has been highly volatile, with periods of relative plenty followed by periods of relative austerity • Spending volatility is not conducive to long-term planning and efficiency; to secure the long-term future of the National Health Service (NHS), there is a need for increased consensus regarding the right level of spending for health and care in the UK • Although responsibility for health and care delivery is devolved to the four nations, spending decisions in England affect Scotland, Wales, and Northern Ireland through proportional allocations set by the Barnett formula • Private spending on health plays a small role in the UK, and a major strength of the NHS is in providing protection against the financial consequences of ill health • For the NHS, to meet cost and demand pressures over the next 15 years, spending needs to grow on average by at least 3·3% per year in real terms; however, to improve the quality of services, reduce waiting times, increase staffing numbers, and invest in capital, spending will need to grow on average by at least 4% per year in real terms • For social care, to meet cost and demand pressures over the next 15 years, spending needs to grow on average by 3·9% per year in real terms; improving financial protection by introducing a means-tested threshold of £100 000 and a maximum contribution of £75 000 in England would require even more in social care spending • In the short term, a further uplift in public spending is needed to address the growing unmet need for health-care services caused by postponing or cancelling elective procedures and diagnostic tests during the pandemic • We also recommend an independent review to examine what additional funds are required to improve the preparedness and resilience of the health and care system to withstand further acute shocks and major threats to health Combined with the impact of a weaker economy, the Office for Budget Responsibility's estimates that government borrowing reached £355 billion in 202010 represent the highest deficit since World War 2. However, there is consensus among economists that immediate reductions in public spending or acute rises in taxation would make the long-term situation worse.14, 15 Increased public spending is needed to support individuals and businesses through, for example, furlough pay, grants, and loans, and to mitigate against potential long-term effects on the economy from otherwise viable businesses failing and high and sustained unemployment. Moreover, the period of austerity preceding the pandemic left the health and care system under-resourced and vulnerable to an acute shock and major threats to health. This state of affairs ultimately exacerbated the economic impact of the pandemic itself and has reinforced the economic case for developing a resilient health and care system. Such a system will require the UK Government to place improving health and societal wellbeing at the heart of policy making and commit to sustained increases in health and care spending. While we acknowledge it will be challenging to achieve this shift in the current economic climate, we argue that it could be achieved through a combination of increased government borrowing in the short term and taxation in the medium-to-long term. What is the contribution of the health and care sector to wider society? The health and care sector is valuable: it improves the health and wellbeing of the population, reduces inequalities, and improves societal welfare. The sector also improves productivity and output through the associated increases in population health, which is especially important as the retirement age is increasing. Furthermore, the health and care sector is a large part of the economy, accounting for 4·5 million jobs in 2018 (approximately one in eight jobs in the UK and nearly one in six jobs in Wales). Health spending and health outcomes The contribution that health spending makes towards improving health outcomes has been difficult to establish because outcomes are influenced by a range of environmental, social, and economic factors beyond the health and care system. Moreover, analysis of historical trends is not necessarily a predictor of future trends. Nevertheless, some studies attempt to quantify the link between health system spending and health outcomes.16 Research using the concept of amenable mortality,17 now incorporated in the Health Access and Quality Index, has shown that effective and timely health care makes a substantial contribution to population health.18 Several analyses of NHS programme budgeting data show a clear link between increased health spending and improved health outcomes in the NHS, with the cost of securing an extra quality-adjusted life year ranging between £5000 and £15 000.19, 20, 21 At the macro level, an analysis of OECD countries concluded that increased health and care expenditure was associated with better health outcomes.22 The return on expenditure varies across countries, being lowest in the USA, partly because high prices mean that expenditure buys a lower volume of health care.23, 24 Research by the OECD in 2017 found that, across 35 member countries between 1995 and 2015, a 10% increase in health spending was associated with a life expectancy gain of 3·5 months,25 although no measures of uncertainty were included in the analysis. Some of these macro-level analyses overlook the fact that the effect of health spending on health outcomes is also dependent on how resources are allocated throughout the system. For example, investments in prevention might increase life expectancy more than those in end-of-life care, and investments in front-line services might improve health outcomes more than those in expensive drugs or medical devices. Therefore, as health systems continue to manage resources in a climate of resource scarcity, optimising allocative efficiency will be an essential strategy to maximise the health gains from health spending. Health outcomes and economic growth There is a growing literature focusing on the effect of improving health outcomes on macroeconomic growth and the mechanisms through which this occurs, although this is a challenging area in which to find causal evidence. Nevertheless, better health has been shown to increase labour market participation and worker productivity, which can increase economic growth.26 There is also evidence that increased life expectancy increases incentives to invest in education,27, 28 which in turn can improve productivity. Poor health during childhood has also been shown to be a predictor of worsened health in later life.29, 30 Therefore, as improved health can increase overall labour force participation, especially near to and after retirement age,31, 32 childhood health can have long-lasting effects on economic growth. Furthermore, illness and disability increase the likelihood of being unemployed in the UK,33 and being unwell at work (so-called presenteeism) is responsible for a considerable cost to the UK economy.34 The International Monetary Fund has also found evidence that providing increased access to health services can reduce the decline in total factor productivity and thus enhance economic growth from an ageing workforce.35 The COVID-19 pandemic has also shown the extreme effect that a health crisis can have on the economy. Health spending, societal welfare, and inequality Beyond the potential benefits for macroeconomic growth, well directed health and care expenditure improves overall societal welfare. For example, improved health in old age can reduce isolation and facilitate greater participation in society. The reverse is also true: care expenditure to reduce social isolation has health benefits.36, 37 People also derive utility from the knowledge that other people can access health care—a so-called caring externality.38 A key founding motivation for the NHS was that the sick deserve care, irrespective of their financial circumstances or contributions to the economy.39 While the NHS has been largely successful in providing care on the basis of clinical need and not ability to pay, there remain substantial inequalities in health outcomes. There is estimated to be a 7·4-year difference in life expectancy and an 18·9-year difference in healthy life expectancy between people in the highest and lowest deprivation deciles (appendix p 1). Although the UK has seen considerable increases in life expectancy, the rate of increase has slowed markedly since 2010 and, at some ages, reversed,40 an issue discussed further within the Health Policy paper on changing health needs linked to the main LSE–Lancet Commission report.41 However, it is important to emphasise the restricted influence of the health and care sector on health and wellbeing inequalities, which are strongly driven by a range of social determinants.42, 43 Nevertheless, it has been argued that the NHS often compensates when other parts of the social safety net fail.44 The NHS is funded through general taxation, which is largely progressive. Resources are also distributed using a needs-based resource allocation formula that reflects deprivation.45 Broadly, people on higher incomes subsidise people on lower incomes, and employed people subsidise unemployed people; in addition, because of the positive association between health and income, healthier individuals subsidise less healthy individuals,46 further reducing inequality.47, 48 The redistributive effect also depends on the utilisation of health care. Evidence from the NHS in England49 suggests that lifetime hospital costs are substantially higher in more deprived populations, thereby increasing the redistributive effect. How does health spending in the UK compare with other countries? The UK spent 10·3% of GDP on health in 2019 (including both public and private spending), similar to the average of the EU15 group of countries (9·4% of GDP; figure 1 ). The highest-spending countries in the EU are Germany (11·7%), France (11·2%), and Sweden (10·9%). The UK spent less than the average of the G7 group of countries (11·5%), which includes the USA (17·0%). In 2018, 78% of health spending in the UK came from public funds—similar to the share in the EU15 (77%), but slightly above that in the G7 (73%). Public spending includes government spending or compulsory health insurance, whereas private spending includes any voluntary health insurance or out-of-pocket payments.50 The OECD definition of health spending includes aspects of long-term care that are conventionally understood as social care spending in the UK context.50 Figure 1 Spending on health in G7 and EU15 countries (2019) Source: Organisation for Economic Co-operation. GDP=gross domestic product. PPP=purchasing power parity. *Public–private split data for the USA is for 2013; although there are more recent data available, older data are used to provide comparable split with data from other countries. Although total spending on health as a proportion of GDP in the UK is above the EU15 average, it is around 6% lower than the EU15 average in terms of $US per person ($3620 vs $3837; figure 1). Furthermore, the UK generally has relatively little capital, such as the number of hospital beds and diagnostic equipment, and a small workforce (eg, nurses and physicians; appendix p 2). Possible explanations for the low number of resources but similar spending levels to other comparable high-income countries could be differences in input prices (eg, physician wages),23 differences in skill mix (eg, greater reliance on non-clinical staff),51 or an ongoing shift towards moving care delivery from hospitals to the community. International comparisons of health spending, capital, and workforce should be interpreted with caution. Data might not be comparable and contextual factors contribute to variations. For example, low numbers of hospital beds could reflect either a scarcity of capital investment or successful efforts to move care away from the hospital to community settings. Similarly, low numbers of physicians and nurses might reflect an understaffed workforce or different approaches to skill mix across health and care workers. It should be noted that, although the UK has comparatively lower numbers of clinical staff per person, such as nurses and physicians, the number of staff per person in the total health and care workforce is just above the average of EU15 and G7 countries (appendix p 2), which suggests that the UK makes greater use of skill mix (eg, non-clinical staff and allied health-care professionals). How has health and care spending changed over time? Public spending on health Since the NHS was founded, spending has increased by more than inflation and GDP, rising by an average of 3·7% a year in real terms (appendix p 3).1 Three major factors determine the path of health spending over the long term: demographic factors, income effects, and other cost pressures.52 Demographic factors include the age structure of the population, health status at given ages, and death-related costs. Income effects reflect the fact that people generally demand more health care as their income rises. Other cost pressures include the effect of technological advancements and the increasing relative cost of health care. Over time, these factors have led health spending in the UK to increase at a faster rate than national income, which is consistent with the pattern seen across OECD countries.53 On only three occasions have there been notable spending reductions: twice in the early 1950s and in 1977–78 when the International Monetary Fund was called upon to support the UK economy. However, year-on-year spending growth has been highly volatile, with periods of relative plenty followed by periods of relative austerity. Between 1948 and 1978, spending increased on average by 3·5% a year. During the Conservative Governments of 1979 to 1997, spending growth was slightly lower, at 3·3% a year. Spending growth increased substantially under the Labour Governments between 1997 and 2009, averaging an increase of 6% a year.54 Between 2010 and 2018, health spending has grown at a markedly slower rate of just 1·2% a year (figure 2 ).54 The UK population has been increasing in size, so per-capita spending has been increasing at a slower rate than NHS expenditure. Moreover, the composition of the population has been changing and becoming older, meaning growth in age-adjusted spending is lower than growth in per-capita spending because older people tend to make greater use of health care. However, it is important not to overemphasise the contribution of population ageing, as individuals generally still see most health expenditure in their last year of life even as the population ages. It has been estimated that, independent of population ageing, cost growth and technological advancements will be the main drivers of future growth in health spending.56 Figure 2 Index of real UK health spending after 2009–10 Total, per-capita, and age-adjusted per-capita spending in 2009–10 each take the value 100. Data are from the UK Government Public Expenditure Statistics Analyses,2 Office for Budget Responsibility,55 and Office for National Statistics. Public spending on social care The health and care sectors are linked, and many ill people require support from both. If health and care services are complementary, reduced spending on social care might put greater pressure on the health sector, and vice versa. While spending on adult social care has been reduced in real terms during the past decade, the reduction is significantly larger when adjusted for per-capita and age-adjusted per-capita spending (figure 3 ).Figure 3 Index of real UK adult social care spending after 2009–10 Total, per-capita, and age-adjusted per-capita spending in 2009–10 each take the value 100. Data are from the UK Government Public Expenditure Statistics Analyses,2 Office for Budget Responsibility,55 and Office for National Statistics. How does health and care spending vary across the UK? Public spending on health across the UK The funding systems in each of the four countries of the UK remain tax-based and free at the point of use, with divergence in the use of prescription charges (see the role of private spending below). Publicly funded health spending per person varies across the four UK countries (appendix p 4). Total funding allocations to each UK country for government spending are based on a combination of historical spending and the Barnett formula, which proportionally adjusts any uplift in government spending in England according to population size to Scotland, Wales, and Northern Ireland.57 Each UK nation then decides how to allocate its resources during annual spending reviews. Within England, around two-thirds of the NHS budget is allocated via weighted capitation payments (ie, predefined payments per head of the population calculated to reflect expected need for health care) to local commissioning bodies, taking account of population factors such as age, gender, and deprivation.45 Public spending on health per person is highest in Scotland and lowest in England (appendix p 4). However, there are regions in England, such as the northeast and London, with higher spending per person than that in Scotland. Differences across the UK in spending per person have narrowed, ranging from £1598–£2471 in 2010–11 to £1915–£2665 in 2017–18 (appendix p 4). This trend warrants further investigation, as it is not clear if demographic changes in relative need between regions are responsible or if other contributory factors exist. Once allocated to local commissioning bodies in England, an internal market exists whereby both the NHS and independent-sector hospitals are eligible to provide treatment for NHS patients. In 2017–18, independent-sector hospitals provided over 600 000 publicly funded elective procedures—6% of all NHS elective activity—growing from less than 2000 elective procedures in 2003–04.58 For some procedures such as hip replacements, independent-sector hospitals now provide 30% of all NHS-funded procedures.58 Analyses indicate that such reforms, despite less complex patients being treated in the independent care sector, might have improved access and outcomes.59, 60 However, concerns have been raised regarding a relative absence of transparency in independent-sector hospitals61 and the potential impact on the sustainability of NHS services.62 During the pandemic, independent-sector hospitals have been used to allow the continuation of NHS cancer treatment and elective procedures in facilities that have low exposure to COVID-19.63 Public spending on social care across the UK The constituent countries of the UK are responsible for social care within their jurisdictions, leading to variation in eligibility criteria and differences in patterns of both funding and delivery. For example, in Scotland, personal and nursing care are free, whereas, in England, all social care is means-tested (appendix p 5). Means-testing can lead to substantial costs incurred by older people needing social care support—the 2011 Dilnot Commission on social care in England found that one in ten people, at age 65, would face future lifetime care costs of £100 000.64 Social care spending per adult is 31% lower in England than in Scotland, where there is a system of free personal care for older people (appendix p 5). Although differences between the four UK nations might reflect differences in eligibility criteria and needs, they also reflect the larger cuts to social care in England since 2011 (appendix p 5). The Institute for Fiscal Studies estimated that between 2009–10 and 2017–18, councils in the most deprived areas made cuts to adult social care of 17% per person, compared with cuts of 3% per person in councils in the least deprived areas.65 These differences in social care eligibility and funding across the UK do not appear to have influenced preparedness against COVID-19, as all constituent countries experienced significantly increased excess mortality in care homes during the pandemic.66, 67, 68 What is the role of private spending on health in the UK? There is no developed country in which private spending is the predominant financing mechanism for health-care services (figure 1). Even in the USA, which has a more extensively privatised financing model, there is still a significant public system to provide coverage for low-income, older, and veteran populations. Indeed, despite substantial private financing, public spending in the USA still accounts for a higher percentage of GDP than it does in the UK (figure 1). Notably, countries with more privatised models have higher inequalities in access to health-care services,69 a lower redistributive effect between income groups,46 and a higher incidence of catastrophic health expenditure.70 In the UK, private spending on health is a little more than a fifth of all spending.54 However, most of the private spending on health is concentrated among individuals in the highest income quintile,71 with those in the lowest income quintile typically exempt from out-of-pocket payments to access NHS services.72, 73 Generally, a major strength of the NHS compared with health-care systems in other high-income countries is financial protection, evidenced by a comparatively low incidence of catastrophic health expenditure, which is defined as out-of-pocket payments for health-care services exceeding a certain proportion of household income (appendix p 3). Factors that influence the level of financial protection in any country include gaps in coverage, the frequency and size of out-of-pocket payments, and whether coverage policy is designed in a manner that minimises out-of-pocket payments for people on low-incomes and regular users of health-care services.74 Household health expenditure accounts for a little less than 70% of private spending in the UK and includes both direct purchases of medical goods and services by households and treatment funded through voluntary health insurance.75 Overall, payments for pharmaceuticals (copayments and over-the-counter payments) make up 34% of household health expenditure, followed by therapeutic appliances and equipment (20%), hospital services (18%), dental services (12%), and outpatient medical services (10%).75 Prescription charges apply only in England (although about 90% of prescriptions are exempt from charges), having been abolished in Wales in 2007, Northern Ireland in 2010, and Scotland in 2011.76 Inequality in unmet need follows income patterns and is greater for dental care than it is for medical care, with people in the lowest income quintile consistently more likely to report unmet need for dental care due to cost, distance, or waiting times than people in the highest income quintile.77 In addition to out-of-pocket expenditure, there is voluntary health insurance for both dental and general health plans. In 2016, 10·5% of the UK population had some form of voluntary health insurance; 8% through employer-paid schemes and 2·5% through individually paid schemes.78 The numbers insured fell slightly following the recession in 2008 but have now stabilised, although there has been a gradual decrease in the number of individually paid subscribers.78 The share of households with voluntary health insurance varies substantially by income quintile, with more than 20% of those in the highest income quintile and less than 5% of those in the lowest income quintile having voluntary health insurance.77 There is also considerable variation regionally, with nearly half of the share of UK spending on voluntary health insurance concentrated in London and the southeast (appendix p 6). What level of spending is needed in the future for a sustainable health and care service? Projections of health spending Projections of health spending are essential to understand the level of spending needed in the future for a sustainable health and care service. These projections need to take into account the goals of the health system, such as maintaining quality and access to a range of services in line with public expectations. Several bodies, such as the Office for Budget Responsibility and the OECD, produce top-down projections of health spending for the UK and other countries (table ). Such projections involve focusing on the three main drivers of health spending, categorised as demographic factors, income effects, and other cost pressures.80 The Institute for Fiscal Studies with the Health Foundation and the Institute for Public Policy Research both have produced bottom-up projections of health, which are populated with component-based data, such as drug costs, provider activity, and salaries (table). These projections were all made before the COVID-19 pandemic and thus do not factor in the consequences of the pandemic or additional funding required for preparedness to withstand further acute shocks and major threats to health. Arguably, the bottom-up projections better capture factors relevant to the UK than the top-down projections and consequently provide more robust forecasts. This approach does, however, require significantly more country-specific data than the top-down approach, making it less feasible if projecting expenditure for many different countries. However, synergies can be identified between the top-down and bottom-up approaches, and both approaches take account of long-term projections of GDP growth, produced by organisations such as the Office for Budget Responsibility81 and the OECD.82 Table Selected projections of public spending on health in the UK Baseline expenditure (% of GDP) Annual real growth Projected expenditure (% of GDP) Top-down projections OECD (cost-containment) 6·5% (2010) Not calculated 7·9% (2030; 1·4% increase) OECD (constant cost-pressure) 6·5% (2010) Not calculated 8·4% (2030; 1·9% increase) Office for Budget Responsibility 7·1% (2017–18) Not calculated 9·9% (2037–38; 2·8% increase) Bottom-up projections Health Foundation with the Institute for Fiscal Studies (status quo) 7·3% (2018–19) 3·3% (2033–34) 8·9% (2033–34; 1·6% increase) Health Foundation with the Institute for Fiscal Studies (modernised scenario) 7·3% (2018–19) 4·0% (2033–34) 9·9% (2033–34; 2·6% increase) Institute for Public Policy Research (England) Not calculated (2016–17) 3·8% (2029–30) Not calculated Data are from the Office for Budget Responsibility,56 OECD,53 Institute for Public Policy Research,79 and The Health Foundation with the Institute for Fiscal Studies.1 GDP=gross domestic product. OECD=Organisation for Economic Co-operation and Development. Alongside demographic and income effects, top-down projections are particularly affected by alternative cost pressure scenarios, which take account of assumptions related to input prices (ie, labour, goods and services, and fixed capital), technological advances, and policy changes. The Office for Budget Responsibility and OECD projections assume that health-care sector productivity is lower than that of the rest of the economy. This difference is partially due to the Baumol effect,83 which suggests that wages in labour-intensive industries such as the health-care sector must keep pace with wages in sectors with higher productivity potential. The significance of the Baumol effect is debated,84 although both the OECD and the Office for Budget Responsibility assume there is a Baumol effect for health care, with pay increasing faster than productivity growth. The Baumol effect is often cited as contributing to rising health spending, although Baumol himself reflected that such increased spending on health is neither necessarily unsustainable nor problematic as long as that spending is seen to be valued by society.85 The relationship between technological advances and health spending is also complex and often conflicting:86 in different cases, technology can increase costs, be cost-neutral, or even save costs. However, even if a technology is cost-saving, overall health expenditure might increase as the new technology allows expansion of treatment, increasing treatment volume, and therefore increasing overall expenditure. Therefore, there is considerable uncertainty regarding to what degree technology will increase costs in the future. The effect of cost pressures is challenging to forecast and, not surprisingly, results in large variability in projections.52 The OECD produces a cost-containment scenario, which assumes that changes in policy act more strongly than in the past to rein in some of the expenditure growth, and an alternative scenario (the cost-pressure scenario), which assumes that cost pressures continue at 1·7% a year, the average historical growth across all countries in the OECD. The cost-containment scenario projects spending for the UK to increase by 1·4% of GDP, whereas the cost-pressure scenario projects an increase of 1·9% of GDP by 2030. The Office for Budget Responsibility's projection draws upon a 2015–16 NHS England estimate of non-demographic cost pressures of 2·7% per year for primary care and 1·2% per year for secondary care.56 The projections assume these pressures will decline over time to 1% per year from 2036–37 onwards. The rationale for this assumption is that this decline might be expected as health spending takes up an even larger share of national income. This approach projects an increase of 2·6% of GDP in health spending by 2037–38. The Institute for Fiscal Studies and Health Foundation bottom-up projections use two alternative scenarios. The status-quo scenario takes account of core demand and cost pressures but does not provide sufficient funding to return waiting times to their target levels, support improvements to quality and outcomes, or modernise the physical infrastructure of the health service. This scenario projects an annual real growth rate of 3·3% for the UK and public spending of 8·9% of GDP by 2033–34. The alternative scenario by the Institute for Fiscal Studies and Health Foundation returns the NHS to previous levels of care quality and allows improvement in key priority areas of unmet need, including Accident and Emergency performance, waiting times for elective care, outpatient appointments, mental health, capital spending, and public health. This scenario projects an annual average real growth rate of 4% and public spending of 9·9% of GDP by 2033–34.1 Further areas of unmet need are identified in other accompanying LSE–Lancet Commission background papers, such as those on the health and care workforce51 and health information technology.87 The 4% growth rate is also broadly consistent with the other bottom-up projections from the Institute for Public Policy Research, which also uses a bottom-up methodology and projects a real annual growth rate of around 3·8%.82 When analysing these approaches together, some conclusions can be made. Top-down projections show that assumptions related to input prices, technological advances, and policy changes significantly affect future estimates of health spending. From bottom-up projections, there is a broad consensus that health spending needs to increase by 3·3–4% per year in real terms. However, if we are to seek improvements in the quality of NHS care rather than oversee gradual reductions in quality of care, increases need to average at least 4% per year in real terms. Further evidence to support such increases in health spending is contained in our background paper on the health and care workforce,51 which estimates that increases in health spending of 4% per year in real terms are necessary to sustain growth in the workforce at 2·3% per year. However, it is important to note that these top-down projections were done before the COVID-19 pandemic and assume that GDP growth will increase on average by 1·9% per year until 2033–34.1 Therefore, these projections give an indication of the level of spending required for a long-term funding settlement for the NHS, assuming GDP growth in the long term returns to pre-pandemic projections. In the short term, further increases in public spending will continue to be needed for the NHS to respond to the pandemic and address the growing unmet need for health-care services caused by postponing or cancelling elective procedures and diagnostic tests. We also recommend an independent review to examine what additional funds are required to improve the preparedness and resilience of the health and care system to withstand further acute shocks and major threats to health. Projections of social care spending With current eligibility criteria maintained, projections from the Personal Social Services Research Unit (now known as the Care Policy and Evaluation Centre), adapted by the Institute for Fiscal Studies and Health Foundation, conclude that public funding for social care needs to increase by 3·9% per year until at least 2033 to meet demand (figure 4 ). These projections estimate future demand for adult social care by including projections of population size, age, gender, prevalence of disability, and future expenditure by projecting the rising cost of providing social care services. Included in the expenditure projections is the assumption that health and social care costs rise in real terms in line with productivity, with an uplift to take account of the planned rises in the national living wage.88 Figure 4 UK social care spending projections Source: Institute for Fiscal Studies and Health Foundation,1 and the Personal Social Services Research Unit.1, 88 It is also important to note that reform of the social care model is long overdue. In England and Northern Ireland, current eligibility criteria and thresholds have remained unchanged since 2010–11, which has contributed to more than 400 000 fewer people accessing publicly funded social care in England in 2016−17 than in 2009−10, despite growing needs associated with population ageing.89 Future public social care spending will be dependent upon whether and how social care funding is reformed. Different options have been explored to reach a long-term funding settlement for social care. The Dilnot Commission on Fairer Care Funding suggested a lifetime cap of individual contributions of £35 000 and a means-tested threshold of £100 000.64 The government responded by initially suggesting the introduction of a lifetime cap for individual contributions of £75 000, although this cap has been postponed indefinitely.90 The 2017 Conservative election manifesto proposed implementing a means-tested threshold of £100 000, as suggested by the Dilnot Commission.91 The 2019 Conservative manifesto recommitted to the concept of improved financial protection,92 but no reform has taken place to date. No matter what reform is introduced for social care, a guiding principle should be to increase financial protection, so a substantial increase in public funding is likely to be required. For example, it has been estimated that implementing a means-tested threshold of £100 000 and a lifetime cap of £75 000 on individual contributions in England alone would cost an additional £3·2 billion, according to 2018–19 prices.93 Productivity and health spending Any claims made for increased spending on health or social care will need to come with the assurance that these funds will be put to good use. Such an assessment is most commonly established by measuring productivity, which compares the amount of output produced against the inputs used by any particular sector of the economy. In the health-care sector, outputs are measured by taking account of factors such as the number of hospital patients treated as elective cases, day cases, or emergency admissions, and the number of outpatient contacts in primary care, mental health, and community trusts.94 These outputs are cost-weighted and quality-adjusted using indicators such as patient-reported outcome measures, waiting times, survival in hospital settings, and the quality and outcomes framework in primary care.94 Health outcomes such as life expectancy are not considered as outputs, as these are not wholly attributable to the health-care sector. Health-care inputs include the number of doctors, nurses, and support staff providing care, the equipment and clinical supplies used, and the hospitals and other premises where care is provided.94 If growth in output exceeds growth in input, health-care productivity increases. However, productivity might increase if inputs are cut. The rate of productivity growth in the health-care sector since the early 2000s compares favourably with that achieved by other public sectors and the economy as a whole.95 However, the NHS, like the economy as a whole, faces challenges in continuing to make productivity gains.96 There are concerns that positive past productivity growth will not persist into the future. Past productivity gains might have been achieved by restricting growth in staffing levels, implying that existing staff have been working harder at a time when wage growth up to 2018–19 was limited to 1% per year—such a position is not sustainable. To retain staff and keep them motivated, especially in a situation of reduced immigration, wages will have to increase in line with economy-wide average earnings. For social care, reductions in productivity might be due to the high turnover of low-paid staff employed in a sector characterised by weak employment conditions, which itself reflects an increasing mismatch between funding and current demand. Low wages and reduced bed availability have negatively affected morale and left providers not capable of improving productivity. Staff also need the right equipment and technology to do their jobs. It has long been recognised that many of the more productive companies are those that have invested more heavily in capital and technology,97 a process termed capital deepening.98 But in recent years, the NHS has experienced the reverse; capital funds have been raided to fund hospital deficits, leading to a backlog in maintenance and poor investment in technology.99 Capital investment per NHS worker has fallen in real terms by 17% between 2010–11 and 2017–18.100 This decline will need to be rectified to secure future productivity growth. Looking forward, working existing inputs harder will not be enough. It will be essential that the NHS becomes better at reducing inefficiency and unwarranted variations in practice. Conclusion This Health Policy paper has covered a series of policy questions, and several conclusions can be drawn. The health and care sectors undeniably play a valuable role in improving population health and societal wellbeing, reducing health and income inequalities, and supporting economic growth. The UK has witnessed a large increase in health spending since the NHS was established, but growth in spending has slowed significantly in recent years. The UK spends around the average of the EU15, but still less than many other comparable high-income nations. Real-term funding for social care has decreased in recent years, which has implications for the NHS because the two sectors are inextricably linked. Within the UK, there is variation in health and care spending, with Scotland, Wales, and Northern Ireland all spending more per person than England does. The role of private spending also varies considerably and is concentrated in high-income groups, particularly in London and the southeast. We conclude that, for a sustainable health and care service, public spending on the NHS and social care will need to increase on average by at least 4% per year in real terms. An independent review is needed to estimate the additional funds required to improve the preparedness and resilience of the health and care system to withstand acute shocks and major threats to health. The pandemic will be responsible for a substantial recession that creates challenges to sustaining increases in health and care spending. It must be remembered that the NHS was established shortly after World War 2, during one of the most economically challenging times the UK has endured. The foundations for today's social care system were also laid at that time. As then, the NHS and social care will be integral to the recovery of the economy and society in general. Declaration of interests We declare no competing interests. Supplementary Material Supplementary appendix Acknowledgments Funding for the LSE–Lancet Commission on the future of the NHS was granted by the LSE Knowledge and Exchange Impact (KEI) fund, which was created using funds from the Higher Education Innovation Fund (HEIF). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Contributors AC led the working group that prepared the paper. AC, MA, and MW drafted the paper. MA and MW managed the processes of the working group, compiled the data and graphics, and contributed to editing. All other authors provided critical input into the content and revisions to the text. ==== Refs References 1 Charlesworth A Johnson P Securing the future: funding health and social care to the 2030s https://www.ifs.org.uk/publications/12994 May 24, 2018 2 HM Treasury Public expenditure statistical analyses 2019 https://www.gov.uk/government/statistics/public-expenditure-statistical-analyses-2019 July 18, 2019 3 Mossialos E McGuire A Anderson M Pitchforth E James A Horton R The future of the NHS: no longer the envy of the world? 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Urology. 2022 Jan 10; 159:27

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Urology

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01237-X 10.1016/S0140-6736(21)01237-X Correspondence Addressing the real trajectory of COVID-19 in the Eastern Mediterranean region Alsaba Khuloud a a Department of Social Policy, University of Edinburgh, Edinburgh EH8 9YL, UK 8 7 2021 10-16 July 2021 8 7 2021 398 10295 116116 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcPierre Nabeth and colleagues1 highlight the resurgence in COVID-19 cases in the WHO Eastern Mediterranean region and identify factors that might have contributed to this rise. They identify changes in testing capacity, mass gatherings, decreased adherence to public health measures, and increased transmissibility of new SARS-CoV-2 variants emerging globally. Alarmingly, Nabeth and colleagues ignore the structural and social determinants of health in the Eastern Mediterranean region, and how these would affect the spread and impact of COVID-19. They did not address the substantial social and economic turmoil taking place in countries across the region. Except for a brief request for a special focus on conflict areas, they neglect the fact that more than a third of countries in this region are active war zones or fragile post-conflict countries.2 Similarly, any reference to countries in the region being among the largest hosting communities for the chronic and severe refugee crisis is omitted. Additionally, there is no reference to the continuing challenges that these countries face in the aftermath of the Arab uprisings, deteriorating livelihoods, and violations of human rights.3 Given the severity of socioeconomic effects across the region, Nabeth and colleagues still choose to focus on decreased public adherence to measures, such as physical distancing, which is particularly concerning. No mention is made of political factors such as the public denial of the pandemic among governments,4, 5 which not only delayed the response but also, catastrophically, further eroded public trust in health authorities. Most regrettable is the simplistic recommendation for “enforcement of, and adherence to, public health and social measures” by the governments in the Eastern Mediterranean region as the effective approach to address the resurge in SARS-CoV-2 infections, without any discussion of how such enforcement can be applied within these coercive contexts where violence is a key contextual determinant in public health. No consideration is shown of how the livelihoods of Syrian, Lebanese, and Sudanese people, among others, are dependent on daily wages in the informal labour markets, or that many social gatherings in these countries are, in fact, queues for food and medication. Such omissions highlight the real dangers inherent to organisations adopting a narrowly epidemiological approach in a region in which the trajectory of the pandemic is so strikingly shaped by the social and political determinants of health. I declare no competing interests. ==== Refs References 1 Nabeth P Hassam M Adib K Abubakar A Brennan R New COVID-19 resurgence in the WHO Eastern Mediterranean region Lancet 397 2021 1348 1349 2 Christophersen E These 10 countries receive the most refugees https://www.nrc.no/perspectives/2020/the-10-countries-that-receive-the-most-refugees/ Nov 1, 2020 3 Amnesty International MENA: repression and violence fail to stamp out Arab activism 10 years since mass uprisings of 2011 https://www.amnesty.org/en/latest/news/2021/02/mena-repression-and-violence-fail-to-stamp-out-arab-activism-10-years-since-mass-uprisings-of-2011/ Feb 25, 2021 4 Abdelaziz M The Egyptian response to coronavirus: denial and conspiracy https://www.washingtoninstitute.org/policy-analysis/egyptian-response-coronavirus-denial-and-conspiracy May 27, 2020 5 Gambrell J A pandemic atlas: no longer in viral denial, Iran struggles https://apnews.com/article/pandemics-iran-coronavirus-pandemic-ali-khamenei-islam-8c9578b5b86963f41cfc893bec9e9a68 Dec 16, 2020

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Lancet. 2021 Jul 8 10-16 July; 398(10295):116

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Lancet

10.1016/S0140-6736(21)01237-X

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00936-3 10.1016/S0140-6736(21)00936-3 Correspondence Gendered effects of COVID-19 on young girls in regions of conflict Nesamoney Sophia N a Darmstadt Gary L b Wise Paul H b a King Center on Global Development, Stanford University, Stanford, CA, USA b Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA 21 5 2021 22-28 May 2021 21 5 2021 397 10288 18801881 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe Series on Women's and Children's Health in Conflict Settings provides important guidance for addressing the health of women and children in areas of poor security and instability. However, we write to call special attention to the gender inequalities in areas of armed conflict and, in particular, the effects of the COVID-19 pandemic on young, school-age girls (aged 5–18 years). In settings of violent conflict, young girls are about 25 times more likely to be out of school than their male counterparts, and the COVID-19 pandemic appears to have exacerbated this disparity.1 The pandemic has also had substantial indirect effects on levels of poverty and child malnutrition which appear to have fallen hardest on young girls. In some areas of civil conflict, the pandemic has increased the power of armed non-state groups that threaten girls' access to education and other public goods. Several of these groups, such as the Taliban in Afghanistan and Boko Haram in Nigeria, routinely threaten girls' education, at times even conducting acid attacks, kidnappings, and killings of young girls and their families.2 The pandemic has also destabilised the security situation in ways that have expanded the exploitation of young girls in the sex trade and as child soldiers, as was seen in Boko Haram's use of girls as young as 7 years as suicide bombers.3 The effects of the COVID-19 pandemic have been far-reaching, but its impact on the health and wellbeing of young girls in areas of conflict and political instability deserves focused, urgent attention. PHW was a contributor to the Lancet Series on Women's and Children's Health in Conflict Settings. We declare no other competing interests. ==== Refs References 1 Georgetown Institute of Women, Peace, and Security Adolescent girls' access to education in conflict-affected settings https://giwps.georgetown.edu/resource/closing-the-gap/ 2016 2 Human Rights Watch Afghanistan: girls struggle for an education https://www.hrw.org/news/2017/10/17/afghanistan-girls-struggle-education/ 2020 3 Bloom M Matfess H Women as symbols and swords in Boko Haram's terror Prism 1 2016 105 121

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00229-4 10.1016/S0140-6736(21)00229-4 Health Policy The changing health needs of the UK population McKee Martin Prof MD a* Dunnell Karen BSc c*† Anderson Michael MSc d* Brayne Carol Prof MD e Charlesworth Anita Prof MSc bf Johnston-Webber Charlotte MSc d Knapp Martin Prof PhD d McGuire Alistair Prof PhD d Newton John N Prof FRCP g Taylor David Prof BSc h Watt Richard G Prof PhD i a Department of Health Services Research and Policy, London School of Hygiene & Tropical Medicine, London, UK b The Health Foundation, London, UK c London, UK d Department of Health Policy, London School of Economics and Political Science, London, UK e Cambridge Public Health, University of Cambridge, Cambridge, UK f College of Social Sciences, Health Services Management Centre, University of Birmingham, Birmingham, UK g Public Health England, London, UK h UCL School of Pharmacy, University College London, London, UK i Department of Epidemiology and Public Health, University College London, London, UK * Correspondence to: Dr Michael Anderson, Department of Health Policy, London School of Economics and Political Science, London WC2A 2AE, UK * Joint lead authors † Dame Dunnell retired in August, 2009 6 5 2021 22-28 May 2021 6 5 2021 397 10288 19791991 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The demographics of the UK population are changing and so is the need for health care. In this Health Policy, we explore the current health of the population, the changing health needs, and future threats to health. Relative to other high-income countries, the UK is lagging on many health outcomes, such as life expectancy and infant mortality, and there is a growing burden of mental illness. Successes exist, such as the striking improvements in oral health, but inequalities in health persist as well. The growth of the ageing population relative to the working-age population, the rise of multimorbidity, and persistent health inequalities, particularly for preventable illness, are all issues that the National Health Service (NHS) will face in the years to come. Meeting the challenges of the future will require an increased focus on health promotion and disease prevention, involving a more concerted effort to understand and tackle the multiple social, environmental, and economic factors that lie at the heart of health inequalities. The immediate priority of the NHS will be to mitigate the wider and long-term health consequences of the COVID-19 pandemic, but it must also strengthen its resilience to reduce the impact of other threats to health, such as the UK leaving the EU, climate change, and antimicrobial resistance. ==== Body pmcIntroduction The UK's National Health Service (NHS) has adapted over time to many changing health needs and to advances in the technical and organisational ability to address them. These changing health needs include major declines in infectious diseases and their evolving nature, as well as the rising importance of non-communicable diseases. Paediatric wards are no longer full of children with gastroenteritis, respiratory infections, and hepatitis A. Instead, these wards now provide specialised neonatal, genetic, and chronic disease services, among others.1 Innovations in the management of mental health and the resulting reconfiguration of services, such as the closure of long-stay institutions, have completely altered treatment pathways, with both positive and negative results. Cardiothoracic surgeons nowadays rarely dilate mitral valves damaged by rheumatic heart disease or resect tuberculous lung cavities; these days, they repair congenital heart disease or do transplants. Orthopaedic surgeons no longer transplant tendons of children affected by polio, they instead replace arthritic joints among older people.2 General practitioners rarely deliver babies in patients' homes but instead contribute clinical expertise to a range of services provided by multi-agency teams based in the community. Dentists very rarely provide full dentures for adults and instead concentrate on prevention and provision of restorative care, including implants and bridges.3 Entirely new clinical careers and specialties have emerged, such as specialist nurses, interventional radiologists, and palliative care specialists, while geriatricians, managing the complex needs of frail and ageing patients, work alongside a growing number of superspecialists.4 International comparative studies, particularly in earlier decades, indicate that the NHS has been relatively good at such adaptations.5 Its system of funding manages to avoid many perverse incentives seen in fee-for-service systems that encourage lucrative interventions to persist long after they have become obsolete, and professional associations, such as the Royal Colleges, emphasise maintaining high standards of training and research rather than negotiating terms and conditions, as is the case with some of their equivalents elsewhere. However, some would argue that progress has been slow and inadequate in adapting to epidemiological transition (eg, in mental health and the rise in dementia) and in adopting research and innovation at pace (eg, for stroke management). More recently, designated funding for health services research has helped build capacity enormously, relative to what exists in many other countries, but there remain many gaps in the evidence base. A culture of evaluation and audit has been promoted and has developed extensively in certain areas, especially in areas supported by systematic national data collection—eg, within the national clinical audit programme. This research capacity is now needed to understand and develop strategies to mitigate the potentially long-lasting physical and mental health impacts of the COVID-19 pandemic.6 The goals of a health system were set out in the World Health Report in 2000.7 They include improving health outcomes, responding to legitimate public expectations, and achieving fair financing. The third of these is addressed elsewhere in the Commission report. The first and second require an NHS that is cognisant of the changing needs of the population and can adapt quickly and flexibly to them, on the basis of evidence; when evidence is not available, the NHS should take steps to generate it. Subsequent thinking, developed more fully in the WHO Tallinn Charter,8 describes mutual relationships between health systems, population health, and economic growth.9 Put simply, the goal of society should be to create a health system that promotes better health and, through improved lives, secures economic growth, which in turn secures revenues to support appropriate health-care provision for all, as well as associated developments elsewhere, such as in social care. Health and health care can therefore be both inputs to and outputs from the economy. Yet, although it seems obvious that a key objective of the NHS should be to maximise the health of the UK population to the extent that this is possible for a health system to achieve, this interpretation has not always been shared by its leadership. The mission of the NHS has, in the past, been framed as the more limited, but potentially more tractable, objective of ensuring the provision of high-quality and safe health care to all in response to expressed need within available resources. This longstanding mismatch between the need for a service that optimises population health and a structure focused predominantly on health-care provision only might well have contributed to the UK's relatively poor performance on health outcomes. It is impossible, in a single paper, to provide a comprehensive analysis of the health of the UK population and its implications for the NHS. Consequently, it has been necessary to be somewhat selective. This paper proceeds as follows. We begin with an assessment of the current situation and how it has developed, starting with the most widely used summary measure of the health of the population: life expectancy. We then review some areas that have important implications for the NHS. These areas are mental health, maternal and child health, oral health (an area that has long existed on the margins of the NHS), and the growing challenge of multimorbidity, with major implications for models of service delivery. Further on, we look at three ways in which the health of the population is still changing: ageing, the composition of the working population, and the burden of disease. The NHS is, in many respects, responding to failures in other areas of policy. Consequently, in a third section, we examine the scope for prevention, including measures to tackle the social determinants of health. Finally, looking ahead, we examine in the concluding section two immediate threats to the NHS: the COVID-19 pandemic and leaving the EU. The health of the population Life expectancy in the UK The health of the UK population is now lagging behind that of many comparable countries. Having been in the middle of the range of high-income countries in 1960, life expectancy at birth is now close to the bottom (figure 1 ). Since 2010, the rate of increase in life expectancy at birth has slowed markedly.10 A 2019 analysis compared life expectancy in England and Wales with that in 22 other high-income countries,11 and showed how England and Wales diverged markedly from the comparator group between 2011 and 2016. This divergence was driven to a similar extent by diverging mortality in people of working age and older people. Although more recent data are lacking for some comparator countries, the situation in the UK now gives substantial cause for concern; there have been continuing increases in death rates in several age groups and regions, and the infant mortality rate in England and Wales rose each year in 2014–17, something that has not happened for more than a century.12 Figure 1 Trends in life expectancy at birth in the UK and comparable high-income countries Source: Organisation for Economic Co-operation and Development. The reasons why the UK is falling behind other high-income countries have been debated intensely. Some of the decline probably reflects historical trends, such as the timing of the smoking epidemic,11 but there is increasing evidence pointing to a link with the wide-ranging austerity measures since 2010 that have affected many areas of public policy. For example, although the explanation for rising infant mortality is disputed, it has been noted that the increase is greatest in the poorest areas.13 There have been substantial cuts to funding for local authorities, with resulting social care service reductions that particularly affect older people and those living in poverty.14, 15 An exceptional surge in numbers of deaths in 2015 also coincided with widespread capacity problems across the NHS and, although the particular strain of influenza circulating that year might have played a role, influenza seems unlikely to have been the only reason for this particular spike in mortality.16 A further spike occurred in 2018. Importantly, although the slowing is not unique and has been seen in some but not all European countries, it has been more pronounced in the UK than elsewhere, and it is not a survival asymptote of maximum life expectancy being reached, as the UK has not achieved the same levels as other comparable high-income countries. Within the UK, when measured by geography or socioeconomic indicators, it is apparent that there is much scope for the health of the most disadvantaged to improve substantially in terms of healthy and disability-free life expectancy. Although differences in life expectancy between the richest and poorest people in the UK narrowed during the 2000s, these differences have widened since 2011.17 The impact of the COVID-19 pandemic on life expectancy is yet to be established, but the combination of excess mortality directly attributable to the acute effects of the virus, emerging evidence of long-lasting health problems caused by the virus,18 and delayed diagnosis of many conditions such as cancer caused by the postponement of screening and reduced access to health-care services19 will probably lead to a sustained reduction in life expectancy in many countries. The knock-on effects on the economy, particularly those that exacerbate existing inequalities, will also have longer-term indirect effects. As the UK has had one of the highest death rates attributable to the COVID-19 pandemic so far, the gap in life expectancy between the UK and other developed nations might grow in the coming years. There are also large differences between the four UK nations (appendix p 1). All have experienced a recent slowing of the rate of increase in life expectancy at birth. Life expectancy has consistently been higher in England than in the other three nations, with Scotland lagging far behind. Between 1998 and 2018, the gain in life expectancy at birth has been much smaller for women than for men. For example, in England, life expectancy increased by 4·3 years for men but only by 3·1 years for women. In Scotland, the gap was even greater, at 4·2 years for men and 2·7 years for women. For both sexes, these gains were among the smallest in industrialised countries. This discrepancy is driven, to a considerable extent, by stagnating or falling life expectancy among women aged 75 years and older, who have been affected especially harshly by austerity policies.20 Life expectancy is, of course, derived from data on deaths. It can be combined with data on people still alive to generate measures of disability-free life expectancy (DFLE) and healthy life expectancy (HLE). DFLE is an estimate of the number of years lived without a long-lasting physical or mental health condition that restricts daily activities. HLE is an estimate of the number of years lived in very good or good general health, based on how individuals perceive their general health. England has the highest life expectancy for both women (83·1) and men (79·6), and Scotland has the lowest life expectancy for both women (81·1) and men (77·0). England has the highest HLE and DFLE for both women (HLE 63·8, DFLE 62·2) and men (63·4, 63·1), whereas Wales has the lowest DFLE for women (59·5) and men (59·9), the lowest HLE for women (62·0), and second-lowest HLE for men (61·4; appendix p 2). Within the four nations of the UK, there is especially poor health among populations in areas that have gone through deindustrialisation since the 1980s, such as the west of Scotland, parts of Northern Ireland, south Wales, and the northeast and northwest of England. Analysis by geography and deprivation shows that, although life expectancy varies by as much as 6 years between the regions of England, most of the difference is accounted for by levels of deprivation.21 This analysis also showed that, even though all the regions of England are subject to broadly similar underlying health policies, regulations, and laws, and all are served by the NHS, outcomes such as life expectancy and years lived with a disability in the more prosperous regions of the UK are similar to those in the best performing advanced high-income countries, such as Sweden and Australia. By contrast, in the less prosperous regions of the UK, these outcomes lag behind the worst-performing advanced high-income countries, such as Denmark and Greece.21 Similarly, disability-free life expectancy varies substantially within each UK nation, the consequence being that, in many parts of the UK, the average person cannot expect to reach the statutory retirement age in good health.22 There are also inequalities between ethnic groups, with estimates suggesting that differences in disability-free life expectancy, at 11·5 years, are twice as large as differences in life expectancy.23 Chinese men and women have the highest disability-free life expectancy at birth, whereas Bangladeshi men and Pakistani women have the lowest. The COVID-19 pandemic has exacerbated these health inequalities, particularly for Black and minority ethnic groups who have experienced persistently elevated mortality rates from COVID-19.24 Differential exposure to SARS-CoV-2 influenced by occupation and housing conditions, differential severity of COVID-19 influenced by existing health conditions, and differential interactions with the health service have all been suggested as potential contributing factors.25, 26 The scale and nature of these differences point to the importance of influences outside the health-care system on health outcomes.22 The Dahlgren and Whitehead model highlights the potential effect of the wider social determinants of health, such as housing, sanitation, unemployment, education, and food production.27 Austerity measures adopted since 2010 have had a disproportionate impact on the poor,28 creating insecurity of income, employment, housing,29 and even food supply, as revealed by the growth of food banks.30 Addressing these social determinants of ill health will require wide-ranging actions across many sectors and at every stage of the human life course, while recognising that disadvantage can be passed down generations, risking a downward spiral.31 These actions must account for intersectionality, whereby some individuals have a combination of characteristics (all of which disadvantage them), and the existence of a health gradient between rich and poor. These considerations point to the need for what is termed proportionate universalism,22 in which provision of services is universal, but measures are taken to increase uptake by those in most need. Mental health The burden of disease attributable to mental illness, including what are termed common mental illnesses (ie, anxiety, depression, panic disorder, phobias, and obsessive-compulsive disorder), has been growing over the past 25 years.32 The COVID-19 pandemic has also had a profound impact on mental health, with many individuals suffering from anxiety, isolation, and difficulties in accessing mental health support.33 High-quality data are needed to understand this effect, particularly for susceptible groups, such as older people, young people, people with pre-existing mental health issues, and health-care workers.34 To mitigate against long-term consequences for mental health, supportive measures are needed, such as providing widespread access to emergency psychological support and increased investment in mental health services.35 The mental health impacts of the COVID-19 pandemic have important implications for health inequalities and the wider economy. Mental illness is more common in socioeconomically deprived populations36 and is the leading cause of lost days of work in the UK; mental ill-health at work is estimated to cost the UK economy between £74 billion and £99 billion per year,37, 38 with important consequences for the labour-intensive health sector. The mental health needs of the older population are substantial. Although the age-specific prevalence of dementia appears to be decreasing slightly,39 population ageing means that the absolute number of older adults experiencing cognitive decline due to Alzheimer's disease or other types of dementia will rise;40 prevalence of dementia increases from 2% for people aged 65–69 years to 18% for those aged 85–89 years.13 However, older people's mental health needs do not just relate to dementia. Depression is the most common mental health disorder in this age group, with an estimated prevalence of 22% in men and 28% in women aged 65 years and older and more than 40% in people living in care homes.41 There is also a high prevalence of anxiety disorder.42 Other disorders, such as bipolar disorder and psychosis, are less common but nonetheless significant. Research shows that older adults with depression are significantly less likely to be diagnosed and treated than younger adults with the condition,43 and services and funding for mental health care for older people is generally considered less of a priority than it is for working-age adults.44 There is growing evidence of a high burden of mental illness among British children and adolescents, to the point that the situation has been described as a crisis.45 Data from 2017 in England showed that one in eight individuals aged between 5 and 19 years had at least one mental illness and that one in twenty met criteria for two or more mental illnesses.46 The same data show a gradual increase in mental illness in young people since 1999, with the prevalence increasing with age, particularly on transition to adolescence and secondary school.46 Of particular concern is the high level of mental illness in girls aged 17–19 years. Nearly one in four in this group have a diagnosable mental illness, and more than half of them reported self-harming behaviour or suicide attempts. Universities have reported a huge increase in pressure on student mental health services and rising numbers of student suicides,47 and research shows an increase in adolescent girls presenting to UK Accident and Emergency departments with self-harm.48 The reasons for the increasing burden of mental illness in young people are complex. Social media, the impending threat of environmental catastrophe and political instability, uncertainty about future prospects, higher rates of family breakdown, and academic pressure have all been proposed as causative factors. Unrealistic social pressure to excel in all areas of life, promoted by social media and an ethos of consumerism, is another toxic, relatively new phenomenon. However, it is crucial to try to address this area of growing need as it is well established that around half of mental illnesses start before the age of 14 years and three-quarters are established by the age of 24 years,49 particularly because adolescence and young adulthood are pivotal life stages for key decisions regarding education, employment, and relationships. The burden of disease due to alcohol and illicit drug use has increased across the UK in recent years. Alcohol-related deaths in the UK increased to an age-standardised rate of 12·2 per 100 000 people in 2017, which is similar to 2008 when alcohol-related deaths were at the highest recorded levels.50 Scotland consistently has the highest rate of alcohol-related deaths in the UK, at 20·5 per 100 000 in 2017, although this number has substantially reduced from a peak of 28·5 per 100 000 in 2006.50 Drug-related deaths in England and Wales have increased from an age-standardised rate of 42·9 per 1 000 000 in 1993 to 66·1 per 1 000 000 in 2017.51 In comparison, Scotland's incidence of drug-related deaths is more than three times the rate in England and Wales, at 192·6 per 1 000 000 in 2017,52 and is the highest drug-related death rate recorded in the EU. There are also substantial inequalities in alcohol-related and drug-related deaths across the UK. For example, more than half of the drug-related deaths in Scotland occur among people from the most deprived quintile,53 and the rate of alcohol-related deaths is more than three times higher in the most deprived quintile than in the least deprived quintile in England. These increases in alcohol-related and drug-related deaths have occurred during a period when drug and alcohol services are under intense financial pressure. For example, in England, local authorities cut budgets by 18% in real terms between 2013–14 and 2017–18,54 which contributed to an 11% reduction in people accessing treatment over the same period. Maternal and child health Maternal mortality in the UK is higher than it is in many countries in central and northern Europe (appendix p 3). Within the UK, there are substantial inequalities in maternal mortality between different ethnic groups and between groups with different levels of deprivation.55 The maternal mortality rate in women from a Black ethnic background is five times higher than that in White women, while the rate in women from an Asian ethnic background is double that in White women. Between the most and least deprived groups, there is a doubling in maternal mortality. Rather than narrowing, these trends have been widening over the past decade.55 The UK's high mortality from conditions such as asthma, epilepsy, pneumonia, and meningococcal disease in childhood, compared with other European countries,56, 57 also suggests a problem with paediatric care, with infant mortality lagging behind many other high-income countries (figure 2 ).58 A recent, extremely detailed comparison with Sweden found that newborn babies in the UK had many more problems at birth than their counterparts in Sweden did, many of which could be traced to their worse socioeconomic status.59 Influences on health outcomes start in utero, and there is a clear social gradient in the extent to which children can access positive experiences in their early years.22 As already mentioned, since 2010, the UK government has chosen to implement prolonged austerity policies, including reductions in entitlements to welfare provision, with measures that have impacted particularly on the most vulnerable.60 Concerns have been expressed about the substantial increase in suicide rates among adolescents in England and Wales since 2010.61 Child poverty in the UK, as of 2017–18, was 30% and has been increasing since 2013–14, when it was 27%.62 This poverty rate is predicted to rise over the next few years, and children in single-parent families, with three or more siblings, in households where no one is in work, or in rented or social housing are known to be at particular risk of poverty.63 Figure 2 Infant mortality in the UK and comparable high-income countries Data are from 2018 or the latest year available. Source: Organisation for Economic Co-operation and Development. Oral health Oral diseases (eg, dental decay, periodontal [gum] diseases, and oral cancers) are highly prevalent chronic conditions that have a considerable impact on quality of life and are costly to health-care systems. The Global Burden of Disease study has highlighted that dental decay in adults is the most prevalent chronic health condition globally—overall, it is estimated that 3·5 billion people are affected by dental diseases.64 A 2019 analysis shows that the treatment of dental diseases among EU countries costs in excess of €90 billion per year, the third most expensive condition behind diabetes (€119 billion) and cardiovascular diseases (€111 billion).65 In recent decades, there has been a striking change in oral diseases among the UK population. When the NHS was first created, the state of oral health in the UK was appalling, with the complete removal of all teeth (edentulism) a relatively common occurrence for even young adults, often taking place before marriage. Nowadays, fewer than 5% of adults in the UK have no natural teeth, and overall oral health in both children and adults has improved greatly.66 The increased retention of natural teeth is a positive change but, as individuals age and become more frail, complex and costly dental treatment is often required. Stark socioeconomic and geographical inequalities in oral health exist. Steep and persistent social gradients are found for oral conditions in both children and adults, and oral health is worse in Northern Ireland and Scotland than it is in Wales and England.67 Oral diseases are caused by the broader social determinants in society and shared risk factors, such as consumption of sugars, tobacco, and alcohol. In the UK, dental services are organised and funded in a different manner than medical services are. The vast majority of the 40 000 dentists in the UK work in primary care, providing general dental services to the population. Across the UK, different payment systems exist but co-payments operate in all countries, according to which adult patients contribute to the costs of their dental treatment. Children and exempt adults do not pay for their dental care. Patterns of dental attendance are strongly influenced by socioeconomic status, and concerns over the cost of treatment are a major barrier to accessing dental services.68 Multimorbidity Older people are, individually, more likely to be healthy than they were in the past. However, the absolute numbers with ill health are increasing. Many will remain healthy by virtue of being treated for hypertension or diabetes, which averts the sequelae of these conditions. Others, although not in perfect health, experience considerable alleviation of their symptoms. The corollary of this and of earlier detection of chronic diseases and their risk factors is that ever more people experience multimorbidity, requiring some health care for multiple disorders, even if they are only reviewed in primary care every few months.36 Research in the UK estimates that around 23% of the population meet current criteria for multimorbidity, a figure that increases with age and attention to early diagnosis—around two-thirds of people older than 65 years meet these criteria, with nearly half having three or more conditions.36 There have been several attempts to classify commonly occurring clusters of conditions. Some diseases frequently co-exist and share common causes, but there is also considerable heterogeneity, and illnesses can also be completely unrelated. Chronic physical conditions often co-exist with mental health disorders—particularly with dementia—with evidence that the relationship is bidirectional.69 There is a clear association between multimorbidity and socioeconomic deprivation, and people living in deprived areas are likely to develop multimorbidity 10–15 years earlier than those living in more affluent areas.36 Multimorbidity has profound implications for how health care is delivered, as it demands a holistic approach delivered by multidisciplinary teams. The model of primary care, with its generalist approach, has found it easier to respond to this challenge than some models used in other countries, but the disadvantage, in a country that has somewhat fewer medical specialists than many others (despite growth in specialist posts in recent years), is that it might be difficult to obtain specialist expertise when needed. Unfortunately, the accessibility of primary care is now being threatened, with insufficient historical investment in these services. To compound the problem, chronic staffing shortages coupled with administrative overload add to falling morale and cause physical and psychological burnout. Such outcomes lead to growing problems in recruiting and retaining general practitioners and community nurses. The changing health needs of the population The UK's ageing population Some changes in future health profiles can be predicted with relative certainty, such as the ageing of the population and, to some extent, a relative fall in those aged 18–65 years, albeit with caveats about future migration.70 Forecasting with some confidence is possible when the association between risks and disease are known and have long time periods, as is the case with smoking. Such forecasting is more difficult when lags between exposure and outcome are short, as with many of the consequences of hazardous drinking, and where public policies can have a major impact in the short term. Although the UK does not have a particularly high proportion of older people relative to other high-income countries, with the share of people older than 65 years and people older than 80 years falling from 4th to 12th between 1995 and 2016 in one comparison of 17 countries (figure 3 ), it will eventually face similar challenges as other countries. Ageing per se does not necessarily affect health-care utilisation or add pressure to constrained NHS resources unless it is associated with increased chronic illness and higher rates of multiple long-term conditions.71 Figure 3 Percentage of population at older ages in selected high-income countries, 2018 Source: Organisation for Economic Co-operation and Development. Considerable variation exists within the UK, with the largest share of older and very old people in the southwest of England and the smallest share in the northeast of England (figure 4 ). There is also a sizable discrepancy in the age distribution of different ethnic groups (appendix p 3). Both the geographical and ethnic spread of the older population matters, as it leads to specific pressure points on NHS access, as well as contributing to the unequal distribution of ill-health within the UK. As ethnicity is not recorded on death certificates in the UK, it is not possible to routinely report on life expectancy stratified by ethnicity. However, some recent studies that have used various techniques to try to estimate life expectancy by ethnicity show significant discrepancies between groups, which vary by region.73, 74, 75 Figure 4 Percentage of population aged 65+ years and 85+ years, 2019 Source: Office for National Statistics.72 The working population The participation of women in the labour force is at an all-time high.76 Thus, as the share of the population who are of working age declines, there is little scope to draw even more into the workforce, an important consideration given their major contribution to the health and care workforce. However, caution is needed. Old-age dependency ratio, a frequently cited measure, has been used in sometimes apocalyptic predictions, typically to argue for the unsustainability of the welfare state. Yet it assumes an economically (and socially) inactive stage of life beyond 65 years of age that is no longer the case. The raising of the retirement age in the UK and many other countries has changed such calculations considerably, even before taking into account the work and informal care of spouses, parents, adult children, and grandchildren provided by older people, sometimes with competing demands.77, 78 There are, however, many uncertainties about the future composition of the UK population. The experience of Japan,79 a country that has had very little immigration albeit for different reasons, is concerning, as the young are attracted to major centres for their early working careers, while older people remain in rural or coastal regions, creating a skill gap for care. In this context, the UK Government's stated goal of reducing migration from the hundreds of thousands to the tens of thousands is a clear cause for concern. The NHS has a long history of relying on foreign recruitment in response to workforce shortfalls. For example, in light of ongoing uncertainty about future EU citizen arrangements, there has been a 90% reduction in nurses from other EU member states joining the UK's register in 2017–18 compared with 2016–17.80 Growing numbers of medical posts remain unfilled, with the government refusing visas to non-EU doctors with job offers and even to those training in this country.81 The social care sector is also heavily dependent on foreign recruitment, yet senior care workers are currently not on the government's so-called shortage occupation list.82 Changing burden of disease The combination of trends in underlying population health, the application of effective preventive interventions, and advances in health care have led to a shift in the predominant share of the burden of ill-health worldwide from conditions causing premature mortality to conditions that cause disability. Health systems everywhere must adapt to the changing nature of health need. The Global Burden of Disease study captures this idea in its analysis of disability-adjusted life years (DALYs). Figure 5, Figure 6 show the percentage change in burden attributed to the top 25 causes of DALYs in the UK for both genders from 1990 to 2019. For both men and women, there have been substantial increases in disease burden due to drug use disorders. In men, these addiction problems have been exacerbated further by increases in disease burden due to alcohol use disorders. Addiction services have struggled to meet this rising demand in the context of ongoing funding cuts over the past decade.83 This situation has had implications for NHS services, as harmful drinking has contributed to the increase in disease burden due to liver cirrhosis. Smoking rates have fallen markedly, reducing the future risk of many smoking-related diseases such as stroke and myocardial infarctions, which have been declining for several decades. However, the benefits of this change are yet to be felt, with increases in disease burden due to chronic obstructive pulmonary disease seen in both men and women. Conversely, rates of obesity at younger ages are increasing, with implications for a range of common disorders, such as diabetes, cancer, and dementia.Figure 5 Percentage change in burden due to the top 25 causes of DALYs in women in the UK, 1990–2019 Source: Global Burden of Disease. DALY=disability-adjusted life year. Figure 6 Percentage change in burden due to the top 25 causes of DALYs in men in the UK, 1990–2019 Source: Global Burden of Disease. DALY=disability-adjusted life year. The proportion of the population aged 65 years and older is predicted to increase from 18·5% in 2019 to 23·9% in 2039.84 Assuming no change in age-specific utilisation, this would increase demand for health and social care in particular.85 The changing population structure has already led to an absolute increase in numbers of deaths, as predicted, after many years of decline.86 A major component of health costs is driven by proximity to death, not by chronological age; many older people are now healthier than their counterparts in previous generations. However, the absolute number of older people with multiple conditions is set to increase substantially over the next few decades, potentially more so as the emphasis on early detection continues. As premature mortality reduces, disabling conditions whose prevalence increases sharply with age (eg, sensory deficits, mobility problems, cognitive decline, and incontinence) will progressively accrue, leading to complex multimorbidity. These trends in common conditions have been brought together with population ageing in a dynamic model.85 This model predicts that the number of people with four or more conditions will increase between 2015 and 2035 by 21% in those aged 65–74 years, 130% in those aged 75–84 years, and 470% in those aged 85 years and older. The changing nature of demand for health and social care that results is a challenge for any health system and requires an explicit response, even more so for a health-care system that encourages people to seek earlier medical care for conditions, sometimes before they are clinically manifest. Therefore, the concern is less ageing per se, but ageing with multiple preventable conditions leading to poor health and wellbeing. Reducing the need for health care The need for a preventive focus One of the key messages of the Tallinn Charter8 was that effective prevention could reduce the need for health care and thus the need for scarce resources. Effective prevention was also a key message of the Wanless Report, commissioned by the UK Treasury,87 which forecast the potential to moderate future NHS expenditure if what it called a fully engaged policy could be adopted. This concept, of investing in health improvement to reduce future costs, also features prominently in the NHS Long-Term Plan.88 An additional consideration is the compelling evidence linking better health to economic growth through higher labour force participation and productivity.89 There are many examples of successes in implementing health-promoting policies in Europe.90 The countries of the UK have been among the leaders internationally in many of the most effective policies to reduce harms associated with use of hazardous substances, such as tobacco, alcohol, and, most recently, junk food. Governments have recognised that the most effective policies are those based on price, availability, and marketing. Examples include minimum alcohol pricing in Scotland and Wales, above-inflation increases in tobacco taxation, a ban on smoking in public places, point-of-sale displays, the sugar tax, and standardised cigarette packaging. However, these face powerful lobbying activities by the corresponding industries, both directly and through several think tanks that they fund.91, 92 For a brief period, the alcohol and food industries benefitted from the creation of so-called responsibility deals, in which the UK Government sought to engage with them in official forums. However, the government's own evaluation found that industry representatives typically proposed the least effective measures and opposed those known to be effective.93 These responsibility deals did lead to pledges from many companies to reduce salt content in food and contributed to a reduction in overall salt intake in the UK of 11% between 2006 and 2014.94 However, eventually, key health advocacy organisations withdrew. Moving forward, there is a need for more joint approaches that bring together different groups working on, for example, tobacco, alcohol, or diet to secure maximum benefit from shifting population norms on the five healthy living imperatives (not smoking, adhering to alcohol guidelines, maintaining a healthy weight, staying physically active, and eating a healthy diet) that influence rates of non-communicable diseases. This strategy will require policies that address these issues specifically and others that take a concerted approach to the upstream determinants of health, including both the well recognised social determinants of health and, even more now, the commercial determinants,95 by looking at how powerful vested interests can subvert health policies. It is also necessary to address the political determinants of health, such as austerity, welfare, and immigration regimes, and the environmental determinants, such as the design of health-promoting cities. Addressing the social determinants of health Although successive governments have adopted effective public health policies, these have struggled in the face of wider societal problems. Consequently, despite noted successes in areas such as tobacco control, the UK ranked only 12th overall in an assessment of public health policies across the European region of WHO.96 Looking ahead, there is clearly a need to address the underlying social determinants of health, or the conditions in which people are born, grow, live, work, and age,22 with policies that address precariousness of employment, income, housing, and food security.97 The UK has high rates of child poverty, lax building standards, and underinvestment in social housing, contributing to many people living in substandard accommodation and, since 2010, a marked rise in food insecurity.30 Other social problems relate to the employment market: although the introduction of a minimum wage was associated with a demonstrable improvement in mental health,98 and official unemployment rates are low, there are growing numbers of people who remain below the minimum wage, a practice that is illegal but rarely policed.99 Growing numbers of people also face severe uncertainty about income and employment in what is termed the gig economy, characterised by piecework and limited employment rights. Against this background of the erosion of wider welfare policies and falling public expenditure in other areas of welfare, the NHS is increasingly left as the one remaining pillar of the UK welfare state. Health care is an important route through which health improvements can be channelled, but other sectors remain important in addressing health promotion and inequalities. There is compelling evidence in many areas that health-promoting policies work, especially those that involve all relevant sectors, enshrined in the concept of Health in All Policies. Wales is pioneering this approach through the Wellbeing of Future Generations Act 2015 and the Public Health Act 2017.100, 101 As a major employer, this is an area where the NHS could play a crucial role, although such an approach would require a substantial culture change in an organisation that is more often associated with high levels of work-related stress and burnout. Health-promoting policies do have the potential not only to alleviate suffering but also to reduce further the demand on the NHS if there is the political will to implement them. Immediate threats to the NHS The need for a resilient NHS The initial version of this paper argued that the NHS must prepare for the unexpected and ensure it was resilient in the face of potential threats, including a pandemic,102 especially given the threat posed by the loss of links with European agencies such as the European Centre for Disease Prevention and Control and the European Monitoring Centre for Drugs and Drug Addiction.103, 104 The COVID-19 pandemic has, tragically, revealed that the UK was less prepared than it could have been. As of April, 2021, the UK was among the worst affected countries in the world, measured by deaths attributed directly to COVID-19 or by excess all-cause mortality (the preferred measure for international comparisons). There will be many lessons to learn from the response: confused messaging by ministers; outsourcing of essential functions to companies lacking expertise; fragmentation of the NHS and public health and social care systems; elevated mortality rates among Black and minority ethnic groups; fraught relationships between central and local government, as well as with devolved nations; serious failures in the procurement of essential items, from ventilators to test kits and personal protective equipment; and entire new but largely unused hospital facilities.105 The response and efforts of those working in the NHS should also be recognised as exceptional, including repurposing existing hospital facilities, rapidly expanding access to teleconsultations, reallocating staff, sharing knowledge about the emerging clinical characteristics of this disease, implementing a world-leading clinical trial programme, and the rapid vaccination of the population triaged by risk factors such as age and comorbodities.106 Impacts in parts of the social care sector, especially in care homes, have been devastating and responses by staff similarly exceptional, again with many lessons to be learnt.107 The UK's response has, however, come at an enormous cost, both financially and in terms of the long-term consequences for health. These consequences can be considered under five headings: the long-term consequences of the infection on the body; delays in care as a consequence of the suspension of certain NHS services; the health effects of the lockdown; the impact on NHS staff; and the long-term economic impact. In the first category, it is becoming clear that many of those who survive COVID-19 have persisting health problems, many apparently associated with the action of the virus on the vascular endothelium and the associated immune response and hypercoagulability.108 In this respect, some have questioned whether it will come to be compared with polio, which also left a long-lasting legacy of ill-health. In the second category, there was a large reduction in primary care attendances,109 storing up considerable unmet need for the future, and routine surgery has been suspended, leaving a massive backlog to be treated in what was an already struggling system. Delayed diagnosis and treatment of early-stage cancer has been estimated to lead to more than 6000 additional deaths in a year.110 Estimates suggest that 3800 early cancers that would have been picked up on screening have been missed.111 In the third category, prolonged isolation coupled with the cessation of specialist services is likely to contribute to an increased burden of mental illness, while the closure of schools is likely to contribute to mental illness in children and young people.6 The fourth category includes the effects of psychological trauma on NHS and social care staff, including responses more usually seen in survivors of armed conflict.112 Fifth, the pandemic is expected to lead to a long-term reduction in economic growth,113 that could see many of the health problems associated with austerity in the period after 2010 return.97 To add to the problems, the ability of the NHS to respond could be complicated by the need for new ways of working, including greater use of personal protective equipment, social distancing, and remote consultations. There are also other threats ahead, some more certain than others. One is antimicrobial resistance, an area where the UK has shown global leadership.114 Another is the consequences of a generation transitioning into retirement in a much more precarious financial state than their parents because of closure or reduction of pension schemes and lower levels of home ownership; this generation might struggle to come to terms with their straitened circumstances.90 A third is climate change, with evidence that the climate is changing even faster than predicted, potentially nearing a tipping point of runaway global warming. The COVID-19 pandemic has ushered in a temporary period of reduced carbon emissions; government actions and economic incentives after the pandemic will determine whether carbon emissions continue on the same path.115 In summary, the future is uncertain. Some of the uncertainties can be anticipated to some extent but for others, it is more difficult. The lesson from the COVID-19 pandemic is that the NHS must both anticipate predictable developments and build in sufficient resilience for the unexpected while working with other sectors to develop holistic solutions. Leaving the EU The UK's decision to leave the EU will have serious consequences for health116 but, as of April, 2021, these consequences have yet to become fully apparent. Although imports to Great Britain have fallen substantially, the full effect of leaving the EU will not be visible until the UK Government introduces the full range of customs checks it is required to impose but has, for now, delayed. In addition, it is difficult to distinguish the economic effects of leaving the EU from those of the pandemic. The problems ahead can, however, be understood from the near collapse of some exports, such as foodstuffs, since the EU has already imposed checks on its side of the border. The problems are also clear from the issues faced by shops in Northern Ireland, no longer able to depend on their historical supply arrangements with Great Britain. It has also become apparent that many commitments made by the UK Government before leaving the EU, many of them suggesting that particular arrangements will continue as before, have not in fact been honoured, either in part or in whole. While UK scientists will continue to be able to participate in some, but not all, of the EU's research programmes, the Turing scheme is substantially inferior to the ERASMUS+ scheme that it relaces, in terms of mobility of staff and students. A Global Health Insurance Card, to replace the European equivalent, no longer includes the non-EU European Economic Area countries. Some arrangements for data sharing during emergencies with the European Centre for Disease Prevention and Control have been agreed but, again, are much inferior to those that existed previously. Further progress is complicated by the loss of trust in the UK among many politicians in the EU27, given the UK's failure to implement measures it had previously committed to, especially in relation to the Northern Ireland Protocol. This situation has not been helped by the nationalist rhetoric that has accompanied AstraZeneca's failure to deliver to EU countries the quantity of vaccines that it had committed to.117 Beyond the immediate problems, the health of the UK population is affected by many other aspects of public policy. Food quality and safety, agriculture, land management, and environmental regulations are just a few of the areas of concern currently addressed by EU legislation that have substantial implications for human health.118 Of particular concern to health and health services will be the nature of any future international trade agreements. Issues around intellectual property rights, technical barriers to trade, and investor protection need to be thought through carefully,119 and protections for health and health care put in place. It is vitally important that, in the new trade agreements, health is not subverted by commercial interests for economic gain.120 Overall economic performance following departure from the EU will also be very important, with implications not just for the available funds to spend on health, but for the wellbeing of the UK population and the consequent demand for health care. Conclusion This Health Policy paper has reviewed the current health of the UK population and the changing health needs and has considered what future challenges lie ahead. From these considerations, we can draw several conclusions. First, despite substantial improvements in life expectancy, many physical and mental health outcomes are suboptimal relative to other high-income countries. Driving this suboptimality is that, across all ages but especially in childhood and old age, the population has high levels of preventable ill-health, which is unfairly distributed across society. As the UK has experienced a relatively high excess mortality rate attributable to COVID-19, the gap in life expectancy between the UK and other developed countries is likely to grow. Second, in the future, there will be relatively fewer people in the working population, especially if current policies on migration continue, and a sharp rise in people with complex multimorbidity. This trajectory will create a mismatch between needs and capacity to address those needs, both through workforce availability and securing the economic basis for sustainable funding. To address these issues, there needs to be an increased focus on prevention and health promotion that takes a multisectoral approach to the social, political, and commercial causes of poor health. The crucial role the NHS can play by setting an example as a healthy employer, reducing risk factors for chronic diseases, promoting healthy ageing, enhancing confidence, and promoting social engagement should be addressed explicitly. However, the NHS is increasingly operating in an environment in which other sectors—especially social care—are being eroded in terms of expenditure and general infrastructure, instead of being maintained as supportive systems. Finally, there are many immediate threats that will affect the health of the population and service provision. Crucially, the UK will need to develop strategies to mitigate against the wider and long-term consequences for health of the COVID-19 pandemic. In addition, the UK's departure from the EU, growing antimicrobial resistance, and increasing climate change are all major challenges with significant consequences for the NHS. Other unforeseen risks, such as economic downturn or even conflict, would impact the NHS but are practically difficult to plan for. Instead, the focus should be on building a resilient and preventive health-care service, so that the NHS is better prepared for any future challenges. Declaration of interests We declare no competing interests. Supplementary Material Supplementary appendix Acknowledgments Funding for the LSE–Lancet Commission on the future of the NHS was granted by the LSE Knowledge and Exchange Impact (KEI) fund, which was created using funds from the Higher Education Innovation Fund (HEIF). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Contributors MM and KD led the working group that prepared the paper. MA and CJ-W managed the processes of the working group, compiled the data and figures, and contributed to editing of the manuscript. 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https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/articles/overviewoftheukpopulation/january2021 Jan 14, 2021 85 Kingston A Robinson L Booth H Knapp M Jagger C Projections of multi-morbidity in the older population in England to 2035: estimates from the Population Ageing and Care Simulation (PACSim) model Age Ageing 47 2018 374 380 29370339 86 Gomes B Higginson IJ Where people die (1974–2030): past trends, future projections and implications for care Palliat Med 22 2008 33 41 18216075 87 Wanless D Securing our future health: taking a long-term view, final report 2002 HM Treasury London 88 NHS England NHS Long-Term Plan https://www.longtermplan.nhs.uk/publication/nhs-long-term-plan/ Jan 7, 2019 89 Suhrcke M McKee M Arce RS Tsolova S Mortensen J Investment in health could be good for Europe's economies BMJ 333 2006 1017 1019 17095786 90 Mackenbach JP Karanikolos M McKee M The unequal health of Europeans: successes and failures of policies Lancet 381 2013 1125 1134 23541053 91 Williams R Alexander G Aspinall R Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK Lancet 392 2018 2398 2412 30473364 92 McCambridge J Daube M McKee M Brussels Declaration: a vehicle for the advancement of tobacco and alcohol industry interests at the science/policy interface? Tob Control 28 2019 7 12 29941544 93 Knai C Petticrew M Durand MA Eastmure E Mays N Are the Public Health Responsibility Deal alcohol pledges likely to improve public health? An evidence synthesis Addiction 110 2015 1232 1246 25807862 94 Public Health England Salt reduction programme https://publichealthengland.exposure.co/salt-reduction-programme Dec 19, 2018 95 McKee M Stuckler D Revisiting the corporate and commercial determinants of health Am J Public Health 108 2018 1167 1170 30024808 96 Mackenbach J Successes and failures of health policy in Europe Eur J Public Health 23 suppl 1 2013 23 97 McKee M Reeves A Clair A Stuckler D Living on the edge: precariousness and why it matters for health Arch Public Health 75 2017 13 28270912 98 Reeves A McKee M Mackenbach J Whitehead M Stuckler D Introduction of a national minimum wage reduced depressive symptoms in low-wage workers: a quasi-natural experiment in the UK Health Econ 26 2017 639 655 27046821 99 UK Low Pay Commission Non-compliance and enforcement of the National Minimum Wage https://www.gov.uk/government/publications/non-compliance-and-enforcement-of-the-national-minimum-wage#:~:text=Enforcement%20of%20the%20National%20Minimum%20Wage,-The%20Department%20for&text=Workers%20can%20complain%20about%20underpayment,helpline%20on%200300%20123%201100 May 7, 2020 100 WHO Sustainable development in Wales and other regions in Europe—achieving health and equity for present and future generations http://www.euro.who.int/en/publications/abstracts/sustainable-development-in-wales-and-other-regions-in-europe-achieving-health-and-equity-for-present-and-future-generations-2017 2017 101 Welsh Government Public Health (Wales) Act 2017 http://www.legislation.gov.uk/anaw/2017/2/contents/enacted July 3, 2017 102 Castleden M McKee M Murray V Leonardi G Resilience thinking in health protection J Public Health (Oxf) 33 2011 369 377 21471159 103 Fahy N Hervey T Greer S How will Brexit affect health services in the UK? An updated evaluation Lancet 393 2019 949 958 30819519 104 Roman-Urrestarazu A Yang J Robertson R Brexit threatens the UK's ability to tackle illicit drugs and organised crime: what needs to happen now? Health Policy 123 2019 521 525 31054860 105 Horton R The COVID-19 catastrophe: what's gone wrong and how to stop it happening again 1st edn. 2020 Polity Press Cambridge, UK 106 Wilkinson E RECOVERY trial: the UK COVID-19 study resetting expectations for clinical trials BMJ 369 2020 m1626 107 Rajan S Comas-Herrera A Mckee M Did the UK Government really throw a protective ring around care homes in the COVID-19 pandemic? J Long Term Care 2020 published online Nov 11. 10.31389/jltc.53 108 Roberts CM Levi M Schilling R Lim WS Grocott MPW McKee M Covid-19: a complex multisystem clinical syndrome https://blogs.bmj.com/bmj/2020/05/01/covid-19-a-complex-multisystem-clinical-syndrome/ May 1, 2020 109 Mansfield KE Mathur R Tazare J COVID-19 collateral: indirect acute effects of the pandemic on physical and mental health in the UK medRxiv 2020 published on Oct 30. 10.1101/2020.10.29.20222174 (preprint). 110 Lai AG Pasea L Banerjee A Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency medRxiv 2020 published on June 1. 10.1101/2020.05.27.20083287 (preprint). 111 Campbell D Millions in UK miss cancer screenings, tests and treatments due to Covid-19 https://www.theguardian.com/society/2020/jun/01/millions-in-uk-miss-cancer-screenings-tests-and-treatments-due-to-covid-19 June 1, 2020 112 Greenberg N Docherty M Gnanapragasam S Wessely S Managing mental health challenges faced by healthcare workers during covid-19 pandemic BMJ 368 2020 m1211 113 McKee M Stuckler D If the world fails to protect the economy, COVID-19 will damage health not just now but also in the future Nat Med 26 2020 640 642 32273610 114 Keown OP Warburton W Davies SC Darzi A Antimicrobial resistance: addressing the global threat through greater awareness and transformative action Health Aff (Millwood) 33 2014 1620 1626 25201667 115 Le Quéré C Jackson RB Jones MW Temporary reduction in daily global CO2 emissions during the COVID-19 forced confinement Nat Clim Chang 10 2020 647 653 116 Fahy N Hervey T Greer S How will Brexit affect health and health services in the UK? Evaluating three possible scenarios Lancet 390 2017 2110 2118 28965715 117 McKee M Covid-19 vaccine wars: developing the AstraZeneca vaccine was a triumph, but then things went wrong https://blogs.bmj.com/bmj/2021/03/26/vaccine-wars-developing-the-astrazeneca-vaccine-was-a-triumph-but-then-things-went-wrong/ March 26, 2021 118 Green L Edmonds N Morgan L The public health implications of Brexit in Wales: a health impact assessment approach http://www.wales.nhs.uk/sitesplus/888/news/50275 Jan 21, 2019 119 van Schalkwyk MCI Jarman H Hervey T Wouters OJ Barlow P McKee M Risks to health and the NHS in the post-Brexit era BMJ 369 2020 m2307 120 British Medical Association Beyond Brexit—international trade and health https://www.bma.org.uk/collective-voice/influence/europe/brexit/bma-brexit-briefings/beyond-brexit-international-trade-and-health Sept 17, 2018

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PMC9751760

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2022-12-16 23:25:10

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Lancet. 2021 May 6 22-28 May; 397(10288):1979-1991

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Lancet

10.1016/S0140-6736(21)00229-4

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01118-1 10.1016/S0140-6736(21)01118-1 Department of Error Department of Error 21 5 2021 22-28 May 2021 21 5 2021 397 10288 18841884 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAnderson M, Pitchforth E, Asaria M, et al. LSE–Lancet Commission on the future of the NHS: re-laying the foundations for an equitable and efficient health and care service after COVID-19. Lancet 2021; 397: 1915–78—In this Commission, the third sentence in the Financial and political context section should read “Efforts to support individuals and businesses—for example, through furloughing, grants, and loans—have substantially increased government borrowing, which reached approximately £350 billion in 2020”. This correction has been made to the online version as of May 20, 2021 and the printed version is correct.

34022987

PMC9751761

NO-CC CODE

2022-12-16 23:25:10

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Lancet. 2021 May 21 22-28 May; 397(10288):1884

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Lancet

10.1016/S0140-6736(21)01118-1

oa_other

==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01460-4 10.1016/S0140-6736(21)01460-4 Perspectives Medicine and the unconscious Gardner Caleb a Kleinman Arthur b a Cambridge Health Alliance, Cambridge, MA 02139, USA b Faculty of Arts and Sciences and Faculty of Medicine, Harvard University, Cambridge, MA, USA 8 7 2021 10-16 July 2021 8 7 2021 398 10295 112113 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcOne morning, in the early days of the first COVID-19 surge in the northeast USA, a colleague left the hospital after a busy stretch in the intensive care unit. It had not been an easy night, but he had seen worse. He pulled over at a grocery store on the way home and walked inside the familiar building's sliding glass doors, looked around at the half-stocked shelves and crowded aisles and had the first panic attack of his life. One does not panic because the store is running low on supplies. One panics because long-standing illusions of certainty and control are undermined or because of the threatened eruption into awareness of what one has tried so hard not to know. More than a century of clinical observation, as well as thousands of years of philosophy, art, and literature attest to the notion that, alongside social disparities and socioeconomic factors, the knowledge and feelings we habitually hide from ourselves form the core of some of our greatest struggles, both internal and communal. Individual and collective self-obfuscation has a role in problems from climate change to implicit biases to the denial of scientific and medical knowledge we have seen from some quarters during the COVID-19 pandemic. The characteristic dynamics of our unconscious life are shaped in early childhood by a multitude of internal and external factors. It has been observed that some of the most powerful communication we receive is neither that which is spoken nor that which is deliberately silenced. Rather, we can be profoundly affected by whatever is unutterable in the milieu of our upbringing. Something becomes unutterable when we know or feel it but do not want to know or feel it. Often this feeling knowledge remains raw and unarticulated, unconscious for the most part. One thinks of Ludmila Dontsova, the radiologist in Aleksandr Solzhenitsyn's novel, Cancer Ward, who uses her intellectual attributes to avoid the reality of her own worsening stomach cancer. René Magritte, Not to be Reproduced (La reproduction interdite), 1937 © 2021 © ADAGP, Paris and DACS, London 2021/Photo © Fine Art Images/Bridgeman Images 2021 Medicine, psychiatry included, tends to give the unconscious a wide berth. It is certainly understandable for fields concerned with quantification and categorisation of clinical data to avoid such a complex and often paradoxical realm of the mind, but we believe this to be an unfortunate omission, entailing two primary problems. One is the intellectual loss of a vast area of inquiry: an area, meanwhile, vigorously explored by art, philosophy, and neuroscience. Another problem is the impoverishment of practical understanding that results from ignoring a complicated yet fundamental element of human experience, which can affect rapport, clinical decision making, diagnostic precision, and ethical judgment, among much else. We have all heard of patients like Ludmila Dontsova, presenting with conspicuous signs and symptoms, even visible malignancies, that have gone unacknowledged by close friends and family members as though subject to some tacit agreement of silence. Although the end results may be dramatic, the everyday, unspoken, and unacknowledged collusions between people, including patients and clinicians, are usually quite subtle. There may be tension or anxiety in the consultation room that gets swept aside by the conveniently insatiable demands of the computer, or a stressful topic may be danced around, or a patient may cultivate an particular affect or attitude that soothes a clinician's own underlying anxieties but obscures harder truths of the presentation. To avoid discomfort and despair, knowledge is sent underground. In medicine we must endeavour to explore the things we tend to keep from ourselves. We should also consider seriously how we are able to keep things from ourselves, and that we routinely do so in ways that receive little attention in education or clinical practice and yet have implications for how we might understand and treat ourselves and our patients. Difficult cases, whether they involve chronic illness or sudden and unexpected clinical scenarios, can contain seemingly contradictory or unintuitive elements. Words do not line up with behaviour. In these moments, it may be helpful to think about what is going on beneath the surface for clinician and patient alike. It can be helpful to ask oneself what is the underlying communication I am giving or receiving? What is the question behind the question? One might also ask what is unutterable here? What have we not thought to put into words? The answers to these questions may not come in the moment they are asked. They may not come ever. But we suggest that the very act of asking oneself these questions might have salutary effects. Just keeping the idea of an unconscious in mind promotes an important interpersonal perspective. Let us call it a general awareness of the mysteries of subjective experience and emotional life. Something that we may sense is present in art and literature and often missing in clinical medicine. This absence may be, in part, what motivates the architects of medical school curricula to send students to museums or offer classes in creative writing. Perhaps this quality is something akin to John Keats's “negative capability”: the capacity to be “in uncertainties, mysteries, doubts, without any irritable reaching after fact or reason”. But it is more radical than that. Although it seems that Keats here makes an artistically useful cartesian split between reason and rawer experience, what we have come to understand about the mind is that there is no such clean distinction to be made. As the work of the neuroscientist Antonio Damasio suggests, cognition is intertwined with emotion, and unconscious processes are foundational to our conscious sense of self. The British paediatrician and psychoanalyst Donald Winnicott wrote about the emergence of our sense of self and how it is influenced by the minds of other people, and he suggested that a task of lifelong development is the constant negotiation between one's subjective, at times hallucinatory, inner world, and the structures, restrictions, and reassurances of external reality. This developmental process is facilitated by what he called a “holding environment”, a concept that might account for elements of the therapeutic value of the clinician–patient relationship. Winnicott suggested that the quality of the first holding environment has to do with the way a caregiver “holds the infant in mind”, the conscious and unconscious attunement to the sublinguistic, unrepresented mental states of the infant. Such mental states remain with us our entire lives and constitute the material of more integrated experience. More recently, clinical psychologist and psychoanalyst Peter Fonagy has used empirical studies to look at the effects of parents' state of mind on personality development and attachment in their children. In a paper that draws from both psychoanalysis and attachment theory, Fonagy and colleagues proposed “the parent's capacity to generate a psychological world for the infant is dependent on coherent representations of the mental world of self and other”. In this sense, we are all mind readers, and the people we care for are especially attuned to how we think about them. “Accurate conscious reflection”, Fonagy and co-authors argued, “presupposes the experience of having been the subject of such confident reflection”. Thus, it may be that the most important use of the concept of the unconscious in clinical medicine is simply the appreciation of its existence and of its constant influence on ourselves and others. Of course, it might be helpful here and there to identify defensive patterns, or to use an understanding of repression or transference phenomena to clarify what is occurring in a particularly charged or confusing encounter. Meanwhile, on a deeper level, medicine will continue to struggle with what many patients and clinicians alike sense to be some sort of loss, or continued absence of human connection and understanding, an absence that has implications for individual care as well as public and global health. There are likely to be clinical benefits from paying attention to the unconscious, in all of its formulations and manifestations. And, more generally, the quality of mind thus cultivated among clinicians could help bring a more nuanced and authentic sense of human connection and understanding to the practice of medicine. Nothing, William Wordsworth wrote in The Recluse, “can breed such fear and awe / As fall upon us often when we look / Into our Minds”. Here we have the discovery in consciousness of feelings and states that have been with us all along. Feelings that perhaps go against the stories we tend to tell ourselves, which others may notice well before we do. It is remarkable and perhaps at times a mixed blessing that we inevitably communicate to others so much of what is in our minds: the content, but also the quality of our attention, comprehension, and curiosity. Winnicott observed that one of the most damaging ways to hold an infant in mind is to see the infant not as they are, but rather as one would wish to see them. To see patients and ourselves as they are means, among much else, to try to acknowledge the ocean of unconscious and unarticulated experience within all of us. Ultimately, it is the trying that matters because it allows for an openness to experiences beyond our own which can be felt by another. Yet even the most sincere effort comes with no formula and no guarantee, for we will always communicate not only more than we are aware of communicating, but also more than we are aware of knowing. ==== Refs Further reading Damasio A Self comes to mind: constructing the conscious brain 2010 Vintage Books/Random House New York Fonagy P Steele M Moran G Steele H Higgitt A Measuring the ghost in the nursery: an empirical study of the relation between parents' mental representations of childhood experiences and their infants' security of attachment J Am Psychoanal Assoc 41 1993 957 989 8282943 Ratner A Gandhi N Psychoanalysis in combatting mass non-adherence to medical advice Lancet 396 2020 1730 Winnicott DW Playing and reality 1971 Tavistock Publications London

34246337

PMC9751778

NO-CC CODE

2022-12-16 23:25:11

no

Lancet. 2021 Jul 8 10-16 July; 398(10295):112-113

utf-8

Lancet

10.1016/S0140-6736(21)01460-4

oa_other

==== Front Environ Sci Policy Environ Sci Policy Environmental Science & Policy 1462-9011 1873-6416 Elsevier Ltd. S1462-9011(21)00151-9 10.1016/j.envsci.2021.05.025 Review Bushmeat, wet markets, and the risks of pandemics: Exploring the nexus through systematic review of scientific disclosures Peros Colin Scott ab Dasgupta Rajarshi b* Kumar Pankaj b Johnson Brian Alan b a Organization for Programs in Environmental Sciences, University of Tokyo, Japan b Nature Resources and Ecosystem Services, Institute for Global Environmental Strategies (IGES), Japan ⁎ Corresponding author. 4 6 2021 10 2021 4 6 2021 124 111 11 1 2021 19 4 2021 27 5 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The novel coronavirus (SARS-CoV-2) is the third coronavirus this century to threaten human health, killing more than two million people globally. Like previous coronaviruses, SARS-CoV-2 is suspected to have wildlife origins and was possibly transmitted to humans via wet markets selling bushmeat (aka harvested wild meat). Thus, an interdisciplinary framework is vital to address the nexus between bushmeat, wet markets, and disease. We reviewed the contemporary scientific literature to: (1) assess disease surveillance efforts within the bushmeat trade and wet markets globally by compiling zoonotic health risks based on primarily serological examinations; and (2) gauge perceptions of health risks associated with bushmeat and wet markets. Of the 58 species of bushmeat investigated across 15 countries in the 52 articles that we analyzed,one or more pathogens (totaling 60 genera of pathogens) were reported in 48 species, while no zoonotic pathogens were reported in 10 species based on serology. Burden of disease data was nearly absent from the articles resulting from our Scopus search, and therefore was not included in our analyses. We also found that perceived health risks associated with bushmeat was low, though we could not perform statistical analyses due to the lack of quantitative perception-based studies. After screening the literature, our results showed that the global distribution of reported bushmeat studies were biased towards Africa, revealing data deficiencies across Asia and South America despite the prevalence of the bushmeat trade across the Global South. Studies targeting implications of the bushmeat trade on human health can help address these data deficiencies across Asia and South America. We further illustrate the need to address the nexus between bushmeat, wet markets, and disease to help prevent future outbreaks of zoonotic diseases under the previously proposed “One Health Framework”, which integrates human, animal, and environmental health. By tackling these three pillars, we discuss the current policy gaps and recommend suitable measures to prevent future disease outbreaks. Keywords Wild meat Global South Nexus Healthcare One health approach Zoonosis ==== Body pmc1 Introduction The novel coronavirus (SARS-CoV-2) outbreak is possibly the greatest humanitarian crisis since the second World War (Anastassopoulou et al., 2020; Arshad Ali et al., 2020). Three months after its initial reporting in Wuhan, China, the World Health Organization declared the 2019 coronavirus disease a pandemic on March 11, 2020 (Cucinotta and Vanelli, 2020). As of April 10, 2021, more than 135 million people across 192 countries have been infected, and global deaths have surpassed 2.9 million (Dong et al., 2020). For the third time this century, a coronavirus poses a grave threat to human health (Memish et al., 2020; Paden et al., 2018; Perlman, 2020). The World Health Organization (WHO) defines Zoonosis as any disease or infection that is naturally transmissible from non-human animals to humans, which requires a natural reservoir (WHO, 2020). For example, dromedary camels are suspected to be the animal hosts responsible for the spillover of the 2012 Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (Mohd et al., 2016). However, origins and reservoirs of zoonotic diseases are often difficult to identify (Haydon et al., 2002; Viana et al., 2014). Thus, despite global efforts by international organizations such as the WHO, the origin of the coronavirus that caused the outbreak of severe acute respiratory syndrome in 2002–2004 (SARS) and the novel coronavirus (COVID-19) remain unresolved (Wacharapluesadee et al., 2021). However, there is some evidence suggesting that previous coronaviruses were transmitted to humans from intermediate animal hosts, and thus are suspected cases of zoonosis (Cui et al., 2019; Han et al., 2016; Li, 2013). In 2002–2004, the coronavirus that caused the outbreak of severe acute respiratory syndrome (SARS-CoV-1) likely originated in horseshoe bats (family Rhinolophidae) (He et al., 2014; Hu et al., 2017; Wendong Li et al., 2005); and was likely transmitted to humans from raccoon dogs (Nyctereutes procyonoides) found in live-animal markets (Guan et al., 2003; Wenhui Li et al., 2006; Song et al., 2005). Although the origin has yet to be described in detail, some scientists, including the recent report from the WHO, theorize that the novel coronavirus likely has wildlife origins and spread to humans via wild meat sold at a wet market in Wuhan, China (Andersen et al., 2020; Lu et al., 2020; Maxmen, 2021; Shereen et al., 2020; Tang et al., 2020; Wu et al., 2020). Therefore, the connection between wild meat, wet markets, and zoonotic diseases should be investigated. In light of the recent COVID-19 pandemic, some have called for bans on wildlife trade and the closure of wet markets altogether. However, others caution that blanket bans on wildlife trade may not necessarily improve pandemic preparedness, while undermining its importance in providing food and financial security for certain communities (Eskew and Carlson, 2020; Roe et al., 2020). Following the outbreak of the Ebola virus disease in West Africa 2013–2016, studies revealed unintended consequences of a wildlife trade ban (Ayegbusi et al., 2016; Bonwitt et al., 2018). Without producing the desired degree of public health awareness, the ban drove illicit activity underground, which not only thwarted surveillance for future disease control efforts, but also weakened community stakeholders' trust in authority and worsened food accessibility for already food-insecure populations (Bonwitt et al., 2018). Bushmeat (aka wild meat) refers to any non-domesticated animal harvested for food (Nasi et al., 2008) and provides food and financial security to millions of people globally (Nielsen et al., 2018). The national value of the bushmeat trade is estimated to be hundreds of millions USD/year for certain African countries (Bowen-Jones et al., 2003; Davies, 2002; Lescuyer and Nasi, 2016). Bushmeat consumption acts as a significant driver behind the disproportionate loss of wildlife, particularly large mammals and herbivores (Ripple et al., 2016). Estimates suggest that about 273 tonnes of bushmeat are transported from Africa to Europe annually (Chaber et al., 2010) and that globally more than 5 million tonnes of bushmeat is consumed every year (Kanagavel et al., 2016). Animal-source foods are a major source of high quality protein and bioavailable nutrients, especially in the poorer regions of the world (Adesogan et al., 2020; Neumann et al., 2003). On the other hand, livestock, such as intensively-raised commercial meat chickens, provide more energy from fat than protein (Wang et al., 2010), further demonstrating the higher nutritional value of bushmeat (Sarti et al., 2015). Factors that trigger bushmeat consumption include, among others, population growth, poverty, limited market access, war and conflict, unequal wealth distribution, occupation as well as preference of wild meat over farm-grown meat (Brashares et al., 2011; Friant et al., 2020; Golden et al., 2014; Kanagavel et al., 2016; Lindsey et al., 2013; Rogan et al., 2018; Schulte-Herbrüggen et al., 2013). Conversely, demand for bushmeat consumption in urban areas are often driven by culture and consumer preferences (Chausson et al., 2019; McNamara et al., 2019; van Vliet and Mbazza, 2011). In recent decades, the spike in production, trade, and consumption of meat has tied Asian countries to each other and global markets through meat commodities, leading to the emergence of a meat complex in Asia (Jakobsen and Hansen, 2020; Nam et al., 2010; Sans and Combris, 2015). This Asian meat complex has the potential to exacerbate the health risks associated with meat consumption. For bushmeat consumption, long-term health risks associated with bushmeat consumption include exposure to hazardous levels of heavy metals, such as lead. (Ahmadi et al., 2018; Cang et al., 2004; Gbogbo et al., 2020; Pain et al., 2010). Short-term risks associated with bushmeat consumption may include exposure to zoonotic diseases, which can be fatal (Jones et al., 2008; Karesh and Noble, 2009; Kurpiers et al., 2015). These same risks also occur from animal-source foods in domestic animals, especially those produced intensively (WHO, 2020). The domestic meat market is roughly 60 times larger than the bushmeat market. However, despite the smaller proportionate risks associated with bush meat consumption, there is evidence connecting the bushmeat trade in the spread of infectious diseases including Ebola (Leroy et al., 2004, 2005; Rewar and Mirdha, 2014) and HIV (Aghokeng et al., 2010; Chitnis et al., 2000; Faria et al., 2014; Peeters et al., 2002; Sharp and Hahn, 2011). Despite associated health and injury risks, bushmeat consumption is widespread across various socio-economic communities. Bushmeat is often sold at wet markets across the Global South (Nielsen et al., 2018), which pose additional health risks to humans. Wet markets and wildlife markets are often conflated. However, not all wet markets sell bushmeat. Therefore, in this paper, we focus on wet markets that include live or slaughtered bushmeat. Generally, wet markets feature densely-packed, open-air vendors that sell produce and various species of bushmeat. Thus, wet markets, like factory-farmed meat, can amplify the risks associated with the bushmeat trade by facilitating cross-species transmissions of zoonotic diseases (Karesh et al., 2005; Parrish et al., 2008). Thus, wet markets have been a major concern of disease experts across the globe (Cui et al., 2019; Webster, 2004). Notably, humans with ties to certain wet markets in Asia have been infected with coronaviruses with suspected animal origins, including the outbreak of the Middle East respiratory syndrome (MERS) in live animal markets (Khudhair et al., 2019; Li et al., 2017; Yusof et al., 2017), SARS (Guan et al., 2003; Li et al., 2006; Park et al., 2020; Song et al., 2005), and COVID-19 in wet markets (Chen et al., 2020; Li et al., 2020). In developing countries, wet markets/slaughterhouses are a significant source of wastewater or effluents (blood flow, hair, gut content, urine and contaminated water) due to meet processing, burning and boiling of bones, hooves, fat, meat, etc. (Seiyaboh and Izah, 2017; Singh et al., 2014). Based on the water quality index, it is reported that wastewater from wet market falls under the lowest category (i.e., severely polluted), making the receiving water bodies highly vulnerable to organic and inorganic pollutants; and hence calls for sustainable management and treatment of the effluents before discharging into the environment (Amneera et al., 2013). Poor management and treatment of this effluent poses different threats to both environment and human health (Singh et al., 2014). These threats are exacerbated in water-scarce places where humans and wildlife are forced into close proximity for available resources, a contributing risk factor for transmission of water-associated diseases (e.g. leptospirosis) (Group, 2011). Despite known health risks and alternative sources of food, wet markets have persisted in both developed and developing parts of the globe. In developing economies, the lack of reliable cold chains could contribute to the continued presence of wet markets (Joshi et al., 2009). Furthermore, culture and consumer preferences for fresh produce has been cited for the persistence of wet markets globally (Huang et al., 2015; Zhong et al., 2020). One Health is an interdisciplinary framework that addresses human health, animal health, and environmental health. Recently, this definition has been expanded to include plants and soil ecosystems, linking the One Health approach to food systems (Durso and Cook, 2019). Thus, the One Health approach provides an avenue to combat emerging infectious diseases, especially zoonotic diseases (Atlas, 2013; Mazet et al., 2009). For example, the Ebola crisis could have been better handled with a One Health approach by proactively monitoring infection and transmission, educating stakeholders about zoonotic disease outbreak and management plans, and enhancing food security to reduce dependence on bushmeat and minimize exposure to zoonoses (Mwangi et al., 2016). Applying the One Health approach can guide research to help prevent the emergence of zoonotic diseases by acknowledging the nexus between bushmeat, wet markets, and disease. This nexus approach provides a framework for transformative change by integrating efforts between health and science experts, government officials, and local stakeholders (Eskew and Carlson, 2020; Roe et al., 2020; World Health Organization, 2012). To our knowledge, however, this nexus has not yet been described in detail. Thus, the nexus between bushmeat, wet markets, and disease must be examined to bolster disease control efforts globally and better prepare for future pandemics. In this study, we reviewed the literature to explore the nexus between bushmeat, wet markets, and disease. Our aim was to evaluate disease monitoring and surveillance efforts within the bushmeat trade by compiling established zoonotic health risks based on serology; and to characterize perceptions of the health risks associated with bushmeat and wet markets to better inform education campaigns and public policy. Based on this review, we provide recommendations to prevent future pandemics by addressing and controlling the nexus between bushmeat, wet markets, and disease control. 2 Methods 2.1 Literature search To explore the nexus between bushmeat, wet markets, and disease, we searched the Scopus literature database (https://www.scopus.com/) on November 9, 2020 using the Boolean search string: TITLE-ABS-KEY (Bushmeat) AND TITLE-ABS-KEY (disease) OR TITLE-ABS-KEY (wet market) OR TITLE-ABS-KEY (wild AND meat). The search was not restricted by publication date nor language. However, only articles that provided full text in English were considered for analyses. The search yielded 299 articles (see Appendix 1 for a full list of articles). Eight articles that did not provide full text in English were omitted. Thereafter, we manually screened the resulting article abstracts to include only primary literature that explicitly established zoonotic pathogens (hereafter risk assessment studies) associated with hunting, handling, or consumption of non-domesticated animals, which the author(s) referred to as 'bushmeat' or matched the definition of the term described in the Convention on Biological Diversity (CBD) Technical Series No. 33 (Nasi et al., 2008). Health risks were determined generally by serological evidence. Our Scopus search yielded inadequate scientific disclosures that calculated actual burden of zoonoses, and thus we did not consider disease burden in determining risk of zoonosis. We also included studies that surveyed the perception of health risks associated with bushmeat (hereafter perception-based studies) directly by questioning respondents about their perceived health risks or indirectly, for example, by measuring behavioral changes in bushmeat consumption following health campaigns on zoonotic diseases. We retrieved the full-text of the articles meeting these criteria and manually screened out the articles that did not provide evidence on the same criteria in full-text. After screening abstracts and full-texts, 247 articles were excluded that did not meet the criteria specified above, leaving 52 relevant articles: 32 risk assessment and 21 perception-based studies. One article met the criteria specified for both risk assessment and perception-based studies (Fig. 1 ).Fig. 1 Flowchart of methods and Scopus literature screening process. Fig. 1 2.2 Meta-analysis We extracted the following information from the relevant risk assessment studies that were identified: (1) type and species of bushmeat investigated, (2) location from which the samples were collected, and (3) type and genus of zoonotic pathogen associated with the bushmeat in question. We categorized bushmeat according to broad taxonomic groups. Pathogen type was categorized as virus, bacteria, helminth, or protozoa. For meta-analysis of the extracted information from the relevant risk studies, we counted each species of bushmeat collected from each country in each article as a case. The results presented in the following section derive from cross-tabulation of the attributes of all cases. For the relevant perception-based studies, we extracted the following information: (1) location from which respondents were surveyed, (2) population type of respondents, (3) type of bushmeat handler surveyed, and (4) perceived health risks associated with the bushmeat trade. We used descriptions of study sites to determine the population type of respondents as either urban or rural. We categorized bushmeat handler as hunter, trader, or other (non-hunter/non-trader). We extracted author's description (both quantitative and qualitative) to categorize respondents' perceived health risks as either high or low. For example, in addition to noting that few participants were aware of transmission of zoonotic infections via bushmeat, Ozioko et al. (2018) reported that 91.2 % and 76.2 % of hunters and traders valued bushmeat more than their health, respectively. For this study, we categorized the perceived health risks as low. On the other hand, we categorized the perceived health risks as high for the study by Gbogbo and Kyei (2017), which reported that 68 % of respondents believed that the consumption of bushmeat can result in zoonotic disease infection. For meta-analysis of information from perception studies, we counted each population type from each country in each article as a case. The results presented in the following section derive from cross-tabulation of the attributes of all cases. 2.3 Data analysis The data on species of bushmeat were subject to phylogenetic analysis. All figures were constructed in R (v.3.6.2) (R Core Team, 2014). We used the package ‘rotl' (Michonneau et al., 2016) to match taxonomic names to the Open Tree of Life (Hinchliff et al., 2015). The unique taxonomic names from the Open Tree of Life matched the 59 species that we compiled. Using the ott identification tags of these species as search properties, we identified studies that included these unique taxonomic tags and found 9 studies that contained relevant phylogenetic trees. We used existing phylogenies from these studies to construct a phylogenetic tree for the species of bushmeat reported in the relevant risk studies. We used the study (Hedges et al., 2015) that contained a rooted phylogeny with branch lengths and kept tips corresponding to the 59 species. The resulting phylogeny contained 58 tips. The blond capuchin (Sapajus flavius) was the only species that could not be included in our reconstructed phylogenetic tree. The number of cases was mapped onto the phylogeny as a continuous variable. We mapped the global distributions of risk assessment and perception-based studies using the package ‘rworldmap’ (South, 2011). 3 Results From all 299 Scopus search results, we observed topical spikes in published papers following the SARS epidemic (2002–2004) and MERS epidemic (2009), as well as the African Ebola epidemic (2013–2016) ( Fig. 2 ). After screening irrelevant studies, our analyses included 52 articles, with 88 % of the total cases (137/156 cases) in Africa; 5% (8/156 cases) in Europe; 4% (7/156 cases) in North America; 2% (3/156 cases) in Asia; and 1% (2/156 cases) in South America.Fig. 2 Distribution of Scopus search results by publication date. Topical spikes of publications following the outbreak of severe acute respiratory syndrome (SARS), the Middle Easter respiratory syndrome (MERS), and the Ebola virus disease illustrate that science retroactively follows disease outbreaks. Fig. 2 For the 32 risk assessment studies, 58 species of bushmeat (and humans [Homo sapiens]) were studied in 15 countries (Fig. 3 a), totaling 133 cases (see Appendix 2 for a list of the 133 risk assessment cases and the type of pathogenic risk(s) established in each case). Several species were reported in more than one article, and one study was conducted in two countries. Mammals were most frequently reported (95 %; 126/133 cases), followed by reptiles (4%; 5/133 cases) and birds (1%; 2/133 cases). Greater white-nosed monkeys (Cercopithecus nictitans) and humans were cited the most times with 9 and 8 cases, respectively (Fig. 4 and see Appendix 3 for a list of the number of cases and type of pathogen for each species of bushmeat). Based on serological evidence, sixty pathogens were established as health risks in 58 bushmeat species, with several species of bushmeat harboring one or more pathogens; furthermore, ten bushmeat species harbored no zoonotic pathogens. Most of the zoonotic pathogens established as health risks were helminth (37 %; 22/60) and bacteria (33 %; 20/60), followed by viruses and protozoa (15 %; 9/60 each). The predominate zoonotic pathogens identified were retroviruses: Lentivirus (immunodeficiency viruses) and Deltaretrovirus (T-cell lymphotrophic viruses), which were identified in 18 and 14 species of bushmeat, respectively. Other predominate zoonotic pathogens identified were parasitic roundworms Ascaris, Strongyloides, and Trichuris, which were identified in 14, 13, and 12 species of bushmeat, respectively. The predominate protozoa and bacteria identified were Entamoeba and Leptospira, which were identified in 9 and 3 species of bushmeat, respectively (Fig. 5 and see Appendix 4 for a full matrix of bushmeat-zoonotic pathogen infections). Four viruses were identified in humans. Regarding pathogen richness in each species of bushmeat, health risks were highest for greater cane rats and greater white-nosed monkeys, harboring 14 genera of pathogens (1 protozoa, 4 bacteria, and 9 helminth) and 13 genera of pathogens (3 viruses, 4 protozoa, and 6 helminth), respectively.Fig. 3 Global distribution of risk assessment (top) and perception-based (bottom) studies on bush meat, represented by the number of cases in each country identified from the literature. Global distributions were depicted using the package ‘rworldmap’ (South, 2011). Fig. 3 Fig. 4 Total number of cases identified for each species of bush meat mapped onto the phylogeny as a continuous variable. The length of the bars indicates the genus richness of zoonotic pathogens identified for each species of bush meat. Phylogenetic scale bar indicates 200 million years. Fig. 4 Fig. 5 Heat map of the number of cases for each bush meat-pathogen infection. As one or more pathogens was established in some species of bush meat, the total of number of cases reported for risk assessment studies do not agree with the total number of bush meat-pathogen infection cases here. Fig. 5 For the 21 perception-based studies, perceived health risks associated with the bushmeat trade was documented in 11 countries (Fig. 3b), totaling 23 cases (see Appendix 5 for a list of the 23 perception cases and the perceived health risk described in each case). Two studies were conducted in both rural and urban population types. Altogether, 12 and 11 cases were reported in rural (52 %) and urban (48 %) population types, respectively. Our analyses found that nearly half (48 %; 11/23 cases) of the perception-based studies were conducted in the context of the Ebola virus disease outbreak. In both urban and rural populations, perceived health risks associated with the bushmeat trade was generally low (Fig. 6 ).Fig. 6 Perceived health risks associated with the bush meat trade. Fig. 6 4 Discussion 4.1 Literature compilation There was a clear dominance of publications following major health crises, such as SARS, MERS, and Ebola, demonstrating that scientific investigations on bushmeat and wet markets retroactively follow disease outbreaks. Furthermore, after screening irrelevant articles, there was geographical bias in the remaining studies, with a majority of studies conducted in Africa. Our analysis clearly revealed studies lacking in Asia and South America, despite the prevalence of the bushmeat trade across the Global South. Altogether, these factors contribute to the speculative narrative surrounding disease outbreaks originating in these regions of the world and expose our knowledge gaps that may thwart disease control efforts. 4.2 Zoonotic pathogens Although disease burden was not calculated, our findings demonstrate that zoonotic viruses may have the potential to pose significant health risks to humans. Based on serological investigations, we found that bushmeat handlers were infected with four zoonotic viruses: Deltaretrovirus, Spumavirus (foamy viruses), Ebolavirus, and Henipavirus (Nipah virus). Our results showed that these virus were found in various bushmeat species, such as fruit bats (Eidolon helvum) and nonhuman primates, which can thus pose greater risk of spillover events to humans. Accordingly, consumers of these species, which can be vectors of these viruses among other zoonotic pathogens, may be at greater risk of infection. In our study, we found that fruit bats hosted Ebolavirus, Lyssavirus (rabies virus), and Henipavirus. The risks of consuming nonhuman primates are multifold. Infectious viruses are abundant in nonhuman primates (Devaux et al., 2019). Accordingly, the total number of cases for nonhuman primates was high (65 %; 86/133 cases). We found that nonhuman primates hosted Lentivirus, Deltaretrovirus, Spumavirus, Cytomegalovirus, Lymphocryptovirus, and Mastadenovirus. Nonhuman primates may also act as intermediate host species and may transmit other zoonotic diseases to humans (Devaux et al., 2019; Han et al., 2015; Weingartl et al., 2012). By contrast, we found that certain species of bushmeat hosted no zoonotic pathogens based on the serological evidence, which may pose less health risks to humans. These lower-risk species can help provide options for safer consumption of bushmeat. Altogether, our results demonstrate how bushmeat-pathogen matrices can inform bushmeat regulation policies and visualize disease surveillance efforts. 4.3 Perceptions Despite multiple disease outbreaks globally and well-documented zoonotic diseases associated with bushmeat, we found that perceived health risks are typically low among bushmeat handlers. We found that, in some cases, simply awareness of zoonoses among respondents was low (Ozioko et al., 2018; Philavong et al., 2020; Pruvot et al., 2019). We also found that there was a critical knowledge gap between awareness of disease and mode of transmission to humans, which can serve an important role in shaping perceived risks associated with bushmeat (Ayegbusi et al., 2016; Bair-Brake et al., 2014; Duonamou et al., 2020; Lucas et al., 2020; Mwangi et al., 2016; Saylors et al., 2021; Subramanian, 2012). For example, one perception-based study found a high level of awareness about the Ebola virus disease outbreak among bushmeat handlers, however, most of the handlers did not believe that wild animals are carriers of Ebola virus disease, citing supernatural and conspiracy theories surrounding its transmission to humans (Ayegbusi et al., 2016). Regarding perceived health risks, the skepticism of respondents from other studies stem from cultural ties to bushmeat practices (Ayegbusi et al., 2016; Bonwitt et al., 2018; Saylors et al., 2021). These views were conflated with trust issues in local authorities, which ultimately frustrated public health campaigns (Ayegbusi et al., 2016; Bonwitt et al., 2018; Saylors et al., 2021). Our analysis on perception-based studies found a deficiency of quantitative reporting, which prevented statistical modeling in our meta-analyses. We highlight the need for standardizing perception-based studies that are grounded in quantitative analyses. Quantitative data is necessary to inform educational campaigns aimed at raising awareness and conveying zoonotic risks associated with bushmeat. 4.4 Importance of nexus approach An interdisciplinary framework is vital to address the nexus between bushmeat, wet markets, and disease. There is extensive research on each of these three topics in isolation, however, few investigations have explored these topics together. Additionally, oversight of these topics is often handled separately by different governing bodies. For example, budgets and policies on bushmeat likely fall under the responsibility of wildlife departments; wet markets likely by commerce departments; and health departments likely handle diseases. However, these isolated efforts fail to acknowledge the synergistic risks induced at the interface of these three issues, as exemplified by the current COVID-19 pandemic. Thus, efforts that extend across the borders of traditional governing bodies is paramount to properly address this nexus. Effective campaigns require coordinated efforts between health and science experts, government officials, and local stakeholders (Roe et al., 2020; Van Vliet, 2011), which is especially important for those communities whose livelihoods depend on the bushmeat trade (Cooney et al., 2018; Friant et al., 2020). The One Health approach by World Health Organization, which addresses human, animal, and environmental health, provides a framework to improve pandemic preparedness across the globe. The One Health framework recognizes that zoonotic diseases, environmental pressures, animal and human health are linked interdependently. As such, a recent study implicated biodiversity loss with increased risk of human exposure to both new and established pathogens (Keesing and Ostfeld, 2021), further demonstrating the need to assess the impacts anthropogenic land-use change on disease spillover (Plowright et al., 2021). In Industrial safety engineering, Fire Triangle is a model that illustrates how to extinguish fires by removing one of its three necessary ingredients: oxygen, heat, and fuel. Similarly, we argue that future disease outbreaks can be prevented by tackling what we call the three pillars of pandemics: bushmeat, wet markets, and disease. A majority (72 %) of emerging infectious diseases are zoonotic (Jones et al., 2008). Opportunities for transmission of zoonotic diseases increase with the hunting, handling, and consumption of bushmeat (Karesh and Noble, 2009; Kurpiers et al., 2015). Further closing the gaps between human and wildlife, wet markets facilitate cross-species disease transmission and spillover events to humans (Chen et al., 2020). Thus, these synergistic effects underscore the importance of acknowledging the nexus between bushmeat, wet markets, and disease to help prevent future pandemics. 5 Recommendations Here we discuss some preventative actions outlining bushmeat consumption, management of wet markets, and controlling disease outbreaks, particularly on the overlapping interfaces. Given the global distribution of bushmeat consumption and wet markets, we provide generic recommendations under the One Health framework that can facilitate transformative change and instigate localized efforts to address context-specific issues. As shown in Fig. 7 , proactive management and regulation of the bushmeat trade can benefit both wildlife and humans. We recommend routine monitoring of wildlife for infectious diseases (Watsa, 2020) in tandem with the Convention on International Trade in Endangered Species and Wild Fauna and Flora (CITES) (D’Cruze and Macdonald, 2016) to better inform bushmeat trade regulations. This may not only reduce spillover events to humans (Halliday et al., 2012; Hattendorf et al., 2017), but also provide information on overall ecosystem health (Leroy et al., 2004; Smith et al., 2009; Thompson et al., 2010). Illegal bushmeat hunting is an existential threat for some species, particularly primates (Benítez-López et al., 2017; Ripple et al., 2016; Rogan et al., 2017). At the national level, regulating the bushmeat trade for higher-risk and endangered species is vital to ensure both animal and human health. Monitoring wildlife for disease may also highlight species suitable for lower-risk consumption of bushmeat, as our results showed that no zoonotic pathogens were associated with other bushmeat species based on serological evidence. We also recommend participatory surveillance of bushmeat sold at wet markets. Species of bushmeat are sometimes misreported in the marketplace (Minhós et al., 2013; Schilling et al., 2020). Even worse, a recent article illustrated the concept of "species deception," in which bushmeat is purposefully misrepresented by sellers and sold as another species of bushmeat (Dell et al., 2020). This can contribute to misinformed knowledge of pathogen spillover risk to humans. Species identification of bushmeat sold in wet markets can also support efforts to better regulate the bushmeat trade. Stakeholder representation, implementing concrete monitoring and evaluation structures, and mutual understandings of disease transmission across disciplines are challenges to implementing a One Health approach (Johnson et al., 2018; Khan et al., 2018). Benefits of participatory monitoring help address these challenges, and include developing research capacity, fostering stakeholder relationships, and earlier detection of emerging infectious diseases (Mooney-Somers and Maher, 2009). Integrating bushmeat policies into CITES enforcement can help consolidate efforts to safeguard both wildlife and human health.Fig. 7 A conceptual framework under the ‘One Health’ approach to prevent future disease outbreaks by tackling the three pillars of pandemics: bush meat, wet markets, and disease. Fig. 7 Wet market policies should focus on sanitization and safe meat storage. The temperature storage and packing conditions impact spoilage and the proliferation of subsequent pathogen populations, particularly bacteria (Chaillou et al., 2015; Doulgeraki et al., 2012). These microbial developments generate volatile organic compounds, which may serve as indicators of meat spoilage (Casaburi et al., 2015). Proper wastewater management from wet markets can minimize threats to humans and surrounding ecosystems. We recommend harnessing wastewater as an alternative superior medium for micro algae biomass (Jais et al., 2015; Maizatul et al., 2017). Microalgae biomass produced during the phycoremediation of wastewater from wet markets provides high quality fish food and reduces the dependency on freshwater for production of micro-algal biomass. Management of wastewater from wet markets around the world have proven successful among different advanced wastewater treatment technologies, like Static granular bed reactor with anaerobic reactor (Debik and Coskun, 2009); Up-flow anaerobic sludge blanket reactors (UASB) reactors (Menezes Lima et al., 2020); Dissolved-air floatation system (de Nardi et al., 2008); and Biological wastewater treatment with combination of anaerobic and aerobic system (Aziz et al., 2019). These treatment technologies not only manage effluent from wet markets but also generate biogas energy (Bustillo-Lecompte and Mehrvar, 2015), and thus provide a sustainable solution to wastewater management. Wastewater generation should be minimized by analyzing their quality at critical stages of production process in wet markets using qualitative and quantitative flow charts (Kist et al., 2009). A decade long study on market characteristics revealed poor sanitization conditions and cross-species blood contamination due to inadequate water availability (Saylors et al., 2021). Also, our findings suggest that those who travel to wet markets, including bushmeat vendors, are not aware of these health risks (Ozioko et al., 2018; Philavong et al., 2020; Pruvot et al., 2019; Saylors et al., 2021). Thus, investments in water supply coupled with increased accessibility to washing stations can minimize health risks to both humans and the surrounding ecosystems (Saylors et al., 2021). Finally, we stress the importance of fostering preventative healthcare infrastructures across national boundaries to improve global pandemic preparedness (Dey et al., 2020; Lal et al., 2020; Yager et al., 2008). The COVID-19 pandemic has showcased the shortfalls of current systems, crippling healthcare infrastructures across the world. Low testing capabilities thwarted efforts to contain the spread of the disease (Babiker et al., 2020), and infected patients were not able to receive proper care due to inadequate hospital capacities (Moghadas et al., 2020; Shoukat et al., 2020). Accordingly, a study found that increasing testing and hospital beds, as well as improving government effectiveness, are associated with lower mortality rates (Liang et al., 2020). Although the timely development of effective vaccines has been possible in the past (Kieny, 2018; Peeling et al., 2019; Roberts, 2019), even in the case of the COVID-19 (Krammer, 2020), funding poses a major barrier for widespread vaccination (Gouglas et al., 2018). Furthermore, socio-economic disparities accentuate the challenges in vaccine development, manufacturing, and delivery at the local and global level (Plotkin et al., 2017). Thus, we recommend proactive research and development to face future likely diseases. Despite having the technological capacity to improve pandemic preparedness, proactive strategies currently do not provide economic stability, failing to prioritize immunologics, such as vaccine or antibody developers (Bloom et al., 2017). This underscores the necessity of routine wildlife surveillance for diseases, which can position stakeholders to better invest in proactive research and development efforts. We also recommend campaigns to increase awareness of the health risks associated with bushmeat, including the transmission of diseases. We found a critical knowledge gap between awareness of disease and spillover risks to humans (Ayegbusi et al., 2016; Bair-Brake et al., 2014; Duonamou et al., 2020; Lucas et al., 2020; Mwangi et al., 2016; Saylors et al., 2021; Subramanian, 2012). This presents an opportunity to not only raise the awareness on health risks associated with bushmeat but more importantly educate bushmeat stakeholders on cross-species transmission of zoonotic diseases. Stakeholders must be more informed decisions on bushmeat practices in order to minimize the risks of future pandemics. 6 Conclusion Assessing the risks of future disease outbreaks require an interdisciplinary approach, such as the previously described, “One Health Framework”, which integrates human, animal, and environmental health. The One Health Framework provides a lens to address what we call the three pillars of pandemics: bushmeat, wet markets, and disease. Although these topics are extensively studied in their respective disciplines, rarely do studies consider this nexus in preparing for future disease outbreaks. In this directed and systematic review, our findings show that scientific investigations on these topics follow major disease outbreaks, which inhibit investments in future pandemic research. Furthermore, the lack of studies in Asia and South America exposes current knowledge gaps and our susceptibility to disease outbreaks originating in these regions of the world. We also demonstrate how bushmeat-pathogen infection matrices can help regulate the hunting and trade of wildlife in tandem with current CITES policies. Despite evidence of bushmeat species harboring various zoonotic pathogens in scientific disclosures, the low perception of risks among stakeholders of the bushmeat trade highlights the importance of educating stakeholders about transmission risks of zoonoses as a tool to implement a proactive One Health approach. Acknowledging the nexus between bushmeat, wet markets, and disease is pivotal to improve pandemic preparedness. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The article has not been submitted elsewhere. Appendix A Supplementary data The following are Supplementary data to this article: Acknowledgements The work was supported by the Strategic Research and Development Area (JPMEERF16S11500) project financed by the Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency of Japan (ERCA). Appendix A Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.envsci.2021.05.025. ==== Refs References Adesogan Adegbola T. “Animal source foods: sustainability problem or malnutrition and sustainability solution? Perspective matters.” Glob. Food Sec. 2020 Aghokeng Avelin F. 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Wet Markets - a continuing source of severe acute respiratory syndrome and influenza? Lancet 2004 Weingartl Hana M. Transmission of ebola virus from pigs to non-human primates Sci. Rep. 2012 WHO Zoonoses 2020 https://www.who.int/news-room/fact-sheets/detail/zoonoses World Health Organization Research Priorities for Zoonoses and Marginalized Infections. 2012 World Health Organization technical report series Wu Fan A new coronavirus associated with human respiratory disease in China Nature 2020 Yager Paul Domingo Gonzalo J. Gerdes John Point-of-care diagnostics for global health Annu. Rev. Biomed. Eng. 2008 Yusof Mohammed Farouk Diversity of middle east respiratory syndrome coronaviruses in 109 dromedary camels based on full-genome sequencing, Abu Dhabi, United Arab Emirates Emerg. Microbes Infect. 2017 Zhong Shuru Crang Mike Zeng Guojun Constructing freshness: the vitality of wet markets in Urban China Agric. Human Values 37 1 2020

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==== Front Gynecol Oncol Gynecol Oncol Gynecologic Oncology 0090-8258 1095-6859 Elsevier Inc. S0090-8258(21)00171-2 10.1016/j.ygyno.2021.02.026 Article Association between definitive chemoradiotherapy wait-time and survival in locally-advanced cervical cancer: Implications during the coronavirus pandemic Matsuo Koji ab1 Huang Yongmei c1 Matsuzaki Shinya a Ragab Omar M. d Roman Lynda D. ab Wright Jason D. c⁎ a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA b Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA c Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY, USA d Department of Radiation Oncology, University of Southern California, Los Angeles, CA, USA ⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA. 1 Contributed equally to the work. 23 3 2021 5 2021 23 3 2021 161 2 414421 26 8 2020 17 2 2021 © 2021 Elsevier Inc. All rights reserved. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objective The current coronavirus pandemic caused a significant decrease in cancer-related encounters resulting in a delay in treatment of cancer patients. The objective of this study was to examine the survival effect of delay in starting concurrent chemo-radiotherapy (CCRT) in women with locally-advanced cervical cancer. Methods This is a retrospective observational study querying the National Cancer Database from 2004 to 2016. Women with stage IB2-IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix who received definitive CCRT with known wait-time for CCRT initiation after cancer diagnosis were eligible (N=13,617). Cox proportional hazard regression model with restricted cubic spline transformation was fitted to assess the association between CCRT wait-time and all-cause mortality in multivariable analysis. Results The median wait-time to start CCRT was 6 (IQR 4–8) weeks. In a multivariable analysis, older age, non-Hispanic black and Hispanic ethnicity, recent year of diagnosis, Medicaid and uninsured status, medical comorbidities, and absence of nodal metastasis were associated with longer CCRT wait-time (P<.05). Women with aggressive tumor factors (poorer differentiation, large tumor size, nodal metastasis, and higher cancer stage) were more likely to have a short CCRT wait-time (P<.05). After controlling for the measured covariates, CCRT wait-time of 6.1–9.8 weeks was not associated with increased risk of all-cause mortality compared to a wait-time of 6 weeks. Similar association was observed when the cohort was stratified by histology, cancer stage, tumor size, or brachytherapy use. Conclusion An implication of this study for the current coronavirus pandemic is that in the absence of aggressive tumor factors, a short period of wait-time to start definitive CCRT may not be associated with increased risk of mortality in women with locally-advanced cervical cancer. Keywords Cervical cancer Concurrent chemo-radiotherapy Wait time Coronavirus pandemic Survival ==== Body pmc1 Introduction In 2021 the world continues to face the impact of a global pandemic crisis caused by a novel coronavirus (COVID-19) that has created unprecedented stress on health service systems creating unique challenges to providing timely care for cancer patients [[1], [2], [3], [4], [5]]. Multiple global studies found that the current COVID-19 pandemic may cause a significant decrease in cancer-related encounters for a variety of malignancies [6,7]. An important concern is a delay in treatment and care for cancer patients [6,7]. A recent high-quality meta-analysis showed that the wait-time for treatment initiation is a critical component for patient prognosis in various malignancies [8]. In women with locally-advanced cervical cancer, the use of radiation remains an essential component in management. The American Society for Radiation Oncology (ASTRO) Clinical Practice Guidelines conclude that concurrent chemo-radiotherapy (CCRT) offers curative intent for women with this disease [9]. To date, evidence examining the effect of wait-time prior to initiation of CCRT on survival for locally-advanced cervical cancer is scarce and has reported mixed results [10,11]. Available evidence is also limited in interpretation due to limited sample size [11], restricted histology (squamous alone), inclusion of non-standard treatment approaches (omission of concurrent chemotherapy), and the inclusion of early-stage disease (stage IA-IB1) [10]. Given the constraints on delivering timely oncologic care due to the current COVID-19 pandemic [6,7], it is of paramount importance to assess the effects of treatment wait-time on survival in oncologic care. The objective of our study was to examine the impact of delay in starting CCRT on survival in women with locally-advanced cervical cancer. 2 Patients and methods 2.1 Data source This is a retrospective observational cohort study using the National Cancer Database (NCDB). NCDB is a nationwide tumor registry that collects data from Commission on Cancer (CoC)-accredited facilities in the United States [12]. National Cancer Database collects >1 million invasive cancer cases per year, representing ~70% of all new invasive cancers in the U.S. Over 1500 CoC-affiliated institutions participate in the database through a joint mechanism of the CoC of the American College of Surgeons (ACoS) and the American Cancer Society (ACS) Society. The study was determined to not be human subjects research by the Columbia University Institutional Review Board. 2.2 Study eligibility Women with the American Joint Committee on Cancer 6th and 7th version and the 2009 International Federation of Gynecology and Obstetrics stage of IB2-IVA squamous carcinoma, adenocarcinoma, and adenosquamous carcinoma of the uterine cervix diagnosed from 2004 to 2016 who received definitive radiotherapy with chemotherapy were examined. All patients had known information for CCRT wait-time, defined as the time interval between the diagnosis of cervical cancer and the time to initiation of CCRT. Exclusion criteria included histologic types and cancer stage other than above, lack of chemotherapy, primary surgical or chemotherapy treatment, and absence of CCRT wait-time information. 2.3 Clinical information Among cases that met the eligibility criteria, the following information was abstracted from the database: Patient demographics included age (<40, 40–49, 50–59, 60–69, 70–79, ≥80 years), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and non-Hispanic others, year of diagnosis (2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, and 2016), medical comorbidity (0, 1, and 2), insurance status (Medicare, Medicaid, private, uninsured, and others), neighborhood average household income (<$40,227, $40,227–$50,353, $50,354–$63,332, and ≥$63,333) and education level (≥17.6%, 10.9–17.5%, 6.3–10.8%, and <6.3%), and residential status (metropolitan, urban, and rural). Facility information included registered location (Eastern, South, Midwest, and West) and facility type (academic / research program, integrated network cancer program, comprehensive community cancer program, and community cancer program). Tumor characteristics included histologic type (squamous cell, adenocarcinoma, and adenosquamous), cancer stage (IB2, IIA, IIB, IIIA, IIIB, and IVA), tumor differentiation (well, moderate, and poor), tumor size (≤20, 21–40, 41–60, 61–80, 81–100, and >100 mm), lympho-vascular space invasion (yes versus no), and regional nodal metastasis (positive versus negative). Radiotherapy type include external beam radiation with brachytherapy versus external beam radiation alone. Survival data included follow-up time after diagnosis of diagnosis and vital status (dead or alive). Overall survival was defined as time interval between the date of radiation initiation and death from all-causes. Women who were alive at last follow-up were censored. 2.4 Statistical analysis We first examined the association between the clinico-pathological characteristics and CCRT wait-time. A generalized linear regression model using a generalized estimating equation with normal distribution and identity link was fitted. All the measured covariates were entered in the model. The residuals were plotted visually to check the violation of linear assumption. The interpretation for the parameters (betas) is that compared to the referent group what is the increased (positive) or decreased (negative) value for the average of continuous outcome. The second step of analysis was to examine the association between CCRT wait-time and all-cause mortality. Cox proportional hazards models with restricted cubic spline transformation of CCRT wait-time were fitted to assess the non-linear associations between CCRT wait-time and survival while adjusting for the measured characteristics [13]. Clinically relevant cut points were applied as 4, 8, 12, and 16 weeks for CCRT wait-time. Six weeks from diagnosis to initiation of therapy was chosen as a reference point as prior work has shown that the median wait-time for initiation of therapy for locally-advanced cervical cancer is approximately 6 weeks [10,11,14]. Effect size for all-cause mortality at each tested week relative to week 6 was expressed with adjusted-hazard ratio and 95% confident interval. Various sensitivity analyses were undertaken to assess the robustness of the study findings. Subcohorts were created as stratified by histology subtypes, cancer stage, and tumor size. CCRT wait-time of week 4 was also tested. The study cohort was stratified based on the use of brachytherapy. The rationale of this analysis is that brachytherapy plays a critical role in definitive radiotherapy for locally-advanced cervical cancer [15]. All statistical analyses were based on two-sided hypothesis, and results were deemed statistically significant at a P<.05. The STROBE guidelines were consulted to display the observational study [16]. 3 Results A total of 13,617 women were identified (Table 1 , Fig. 1 ). The median age was 51 (interquartile range 42–61). The majority of patients were non-Hispanic white (59.3%), had squamous tumors (86.1%), and received brachytherapy (64.6%). The most frequent cancer stage was IIIB (43.3%), and nearly a quarter of tumors were >6 cm in diameter (25.1%). The median CCRT wait-time was 6 (interquartile range 4–8) weeks. The median duration of definitive radiotherapy was 7.6 (interquartile range 6.3–9.0) weeks. The median of total radiation dose for external beam treatment was 48.6 (interquartile range 45–54) Gy.Table 1 Patient demographics and factors associated with CCRT wait-time. Table 1 N (%) Mean (SD) Estimated parameters (beta) (95%CI) § Overall 13,617 (100.0) 6.6 (4.3) Age (y)  <40 2535 (18.6) 6.7 (4.5) Referent  40–49 3737 (27.4) 6.4 (4.3) −0.04 (−0.25,0.17)  50–59 3569 (26.2) 6.6 (4.1) 0.19 (−0.03,0.40)  60–69 2266 (16.6) 6.8 (4.3) 0.51 (0.25,0.76)**  70–79 1138 (8.4) 6.8 (4.3) 0.53 (0.19,0.87)*  ≥80 372 (2.7) 6.4 (4.7) 0.29 (−0.20,0.79) Race/ethnicity  Non-Hispanic: White 8071 (59.3) 6.2 (3.9) Referent  Non-Hispanic: Black 2240 (16.5) 7.1 (4.8) 0.89 (0.69,1.10)**  Hispanic 1860 (13.7) 7.9 (5.1) 1.07 (0.84,1.29)**  Non-Hispanic: Other 746 (5.5) 6.9 (4.2) 0.10 (−0.21,0.42)  Unknown 700 (5.1) 5.8 (3.9) −0.01 (−0.33,0.32) Year of diagnosis  2004 728 (5.3) 5.7 (4.3) Referent  2005 745 (5.5) 5.8 (4.4) 0.00 (−0.42,0.42)  2006 793 (5.8) 6.0 (4.3) 0.29 (−0.13,0.70)  2007 885 (6.5) 6.4 (4.9) 0.81 (0.41,1.22)**  2008 951 (7.0) 6.1 (4.0) 0.36 (−0.04,0.75)  2009 948 (7.0) 6.5 (4.4) 0.72 (0.32,1.12)*  2010 1019 (7.5) 6.6 (4.4) 0.83 (0.43,1.23)**  2011 1093 (8.0) 6.7 (4.1) 0.93 (0.54,1.32)**  2012 1168 (8.6) 6.6 (4.5) 0.84 (0.45,1.23)**  2013 1197 (8.8) 6.7 (4.3) 0.87 (0.49,1.26)**  2014 1303 (9.6) 6.9 (4.0) 1.16 (0.78,1.54)**  2015 1407 (10.3) 6.9 (4.1) 1.19 (0.82,1.57)**  2016 1380 (10.1) 7.3 (4.4) 1.64 (1.26,2.01)** Insurance Status  Not Insured 1769 (13.0) 6.9 (4.8) 0.56 (0.33,0.79)**  Private 5326 (39.1) 6.2 (3.9) Referent  Medicaid 3574 (26.2) 7.0 (4.6) 0.55 (0.37,0.73)**  Medicare 2539 (18.6) 6.5 (4.2) 0.08 (−0.16,0.33)  Other Government 155 (1.1) 7.6 (5.7) 1.50 (0.84,2.16)**  Unknown 254 (1.9) 6.7 (4.0) 0.40 (−0.12,0.92) Household income¶  <$40,227 3682 (27.0) 6.8 (4.5) Referent  $40,227 - $50,353 3479 (25.5) 6.5 (4.2) 0.13 (−0.07,0.34)  $50,354 - $63,332 3066 (22.5) 6.5 (4.4) 0.15 (−0.08,0.38)  ≥$63,333 3200 (23.5) 6.5 (4.2) 0.21 (−0.06,0.48) Not Available 190 (1.4) 6.1 (3.8) −0.74 (−2.27,0.79) Neighborhood average education†  ≥17.6% 4393 (32.3) 7.1 (4.7) Referent  10.9% - 17.5% 3922 (28.8) 6.5 (4.2) −0.27 (−0.46,-0.08)*  6.3% - 10.8% 3270 (24.0) 6.2 (4.0) −0.56 (−0.79,-0.33)**  <6.3% 1870 (13.7) 6.0 (4.0) −0.88 (−1.18,-0.59)**  Not Available 162 (1.2) 6.2 (4.0) 0.25 (−1.41,1.91) Urban/Rural  Metropolitan 11,021 (80.9) 6.7 (4.4) Referent  Urban 2030 (14.9) 6.1 (3.9) −0.25 (−0.45,-0.04)*  Rural 269 (2.0) 5.8 (3.9) −0.35 (−0.86,0.15)  Unknown 297 (2.2) 6.7 (4.1) 0.28 (−0.20,0.76) Charlson/Deyo comorbidity  0 11,729 (86.1) 6.6 (4.3) Referent  1 1474 (10.8) 6.6 (4.5) −0.03 (−0.25,0.20)  2 414 (3.0) 7.1 (4.8) 0.46 (0.05,0.86)* Facility location  Eastern 2566 (18.8) 6.9 (4.4) Referent  South 3892 (28.6) 6.1 (4.1) −0.80 (−1.01,-0.58)**  Midwest 4901 (36.0) 6.4 (4.1) −0.52 (−0.72,-0.31)**  West 2253 (16.5) 7.5 (4.8) 0.33 (0.09,0.57)*  Unknown – 6.6 (1.9) −1.05 (−4.67,2.58) Facility type  Community Cancer Program 734 (5.4) 6.7 (4.6) Referent  Comp Community Cancer Program 4320 (31.7) 6.1 (4.2) −0.52 (−0.84,-0.19)*  Academic/Research Program 6769 (49.7) 7.0 (4.4) 0.00 (−0.31,0.32)  Integrated Network Cancer Program 1789 (13.1) 6.1 (3.9) −0.70 (−1.06,-0.34)*  Other / unknown – 6.6 (1.9) ‡ Histology  Squamous cell 11,722 (86.1) 6.5 (4.3) Referent  Adenocarcinoma 1529 (11.2) 6.9 (4.4) 0.21 (−0.01,0.44)  Adenosquamous 366 (2.7) 6.6 (4.5) 0.01 (−0.42,0.44) Stage  IB2 1339 (9.8) 7.2 (4.9) Referent  II NOS 172 (1.3) 6.2 (3.5) −0.74 (−1.40,-0.08)*  IIA NOS 586 (4.3) 7.1 (4.6) 0.13 (−0.28,0.54)  IIA1 132 (1.0) 7.8 (4.2) −0.27 (−1.02,0.49)  IIA2 266 (2.0) 6.9 (3.5) −0.37 (−0.91,0.17)  IIB 3884 (28.5) 6.8 (4.2) −0.36 (−0.63,-0.10)*  III NOS 157 (1.2) 6.3 (4.7) −0.79 (−1.47,-0.10)*  IIIA 341 (2.5) 6.1 (3.9) −0.99 (−1.49,-0.49)**  IIIB 5897 (43.3) 6.4 (4.3) −0.83 (−1.08,-0.58)**  IVA 843 (6.2) 5.6 (4.1) −1.30 (−1.67,-0.93)** Tumor differentiation  Well 575 (4.2) 7.1 (4.6) Referent  Moderate 4508 (33.1) 6.5 (4.2) −0.61 (−0.97,-0.25)*  Poorly 4489 (33.0) 6.5 (4.3) −0.59 (−0.95,-0.23)*  Unknown 4045 (29.7) 6.7 (4.4) −0.36 (−0.72,0.00) Tumor Size  ≤20 mm 285 (2.1) 6.9 (3.8) Referent  21–40 mm 1495 (11.0) 7.6 (4.6) 0.57 (0.05,1.09)*  41-60 mm 4044 (29.7) 6.8 (4.1) −0.29 (−0.79,0.21)  61-80 mm 2579 (18.9) 6.1 (4.2) −0.81 (−1.32,-0.31)*  81-100 mm 634 (4.7) 5.5 (4.1) −1.31 (−1.89,-0.73)**  >100 mm 202 (1.5) 5.2 (3.8) −1.37 (−2.11,-0.62)*  Unknown 4378 (32.2) 6.5 (4.5) −0.18 (−0.67,0.32) LVSI  No 1320 (9.7) 7.0 (4.5) Referent  Yes 437 (3.2) 7.2 (5.0) 0.35 (−0.09,0.80)  Unknown 11,860 (87.1) 6.5 (4.3) −0.16 (−0.40,0.08) Regional lymph nodes  Negative 473 (3.5) 7.7 (4.4) 1.33 (0.83,1.84)**  Positive 599 (4.4) 8.9 (4.7) −1.26 (−1.64,-0.88)**  Unknown 12,545 (92.1) 6.4 (4.3) Referent Radiation type  External bean / brachytherapy 8803 (64.6) 6.6 (4.2) 0.03 (−0.12,0.18)  External beam 4814 (35.4) 6.4 (4.5) Referent Mean (standard deviation) wait-time (weeks) from cervical cancer diagnosis to CCRT initiation is shown. § Estimated parameters (beta) from generalized linear regression model. *P<.05, **P<.001. – Number suppressed per the NCDB instruction. † % of not graduating from high school. ‡ Con-linearity with unknown in facility location. ¶ Neighborhood average. Abbreviations: y, year; N, number; SD, standard deviation; CI, confidence interval; CCRT, concurrent chemo-radiotherapy; LVSI, lympho-vascular space invasion; comp, comprehensive; and NOS, not otherwise specified. Fig. 1 Study cohort selection criteria. Abbreviations: N, number; unk, unknown; hyst, hysterectomy; exent, exenteration; and trach, trachelectomy. Fig. 1 There were 13 factors independently associated with CCRT wait-time on multivariable analysis (Table 1). Older age, non-Hispanic black and Hispanic race/ethnicity, more recent year of diagnosis, Medicaid and uninsured status, greater medical comorbidity, and absence of nodal metastasis were associated with longer CCRT wait-time (all, P<.05). In contrast, women living in urban regions, residents of the Midwest and South, residents in neighborhoods with higher educational attainments (lower percentage of not graduating from high school), those who received care at a comprehensive community cancer program or integrated network cancer program, and those with aggressive tumor factors (higher grade, large tumor size, nodal metastasis, and higher stage) were more likely to have shorter CCRT wait-time (all, P < .05). There were 12,237 women who had survival information. The median follow-up time was 30.6 (interquartile range 14.2–63.1) months, and there were 5019 (41.0%) women who died of any cause. After controlling for patient factors (age, race/ethnicity, year of diagnosis, insurance status, household income, educational status, residential status), facility factors (location and type), tumor factors (histology, cancer stage, tumor differentiation, tumor size, LVSI, and nodal status), and treatment factors (radiotherapy type and radiotherapy duration), women who had CCRT wait-time of 6.1–9.8 weeks were not at increased risk for all-cause mortality compared those who had a 6-week wait-time (Fig. 2 ). In contrast, women with a short CCRT wait-time had increased all-cause mortality risk versus those with 6-week wait-time (Fig. 2). Similar trends were observed when the cohort was stratified by cancer stage (Fig. 3A-D), histologic type (Fig. 4A-B), tumor size (Fig. 4C-D), and brachytherapy use (Fig. 5A-B and Supplemental Figs. S1-4). Lastly, similar results were observed when the referent group was set as 4-week CCRT wait-time (data not shown).Fig. 2 Adjusted associations between CCRT wait-time and all-cause mortality. Adjusted-hazard ratio for all-cause mortality controlling for patient factors (age, race/ethnicity, year of diagnosis, insurance status, household income, educational status, residential status), facility factors (location and type), tumor factors (histology, cancer stage, tumor differentiation, tumor size, LVSI, and nodal status), and treatment factor (radiotherapy type and radiotherapy duration) is shown by week of CCRT wait-time for the whole cohort. CCRT wait-time was coded using restricted cubic spline transformation with four knots located at 4, 8, 12, and 16 weeks (shown as knots). At CCRT wait-time of 9.8-week, the upper-boundary of confidence interval was <1.00 (aHR 0.95, 95%CI 0.90–0.99) that the value crossed 1.00 afterwards. The Y-axis represents the effect size for all-cause mortality. The X-axis represents the wait-time (week) from cervical cancer diagnosis to CCRT initiation. Week 6 is set as the referent group. The solid line represents the estimate as effect size. The dashed lines are 95% confidence interval. Abbreviations: CCRT, concurrent chemo-radiotherapy; aHR-adjusted-hazard ratio; and CI, confidence interval. Fig. 2 Fig. 3 Adjusted associations between CCRT wait-time and all-cause mortality (cancer stage stratification). Adjusted-hazard ratios for all-cause mortality are shown by week of CCRT wait-time for (A) stage IB2, (B) stage II, (C) stage III, and (D) stage IVA. CCRT wait-time was coded using restricted cubic spline transformation with four knots located at 4, 8, 12, and 16 weeks (shown as knots). The Y-axis represents the effect size for all-cause mortality. The X-axis represents wait-time (week) from cervical cancer diagnosis to CCRT initiation. Week 6 is set as the referent group. The solid line represents the estimate as effect size. The dashed lines are 95% confidence interval. Abbreviations: CCRT, concurrent chemo-radiotherapy; aHR-adjusted-hazard ratio; and CI, confidence interval. Fig. 3 Fig. 4 Adjusted associations between CCRT wait-time and all-cause mortality (histology stratification and tumor size stratification). Adjusted-hazard ratios for all-cause mortality are shown by week of CCRT wait-time for (A) squamous carcinoma, (B) adenocarcinoma, (C) tumor size ≤6 cm, and (D) tumor size >6 cm. Wait time was coded using restricted cubic spline transformation with four knots located at 4, 8, 12, and 16 weeks (shown as knots). The Y-axis represents the effect size for all-cause mortality. The X-axis represents wait-time (week) from cervical cancer diagnosis to CCRT initiation. Week 6 is set as the referent group. The solid line represents the estimate as effect size. The dashed lines are 95% confidence interval. Abbreviations: squamous, squamous cell carcinoma; adeno, adenocarcinoma; CCRT, concurrent chemo-radiotherapy; aHR-adjusted-hazard ratio; and CI, confidence interval. Fig. 4 Fig. 5 Adjusted associations between CCRT wait-time and all-cause mortality (brachytherapy stratification). Adjusted-hazard ratios for all-cause mortality are shown by week of CCRT wait-time for (A) external beam and brachytherapy and (B) external beam without brachytherapy. CCRT wait-time was coded using restricted cubic spline transformation with four knots located at 4, 8, 12, and 16 weeks (shown as knots). The Y-axis represents the effect size for all-cause mortality. The X-axis represents the wait-time (week) from cervical cancer diagnosis to CCRT initiation. Week 6 is set as the referent group. The solid line represents the estimate as effect size. The dashed lines are 95% confidence interval. Abbreviation: CCRT, concurrent chemo-radiotherapy; aHR-adjusted-hazard ratio; and CI, confidence interval. Fig. 5 4 Discussion Our study highlights that the effect of time to initiation of CCRT on survival for locally-advanced cervical cancer is complex, reflecting various underlying patient, facility, and tumor factors. Women whose tumors had poor prognostic factors were more likely to initiate therapy more rapidly. Thus, increased mortality in the short wait-time cases may reflect pre-existing advanced tumor factors. In contrast, the trend towards gradually increasing mortality with longer time to initiation of therapy may reflect the effect of delay in treatment initiation. Data from a multi-continent study from the COVID and Cancer Research Network (CCRN) raise concern for cancer patients [6]. The results of this study imply not only that there will be a significant delay in starting treatment for cancer patients but also that there will be a stage shift as a consequence of the current global pandemic [6]. These concerns are particularly relevant to radiation oncologists because cervical cancer is more common in minority populations and socioeconomically disadvantaged groups, such groups have been particularly affected by the pandemic [[17], [18], [19]]. Moreover, the Society of Gynecologic Oncology (SGO) suggests non-surgical therapy with definitive radiotherapy as an alternative treatment approach for women with early-stage disease if treatment delay for radical hysterectomy will be prolonged due to the COVID-19 pandemic [20]. Studies examining survival effect of radical hysterectomy wait-time for early-stage cervical cancer are also limited in the current literature and warrant further investigation [21,22]. Our recent analysis of stage IB-IIA cervical cancer showed that longer hysterectomy wait-time was associated with increased risk of pathological parametrial invasion and all-cause mortality [22]. To date, limited data has been reported describing the impact of time to initiation of radiation and survival for locally-advanced cervical cancer. One study showed that longer wait-time to initiation of CCRT was associated with decreased survival although the sample size was limited (n=195) [11]. Another study concluded that longer wait-time to CCRT was not associated with increased mortality [10]. As wait-time was grouped by four week increments in this study, our data illustrate the association between time to initiation of therapy by week. One major concern observed in this study was that nearly one-third of study population did not receive brachytherapy for the definitive radiotherapy in women with locally-advanced cervical cancer. Notable significance is that this was observed in the CoC-affiliated centers in the recent years (2004–2016). In 2019, American Brachytherapy Society (ABS) and SGO endorsed the importance of brachytherapy as a critical component of definitive radiotherapy for cervical cancer [15]. While this was not the primary objective of current study, the importance of brachytherapy needs to be emphasized. Strengths of this study include rigorous selection criteria, large sample size and measured covariates, use of a modern analytic approach, and multiple sensitivity analyses. However, there are several limitations in this study. First, unmeasured bias is inherent to the retrospective nature of this study. For example, the data on the underlying cause of treatment delay is not available. It may be possible that urgent initiation of CCRT may have been indicated for patients who had vaginal bleeding in women with large tumor or higher cancer stage, but the database does not have this information. Second, there were few women with long periods of treatment delay thus limiting our statistical power to detect changes in survival. The restricted cubic spline curves suggest that mortality risk may be increased after a certain wait-time. The ASTRO has compiled COVID-19 Clinical Guidance for a number of malignancies [23]. This includes treatment prioritization, approaches, and practice recommendations during the COVID-19 pandemic. Given the possible survival effects of CCRT wait-time as well as possible pandemic-related demographic change in cervical cancer, establishing clinical guidance for cervical cancer treatment in the current situation would be of utmost use. Recent international expert consensus recommendations for radiotherapy during the COVID-19 pandemic categorize that women with locally-advanced cervical cancer has the highest priority for radiotherapy [24]. Recommendation on wait-time for CCRT initiation was not addressed. In conclusion, our study suggests that in the absence of aggressive tumor factors, a short period of wait-time to start definitive CCRT (approximately 3 additional weeks from the cohort median wait-time) may not be associated with increased risk of mortality in women with locally-advanced cervical cancer. While treatment delay at COVID-19 burdened hospitals may be necessary for patient safety purposes, when feasible, attempts should be made to avoid prolonged delays to start CCRT for women with locally-advanced cervical cancer. This study also observed variable differences in CCRT wait-time per patient and facility factors. This inequity of cancer treatment merits further investigation. Contributors K.M. designed the study, initiated the collaborations, cleaned and analyzed the data, created the figures and tables, interpreted the results, and drafted and revised the manuscript with others. Y.H. accessed the data, contributed to the analysis, interpreted the results and revised the manuscript. S.M. contributed to the literature overview, intellectual inputs, interpreted the results, and edited the manuscript. L.D.R. supervised the study, and revised manuscript. P.H. contributed to the intellectual aspect of the study, reviewed the results, and revised manuscript. J.D.W. contributed to the study concept and design, instructed the analytic approach, interpreted the results, and revised the manuscript. He is the corresponding author of the study. Funding support Ensign Endowment for Gynecologic Cancer Research (K.M.). Role of the funding source The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Data availability statement The data on which this study is based are publicly available upon request at https://www.facs.org/quality-programs/cancer/ncdb. Transparency The manuscript's corresponding author (J.D.W.) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The program is the source of the de-identified data used; and the program has not verified and is not responsible for the statistical validity of the data analysis or the conclusions derived by the study team. Declaration of Competing Interest Consultant, Clovis Oncology, and research funding, Merck (J.W.); consultant, Quantgene (L.D.R.); honorarium, Chugai, textbook editorial, Springer, and meeting expense, VBL therapeutics (K.M.); research grant, MSD (S.M.); none for others. Appendix A Supplementary data Supplementary material Image 1 Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ygyno.2021.02.026. ==== Refs References 1 Zhu N. Zhang D. Wang W. A novel coronavirus from patients with pneumonia in China, 2019 N. Engl. J. Med. 382 2020 727 733 31978945 2 Wang C. Horby P.W. Hayden F.G. Gao G.F. A novel coronavirus outbreak of global health concern Lancet 395 2020 470 473 31986257 3 Li Q. Guan X. Wu P. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia N. Engl. J. Med. 382 2020 1199 1207 31995857 4 Wang D. Hu B. Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 323 11 2020 1061 1069 10.1001/jama.2020.1585 32031570 5 WHO Coronavirus Disease (COVID-19) Dashboard World Health Organization https://covid19.who.int/ (accessed 2/6//2021) 6 London J.W. Fazio-Eynullayeva E. Palchuk M.B. Sankey P. McNair C. Effects of the COVID-19 pandemic on cancer-related patient encounters JCO Clin Cancer Inform 4 2020 657 665 32716647 7 Jazieh A.R. Akbulut H. Curigliano G. Impact of the COVID-19 pandemic on cancer care: a global collaborative study JCO Glob Oncol. 6 2020 1428 1438 32986516 8 Hanna T.P. King W.D. Thibodeau S. Mortality due to cancer treatment delay: systematic review and meta-analysis BMJ m4087 2020 371 9 Chino J. Annunziata C.M. Beriwal S. Radiation therapy for cervical cancer: executive summary of an ASTRO clinical practice guideline Pract Radiat Oncol 10 2020 220 234 32473857 10 Ramey S.J. Asher D. Kwon D. Delays in definitive cervical cancer treatment: an analysis of disparities and overall survival impact Gynecol. Oncol. 149 2018 53 62 29605051 11 E C. Dahrouge S. Samant R. Mirzaei A. Price J. Radical radiotherapy for cervix cancer: the effect of waiting time on outcome Int. J. Radiat. Oncol. Biol. Phys. 61 2005 1071 1077 15752886 12 National Cancer Database American College of Surgeons https://www.facs.org/quality-programs/cancer/ncdb (accessed 8/9/2020) 13 Croxford R. Restricted Cubic Spline Regression: A Brief Introduction https://support.sas.com/resources/papers/proceedings16/5621-2016.pdf 14 Ramirez P.T. Chiva L. Eriksson A.G.Z. COVID-19 global pandemic: options for Management of Gynecologic Cancers Int. J. Gynecol. Cancer 30 2020 561 563 32221023 15 Holschneider C.H. Petereit D.G. Chu C. Brachytherapy: a critical component of primary radiation therapy for cervical cancer: from the Society of Gynecologic Oncology (SGO) and the American brachytherapy society (ABS) Gynecol. Oncol. 152 3 2019 540 547 30665615 16 von Elm E. Altman D.G. Egger M. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies BMJ 335 2007 806 808 17947786 17 Coronavirus Disease 2019 (COVID-19) Center for Disease Control and Prevention https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html (accessed 8/9/2020) 18 United States Cancer Statistics Data visualizations. Center for Disease Control and Prevention https://gis.cdc.gov/Cancer/USCS/DataViz.html (accessed 8/9/2020) 19 COVID-19 in Racial and Ethnic Minority Groups Center for Disease Control and Prevention https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/racial-ethnic-minorities.html (accessed 8/9/2020) 20 Pothuri B. Alvarez Secord A. Armstrong D.K. Anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the COVID-19 pandemic crisis Gynecol. Oncol. 158 2020 16 24 32386911 21 Matsuo K. Novatt H. Matsuzaki S. Hom M.S. Castaneda A.V. Licon E. Nusbaum D.J. Roman LD. Wait-time for hysterectomy and survival of women with early-stage cervical cancer: a clinical implication during the coronavirus pandemic Gynecol. Oncol. 158 2020 37 43 32425268 22 Matsuo K. Huang Y. Matsuzaki S. Klar M. Wright J.D. Effect of delay in surgical therapy for early-stage cervical cancer: an implication in the coronavirus pandemic Eur. J. Cancer 139 2020 173 176 32992156 23 COVID-19 Clinical Guidance American Society of Radiation Oncology https://www.astro.org/Daily-Practice/COVID-19-Recommendations-and-Information/Clinical-Guidance (accessed 8/9/2020) 24 Elledge C.R. Beriwal S. Chargari C. Chopra S. Erickson B.A. Gaffney D.K. Jhingran A. Klopp A.H. Small W. Jr. Yashar C.M. Viswanathan A.N. Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: international expert consensus recommendations Gynecol. Oncol. 158 2 2020 244 253 32563593

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Gynecol Oncol. 2021 May 23; 161(2):414-421

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10.1016/j.ygyno.2021.02.026

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01287-3 10.1016/S0140-6736(21)01287-3 Perspectives Narrative complexity in the time of COVID-19 Gubrium Aline a Gubrium Erika b a School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA b Department of Social Work, Child Welfare and Social Policy, Oslo Metropolitan University, Oslo, Norway 10 6 2021 12-18 June 2021 10 6 2021 397 10291 22442245 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcDuring the COVID-19 pandemic, medicine and public health have grappled with challenges related to individual behaviour and decision making, both in terms of infection and more recently concerning the uptake of COVID-19 vaccines. Social theory has long pointed to the role of narrative when trying to grasp the complexity of understanding and decision making in times of crisis. Such theory has underscored the importance of context to the ways that people understand specific experiences or phenomena, and, consequently, to the understandings that they relay to others. In 1955, the British philosopher J L Austin, in his seminal book, How to Do Things with Words, argued that one cannot evaluate the truths of language as unconnected and operating in isolation. Rather, to understand the meaning of words or extended accounts, one needed to understand how they were used in acts of speaking; how, in practice, speakers used words and accounts to actively produce assemblages of meaning, or narratives. Furthermore, he argued, narratives took on different meanings in varied contexts and were actively enacted in the complex flow of communication in time and place. Austin argued that studying words outside of the narrative contexts in which they were presented ignored the realities created by everyday speech situations. Austin's idea of narratives as active, changing, and contingent on context resonates during the COVID-19 pandemic. We see narrative action in the contemporary connections public health campaigns make between safety and the use of face masks or the decision to self-isolate. Campaign slogans tend to be framed in a medical discourse, where safety relates in a straightforward way to individual choice and public health behaviour. However, the connections that individuals or communities may make between safety, use of face masks, and self-isolation are also socially and contextually informed by lived experience. For instance, the concept of “safety” may change in relation to intersectional lived experiences, such as systemic racism, gendered division of labour within the home, and economic inequality. We draw from Austin and offer two points to substantiate how narrative action and complexity can illuminate such diverse experiences and implications for public health. © 2021 Alex Schwab/Getty Images 2021 The first point centres on the crucial need to acknowledge the relevance of broader narrative contexts when developing public health responses to illness and disease. COVID-19 has made it abundantly clear that responses based on biomedical knowledge alone are not enough. Responses must also recognise and adapt to ongoing social, institutional, and political contexts. The risk of catching the virus is not only about getting sick and healing or dying. The pandemic has viscerally revealed how identity and socioeconomic status intersect with place and movement in everyday life to constitute radically different consequences of infection across nations, regions, communities, and neighbour-to-neighbour. Multiple factors shape the experience of living with or through COVID-19, including: intersectional identities cutting across gender, ethnicity, age, and class, among others; the specific opportunity structures connected to place, such as national and local safety nets and labour rights; local services, support, and practices; local labour markets, employment possibilities, and job security; and everyday means of transport. In the USA, for instance, accounts of the risk of COVID-19 might relate to risking one's health to keep working or not going to the workplace and risking losing one's only means of economic support. In Norway, it might mean reducing risk by staying home for those who do not work on the front lines and for the many who have access to extensive state-paid sick leave and unemployment provisions. As in the USA, however, it also might mean a very real risk for people working in precarious and low-income labour sectors. Public health responses aimed at reducing risk need to consider how individual decision making might be shaped by these relational contexts. Our second point builds on the first. It turns to the expanded possibilities offered by using a narrative approach to better understand the relational processes involved when individuals make meaning of and respond to illness. Social science research has a long track record in this area. An early example is sociologist Julius Roth's 1963 documentation of patients' time-and-recovery reckoning in tuberculosis sanatoriums, while he himself was a tuberculosis patient. Roth described how patients relied not only on medical information to make sense of their recovery, but also on other patients by comparing recovery experiences with one another. For both Roth and the patients studied, narratives of similarity and difference were as important as medical knowledge when constructing meaning. Sociologist Jaber Gubrium's 1975 ethnography of nursing home care described the complex experience of death and dying in institutional settings. Everyday practices of caregiving and care receiving were anything but uniformly understood by residents. Narratives of the otherwise seemingly objective medical conditions were often contradictory because the lives of carers and residents that informed these understandings were varied. Such works underline the power of using a narrative ethnographic approach to explore understandings and responses to ill health. Since then, social scientists have used diverse narrative approaches to make explicit what wellbeing, ill health, or disease mean, challenging reductionist thinking. In a social policy study on perspectives and practices relating to poverty and social exclusion, we interviewed research participants from a small New England city in the USA and from the greater Oslo area in Norway about their everyday experiences of life and wellbeing on low or no incomes. Using a narrative social–psychological approach, we explored how research participants made sense of encounters with vastly different welfare and political systems. In the USA, participants spoke of feeling actively shamed by a harsh and precarious welfare system. In Norway, despite a more generous and stable system, participants' sense of marginalisation was heightened by the fact that their experiences did not align with the public narrative of a strong safety net “from cradle to grave”. Despite differences in how they perceived and described experiences of and barriers to wellness, they shared the common experience of shame related to poverty's potentially stigmatised status. Most described using individual strategies to hide their difficult socioeconomic situations, strategies leading to withdrawal from personal networks, to a heightened sense of stigma, and to social alienation. Stigmatising public and institutional narratives about poverty and marginalisation further reinforced the decision to withdraw from social and civic life. These sorts of discussions and responses reduced the possibility of bringing significant personal experiences to light, much less the possibility of building a solidarity movement based on shared experiences of risk. Across the USA and Europe we have seen public narrative contexts in which active connection is made between already marginalised minority group identities and the spread of COVID-19—for example, through use of terms such as “import infection”, “the Chinese virus”, and “the Indian variant”. Considering the connection between social exclusion, shame, and stigma, an analysis of individual and social responses to COVID-19 might acknowledge how personal coping strategies may change in the face of potentially stigmatising public COVID-19 narratives. Such a framework might be instructive for understanding the rather limited political mobilisation there has been in differing political and social contexts in response to the extensive socioeconomic health inequalities made hypervisible during the pandemic. One way of highlighting the ways people make meaning of and potentially act on experiences of illness, health, and inequality is through participatory research that documents personal narratives. Researchers have effectively used the participatory narrative approach of digital storytelling to alter the balance of power in health promotion, in terms of who gets to tell their stories. Digital storytelling is a group-based process in which participants receive training to write and produce short videos—digital stories—about important experiences in their lives. In an ongoing public health study titled MOCHA Moving Forward, one of us (AG) has been part of a research team that has included the Men of Color Health Awareness (MOCHA) movement, exploring the everyday experiences of men of colour living and surviving systemic racism, embodied stress, and chronic disease in a small New England city. Through digital storytelling, the men narratively transform themselves from the objectified—and often stigmatised—figures portrayed in the news media and scientific literature to agentic storytellers narrating the scope of their lives on their own terms. The stories that are told are the ones that the men, themselves, wish to share, thus extending the notion of research ethics and consent to afford study participants greater control over articulating what living with inequality and disease means. The digital stories are both personal and political. The men relate experience of dealing with chronic disease to stories of migration from rural southern US states, experiences with job insecurity, home foreclosure, police brutality, and white supremacy, while also speaking of sacrifice, love, hope, yearning, and deep spirituality. By relating experience with chronic disease to narratives of emotionality, digital storytelling methods create the potential for a more nuanced understanding about the dynamics of ill health and a more attuned path for moving forward. The methods could also provide necessary information for crafting responses to COVID-19 that are adjusted to varied life experiences, and are thus more effective. The weight of narrative evidence adds complexity to an often oversimplified picture of medical and public health issues. COVID-19 has revealed a blurred conceptual divide between illness and wellness; between medical and social risks; between safety and harm. Narrative contexts such as the workplace, the home, schools, the community, and health-care settings have shifted in meaning in this pandemic. These changes continue to shape the way we think about and respond to COVID-19. In the short-term, public health campaigns might consider how narrative contexts and personal meaning-making shape how people understand and respond to calls to “stay safe” in the face of the pandemic. In the longer term, accounting for narrative complexity with reference to wellness, illness, and disease is crucial if we are to develop effective and socially just public responses to health crises. ==== Refs Further reading Austin JL How to do things with words 1955 Harvard University Press Cambridge, MA Gubrium A Harper K Participatory visual and digital methods 2013 Routledge New York, NY Gubrium AC Lowe S Douglas H Jr Scott L Buchanan D Participant engagement and ethical digital storytelling: the MOCHA Moving Forward Study Int Q Community Health Educ 40 2020 263 271 31318635 Gubrium E Pellissery S Anti-poverty measures: the potential for shaming and dignity building through delivery interactions Int J Soc Qual 6 2016 1 17 Gubrium E Sylvester L Dhakal S Gubrium A Sisphyean struggles: encounters and interactions within two U.S. public housing programmes J Soc Qual 6 2017 89 108 Gubrium E Johnstone L Lødemel I Building dignity? Tracing rights, discretion and negotiation within a national labour activation trajectory J Soc Qual 6 2016 52 70 Gubrium JF Living and dying at Murray Manor 1975 Blackwell Press Oxford Lambert J Hessler B Capturing lives, creating community 5th edn. 2018 Routledge New York Mullany A Valdez L Gubrium A Buchanan D Precarious work, health, and African-American men: a qualitative study on perceptions and experiences Int J Health Serv 51 2021 135 145 33327847 Roth J Timetables: structuring the passage of time in hospital treatment 1963 Bobbs-Merrill Company Indianapolis, IN

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01013-8 10.1016/S0140-6736(21)01013-8 Correspondence Vaccines can save children with non-preventable diseases Saha Senjuti a Saha Samir K ab a Child Health Research Foundation, Dhaka 1207, Bangladesh b Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka, Bangladesh 10 6 2021 12-18 June 2021 10 6 2021 397 10291 22502250 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcXiang Li and colleagues1 modelled the health impact of vaccination programmes in low-income and middle-income countries and predicted that approximately 120 million deaths will be averted in children born between 2000 and 2030. They took into consideration both the direct effect of vaccination on vaccinated cohorts and the indirect effects in the population through herd immunity. Although these data are immensely helpful for policy makers, we believe that the indirect impacts of vaccination go even further than suggested. At the largest paediatric hospital in Bangladesh, a large proportion of the more than 20 000 admissions per year are due to vaccine-preventable diseases such as rotavirus and typhoid, against which vaccines are yet to be introduced.2, 3, 4 One in four children requiring hospitalisation (ie, approximately 6000 children each year) are refused admission because of unavailability of beds. Refused admissions include patients with severe perinatal asphyxia, preterm birth complications, neonatal sepsis, or meningitis who are at high risk of death or disability.2 According to hospital bed data from the World Bank, Bangladesh, like most low-income and middle-income countries, has a small number of beds for the population (ie, only 0·8 beds per 1000 people), suggesting a similar admission scenario in other resource-constrained settings. In southern Asia, more than 25% of about 1·9 million deaths of children younger than 5 years every year are caused by meningitis, sepsis, and pneumonia.5 Preterm birth complications account for another 25% of deaths.5 Thus, any vaccine-preventable disease that has a large effect on admissions to hospital will exacerbate treatments and outcomes of other diseases in the context of reduced hospital capacity. Hence, in estimating vaccine impact, we should also consider the impact on mortality of the number of people who are refused admission because of vaccine-preventable hospital admissions. We declare no competing interests. ==== Refs References 1 Li X Mukandavire C Cucunubá ZM Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study Lancet 397 2021 398 408 33516338 2 Saha S Santosham M Hussain M Black RE Saha SK Rotavirus vaccine will improve child survival by more than just preventing diarrhea: evidence from Bangladesh Am J Trop Med Hyg 98 2018 360 363 29210350 3 Saha S Sayeed KMI Saha S Hospitalization of pediatric enteric fever cases, Dhaka, Bangladesh, 2017–2019: incidence and risk factors Clin Infect Dis 71 2020 S196 S204 33258942 4 Tanmoy AM Ahmed ANU Arumugam R Rotavirus surveillance at a WHO-coordinated invasive bacterial disease surveillance site in Bangladesh: a feasibility study to integrate two surveillance systems PLoS One 11 2016 e0153582 5 Liu L Oza S Hogan D Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals Lancet 388 2016 3027 3035 27839855

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==== Front Cell Cell Cell 0092-8674 1097-4172 Elsevier Inc. S0092-8674(21)00175-6 10.1016/j.cell.2021.02.025 Conversations Scientific misinformation: A perfect storm, missteps, and moving forward 18 3 2021 18 3 2021 18 3 2021 184 6 14021406 © 2021 Elsevier Inc. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The spread of scientific misinformation is not new but rather has long posed threats to human health, environmental well-being, and the creation of a sustainable and equitable future. However, with the COVID-19 pandemic, the need to develop strategies to counteract scientific misinformation has taken on an acute urgency. Cell editor Nicole Neuman sat down with Walter Quattrociocchi and Dietram Scheufele to gain insights on how we got here and what does—and does not—work to fight the spread of scientific misinformation. Excerpts from this conversation, edited for clarity and length, are presented below, and the full conversation is available with the article online. ==== Body pmc (L to R) Walter Quattrociocchi, Sapienza Università di Roma, Nicole Neuman, Cell, and Dietram Scheufele, University of Wisconsin-Madison It is an echo chamber, and it’s really difficult to inject information into an echo chamber, because the reaction to dissenting information is to ignore, to push out, or to react to that information. There are a lot of initiatives that are working. The most effective ones are trying to explain to users how our brain works when we are processing information. Creating awareness of our biases, awareness of echo chambers. … we wanted to correct misinformation that we knew to be wrong with science that we weren’t quite sure yet would turn out to be right. The moment science is seen as a partisan actor, and not as a neutral arbiter of the best available information that we as society can produce, we’re in big trouble. Main Text Nicole Neuman: Why don’t we start with a simple question about common terminologies. When we say misinformation, what do we really mean by that? Is there a distinction between this and disinformation? Walter Quattrociocchi: When we talk about misinformation or disinformation, we are just outlining the intentionality. It may be an error, or it may be engineering of the information spreading process. However, both are side effects of a change in the business model of the information cycle. Information, until 30 years ago, was selected from experts and journalists, who were setting the agenda of discussion. There are still the experts selecting information, but people, through social media, are selecting the information they like the most. The second element that created the total collapse of the present business model is that social media are not intended for dissemination of complex content. They are made for entertainment. NN: In the case of COVID-19–related misinformation, what role did the massive explosion of scientific information play in the dissemination of scientific misinformation? WQ: COVID-19 is the perfect storm to study misinformation. Our capacity to process all the information is not at the level of the request. This process created a situation in which we are really eager to have information about what is going on, because it’s scary. This need for information created an increase in the authoring of content. The second issue is the dynamics of science, in which there is hypothesis verification. The scientific method is ongoing, and so with COVID-19 we have a kind of reality show of science. It wasn’t clear to everyone that the scientists were just humans trying to understand something. That a good paper could be proven wrong in the long run, because that is the scientific method. And so these two layers basically collapse because the scientific process, which was unknown for the audience, was causing distrust because it seems like science is not giving correct information. Then the third ingredient is that institutional communication—at least in Italy, in Europe—was not so good. Managing the communication of science is so critical, to an extent that the World Health Organization coined the term “infodemic,” just to talk about the overabundance of information all over the world. NN: One thing about misinformation that I think is very frustrating to many people is that it’s very tenacious. Even when confronted with many facts to the contrary, misinformation seems to keep coming back. What’s your take on why it persists? WQ: We did an experiment in 2015. By measuring how conspiracy users respond to debunking information, we found that they ignore dissenting information. The real anatomy of social dynamics online is that we seek information adhering to our system of beliefs. We seek a group of like-minded peers in which we frame our narrative and tribe. It is an echo chamber, and it’s really difficult to inject information into an echo chamber, because the reaction to dissenting information is to ignore, to push out, or to react to that information. This is the process behind what we are seeing right now. It’s frustrating, yes, but we are human beings. And every one of us has his own bias. NN: If confronting people with facts that are contrary to their worldview and their beliefs doesn’t really work, what approaches may work? Do you have any optimism about making progress in fighting misinformation? WQ: There are a lot of initiatives that are working. The most effective ones are trying to explain to users how our brain works when we are processing information. Creating awareness of our biases, awareness of echo chambers. There is even a good effect from this change in the business model of information—that we can access a huge amount of information. We have to learn to deal with that, and it’s a work in progress. Foolish people will be around forever, but I think that the majority of people are just adapting to these new systems, to these new environments. NN: Dietram, are you optimistic about making progress in combating misinformation? And if so, why and how do you think that we need to be approaching this? Dietram Scheufele: I’ll backtrack just a little bit. We’ve had lots of conspiracy theories going around, but it’s never been as economically viable as it is in a social media environment. The economic incentives for a social media platform to feed this economy of outrage is at a level where we’ve never seen it before. There’s a complete disincentive to dial down the outrage and to focus on the things that we should know, rather than the things that we want to hear. That’s both good and bad, because it’s not a new problem, but the perfect storm is there. There’s a machinery of people who produce this stuff, and in the US, we of course managed to put one of the biggest producers of misinformation at the center. It’s reasonable for citizens to turn to their President and say, “Well, that person is telling me the truth.” In normal times, that’s just me looking for the best available information. We were in the situation where we had somebody in charge of a democratically elected government that intentionally tells you things that are wrong. So one of the pernicious elements of that perfect storm that we’re in right now is that we also have governments in Brazil and the US, also the UK a little bit, that have contributed to the problem. For COVID in particular, the issue is confounded by the fact that we knew in the beginning that we would produce research that would not replicate. We knew that we would go down dead ends, and we knew we would do this really fast, and in the public eye, more so than ever before. Every misstep would be seen by people who normally don’t pay attention. And I think we made two mistakes there. Mistake number one is we said, “That’s just how science always works.” And that’s incorrect, science doesn’t retract papers from high profile journals when science has just moved on. We retract studies if they shouldn’t have been published in the first place. And we did a whole bunch of that very visibly, and we paid for it with political commentators saying, “If they ever tell you to trust science again, look at all these retractions.” That was our big first misstep, that we said this is just science as it normally works, and it wasn’t. This is science under intense pressure to produce results. And I think the second mistake is that we wanted to correct misinformation that we knew to be wrong with science that we weren’t quite sure yet would turn out to be right. Very often, we didn’t say that this is where the science is right now, it will develop. The upside of that is we learned as much about how to navigate a political information environment as we learned about the virus and vaccines. That’s really important because the vaccines themselves won’t stop COVID, people getting vaccinated will stop COVID. That means half the challenge is to navigate this new information environment successfully, where we persuade people to do what’s best, not just for them, but for everyone around them. I’m actually hopeful that we’ve learned a bunch from this not just in bench science, but in social science. If anything, it has pushed that to the forefront of thinking in the bench sciences as well. The last time we had a moment like this, I think was climate change where we really realized that we weren’t doing a very good job and wide gaps were opening up between people living in different realities. This was another one of those moments, but with a lot more urgency. NN: Dietram, you just mentioned that we’re going to have a challenge with getting people vaccinated. Vaccine skepticism and misinformation around vaccines has been around for quite a while now, and despite a lot of really great efforts, it persists. How are we going to take what we’ve learned and do things differently to get people to take a SARS-CoV-2 vaccine? DS: There’s a couple of things that are really important. One is a cautionary note about correcting misinformation. One of the things that has come up again, and again, is people are saying, “Well, mRNA vaccine platforms will change your DNA. And it’s really dangerous you shouldn’t take them.” Our response to that has been, “No, don’t worry, it won’t change your DNA.” But what we’re actually saying is that changing somebody’s DNA is a bad thing. This year, we gave a Nobel prize in chemistry for breakthroughs in CRISPR that do that very thing, that changed people’s genetic makeup, in order to cure sickle cell, Tay-Sachs disease, and so on. So we’re setting up the contrast as something that’s bad, except that contrast is crucially important for therapies moving forward. There are unintended consequences of some of these corrections. Number two, we know from social science that a lot of what we do has zero to do with information. In fact, it’s the opposite. I know that I’m being manipulated by an industry to change my behavior all the time. I know it’s stupid to do it, and I still do it. Why? Because everybody else does. We know that people get solar panels on their roofs not because they understand renewable energies, but because their neighbors got them. So this idea of modeling behavior, this idea of establishing a social norm is a really important one. Then the last thing is that in the US for the first time, we’re seeing from survey data that ideology strongly predicts vaccine hesitancy. Normally, there are other factors and ideology is not as strong, but right now ideology is a strong predictor, which puts this right back into politics. This goes back to what we said earlier. Normally, we don’t have the executive branch of the government producing misinformation. That means that in order to get over vaccine hesitancy, scientists will have to play in the political realm, like it or not. That is tricky, because how can you be successful in the political realm without being partisan? That’s going to be the interesting part. We’re seeing some of the same things playing out in some European countries with the ultraconservative movement—the AfD in Germany, for instance—also aligning with anti-vaccine rhetoric and anti-climate rhetoric. All of a sudden, we’re layering a political map on top of what the best available science tells us, and that forces the scientific community into politics. That’s a game that’s played with very different rules than what we’re used to from our labs and our faculty meetings. NN: A question that’s on a lot of scientists’ minds is: should scientists become political, should scientists get involved? There’s a lot of mixed feelings within the scientific community about this. DS: Scientists will need to make sure that their science informs politics and informs political choices. That’s complicated in two ways. One is, scientists very often believe that policy should be determined by science and it never has been, and it never will be. We drive faster than we should. We know that if we lowered the speed limit by 10 miles an hour, we could literally save tens of thousands of lives. But we don’t, because we take science and we take a lot of other considerations, and we integrate those into a larger set of decisions that are informed by the best available science, but not determined. For us as scientists, that’s very often hard to grasp, because we think we know what the best outcomes are. For vaccines, there’s a really good parallel: scientists can tell us what the likelihood is of an epidemic if X percent do or don’t get vaccinated. That’s a scientific question. They cannot answer the question of whether that means we should force every parent to vaccinate their child before they send them to a childcare facility. That’s a political question because it clearly infringes on some individual rights. So yes, science needs to be political, but it needs to understand that it’s one of many stakeholders that try to influence political decisions. And that’s not bad, that’s exactly how it should be. The second thing is the partisan part, and this is where science missteps routinely: we feel that the policy choices that we favor are scientific and are not partisan. But that’s not always true. We did a study when nanotechnology first emerged and there were a lot of questions, and we did surveys of the leading scientists. When we asked what predicts their attitudes on regulation, after everything is controlled out, you still have a significant predictor of ideology, with conservatives favoring less regulation and liberals favoring more regulation. This is because scientists are citizens like everybody else. So the tricky part about playing in politics is that it’s really hard to extract yourself from your own politics. The moment science is seen as a partisan actor, and not as a neutral arbiter of the best available information that we as society can produce, we’re in big trouble. The moment that happens, we have a crack in Enlightenment. That’s why I would always urge scientists to steer away from partisanship. WQ: I totally agree with you. And the level of education of the policy makers sometimes also could be better. Now, we’re passing some analysis to the ministry of innovation in Italy, and they were contextualizing the information, which was really difficult because there are two different languages. They want something that is useful for immediate changes while the scientific perspective is complex. The level of complexity produces distrust because they are not able to grasp what is happening. So, science has to inform policy makers, but the final decision is political. But for this to happen we have to set up a common ontology. Otherwise, we are not talking the same language. DS: I totally agree. For the disciplines that I work in, there’s a little bit of responsibility that also comes our way because when we’re saying our data are not being used, or are not being used in the right way, part of that is also because we don’t curate our scientific findings in a way that makes it easy for policy makers to access those findings. Hopefully, we’re learning from COVID how to better utilize social, behavioral, and economic sciences. In the US the National Science Foundation funded, about a year ago, what they call a Societal Experts Action Network that brings together social scientists, economists, and others. Over the course of COVID, they wrote short reports that can be used by various stakeholders, including policymakers. One of them was actually about how to read data and how to make sense of large trend data and statistics. Almost a primer for COVID data, for policy makers, because they identified exactly the problem that you’re describing. If, and how, that will be effective, we will see down the road. I thought this was an interesting experiment at just the right time, and I’m not involved in it, so I can say it’s awesome. NN: It’s interesting that you bring up data curation. Within the scientific community, there’s been a push toward making more data available sooner and with fewer hurdles and letting the scientific community, and even to a certain extent, the broader public at large, self-curate that rather than using the traditional gatekeepers of journal editors and reviewers. These things are a bit in conflict, because for instance, we’re seeing news reporters pick up on research before peer review, publishing stories on them as though this is fact, and then that becoming part of the general public knowledge. There’s value in getting more data out more quickly, but at the same time, that push for less curation is causing some problems. How do we resolve this? WQ: The quality of the content is really heterogenous, and information overload is a real problem. Curation is very important in decision-making, and I’m really happy to know there is something happening in the US in this direction. In Italy, we are pretty far from that. Still, the problem is information overload because of interpretation of data. I am scared if a journalist has printed up data from my research, because it’s difficult. Curation implies a collaboration between academics, journalists, and policy makers. We have to find a way to create a common language. DS: And I think a good illustration of that is actually the Obama administration in the US, which has often been lauded as one of the most transparent administrations because they did gigantic data dumps that anybody could use. But what happened is that nobody ended up using them because nobody was qualified to actually go through them. Even a lot of the high-end journalists for the New York Times who do data journalism just barely scratched the surface. Nobody was ready to make sense of these data. So just making data available very often doesn’t mean anything because without those collaborations that Walter mentioned, there’s just no meaningful narrative that comes out. There’s a couple of other things that are tricky. One, is that the values that we hold dear in science, like open science and transparency, all of a sudden conflict with a world that doesn’t think the same way. They don’t see this as a preliminary product that’s still undergoing vetting. That thing is a product that is now available, and more often than not, you have teams of researchers who give into the temptation to talk about their pre-prints and not make that distinction when they get the call from the New York Times or the Washington Post. In the US right now, we’re seeing that whole transparency movement being pushed to the extreme. At the tail end of the Trump administration we saw EPA rules being implemented that mandated that you can only use data for regulations that are totally transparent and open for everybody to look at. The problem is most of the data that we use for toxicology and other things are based on very finite samples, where we know who all the respondents are, because they’re the ones who are really affected by this. By definition, we cannot make these data public because we’re going to reveal who’s been affected. So the data needed for regulation is data that cannot be shared. By saying we need to put more data out so that everybody can make sense of it, we’re leaving ourselves open to some of those vulnerabilities. The last thing I’ll say is that we now require that our master’s journalism students all take statistics. That doesn’t take away from Walter’s point that the ideal scenario is you working with data scientists to make sense of these data, but in order to even meaningfully ask questions to a data scientist, you need to understand at least the basic of statistics and computational work in order to ask the right question. It’s almost like saying if you cover politics and you don’t understand the basic rules of how congress gets elected, you’re probably not going to cover this right. The same thing is true for data. NN: One theme from this discussion is the need to break down silos and to have data scientists talking to social scientists, talking to clinical and bench researchers, talking to politicians, and all of these people engaging in conversation. For any Cell readers who might be part of these different disciplines and interested in helping to combat misinformation and scientific misinformation what is your advice on how to approach this? How do we break down silos? WQ: That’s a million dollar question. One answer for sure is to be curious, and curiosity has to be the driver. The second one is that, to break out of our echo chamber we have to learn to talk with people because most of the time when we have discussions with other fields people are not talking the same language. I totally agree that data science has to be one of the fundamental pillars for scientific understanding. Right now, there is no option to avoid data science in decisions. Otherwise, it is just regulation. DS: Data science already is becoming a pillar—especially for fields like biology. For example, how we look at the interplay of environmental factors in genomics: we’re looking at cell phone data, location data, respondent data, and matching that up over long periods of time and large numbers of respondents with DNA data, to see how particular genes or combinations of genes interact with environmental factors. That’s inherently a data science problem. If you look at the medical field and what DeepMind and those places are doing; that Google has an algorithm that can take a picture of a human retina and predict the gender, which no human doctor can, and we don’t understand fully yet what the algorithm it is actually using to make that prediction. It shows both the potential and the importance for collaborations. I really like Walter’s comment about echo chambers, because we think in academia that we’re immune from those things. But of course, with our disciplines, we’ve done exactly that. We’ve actually created the perfect echo chambers and we specialized them more and more so that people work in a different hallways of the same building but don’t always speak the same language. So I think we’re seeing the integration of toolkits from statistics and data science. For example in genetics, now people are talking about principal component analysis as a new tool, and the social sciences used that in the ’70s. That doesn’t mean the social sciences are more advanced. It simply means we have so much to learn from one another. What we have are problems that need solving—not disciplines that need building. Then I think once we figured that out, that disciplines are a means to an end. Then, we’re really ready for whatever post-COVID challenges there are. Supplemental information Audio S1. A Conversation with Walter Quattrociocchi and Dietram Scheufele Supplemental information can be found online at https://doi.org/10.1016/j.cell.2021.02.025.

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2022-12-16 23:25:14

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Cell. 2021 Mar 18; 184(6):1402-1406

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Cell

10.1016/j.cell.2021.02.025

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(20)32389-8 10.1016/S0140-6736(20)32389-8 Correspondence Universal health coverage for the poorest billion: justice and equity considerations – Authors' reply Bukhman Gene abc Mocumbi Ana de a Department of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, MA 02115, USA b Division of Global Health Equity and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA c NCD Synergies Project, Partners In Health, Boston, MA, USA d Universidade Eduardo Mondlane, Maputo, Mozambique e Instituto Nacional de Saúde, Maputo, Mozambique 4 2 2021 6-12 February 2021 4 2 2021 397 10273 474474 © 2020 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAs co-chairs of The Lancet NCDI Poverty Commission,1 we thank Jordan Jarvis and Belinda Townsend, and Michelle Amri for their thoughtful comments. Jarvis and Townsend highlight the role of global power arrangements that perpetuate the existence of extreme poverty. Specifically, they refer to the examples of tax avoidance by multinational corporations that starve the poorest countries of potential revenue, and the influence of billionaires on a global health agenda that has excluded non-communicable disease and injury (NCDI) poverty. Amri asks us to clarify our approach to health equity, recalling the capability approach to poverty measurement. Our Commission1 calls for a global focus on individuals doubly afflicted by extreme poverty and severe NCDIs. This call to action stems from our definition of equity as a priority to the worst off in terms of material conditions and health (see appendix of the Commission report1). We agree that much more should be said, and must be done, about a world in which a staggering accumulation of individual wealth is possible while 750 million people continue to experience hunger or severe food insecurity.2, 3 In our view, the framing of NCDIs that has been constructed over the past half century has aided and abetted a world system that is highly tolerant of cruel inequalities. By presenting NCDs as “preventable, mostly lifestyle- and diet-related illnesses”,4 high-income countries have been absolved of responsibility, particularly for obscene gaps in NCDI treatment among the world's poorest people. As Amartya Sen noted 25 years ago in his discussion of targeting resources to the poor: “I sometimes wonder whether there is any way of making poverty terribly infectious. If that were to happen, its general elimination would be, I am certain, remarkably rapid…Infections break down social divisions. Anything else that can do so can be similarly positive in its results.”5 So, is targeting possible for NCDI poverty? Can this category break down social divisions? In the end, the value of non-communicable diseases as a concept is the possibility of integration. We are hopeful that the next decade will see new forms of global solidarity that bring together people in high-income and low-income countries affected by groups of conditions that share common characteristics of issues and common solutions. These solutions include, for example, the PEN-Plus strategy to address type 1 diabetes, rheumatic heart disease, and sickle cell disease.6 Forging the partnerships needed to implement these solutions at the necessary scale will require a new science of integration in global health delivery. We declare no competing interests. ==== Refs References 1 Bukhman G Mocumbi AO Atun R The Lancet NCDI Poverty Commission: bridging a gap in universal health coverage for the poorest billion Lancet 396 2020 991 1044 32941823 2 Kim JY Millen JV Irwin A Gershman J Dying for growth: global inequality and the health of the poor 2000 Common Courage Press Monroe, ME 3 Food and Agriculture Organization of the United NationsInternational Fund for Agriculture DevelopmentUNICEFWorld Food ProgrammeWHO The state of food security and nutrition in the world. Transforming food systems for affordable healthy diets 2020 Food and Agriculture Organization of the United Nations, International Fund for Agriculture Development, United Nations International Children's Emergency Fund, World Food Programme, World Health Organization Rome 4 UN News UN gathering on non-communicable diseases considers ways to combat scourge https://news.un.org/en/story/2011/09/387532#.We-R50yZMUE Sept 20, 2011 5 Sen A The political economy of targeting van de Walle D Nead K Public spending and the poor: theory and evidence 1995 Johns Hopkins University Press Baltimore, MD 11 24 6 WHO Regional Office for Africa Report on regional consultation. WHO PEN and integrated outpatient care for severe, chronic NCDs at first referral hospitals in the African region (PEN-Plus) 2019 World Health Organization Geneva

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Lancet. 2021 Feb 4 6-12 February; 397(10273):474

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Lancet

10.1016/S0140-6736(20)32389-8

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==== Front Cell Cell Cell 0092-8674 1097-4172 Elsevier Inc. S0092-8674(21)00534-1 10.1016/j.cell.2021.04.031 Preview Coming to America: Genomic surveillance and how B.1.1.7 arrived in the US Qiu Xueting 1∗ Hanage William P. 1 Taylor Bradford P. 1 1 Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA ∗ Corresponding author 13 5 2021 13 5 2021 13 5 2021 184 10 25322534 © 2021 Elsevier Inc. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. In this issue of Cell, Washington et al. and Alpert et al. demonstrate the value of genomic surveillance when studying the introduction of the B.1.1.7 variant to the US and illustrate the challenge that results from the lack of good sampling strategies. In this issue of Cell, Washington et al. and Alpert et al. demonstrate the value of genomic surveillance when studying the introduction of the B.1.1.7 variant to the US and illustrate the challenge that results from the lack of good sampling strategies. ==== Body pmcMain text In late 2020, scientists in the United Kingdom studying the SARS-CoV-2 pandemic noticed something unusual. In the southeast region of Kent, there was a sudden uptick in the number of samples of a particular lineage—separate infections without known links or shared exposures that nevertheless had extremely closely related genomes suggestive of being proximal infections in a relatively short transmission chain. Moreover, the mutations that defined the lineage included several that had been independently implicated in changing the properties of the virus for the worse (from a human perspective), here all together in one tidy package. Over the next few weeks, frantic efforts to define the characteristics of this “variant” confirmed that it was a serious event in the evolution of the pandemic, more transmissible and virulent, and we now know it as the “variant of concern” B.1.1.7 (Volz et al., 2021). In this issue of Cell, two papers (Washington et al., 2021; Alpert et al., 2021) document and describe the introduction of B.1.1.7 to the United States, dating the first of multiple independent introductions to around Thanksgiving 2020. At the time of writing a few months later, B.1.1.7 is now the dominant lineage in the country and likely to be at least partially responsible for spiking infections from Michigan to Florida (CDC, 2021a). Though both handle it cautiously and candidly, a common challenge for these two papers is that when B.1.1.7 was making landfall and becoming established in the US, genomic data from COVID cases in this country was very limited and efforts to collect it were unevenly distributed. Globally, it is hard to overstate how different the UK’s genomic surveillance program is from that of other nations, but the comparison with the US is instructive. As described in Alpert et al. (2021), for the 3-month period included in the paper (December 2020 to February 2021), only 0.43% of the US COVID cases were sequenced and deposited in public databases. In contrast, the sequencing effort that allowed the emergence of B.1.1.7 in Kent to be detected covered around 5% of all positive cases (Vavrek et al., 2021); in other words, around 10-fold more than the US. Genomic surveillance is valuable, whether to detect variants or to infer or rule out transmission across scales (Figure 1 A). But how can we manage national surveillance for an infectious disease when some places are not looking as hard as others? One possible work-around used by Washington et al. (2021) is to sequence a fraction of samples from commercial test providers. This is smart but imperfect as the resulting surveillance will be good in the places where that test is widely used and poor where it isn’t. Multiple cooperating commercial labs will do a lot to help this. Nevertheless, while sequencing truly random samples from commercial labs will provide a better estimate of the rise of known variants than an ad hoc alternative, or preferential sequencing of clusters of transmission (e.g., long-term care facilities), it is still not a substitute for a national strategy.Figure 1 Genomic surveillance and lag time in sequencing data (A) Steps of genomic surveillance. Genomic surveillance can produce important findings during an outbreak only when built upon comprehensive and unbiased sampling strategies coupled with timely data availability. When an outbreak occurs in a population, epidemiological surveillance and outbreak investigation is initiated to capture infected individuals (orange circles). Good sampling strategies are in place to plan out representative samples for sequencing, with less biased sampling leading to less biased statistics. This step is critical but often lacks careful consideration or emphasis. Then sequencing and bioinformatic pipelines generate genomic data, which together with associated metadata are deposited to the public databases for analysis. Genomic data and metadata enable tracking of evolutionary lineages and inference of phylodynamics during an outbreak to study the interactions between epidemiological, immunological, and ecological factors. (B) Distribution of the lag time between collection and submission of samples to the Global Initiative on Sharing All Influenza Data (GISAID) in the US and the UK. The median days of submission delay are 37 days in the US and 19 days in the UK, respectively. Submission delay was calculated by comparing collection and submission dates of sequences from the variant surveillance table downloaded from GISAID on March 31st, 2021. We retained sequences from the US or the UK with the full collection date (days, month, and year) and a sequence length >29,000 nucleotides. The challenge is not only to sequence more but to collect appropriate metadata, like date of sampling or epidemiologic and clinical features of infection, because without it, genomes are reduced to a much less useful string of As, Cs, Gs, and Ts (and Ns). This, like sequencing, is easier said than done for a nation of diverse states with different attitudes toward an investment in public health (Maxmen, 2021). Furthermore, the scientific community should also give fair credit to those who contribute sequence and other data to the public databases that make work of this sort possible. This is a truly valuable contribution that too often goes unrecognized and unrewarded by grant-making bodies and promotion committees. Researchers must be motivated to share data openly and in a timely fashion; perverse incentives that stand in the way of sharing data could literally cost lives. It is the nature of things that during a pandemic of this kind, events overtake the patient collection of evidence and publication. This work documenting the introduction of B.1.1.7 to the US is being published when B.1.1.7 has already been acknowledged as the dominant lineage there. The significance is not limited to the findings of the papers but in demonstrating what can be done provided data are promptly available to inform policy and encourage future research. The issue of prompt reporting is shown clearly if we compare the lag time between samples being collected and submitted to the Global Initiative on Sharing All Influenza Data (GISAID, 2021) in the US and the UK (Figure 1B, median days of submission delay: 37 days in the US versus 19 days in the UK). Even had the US been sequencing as rigorously as the UK, such a lag in submissions would delay the detection of variants. This is an ongoing concern. Lack of sampling strategies, limited sequencing, and delays in genomic surveillance continue to hinder detection of other emerging variants. B.1.1.7 has been joined by emerging variants of concern B.1.351 and P.1, the last responsible for a concerning surge of cases in a population thought to have high levels of prior immunity from previous infection (Sabino et al., 2021). Of these three, P.1 has recently been introduced to the US and is apparently rapidly becoming established in states including Illinois, Florida, and Massachusetts (CDC, 2021b). Prompt reporting of genomic data is crucial to determining the epidemiological and clinical characteristics of this variant. Other variants continue to emerge. B.1.427/1.429 has recently been designated by CDC as “of concern,” and multiple lineages that are descended from or closely related to B.1.526 merit close attention (CDC, 2021b). This is not only an issue for the United States. Recently screening revealed three travelers arriving from Tanzania into Angola infected with another “variant” that is more divergent than any yet reported (De Oliveira et al., 2021), showing how much might be happening in the peripheral vision beyond our current sampling frame. Surveillance might not seem the most exciting of topics, but it determines our ability to know almost anything about the status of the pandemic. This is reflected by the $1.7 billion investment in genomic epidemiology announced by the White House on the 16th of April (The White House, 2021), which will hopefully jumpstart programs across the country and mitigate the patchy sampling we have described here, even if it will take time and effort. Altogether, the work published in Washington et al. (2021) and Alpert et al. (2021) shows us how important it is to keep an eye on our adversary even, especially, as we deploy effective vaccines against it. Acknowledgments X.Q. and W.P.H. were supported by the National Institute of General Medical Sciences of the 10.13039/100000002 National Institutes of Health under award number U54GM088558. W.P.H. and B.P.T. were supported by the National Institute of Allergy and Infectious Diseases of the 10.13039/100000002 National Institutes of Health under award number R01AI128344. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ==== Refs References Alpert T. Brito A.F. Lasek-Nesselquist E. Rothman J. Valesano A.L. MacKay M.J. Petrone M.E. Breban M.I. Watkins A.E. Vogels C.B.F. Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States Cell 184 2021 2595 2604 this issue 33891875 CDC COVID Data Tracker - Variant Proportions 2021 Accessed April 16, 2021 https://covid.cdc.gov/covid-data-tracker/#variant-proportions CDC SARS-CoV-2 Variant Classifications and Definitions - Variants of Concern 2021 Accessed April 16, 2021 https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html de Oliveira T. Lutucuta S. Nkengasong J. Morais J. Paixão J.P. Neto Z. Afonso P. Miranda J. David K. Inglês L. A novel variant of interest of SARS-CoV-2 with multiple spike mutations detected through travel surveillance in Africa medRxiv 2021 10.1101/2021.03.30.21254323 GISAID, (2021). GISAID - hCov19 Variants Surveillance Data. Accessed April 16, 2021. https://www.gisaid.org/hcov19-variants/. Maxmen A. Why US coronavirus tracking can’t keep up with concerning variants Nature 592 2021 336 337 33828280 Sabino E.C. Buss L.F. Carvalho M.P.S. Prete C.A. Jr. Crispim M.A.E. Fraiji N.A. Pereira R.H.M. Parag K.V. da Silva Peixoto P. Kraemer M.U.G. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence Lancet 397 2021 452 455 33515491 The White House Fact Sheet: Biden Administration Announces $1.7 Billion Investment to Fight COVID-19 Variants | The White House 2021 https://www.whitehouse.gov/briefing-room/statements-releases/2021/04/16/fact-sheet-biden-administration-announces-1-7-billion-investment-to-fight-covid-19-variants/ Vavrek D. Speroni L. Curnow K.J. Oberholzer M. Moeder V. Febbo P.G. Genomic surveillance at scale is required to detect newly emerging strains at an early timepoint medRxiv 2021 10.1101/2021.01.12.21249613 Volz E. Mishra S. Chand M. Barrett J.C. Johnson R. Geidelberg L. Hinsley W.R. Laydon D.J. Dabrera G. O’Toole Á. Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data medRxiv 2021 10.1101/2020.12.30.20249034 Washington N.L. Gangavarapu K. Zeller M. Bolze A. Cirulli E.T. Schiabor Barrett K.M. Larsen B.B. Anderson C. White S. Cassens T. Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States Cell 184 2021 2587 2594 this issue 33861950

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2022-12-16 23:25:15

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Cell. 2021 May 13; 184(10):2532-2534

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Cell

10.1016/j.cell.2021.04.031

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==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Elsevier B.V. S0048-9697(21)05903-9 10.1016/j.scitotenv.2021.150825 150825 Article No widespread signature of the COVID-19 quarantine period on water quality across a spectrum of coastal systems in the United States of America Wetz Michael S. ab⁎ Powers Nicole C. a Turner Jeffrey W. a Huang Yuxia c a Department of Life Sciences, Texas A&M University-Corpus Christi, TX 78412, USA b Harte Research Institute for Gulf of Mexico Studies, Texas A&M University-Corpus Christi, TX 78412, USA c School of Engineering and Computing Sciences, Texas A&M University-Corpus Christi, TX 78412, USA ⁎ Corresponding author at: Texas A&M University-Corpus Christi, 6300 Ocean Dr., Unit 5869, Corpus Christi, TX 78412, USA. 8 10 2021 10 2 2022 8 10 2021 807 150825150825 1 6 2021 1 10 2021 2 10 2021 © 2021 Elsevier B.V. All rights reserved. 2021 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. During the recent COVID-19 related quarantine period, anecdotal evidence emerged pointing to a rapid, sharp improvement in water quality in some localities. Here we present results from an analysis of the impacts of the COVID-19 quarantine period using two long-term coastal water quality datasets. These datasets rely on sampling that operates at appropriate timescales to quantify the influence of reduced human activity on coastal water quality and span coastal ecosystems ranging from low human influence to highly urbanized systems. We tested two hypotheses: 1) reduced tourism during the COVID-19 quarantine period would lead to improved coastal water quality, and 2) water quality improvements would scale to the level of human influence, meaning that highly urbanized or tourist-centric watersheds would see greater improvement than more rural watersheds. A localized reduction in fecal indicator bacteria was observed in four highly impacted regions of the Texas (USA) coast, but this pattern was not widespread. In less impacted regions, the signature of natural, decadal environmental variability (e.g., dissolved oxygen and turbidity) overwhelmed any potential signature of reduced human activity. Results from this study add to the growing body of literature on the environmental impacts of the COVID-19 quarantine period, and when considered with existing literature, emphasize that coastal water quality improvements appear to be ephemeral and reserved for the most severely affected (by human activity) systems. Furthermore, results show the importance of assessing COVID-19 signatures against long-term, decadal datasets that adequately reveal a system's natural variation. Graphical abstract Unlabelled Image Keywords COVID-19 Coastal Water quality Bacteria Dissolved oxygen Turbidity Editor: Damia Barcelo ==== Body pmc1 Introduction Humans can have a considerable influence on coastal water quality, primarily through actions that result in pollutant discharge to waterbodies (Hopkinson and Vallino, 1995; Bricker et al., 2008). For example, numerous studies have documented the growing prevalence of cultural eutrophication in coastal ecosystems worldwide (see e.g., Bricker et al., 2008), which arises from excessive nutrient (nitrogen and phosphorus) loadings from watersheds influenced by human activity. Indeed, coastal systems with watersheds that are urbanized or that have significant agricultural influence tend to be more prone to eutrophication than systems with less disturbed watersheds (NRC, 2000; Bricker et al., 2008). Common symptoms of eutrophication include persistent algal blooms, occasionally including harmful taxa, as well as decreased light penetration and hypoxia/anoxia (NRC, 2000; Bricker et al., 2008). Coastal systems with urbanized watersheds also tend to have a greater propensity for fecal bacterial pollution, which carries with it significant risks for human health (Mallin et al., 2001, Mallin et al., 2009; Handler et al., 2006). Natural environmental variability, and rainfall in particular, also influences the magnitude of loadings and thus affects coastal water quality. For example, high rainfall conditions that lead to high river discharge to coastal systems often delivers significant quantities of pollutants and sediment, whereas drought conditions can lead to sharp reductions in loadings (e.g., Paerl et al., 2006; Wetz and Yoskowitz, 2013). During the recent COVID-19 related quarantine period, anecdotal evidence emerged pointing to a rapid, sharp improvement in water quality. For example, it was reported that canals in Venice, Italy, experienced an unprecedented (in modern times) improvement in visibility due to a reduction in human activity: “Venice canals are clear enough to see fish as coronavirus halts tourism in the city”, March 18th, 2020 edition of ABC News, https://abcnews.go.com/International/venice-canals-clear-fish-coronavirus-halts-tourism-city/story?id=69662690. In particular, emphasis was placed on a reduction in tourists as being a major contributor to this improvement in estuarine water quality. Other studies have now been published from rivers, lakes, and coastal waters worldwide documenting localized improvements in various water quality constituents as a result of the COVID-19 quarantine period (Lotliker et al., 2021; Mishra et al., 2020; Yunus et al., 2020). Observations of improved water quality highlight how the COVID-19 quarantine period and data collected during it may offer a rare opportunity to directly quantify human influence on aquatic ecosystems as well as potential recovery times from various forms of human influence. Nonetheless, assessments such as this are challenged by a need for long-term datasets in order to tease apart effects of the reduction in human influence from natural variability. For example, the aforementioned improvement in Venice's canal water clarity was subsequently attributed to a combination of reduced boating activity that would otherwise resuspend sediments, and a >50% reduction in precipitation in 2020 compared to historical conditions that resulted in less sediment-laden runoff and nutrients that would otherwise stimulate algal blooms (Braga et al., 2020). Here we present results from an analysis of the impacts of the COVID-19 quarantine period using two coastal water quality datasets. These datasets rely on sampling that operates at appropriate timescales to quantify the influence of reduced human activity on coastal water quality and span coastal ecosystems ranging from low human influence to highly urbanized systems. They are also of long duration, allowing for shorter-term effects of the COVID-19 quarantine to be placed in a longer-term context and to separate out the effects of the quarantine from natural variability. The primary hypothesis was that reduced tourism during the COVID-19 quarantine period would lead to improved coastal water quality, namely lower fecal indicator bacterial abundance and turbidity as well as higher dissolved oxygen. A secondary hypothesis was that water quality improvements would scale to the level of human influence, meaning that highly urbanized or tourist-centric watersheds would see greater improvement than more rural watersheds. 2 Methods 2.1 Data acquisition Water quality data were obtained from the National Estuarine Research Reserve's (NERR; https://coast.noaa.gov/nerrs/) long-term water quality monitoring program and the Texas Beach Watch bacterial sampling program (https://cgis.glo.texas.gov/Beachwatch/). The NERR maintains long-term monitoring stations at sites throughout the United States. For this study, we utilized water temperature (°C), salinity, dissolved oxygen (DO; % saturation) and turbidity (FNU/NTU) data from five NERR sites that are representative of various geographic regions of the United States that have distinct hydrologic drivers and different levels of human influence. These include three NERR sites from the southern United States where seasonal tourism and subsequent human influence on the environment would be most pronounced (North Inlet-Winyah Bay NERR, South Carolina; North Carolina NERR; Mission-Aransas NERR, Texas), one upwelling-influenced site on the United States West Coast (Elkhorn Slough NERR, California), and one urbanized site on the United States Northeast Coast (Narragansett Bay NERR, Rhode Island) (Fig. 1; Supplemental Table 1). The Texas Beach Watch program is managed by the Texas General Land Office and assesses the fecal indicator bacteria (FIB), enterococci, for the purpose of notifying the public via beach advisories when FIB levels are above the EPA's beach action value (USEPA, 2012). Routine water sampling has been on-going for over 15 years, with samples being collected on a weekly basis during peak season (i.e., March and May through September) and a bi-weekly basis during non-peak season. Data from 2009 to 2020 were obtained from 159 monitoring sites in 61 beaches throughout the following eight coastal counties: Jefferson, Harris, Galveston, Brazoria, Matagorda, Aransas, Nueces, and Cameron (coordinates available at www.texasbeachwatch.com). In accordance with an EPA-approved Quality Assurance Project Plan (QAPP) (Texas Beach Watch Program, 2015), enterococci were quantified using the Enterolert test method (IDEXX Laboratories, Westbrook, Maine, US) and reported as the most probable number (MPN) 100 mL-1. A small subset of the earlier samples obtained in 2009 and 2010 were analyzed with the EPA 1600 membrane filtration method (USEPA, 2006), also in accordance with the QAPP, and reported as colony forming units (CFU) 100 mL-1. For the purpose of this study, enterococci units are reported as MPN 100 mL-1.Fig. 1 Map of the National Estuarine Research Reserve study sites. Fig. 1 Hotel locations and visit patterns provide insights into coastal tourism activity (Silva et al., 2021). To assess coastal tourism prior to and during the COVID-19 pandemic, weekly hotel visits were obtained from SafeGraph (https://www.safegraph.com), which were generated from privacy-compliant and anonymized mobile device location data. This dataset includes visitor aggregations from 4.5 million points of interest in the U.S. The hotels were identified within the North American Industry Classification System (NAICS) code 721110. To capture hotel visits in the Texas Beach Watch and NERR stations, all hotels in the eight coastal counties in Texas where the Beach Watch sites were located and all 13 counties whose centers are located within 30 miles of the five NERR sites were included. 2.2 Data analysis 2.2.1 NERR water quality High frequency water quality data including turbidity, salinity, DO, and water temperature were recorded in 15-minute intervals at the five NERR sites. Each site had 3-4 sampling stations from which data were utilized (see Table 1 for list of stations). States/counties in which the sites are located began implementing quarantine orders in the timeframe of mid-March 2020. Data from March-July 2020 were compared to data from March-July 2010-2019 with a t-test using R (version 3.6.1) and RStudio (version 1.2.1335). Due to a non-normal distribution, turbidity data were log-transformed prior to analysis. Linear models were generated for each NERR station to relate deviations from the long-term average (i.e., daily mean values in 2020 minus daily mean values in 2010-2019) for response variables (DO and turbidity) to the explanatory variables (salinity, temperature, and weekly hotel visits as a proxy for coastal tourism). Finally, weekly visit patterns in 2020 were compared to 2019 with a t-test.Table 1 Comparison of turbidity (FNU/NTU), salinity, dissolved oxygen (%), and water temperature (°C) in 2020 (March-July) to average values from 2010 to 2019 (March-July). *Due to a non-normal distribution, turbidity data were log-transformed prior to analysis. Green boxes indicate the variable was significantly lower in 2020; red boxes indicate the variable was significantly higher in 2020 (t-test; p < 0.001). White boxes indicate no significant difference. Table 1 2.2.2 Beach Watch bacteria The presence of censored data in the enterococci measurements required the use of censored statistical tests from the NADA package in R (Lee, 2017). Data from 2020 were compared to historical data (i.e., 2009-2019) using the cendiff test; as data had only been recorded through October 2020 at the time of this analysis, data from November and December of each year were excluded from the comparison. Correlations between enterococci levels and weekly visits in 2020 were computed using the cenken test in R (Kendall's tau correlation coefficient) and weekly visit patterns in 2020 were compared to 2019 with a t-test. 3 Results 3.1 NERR water quality A sharp decline in the number of visits to hotels surrounding NERR stations occurred immediately following stay-at-home orders in March 2020 (Fig. 2 ). Whereas North Inlet, North Carolina, and Mission-Aransas visits increased to pre-COVID (2019) levels by summer 2020, Elkhorn Slough and Narragansett Bay maintained lower levels of hotel visits throughout the entire timeframe of this study (t-test; p < 0.05).Fig. 2 Number of weekly visits to hotels in 2019 compared to 2020 in A) Elkhorn Slough, B) Mission Aransas, C) Narragansett Bay, D) North Carolina, and E) North Inlet. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 2 March-July water temperature was significantly higher in Mission-Aransas during 2020 at all stations compared to 2010-2019 (Fig. 3 , Table 1). Elkhorn Slough and North Inlet had at least two stations with higher temperatures in 2020, while cooler temperatures were observed at Narragansett Bay. Water temperature trends were spatially variable in North Carolina. In general, the water temperature data showed a high degree of temporal variability in each estuary. Salinity was lower in 2020 compared to 2010-2019 at all stations in Elkhorn Slough, North Carolina, and North Inlet, but higher in Mission-Aransas (Fig. 4 , Table 1). Salinity trends were spatially variable in Narragansett Bay. Turbidity was higher in 2020 compared to 2010-2019 in North Inlet and Narragansett Bay, but spatially variable in the other three estuaries (Fig. 5 , Table 1). A high degree of temporal variability was also observed. DO was lower in North Inlet in 2020, but spatially variable in the other estuaries, with all sites showing a high degree of temporal variability (Fig. 6 , Table 1).Fig. 3 Daily mean water temperature in 2020 compared to 2010-2019; shaded regions represent +/- standard deviation. A) Elkhorn Slough (n = 4 stations), B) Mission-Aransas (n = 3 stations), C) Narragansett Bay (n = 3 stations), D) North Carolina (n = 4 stations), E) North Inlet (n = 3 stations). Fig. 3 Fig. 4 Daily mean salinity in 2020 compared to 2010-2019; shaded regions represent +/- standard deviation. A) Elkhorn Slough (n = 4 stations), B) Mission-Aransas (n = 3 stations), C) Narragansett Bay (n = 3 stations), D) North Carolina (n = 4 stations), E) North Inlet (n = 3 stations). Fig. 4 Fig. 5 Daily mean turbidity in 2020 compared to 2010-2019; shaded regions represent +/- standard deviation. A) Elkhorn Slough (n = 4 stations), B) Mission-Aransas (n = 3 stations), C) Narragansett Bay (n = 3 stations), D) North Carolina (n = 4 stations), E) North Inlet (n = 3 stations). Fig. 5 Fig. 6 Daily mean dissolved oxygen in 2020 compared to 2010-2019; shaded regions represent +/- standard deviation. A) Elkhorn Slough (n = 4 stations), B) Mission-Aransas (n = 3 stations), C) Narragansett Bay (n = 3 stations), D) North Carolina (n = 4 stations), E) North Inlet (n = 3 stations). Fig. 6 Deviations in salinity and temperature as well as hotel visits explained approximately 11-35% of the variance in turbidity and DO, depending on the site (Table 2 ). In the case of turbidity, four sites (Elkhorn Slough, Narragansett Bay, North Carolina, North Inlet) showed a significant negative correlation with salinity and none showed a positive correlation (Table 2). The relationship between turbidity and water temperature was less consistent, with a positive correlation observed in North Carolina and North Inlet and a negative correlation observed in Narragansett Bay (Table 2). In terms of weekly hotel visits, one site had a positive correlation with turbidity (Elkhorn Slough) and two sites had a negative correlation (North Carolina and North Inlet). In the case of DO, three sites (Elkhorn Slough, Mission-Aransas, North Inlet) showed a significant positive correlation with salinity and none showed a negative correlation (Table 2), while all five sites showed a negative correlation with water temperature. Two sites had a positive relationship between DO and hotel visits (Elkhorn Slough and Narragansett Bay) and two had a negative relationship between these variables (North Carolina and North Inlet).Table 2 Results of linear models relating deviations in explanatory variables to deviations in response variables (p < 0.05). ns = nonsignificant model. Table 2NERR site Response variable Significant explanatory variable(s) and sign of relationship (+ or -) Adjusted R2 Elkhorn Slough Turbidity Salinity (-) Hotel visits (+) 0.27 DO Salinity (+) Temperature (-) Hotel visits (+) 0.35 Mission-Aransas Turbidity ns ns DO Salinity (+) Temperature (-) 0.15 Narragansett Bay Turbidity Salinity (-) Temperature (-) 0.30 DO Temperature (-) Hotel visits (+) 0.11 North Carolina Turbidity Salinity (-) Temperature (+) Hotel visits (-) 0.28 DO Temperature (-) Hotel visits (-) 0.19 North Inlet Turbidity Salinity (-) Temperature (+) Hotel visits (-) 0.32 DO Salinity (+) Temperature (-) Hotel visits (-) 0.33 3.2 Beach Watch bacteria Nearly every Texas county in this study had a notable decrease in weekly visits during the stay-at-home order in March-April 2020, and the majority of counties also experienced significantly fewer visits in 2020 than 2019. The exception to this was Matagorda, which received more visits in 2020, and Aransas and Cameron, which had no difference in weekly visits (t-test; p < 0.05; Fig. 7 ). To test if FIB levels were lower during the stay-at-home order compared to previous years, enterococci concentrations in March-July 2020 were compared to the historical concentrations from 2009 to 2019. In January through March of 2020, FIB levels tracked with historical concentrations with the exception of Matagorda, where FIB levels were slightly higher than the historical average (Fig. 8 ). Following the quarantine orders in March, the counties showed diverging trends (Fig. 8). The majority of counties showed increasing FIB levels that accompanied the onset of spring and early summer with the exception of Harris and Cameron. Nueces, Aransas, Jefferson, and Galveston exhibited positive correlations between enterococci and the number of weekly hotel visits (Kendall's tau: 0.17, 0.14, 0.12, and 0.05 respectively), whereas Matagorda exhibited an inverse correlation (Kendall's tau: −0.07). Cameron and Harris Counties did not experience significant relationships between these variables.Fig. 7 Number of weekly visits to hotels in 2019 compared to 2020 in A) Jefferson, B) Harris, C) Galveston, D) Brazoria, E) Matagorda, F) Aransas, G) Nueces, and H) Cameron Counties of Texas (United States of America). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 7 Fig. 8 Concentration of enterococci (data aggregated based on daily median values) in 2020 (red triangles) compared to the long-term average in 2009-2019 (blue circles) in A) Jefferson, B) Harris, C) Galveston, D) Brazoria, E) Matagorda, F) Aransas, G) Nueces, and H) Cameron Counties. Loess curves are shown as red lines for 2020 data and blue lines for 2009-2019 data. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 8 4 Discussion The COVID-19 pandemic resulted in unprecedented changes to economic and social behaviors worldwide. One such change was the drastic reduction in the number of people traveling for vacations and holidays. This study set out to answer the question: did the COVID-19 quarantine period lead to a reduction in human influence on coastal ecosystems, manifesting as improved water quality? The primary hypothesis, that reduced tourism during the COVID-19 quarantine period would lead to improved coastal water quality, and the secondary hypothesis, that water quality improvements would scale to the level of human influence, were supported at four highly impacted regions where FIB concentrations decreased during the quarantine period. However, these hypotheses were generally not supported for other water quality indicators, such as dissolved oxygen and turbidity, that commonly demonstrate high natural environmental variability. An emerging theme from these results and current literature findings is that temporary, quarantine-associated water quality improvements appear to only occur in ecosystems severely impacted by human activity, such as those receiving significant quantities of industrial discharge or poorly treated sewage. Furthermore, an important theme from our analysis of the NERR data in particular is that natural climate variability can easily overwhelm the COVID-19 quarantine signature, emphasizing the need for data collections at appropriate timescales and datasets that are of sufficient duration to separate the signature of events such as a COVID-19 quarantine from this natural variability. We elaborate on these themes below. 4.1 Findings from the NERR data analysis – a key role for natural variability Water temperature and salinity are integrative of the effects of natural environmental drivers such as weather and climatological conditions that affect air temperature and rainfall, wind-forcing of ocean circulation features (in the case of upwelling systems), and tides, among other factors. These same features are also important natural drivers of water quality indicators such as turbidity and DO through their effects on material loadings to coastal systems as well as on gas solubility (in the case of DO). Thus, water temperature and salinity can serve as proxies for the larger-scale drivers of variability in turbidity and DO, as well as other water quality indicators. As observed in the Venice Canal, humans can have an important influence on estuarine turbidity, either as an artifact of what we put into a system (e.g., wastewater effluent that fuels algal blooms) or as a direct impact of activities such as boating (Braga et al., 2020). Nonetheless, results from this study suggest that natural environmental variability likely overwhelmed any signature of human influence on turbidity in the systems that were examined. For example, turbidity was negatively correlated with salinity at four NERR sites (Elkhorn Slough, Narragansett Bay, North Carolina, North Inlet), emphasizing the role of rainfall that either leads to increased (high rainfall, low salinity) or decreased (low rainfall, high salinity) particle loading from watersheds and turbidity in the estuary. In the case of Elkhorn Slough, turbidity was generally below average for the first half of 2020, but natural environmental variability can at least partially explain this as it coincided with above average salinities and below average late winter rainfall. Turbidity subsequently increased through mid-April as rainfall increased, but nonetheless turbidity remained below average through early June until upwelling commenced. We cannot rule out a role for decreased human activity in the below average turbidity as well, given its correlation with hotel visits and the low number of visits during that timeframe. In contrast to the below average turbidity in Elkhorn Slough during the first half of 2020, instances of above average turbidity were documented in Narragansett Bay (April-May 2020), North Carolina (early January, March-April 2020), and for much of the first half of 2020 at North Inlet. In each of these cases, the above average turbidity corresponded with either a sharp drop in salinity (Narragansett Bay) or prolonged periods of below average salinity (North Carolina, North Inlet), pointing to the likelihood of increased input of riverine particulate matter as being a driver. It must be acknowledged that the R2 for turbidity-environmental relationships was low, which indicates that other factors not represented by temperature or salinity may have also affected turbidity. One obvious factor is wind-driven resuspension of sediments, which is known to play a role in estuarine turbidity (Bever et al., 2018; McCarthy et al., 2018), with some systems being more susceptible than others. DO is often used as an indicator of human influence on coastal environments, namely because it is affected by factors such as algal production and bacterial respiration that are themselves influenced by the eutrophication process (Cloern, 2001; Anderson et al., 2002; Rabalais et al., 2009, Rabalais et al., 2010). Indeed, both short- and long-term declines in DO have been linked to excessive algal production and subsequent biomass degradation in eutrophying waterbodies (Kemp, 2005; Diaz and Rosenberg, 2008; Rabalais et al., 2010). Watershed organic matter loadings can also fuel bacterial respiration (Paerl et al., 1998; Servais et al., 1987; Abril et al., 2002; Mallin et al., 2002; Petrone et al., 2009) and tend to be enhanced in systems with land use that is influenced by humans (Servais et al., 1987; Abril et al., 2002). In addition to biological influences, environmental variability also affects DO. For example, rainfall often modulates the loadings of organic matter, and both salinity and temperature directly affect DO solubility, with DO solubility showing inverse correlations with both. Because of the expected reduction in human waste streams during the COVID-19 quarantine period due to reduced tourism, we hypothesized that DO would be above average in 2020. The NERR data did not show this, however, and instead displayed a high degree of both short timescale and spatial variability in DO. Where significant trends were observed, ten out of seventeen sampling stations in the NERR system showed below average DO while only five out of seventeen showed above average DO. The below average DO was centered in the Elkhorn Slough, North Carolina, and North Inlet systems, which we attribute to higher riverine loadings of organic matter that fueled bacterial respiration, an observation supported by prolonged periods of below average salinity in those systems in 2020. At the five stations where DO was above average in 2020, three can be explained, at least in part, by higher oxygen solubility due to below average temperature (Potters Cove, T-Wharf of Narragansett Bay; Research Creek of North Carolina; Table 1). In the case of the North Carolina station, we cannot rule out a role for decreased human activity in the above average DO as well, given its negative correlation with hotel visits and the low number of visits for part of the record in 2020. Nonetheless, there are no other examples of reduced visitors leading to increased DO in this dataset. Thus, there was no obvious improvement in DO as a result of the COVID-19 quarantine. Only Copano West (Mission-Aransas) displayed above average DO that cannot be explained based on temperature and salinity. 4.2 Findings from the Beach Watch data analysis – conflicting site-specific patterns in relation to human populations FIB levels were frequently higher in 2020 than the long-term average (i.e., 2009-2019), which agrees with a decade-long increase in enterococci throughout coastal Texas (Powers et al., 2021a). This finding was particularly true in the months following the original stay-at-home order and throughout the summer. However, several counties also experienced lower FIB levels sporadically throughout 2020. This trend was prominent in Matagorda and Cameron, the latter of which has rarely recorded enterococci levels in exceedance of the beach action value in the past decade (Powers et al., 2021a). In fact, Cameron was the only county in this study that has shown an inverse correlation between time and long-term measurements of enterococci (Powers et al., 2021a). The low FIB levels may be attributed to watershed protection plans and subsequent water quality improvements that are taking place in the Lower Laguna Madre and Arroyo Colorado (TCEQ, 2020a; TCEQ, 2020b). In terms of the number of hotel visits, Matagorda was the only county that received more visits in 2020 than 2019, although it did not see a simultaneous increase in FIB levels. Rather, this county showed a unique trend of lower levels of FIB accompanying an increase in visits. It is possible that the enterococci originated from animal sources other than humans, and wildlife inputs could be obfuscating the impacts of human fecal pollution. For example, Matagorda is home to many critical wildlife habitats, including several coastal bird rookeries and sanctuaries (Weber et al., 2015) and it has one of the largest cattle populations in coastal Texas (http://www.texascounties.net/statistics/cattle2017.htm). Nueces, Aransas, Jefferson, and Galveston Counties experienced direct correlations between FIB and the number of hotel visits. This direct relationship suggests that a larger portion of enterococci in these counties may be attributed to human waste than in the other locations throughout the study. All four reported a spike in June, when anecdotal evidence from news reports indicated that there was a sharp increase in beach tourism due to the lifting of some COVID-19 restrictions (https://www.kristv.com/news/coronavirus/beaches-draw-crowds-saturday; https://www.kiiitv.com/article/news/beaches-will-remain-open-this-fourth-of-july-but-there-could-be-some-rule-changes-heres-why/503-58d8bab2-9af8-42aa-b16f-5b8c5ac6271e). These findings offer some support for our secondary hypothesis that water quality improvements would scale to the level of human influence, as all of these counties belong to a region characterized by high levels of coastal tourism. Nueces has previously been identified as a hotspot of bacterial pollution (TCEQ, 2018), and in September of 2020, the EPA and the city of Corpus Christi (Nueces) entered into a consent decree which requires the city to improve its sanitary sewer system to prevent violations of the Clean Water Act, including illegal discharge of sewage waste into receiving environments (https://www.epa.gov/sites/production/files/2020-09/documents/corpuschristi-cd.pdf). Furthermore, previous source tracking studies have identified abundant human waste in both Nueces and Aransas (Powers et al., 2020; Powers et al., 2021b). Nonetheless, the low correlation values in these counties and the lack of correlation elsewhere indicate that fecal bacteria pollution is likely influenced by a multitude of additional factors that were not included in this study, including rainfall, sanitary sewer overflows, onsite sewage facilities, and underlying infrastructure conditions (Converse et al., 2011; Passerat et al., 2011; Sauer et al., 2011; Sowah et al., 2017; Zeki et al., 2020). 5 Conclusions Results from this study highlight the lack of a widespread impact of the COVID-19 quarantine period on estuarine water quality. In the 2020 NERR data, turbidity and DO variance from the long-term average could be explained largely by natural fluctuations in the environment, as denoted by salinity and temperature variability. This was despite inclusion of NERR sites spanning a continuum of watershed land uses from high impact (significant urban influence) to low impact (e.g., forests and wetlands), and susceptibility to pollutants as shown by the range of residence times. In the Texas bacterial data, four locations demonstrated a direct relationship between bacteria levels and the number of visits: Aransas, Jefferson, Galveston, and Nueces Counties, which have a long history of impaired water quality due to suspected sewage infrastructure degradation. Overall, these results add to the growing body of literature on the environmental impacts of the COVID-19 quarantine period, and when considered with existing literature, emphasize that coastal water quality impacts appear to be ephemeral and reserved for the most severely affected (by human activity) systems. In addition, the results suggest caution is in order when interpreting conclusions from studies that lack historical baseline data or that do not account for natural variability. The following is the supplementary data related to this article.Supplemental Table 1 Characteristics of National Estuarine Research Reserve study sites. Information obtained from Bricker et al., 2007 or metadata that accompanied water quality data from each site. “Ag” represents agricultural land use. Supplemental Table 1 CRediT authorship contribution statement Michael Wetz: Conceptualization, Methodology, Validation, Data Curation, Writing, Supervision, Project administration, Funding acquisition. Nicole Powers: Methodology, Software, Validation, Formal Analysis, Data curation, Writing, Visualization. Jeffrey Turner: Conceptualization, Writing, Supervision, Funding acquisition. Yuxia Huang: Methodology, Software, Data Curation, Writing. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements Funding support for this project was provided by 10.13039/100005794 Texas Sea Grant (award number NA18OAR4170088) and by the Texas General Land Office (contract 20-226-000). This publication was also made possible by the National Oceanic and Atmospheric Administration, Office of Education Educational Partnership Program award (NA16SEC4810009). Its contents are solely the responsibility of the award recipient and do not necessarily represent the official views of the U.S. Department of Commerce, National Oceanic and Atmospheric Administration. ==== Refs References Abril G. Nogueira M. Etcheber H. Cabecadas G. Lemaire E. Broguiera M.J. Behaviour of organic carbon in nine contrasting European estuaries Estuar. Coast. Shelf Sci. 54 2002 241 262 Anderson D.M. Glibert P.M. 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10.1016/j.scitotenv.2021.150825

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==== Front Rev Malad Respir Actual Rev Malad Respir Actual Revue Des Maladies Respiratoires Actualites 1877-1203 1877-122X SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS S1877-1203(22)00774-1 10.1016/S1877-1203(22)00774-1 Transplantation Pulmonaire Avancées en transplantation pulmonaire Mal H. 1* 1 Service de Pneumologie et Transplantation Pulmonaire, Hôpital Bichat-AP-HP, Paris, France * Correspondance. Adresse e-mail : herve.mal@aphp.fr (H. Mal). 15 12 2022 12 2022 15 12 2022 14 2 2S4232S425 Copyright © 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS All rights reserved. 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTransplantation pulmonaire chez les patients COVID-19 compliqué de SDRA : une option possible mais avec des indications très restrictives La survenue d’un syndrome de détresse respiratoire aiguë (SDRA) est une complication bien connue et redoutée du COVID-19 se traduisant par une mortalité significative malgré la prise en charge optimale en réanimation. Pour les patients qui restent en détresse respiratoire à plusieurs semaines du début du SDRA, la discussion d’une transplantation pulmonaire (TP) peut maintenant se poser alors que le SDRA représentait, jusqu’à l’épidémie actuelle, une indication exceptionnelle de TP. Dans le cadre d’une session animée par les éditeurs du « JAMA » et du « New England Journal of Medicine » (session A2), portant sur les articles à paraître ou parus récemment dans ces journaux, GS. Budinger (Chicago, USA) a présenté les données rétrospectives de son centre concernant la TP pour SDRA lié au COVID-19 [1]. Sur les 102 TP réalisées dans ce centre, de janvier 2020 à septembre 2021, 30 portaient sur des patients COVID-19 atteints de SDRA. Les patients dont l’âge médian était de 53 ans (extrêmes allant de 27 à 62 ans) ont été transplantés après un délai minimum de 40 jours après le début du SDRA (médiane > 100 jours). Au moment de la TP, 17 patients étaient sous ECMO (« extracorporeal membrane oxygenation ») veino-veineuse, 7 sous oxygène nasal, 4 sous ventilation mécanique invasive et 2 sous oxygène à haut débit. Les suites opératoires des patients COVID-19 ont été marquées par un taux plus élevé de transfusion peropératoire, une durée d’intervention plus longue que chez les patients non-COVID. En postopératoire, en comparaison avec les 72 patients non-COVID-19, les patients COVID-19 transplantés avaient une plus grande fréquence de dysfonction primaire du greffon (de grade 1 à 3) à J3 et de recours à l’hémodialyse, avec une durée d’hospitalisation plus longue. La survie des patients COVID-19 transplantés était excellente puisqu’en novembre 2021, 100 % des patients étaient en vie (suivi médian de 351 jours). Ces résultats remarquables, montrant que la TP est réalisable chez des patients COVID-19 en SDRA, ne doivent pas faire oublier que ce traitement ne s’adresse qu’à un sous-groupe minoritaire et ultra sélectionné. En effet, les patients doivent satisfaire des critères très stricts. En particulier, en sus des critères habituels exigés pour envisager une TP, il faut laisser au poumon l’opportunité de se réparer (un délai minimum de 4 à 6 semaines après le début du SDRA est exigé), et s’assurer que le patient présente des signes d’atteinte pulmonaire irréversible, qu’il n’est plus porteur du SARS-CoV2, qu’il est réveillé et capable de comprendre le projet de TP, qu’il est capable de faire une réhabilitation musculaire minimale. Il ne doit pas non plus avoir de défaillance d’un autre organe que le poumon, la transplantation multi-organes étant contre-indiquée Ce processus strict de sélection est illustré par un diagramme explicite figurant dans la publication : entre Novembre 2020 et Décembre 2021, sur un total de 234 patients avec SDRA compliquant un COVID-19 dont les dossiers ont été adressés pour discussion d’un projet de TP, 80 % ont été récusés pour des motifs divers et seuls 9 % ont été transplantés dans ce centre. Controverses en transplantation pulmonaire Un symposium (session C83) a abordé trois points de controverse en matière de sélection des candidats pour la TP. Le premier portait sur la question de l’usage du cannabis chez un receveur potentiel. Aux USA, l’usage du cannabis est illégal au niveau fédéral. Cet usage est également illégal dans certains états mais est autorisé dans d’autres (à but récréatif ou seulement médical selon les états). Il n’y a pas aux USA de règles strictes sur l’usage du cannabis destinées aux centres de TP. Les deux intervenants de la controverse s’accordaient sur le fait que le cannabis inhalé doit être vu comme une contre-indication à la TP. M. Budev (Cleveland, USA) qui défendait la thèse « CON » a insisté sur les effets secondaires attribués à l’usage du cannabis, notamment cardiovasculaires et neuropsychiques, ces derniers pouvant conduire à une mauvaise compliance à la prise en charge post-TP. Un risque d’interaction médicamenteuse notamment avec les anticalcineurines a aussi été évoqué. M. Budev (Cleveland, USA) concédait néanmoins que le cannabis à usage médical, utilisé uniquement par voie orale et sur prescription, peut être envisagé au cas par cas. C’est d’ailleurs la position adoptée par les dernières recommandations de l’ISHLT (International Society for Heart and Lung Transplantation) qui mentionnent le cannabis comme une contre-indication relative [2]. Sans nier les effets toxiques potentiels du cannabis, E. Lease (Seattle, USA), qui défendait la cause du « PRO » a rappelé pour sa part que les (rares) études qui se sont intéressées au retentissement de l’usage de cannabis après greffe rénale ou hépatique n’ont pas mis en évidence d’effets délétères et que les enquêtes concernant la politique des centres américains de TP sur le sujet du cannabis dans la sélection des receveurs montraient que l’attitude était très variable d’un centre à l’autre. Une autre controverse abordée a été celle de considérer ou non la séropositivité VIH comme une contre-indication à un projet de TP. L’argumentaire développé par le tenant du « PRO », A. Kumar (Houston, USA) reposait sur les éléments suivants : le traitement anti-rétroviral, qui a changé radicalement le pronostic des patients, est lui-même associé à des comorbidités ; des données obtenues chez des greffés de rein et de foie suggèrent que les taux de rejet, d’infections opportunistes et de néoplasies seraient plus élevés chez les patients VIH+. Pour C. Koval (Cleveland, USA), les données obtenues dans les greffes thoraciques chez les patients VIH+ sont rassurantes, même si l’effectif de patients étudiés est faible et si elle admet un surcroît de risque d’infection et de rejet [3]. Selon les dernières recommandations d’experts de l’ISHLT, l’infection VIH qui était initialement considérée comme une contre-indication absolue est maintenant une contreindication relative à la TP (2). La TP est donc envisageable sous réserve d’un contrôle virologique parfait (charge virale nulle, CD4 > 200/mm3. Il importe aussi d’éviter certaines interactions médicamenteuses (antiprotéases, efavirenz, cobicistat) et d’éviter les molécules d’induction type sérum anti-lymphocytaire. Il s’agit néanmoins d’une TP présentant des difficultés prévisionnelles. Ceci est illustré par le fait que, malgré un nombre élevé de candidats potentiels VIH+ à une TP, le nombre de TP réalisées en 2021 aux USA dans cette indication n’a été que de 16 [3]. La dernière controverse portait sur le concept de « frailty », c’est-à-dire la « fragilité » du receveur. Cette « frailty » s’évalue par des échelles diverses telles que I’échelle FFP (« Fried Frailty Phenotype »), le « Frailty Index » ou la SSPB (« Short Physical Performance Battery »). Il s’agit d’un concept, connu des gériatres, qui a émergé il y a quelques années dans le domaine de la TP. Ce concept fait sens car on comprend bien qu’un patient avec « frailty » est plus à risque de suites opératoires difficiles. Il a d’ailleurs été montré que la« frailty » est associée à un risque majoré de décès sur liste d’attente [4] et de mortalité postopératoire [5]. Faut-il pour autant considérer que la « frailty » est une contre-indication à la TP ? MV. Subramani (Cleveland, USA) a soutenu cette thèse, arguant du fait que 1) la « frailty » est une comorbidité de plus et que, dans la TP, les comorbidités ne sont pas additives mais multiplicatives, ce qui est vrai ; 2) la « frailty » n’impacte pas seulement la survie des patients mais aussi leur qualité de vie après TP ; 3) greffer des patients en situation de « frailty » s’associe à une augmentation des coûts liés à la transplantation. L’orateur a cependant concédé que certains patients améliorent leur indice de « frailty » après la TP. C. Kennedy (Rochester, USA) a défendu la thèse inverse avec les arguments suivants : 1) la « frailty » est très répandue chez les patients atteints de maladie respiratoire chronique avancée (20 à 45 % des cas selon les échelles). Exclure les patients avec « frailty » conduit à exclure de la TP beaucoup de patients ; 2) la « frailty » est potentiellement réversible avant la TP par le biais de la réadaptation respiratoire ; 3) la « frailty » est potentiellement réversible après la TP. Pour les patients avec « frailty », C. Kennedy (Rochester, USA) propose de les faire rentrer dans un programme de réhabilitation respiratoire : si les patients sortent de la zone de « frailty », il est possible de poursuivre le projet de TP ; si les patients restent dans la zone de « frailty » la poursuite du projet de TP dépendra de la balance bénéfices/risques de la TP. Liens d’intérêts H. Mal déclare n’avoir aucun lien d’intérêt pour cet article. Cet article fait partie du numéro supplément Congrès annuel de l’American Thoracic Society 2022 réalisé grâce au soutien institutionnel apporté par GSK à la mission post ATS de la SPLF. ==== Refs Références 1 Kurihara C Manerikar A Querrey M Felicelli C Yeldandi A Garza-Castillon R Lung K Clinical characteristics and outcomes of patients with COVID-19-associated acute respiratory distress syndrome who underwent lung transplant JAMA 327 2022 652 661 35085383 2 Leard LE Holm AM Valapour M Glanville AR Attawar S Aversa M Campos SV Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation J Heart Lung Transplant 40 2021 1349 1379 34419372 3 Koval CE Farr M Krisl J Haidar G Pereira MR Shrestha N Malinis MF Heart or lung transplant outcomes in HIV-infected recipients J Heart Lung Transplant 38 2019 1296 1305 31636044 4 Singer JP Diamond JM Gries CJ McDonnough J Blanc PD Shah R Dean MY Frailty phenotypes, disability, and outcomes in adult candidates for lung transplantation Am J Respir Crit Care Med 192 2015 1325 1334 26258797 5 Wilson ME Vakil AP Kandel P Undavalli C Dunlay SM Kennedy CC. Pretransplant frailty is associated with decreased survival after lung transplantation J Heart Lung Transplant 35 2016 173 178 26679297

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Rev Malad Respir Actual. 2022 Dec 15; 14(2):2S423-2S425

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Rev Malad Respir Actual

10.1016/S1877-1203(22)00774-1

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==== Front Acad Radiol Acad Radiol Academic Radiology 1076-6332 1878-4046 The Association of University Radiologists. Published by Elsevier Inc. S1076-6332(22)00637-7 10.1016/j.acra.2022.11.032 Original Investigation Scenario Planning Approach to Adapting in the COVID Era Rawson James V. MD ab⁎ Stevens Jennifer P. MD, MS cd a Harvard Medical School, Boston Massachusetts b Department of Radiology, Beth Israel Medical Center, One Deaconess Rd, Boston, MA 02215 c Center for Healthcare Delivery Design, Beth Israel Deaconess Medical Center, Massachusetts d Division of pulmonary, critical care, and sleep medicine, Beth Israel Deaconess Medical Center, Massachusetts ⁎ Address correspondence to: J.V.R. 15 12 2022 15 12 2022 5 11 2022 25 11 2022 25 11 2022 © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. 2022 The Association of University Radiologists Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Rationale and Objectives The COVID-19 pandemic has caused much uncertainty and disruption in healthcare resulting in many challenges for strategic planning. Scenario planning is a tool that allows healthcare leaders to plan healthcare delivery strategies by incorporating the uncertainties into the analysis and planning process. Materials and Methods Variables were identified which will have major impact on the future, but whose future direction is uncertain. The extremes of these drivers were used to generate multiple scenarios. A subset of scenarios was used to evaluate potential tactics to determine which may be high yield in the face of uncertainty. Results Unlike traditional strategic planning, scenario planning does not develop a single future with a path to that future. Scenario planning evaluates tactics to determine which would be helpful in specific scenarios, multiple different futures or under specific conditions. Conclusion We present a scenario planning model which can be used to determine specific tactics to accommodate the uncertainty due to variable healthcare delivery needs in the COVID-19 era. KEY WORDS COVID Coronavirus Scenario Planning Change management Strategic planning ==== Body pmcINTRODUCTION Much has been learned in the radiology community during the COVID-19 pandemic and predicting the next steps, as well as anticipating short and long term needs and consequences, involves many variables and much uncertainty (1). From the initial waves in 2020 to the subsequent waves of pandemic as COVID variants emerged, the resulting disruptions impacted all aspects of society including the workforce, supply chain as well as individual and population health. The impact varied with each wave and was felt differently by different communities. As of October 2022, the Kaiser Family Foundation estimates global death toll over 6.5 million deaths (2). Given the variation in vaccine adoption among different populations, the continued emergence of variants and the unknown long term health consequences on COVID 19 infection, there is much uncertainty that needs to be considered in any healthcare organizational planning. In a world of limited resources, how should you decide how to best prepare for the uncertainty that is healthcare in the COVID era? Scenario planning is a planning tool that allows organizations to consider multiple possible futures called “scenarios,” permits organizations to plan and prepare for several different specific scenarios as well as identify the elements in common across several scenarios. The technique originated with Herman Kahn and his RAND Corporation work for the US military, helping the United States plan for uncertain shifting military needs during the Cold War. Royal Dutch/Shell used scenario planning in the 1970s prior to the gas crisis (3). Rather than viewing the oil industry as on a continued trajectory of high availability of oil and low oil prices, Royal Dutch/Shell recognized that major disruptions in the oil industry were possible and could be planned for. This frame shift informed strategic decisions and investments and allowed Royal Dutch/Shell to be better prepared for the oil crisis than its competitors. Scenario planning has been used in Radiology by the Society of Chairs in Academic Radiology in the early 2000s (4). One advantage of scenario planning is the ability to determine the necessary or high yield strategies and tactics despite the uncertainty of the future. Scenario planning does not predict the future. It identifies tactics that will be helpful for the scenarios studied as well as tactics that might be beneficial in several scenarios or under specific conditions. This is distinctly different from traditional strategic planning that decides on a desired future and builds a strategic plan to get to that single desired future. In this paper, we apply principles of scenario planning to healthcare delivery in the COVID era in the United States. Rather than planning a single desirable future, we use the scenario planning approach to determine the likely drivers, develop several scenarios and how best to prepare for individual scenarios and the common elements shared by multiple possible futures. The advantage of this approach is that it acknowledges the multiple uncertainties while focusing on the things that would be most useful for healthcare organizations to do without committing to a single defined future. MATERIALS AND METHODS In fall 2021, in the midst of a COVID-19 pandemic wave, in an attempt to balance the immediate needs with the longer-term needs, a scenario planning exercise was initiated. There are many possible drivers for the future success including organizational mission, local and national markets/trends, technology changes, etc. An axis of uncertainty is a variable where experts cannot agree and have opposing predictions. Will there more or less COVID cases? It is unknown what direction the virus will take as it continues to evolve with new strains and how will this impact the health of our communities. Will patients return to hospitals for their care all at once or will people continue to avoid coming to hospitals? Of all potential drivers and variables reviewed, three were chosen to be the axes of uncertainty: COVID clinical demand, non-COVID clinical demand and healthcare workforce (Fig 1 ). Other drivers were considered. For example, it is hard to imaging financial success without clinical volume. Yet clinical volume is a balance between the demand for non-COVID care and COVID care. Financial margins are a balance between expense and revenue with human resources being a major expense. Uncertainties in clinical demand make staffing needs unpredictable, introducing more uncertainty and risk.Figure 1 Axis of uncertainty in scenario planning. (Color version of figure is available online.) Figure 1 Nine scenarios (Table 1 ) were created by taking combinations of the extremes of high and low values of the three axes. By narrowing the focus to just three potential scenarios, which include all three variables at both extremes, we have a comprehensive set of possible futures which has incorporated the uncertainty into the model. There is no correct subset of scenarios to study. When choosing scenarios, one could try to choose scenarios that seem to be the most likely futures and develop specific plans for them. Alternatively, one could choose a combination of probable futures balanced with scenarios that ensure that all extremes of the axes are represented. One value of the scenario planning approach is to disrupt the mental model of how the future is viewed for an organization. Adding a fourth scenario to such an analysis would not add additional variables or extreme considerations and would likely have little incremental yield in the identification of high yield tactics in the face of uncertainty.Table 1 Scenarios Table 1Scenarios Non-COVID clinical demand Healthcare workforce COVID clinical demand Clinical system over run High volume High vacancy High volume No volume but staff Low volume Low vacancy Low volume Clinical system over run by routine care High volume High vacancy Low volume Tight balancing act High Volume Low vacancy High volume Taking care of COVID Low volume Low vacancy High volume No volume, no staff Low volume High vacancy Low volume Taking care of non-COVID High Volume Low vacancy Low volume Clinical system over run by COVID Low volume High vacancy High volume RESULTS The Axes Axis 1: COVD Clinical Demand There are 6093 hospitals in the United States with a combined staffed inpatient bed capacity of 90,531 with over 75,000 critical care beds and 33,356,853 annual admissions (5). The Center for Disease Control estimates 5,319,921 cumulative confirmed COVID hospital admissions between August 1, 2020 and October 22, 2022 (6). COVID surges impacted the need for inpatient and critical care beds differently in different communities which in turn varied with each surge. The advent of vaccines led to lower infections and less severe/fewer admissions. In the United States, 68.2% of the population has been vaccinated with the complete primary COVID vaccine primary series, but fewer have gotten the first or second booster (7). Another uncertainty is how much of future COVID care will require inpatient management, including the use of hospital or ICU beds as opposed to outpatient management alone. Some of the COVID care is going to be nonacute and may be managed in outpatient or urgent care settings if vaccines and boosters are more widely deployed. In a similar fashion, we must consider the COVID volumes that may become chronic diseases as we learn more about “long COVID,” which will add to the health care needs of the population. This could result in a shift of some healthcare from hospital-centric or inpatient-centric COVID care to a sub-acute care and ambulatory model of care. In addition to a possible increase in chronic care needs, there is evidence that there is likely to be an increase in acute care needs secondary to COVID infection. Preliminary data shows individuals with prior COVID infection have an increased risk for cardiovascular disease including stroke, myocardial infarction and thromboembolic disease (8). Axis 2: Non-COVID Clinical Demand Non-COVID clinical volumes were disrupted throughout the pandemic. During the pandemic some routine care was delayed, some avoided and other clinical demand decreased during lockdowns. Cancer screening exams were delayed during the pandemic (9). This allowed redeployment of staff to address other clinical needs. Other care needed to be provided but wasn't; it is unclear how much was through patient choice or changes in access. There was a 38% reduction in United States cardiac catheterization ST elevation myocardial infarction activations (STEMI) (10). Some care no longer needed to be provided. For example, California saw a 50% reduction in car collisions of all types during “the shelter in pace order” (11). Patients also delayed care to avoid contact with COVID. The impact of COVID volumes and workflow changes on the non-COVID radiology volumes varied with different waves with initial reductions as high as 70% reduction followed by rebound and relative stability through subsequent waves (12,13). The nature of care also changed with a significant portion of ambulatory clinic visits shifting to virtual visits during the initial surge. While these virtual exams had limited physical exams, they had reduced travel time for patients. Virtual visits may present opportunities for specialist care to be brought into more rural environments, possibly increasing both access and clinical volumes. Axis 3: Workforce The current state of the healthcare workforce is concerning. The great resignation saw approximately 18% of healthcare workers quit their jobs during pandemic (14). On a 2021 McKinsey survey, 22% of nurses indicated they may leave their current positions (15). The replacement pipelines are not prepared to produce new graduates at this scale. An American Association of Colleges of Nurses report stated over 80,000 nursing school applicants were turned away from baccalaureate and graduate programs due to lack of qualified faculty, clinical study sites, classroom space and budget constraints in 2020 (16). The American Society of Radiologic Technologists listed 53.6% of radiologic technology schools at full enrollment and 32% of nuclear medicine technology schools at full enrollment in 2020 (17). A 2021 Doximity Survey estimated that during the pandemic approximately 1% of the physician workforce retired before expected (18). The same report noted that three quarters of physicians reported being overworked with 22% considering early retirement because of overwork. Given continued physician burnout/moral hazard, additional loss of physician workforce is likely. The nature of our workforce is changing. There has been a multiyear decline in the percent of 16–64 year-old males in the US workforce with the most recent value at 67.7% (19). Our workforce is more mobile and may not be on-site. Remote work (from home) reduces the need for office space and parking and reduces the environmental impact. An estimated 60% of Americans working hours were from home in May 2020, falling to 40% in October 2021; this compares to a pre-pandemic February 2020 baseline of 5% (20). The mobility of the workforce extended beyond working at the same job from home. Licenses and registrations were fast tracked during the pandemic and scopes of service were expanded during the initial COVID surge. The nursing shortage during the pandemic lead to increased use of traveler nurses with an associated significant increase in the cost. Increased hourly rates charged to hospitals for traveler nurses by staffing companies have increased over 200% compared to prepandemic levels. In January 2022, hospitals spent a median of 38.6% of their total nursing labor expenses for nursing traveler contracts compared to prepandemic 2019 levels of a median of 4.7% (21). Hospitals have also increased their use of temporary allied healthcare staff from pre-pandemic levels of 25% to 30% to cover the staffing vacancies(22). Hospitals responded to the workforce shortage with increased compensation for existing staff and paying higher costs for travelers. This resulted in the increase in labor expenses per adjusted discharge between 2019 and March 2022 by 37% on average (23). The increasingly mobile nature of the healthcare workforce and the turnover in staff has highlighted challenges in rapid on-boarding and standardization of workflow that have been obtained as part of quality improvement projects for example, central line-associated bloodstream infection , catheter-associated urinary tract infection. The result is a loss of institutional knowledge and nationwide shortage of healthcare workforce which existing pipelines are inadequate to rebuild. In addition, the higher personnel expenses for healthcare compared to pre-pandemic levels have no sustainable new revenue source to cover this incremental expense in a low margin industry. When combined with lower volume of discharges and increased length of stay, the net effect is negative hospital margins (24). Scenarios None of the three variables is static. How these variables change over time introduces significant uncertainty which can hinder hospital and practice planning. By converting these variables to axis with extreme ranges, the uncertainty can be modeled. Nine scenarios were created using these three axes (Table 1). A subset of scenarios was chosen which included the extremes (high and low) for all of the variables. The three scenarios chosen were 1) Clinical system overrun, 2) No volume, but staff and 3) Tight balancing act. In Clinical system over run scenario, both the COVID and non-COVID clinical demand and volumes were high. The workforce staffing vacancy levels were high as well. In this first scenario adequate healthcare workforce is not available and COVID care demands continue to be high in addition to non-COVID care demands. This is the environment of care rationing, expanding scope of practice and likely high mortality. Examples of a similar scenario were seen in Italy early in the pandemic and in India in 2022 when the health systems were literally overwhelmed and unable to meet the demand for care to COVID patients. In the second scenario, No volume but staff, the other extreme in clinical demand would occur. There would neither be on-going severe COVID surges nor unmanageable clinical demand from the deferred non-COVID care or routine care. There would be low vacancy rates in the healthcare workforce with an adequate staff to manage the care and meet demands of both the COVID and non-COVID demand. This may lead to overstaffed hospitals with increased cost and decreased clinical volume and revenue, resulting in staff and service reductions. In the final scenario, Tight balancing act, both COVID and non-COVID clinical demand is high, but the healthcare workforce vacancy is low. This most likely requires healthcare systems to manage the capacity by doing most non-COVID routine care, while maintaining the capacity for COVID admissions. This results in deferring of some routine/nonemergent non-COVID care during COVID surges. Difficulties arise in defining what routine care can be deferred and for how long. This scenario was seen in some communities in the later surges in the United States with hospitals trying to load balance between COVID and non-COVID care needs. Next Steps The next step would be to identify possible tactics that would be helpful in individual scenarios. A comparison of those three lists would yield tactics which would be helpful in all three scenarios. In other words, what we will we need to do regardless of which scenario happens? This approach allows planning for specific scenarios as well as across several scenarios. There is no one correct answer because each local healthcare environment must be considered as well as the healthcare organization(s) in that community. Tip O'Neil said “all politics are local”. During the pandemic, each healthcare organization has evolved and matured and developed (and lost) some organization capacity and capabilities, but those vary from organization to organization. Thus, a tactic that one organization might need to develop, another organization may already have in place or might not even be helpful in that local environment. A systematic review of people, process and physical plant at a hospital/health system/practice or community level for each scenario would reveal tactics that need to be locally evaluated. For people/human resources, considerations might include cross training, flexible work hours, staff development, wellness programs or remote work options. One approach to addressing the work force shortage might include the recruitment of international physicians and nurses. The American Board of Radiology has a pathway for International Medical Graduates which includes completing four years of radiology residency training, fellowship, and/or full-time faculty appointment in one institution with a diagnostic radiology training program and allows the candidate to take the board certification exams (25). In prior nursing shortages, nurses have been recruited from the Philippines. The Philippine government has supported overproduction of nurses in the Philippines to create a surplus of bachelors’-trained nurses who would work internationally and send money home regularly (26). For process/workflow, considerations might rely on adaptations from the pandemic surges or focus on tasks deferred during pandemic, automation of manual tasks or improved efficiency of rate limiting step processes. A review of physical plant and infrastructure might increase the flexibility of space or explore off-campus locations possibly closer to where patients or staff live. In radiology, one modality or site may be in one scenario while another modality or site within the same organization is experiencing a different scenario. Many of these tactics will seem familiar and were explored during the pandemic. So, what is different? In the short term, the benefits of improving workforce pipelines seem obvious. Retention of workforce, reducing burnout and increasing joy in work would also likely be beneficial in multiple environments. These tactics are the reaction to an acute staffing crisis and lack the refinement of a more complex time horizon. Workforce is likely to be both an acute problem as well as a long-term challenge. The question is how will this evolve over time? Looking at the three scenarios, two of them would benefit from increased workforce, but one of them has excess workforce for the low volumes. While having too many staff seems unimaginable at this time, scenario planning highlights the need to balance the workforce to the uncertain clinical demand as demand changes. Considering the increased labor costs per adjusted discharge, staffing at the current cost is unsustainable and will likely lead to reduced services and staff layoffs in some markets if no other changes are made. Developing this insight further raises the question of whether there is a flexible staffing model that fits all three scenarios. (Figure 2 ) What new infrastructure would be needed to have a more flexible staffing? What is the correct balance between full-time and part-time workforce. How can staff performance and productivity be improved? What tasks can be automated? How many hospitals administrative processes are inefficient? Which workflows could be improved so that staff time is not wasted, thus increasing the efficiency of the staff? Alternatively, if no other changes are made the unsustainable higher cost per discharge could result in reduced services and lay-offs. Reduced services by one practice may be an opportunity for another practice if they have more flexible capacity or can provide the care more efficiently at a lower cost.Figure 2 Venn diagram of three scenarios and a tactic that meets needs of all three scenarios. “(Color version of figure is available online.) Figure 2 In considering the human resources needs of the organization for each of the three scenarios, one might apply a framework such as the Baldrige Criteria (27). Such a comprehensive review would allow the reassessment of the processes for functions such as predicting organizational workforce needs, planning for workforce capacity and engaging workforce for retention and high performance would allow the beginning of a discussion. (Table 2 ) Work force is not homogeneous and is segmented in multiple roles including receptionists, technologists, nurses, physicians, and advanced practitioners-each with different needs, skills and pipelines. In academic radiology, the faculty segment needs processes for promotion as well as non-promotion faculty development pathways. Some medical schools may expand the criteria for academic promotion by recognizing activities in clinical work, administration, quality initiatives and education that were undervalued earlier in an effort to improve job satisfaction and presumably retention. Dissatisfied and unengaged staff and faculty may ultimately leave. In general replacement cost is 1.5-2.0 times the salary of the individual who has left further adding to the cost of providing care (28). If they do not leave, dissatisfied faculty may also exhibit disruptive behavior which in turn adds incremental costs which could be as high as $1 million per radiologist annually in a 400-bed hospital (29). Further segmentation of work force needs may cause some organizations to re-evaluate and redesign fundamental processes such as recruiting, on-boarding, staff development, hours and location of work. In academics, virtual interviews are now routine, but can they be improved? Virtual education has exploded but there is still much opportunity in both asynchronous learning and synchronous and interactive learning.Table 2 Baldrige Criteria Workforce Table 2Capability and Capacity Needs New workforce members Workforce change Work accomplishment Workplace environment Workforce benefits and policies Drivers of workforce engagement Assessment of Workforce engagement Organizational culture Performance management Performance development Learning and development effectiveness Career development Equity and inclusion In all three scenarios being able to flex organizational resources to meet demand and to efficiently use existing resources is advantageous. This is not limited to human resources. Similar to flexible staffing, facility renovations and space utilization may need to be done with more intentional flexibility. This could include site selection for new clinical sites or renovation of existing sites. Processes, such as admission, discharges and transfer can also be redesigned and made more efficient. Reduced length of stay would provide increased inpatient capacity with the same staff and physical plant. Academic processes such as research can also be approached differently. Chesbrough describes an approach called “open innovation” (30) where innovation is not done in secret and in silos. Organizations promote collaboration with outside people and organizations by placing some of its resources outside of its walls through partnership, licensing and allowing others to develop your non-strategic initiatives. This allows both cost sharing (reduced expenses) and potential new revenue generation for existing resources. Other tactics may only be valuable in a unique set of circumstances. Identifying both the tactics and the unique circumstances sets a sign post for when resources should be directed towards such a tactic. Systemic analysis of the organization in light of the three scenarios and identification of best practices would be needed. As landscapes within each scenario are further developed, secondary scenarios and special cases can be developed. Change is likely to be part of the healthcare landscape for the next generation. What new infrastructure or training should we be putting in place? Should change management training be part of staff orientation, graduate medical education training or faculty development? DISCUSSION Unlike traditional strategic planning, scenario planning does not predict or plan for a single future. Our scenario planning model provides scenarios which when considered would yield potential tactics. One advantage of scenario planning is the ability to do pre-work before the actual disruption occurs which allows the organization to react to unexpected situations and conditions more rapidly and with an existing process-based approach. Applications of scenario planning in other industries allowed investments to be made strategically in high yield long term activities. Some tactics represent work we are likely going to need to do in healthcare. Starting some of the pre-work or removing barriers now may enable us to get these done faster than being reactive later or starting later during crisis. If our workforce pipeline is a small, then addressing it will require time. There are long lead times during which needs will change. Nursing schools and radiology technologist programs have entry requirements that need to be met prior to admission to 4-year programs. Residencies plus fellowship for radiology can be 6 or more years after a 4-year medical school. How do we address the generational differences in the multiple segments of our workforce? We may not be able to train the next generation the same way the last generation was trained. Healthcare may have to adapt to how the next generation of learners wants to be trained and how they optimally learn (31). If a workforce cannot be developed fast enough, an organization may shift its focus from people to changes in process/workflow (eg, reduced length of stay) to optimize the clinical work that can be done with the existing workforce. If a balance is not found between the care provided and its cost with the clinical demands, then services will likely need to be decreased to maintain financial viability of the organization. The study has several limitations. It could be argued that the axis chosen are not the biggest drivers. While demand for COVID and non-COVID healthcare are likely to be included in any analysis, workforce as an axis has some limitations. We looked at the workforce supply chain problems and the issues of pipelines for workforce. However, workforce could be a surrogate for supply chain. There are multiple examples of non-human resource supply chain/pipeline challenges impacting the ability to provide healthcare. Currently the Food and Drug Administration has an on-line database of drug shortages listing nearly 200 agents listed as currently in shortage or resolved shortage. (https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm) The computer chip shortage limited access to computers which limited replacement and additional computer and medical equipment. Radiology has seen shortages of helium impacting MRI. The shutdown of the Shanghai contrast manufacturing plant during the 2022 summer due to a COVID lockdown resulted in a global reduction of iodinated contrast for over 2 months with extensive changes in clinical practice (32,33). Much of the supply chain issues are external to hospitals but they will impacted by them. Having a systematic approach to managing critical shortages may become an essential skill. Building new or redundant pipelines for both human resources and non-human resources will likely require new approaches. Other limitations include barriers to implementing scenario planning. Despite these potential benefits, many health centers will not undertake this process. In an acute crisis where, daily staffing is a challenge and monthly volumes and revenue are highly variable, organizational resources are more likely to be focused on the acute needs and looking at longer term may seem an unaffordable luxury. Organizations that remain financially viable initially may have fewer reasons to look for new approaches at this time. In resource constrained organizations, it may not be possible to develop detailed plans for each scenario. Such organizations could look at what tactics are common to several scenarios to be more prepared. Another potential limitation is that organizations may be focused on local needs and solutions. Tactics might address local needs but they are not restricted only to local resources. Advocacy efforts could result in the development or acceleration of state or federal funding or policy changes. Health and Human Services recently announced a $60 million investment in rural healthcare workforce (34). While this includes $9.7 million to establish new rural residency programs in rural communities, a bigger investment in Graduate Medical Education expansion would be needed to increase the pipeline of physicians. CONCLUSION The uncertainty that COVID has brought to planning in healthcare has shifted much of healthcare to adapt to changes as they occur. Scenario planning offers an opportunity to assess the uncertainty and try to anticipate what planning will likely be needed despite the uncertainty. This allows some of these steps to begin earlier. Some of the tactics identified will be generalizable to many healthcare organizations. This may allow collaboration and cooperation between healthcare organizations, professional societies or state/federal government. Potentially some steps, which in the longer term are counterproductive, might be avoided. Scenario planning represents a tool that health systems could use to better prepare for the uncertainty in the COVID era. We don't want to be the last ones to recognize that the world has changed and new approaches are needed to manage an uncertain future. ==== Refs REFERENCES 1 Tan BS Dunnick NR Gangi A RSNA International Trends: a Global Perspective on the COVID-19 Pandemic and Radiology in Late 2020 Radiology 299 2021 E193 E203 33289616 2 Kaiser Family Foundation Global COVID-19 Tracker, https://www.kff.org/coronavirus-covid-19/issue-brief/global-covid-19-tracker/, Accessed October 24, 2022. 3 Wack P Scenarios: uncharted waters ahead Harvard Business Review 1985 73 89 4 Enzmann DR Beauchamp NJ Norbash A Scenario Planning J Am Coll Radiol 8 3 2011 175 179 21371667 5 Fast Facts on U.S. Hospitals, 2022, https://www.aha.org/statistics/fast-facts-us-hospitals, Accessed October 25, 2022. 6 CDC COVID Data Tracker, https://covid.cdc.gov/covid-data-tracker/#new-hospital-admissions, Accessed October 25, 2022. 7 COVID Data Tracker, https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-people-additional-dose-totalpop, Accessed October 25, 2022. 8 Xie Y Xu E Bowe B Al-Aly Z Long-term cardiovascular outcomes of COVID-19 Nature Med 28 2022 583 590 35132265 9 Fedewa SA Star J Bandi P Changes in cancer screening in the US during the COVID-19 pandemic JAMA Network Open 5 6 2022 e2215490 10 Garcia S Albaghdadi M Meraj P Reduction in ST-segment elevation cardiac catheterization laboratory activations in the United States during COVID-19 pandemic J Am Coll Cardiol 75 22 2020 2871 2872 32283124 11 Impact of COVID-19 on Traffic, Crashes, and Wildlife Vehicle Collisions,https://roadecology.ucdavis.edu/conference-proceedings-and-papers/impact-covid-19-traffic-crashes-and-wildlife-vehicle-collisions, Accessed on October 25, 2022. 12 Norbash AM Van More A Recht M Early-stage radiology volume effects and considerations with the coronavirus disease 2019 (COVID-19) pandemic: adaptations, risks, and lessons learned J Am Coll Radiol 17 2020 1086 1095 32717183 13 Schwertner A McMenamy J Naeger DM Radiology imaging volume changes during discrete COVID-19 pandemic waves: implications for the delta variant of coronavirus and future pandemics J Am Coll Radiol 19 2022 415 422 34883068 14 Nearly 1 in 5 Health Care Workers Have Quit Their Jobs During the Pandemic. https://morningconsult.com/2021/10/04/health-care-workers-series-part-2-workforce/ Accessed October 25, 2022. 15 Nursing in 2021: Retaining the healthcare workforce when we need it most,https://www.mckinsey.com/industries/healthcare-systems-and-services/our-insights/nursing-in-2021-retaining-the-healthcare-workforce-when-we-need-it-most, Accessed October 25, 2022 16 American Association of Colleges of Nursing, “Student Enrollment Surged in U.S. Schools of Nursing in 2020 Despite Challenges Presented by the Pandemic,” April 1, 2021:https://www.aacnnursing.org/News-Information/Press-Releases/View/ArticleId/24802/2020-survey-data-student-enrollment. Accessed October 25, 2022 17 Enrollment Snapshot of Radiography, Radiation Therapy, and Nuclear Medicine Technology Programs — 2020,https://www.asrt.org/docs/default-source/research/enrollment-snapshot/enrollment-snapshot-of-radiography-radiation-therapy-and-nuclear-medicine-technology-programs-2020.pdf?sfvrsn=8c650cd0_8#:∼:text=Enrollment%20Analysis,-Based%20on%20the&text=On%20average%2C%20radiation%20therapy%20programs,in%20each%20radiation%20therapy%20program. Accessed October 25, 2022. 18 2021 doximity compensation report, December 2021, https://c8y.doxcdn.com/image/upload/v1/Press%20Blog/Research%20Reports/Doximity-Compensation-Report-2021.pdf, Accessed October 25, 2022. 19 7 Ways men live without working in America,https://finance.yahoo.com/news/7-ways-men-live-without-working-in-america-092147068.html, Accessed October 25, 2022. 20 Remote-first work is taking over the rich world, The Economist, October 31, 2021, https://www.economist.com/finance-and-economics/2021/10/30/remote-first-work-is-taking-over-the-rich-world, Accessed October 25, 2022. 21 Massive growth in expenses and rising inflation fuel continued financial challenges for america's hospitals and health systems, American Hospital Association, April 2022,https://www.aha.org/system/files/media/file/2022/04/2022-Hospital-Expenses-Increase-Report-Final-Final.pdf Accessed November 4, 2022. 22 2022 Survey of Allied Healthcare Professional New Graduate Hiring Patterns, AMN Healthcare,https://www.amnhealthcare.com/amn-insights/allied/whitepapers/survey-of-allied-healthcare-professional-new-graduate-hiring-patterns/Accesses November 4, 2022. 23 KaufmanHall special workforce edition of the national hospital flash report, the financial effects of hospital workforce dislocation, May 2022,https://www.kaufmanhall.com/sites/default/files/2022-05/KH-NHFR-Special-Report-2.pdf Accessed November 4, 2022. 24 KaufmanHall National Hospital Flash Report: October 2022, https://www.kaufmanhall.com/sites/default/files/2022-11/KH-NHFR_10-2022.pdf Accessed November 4, 2022. 25 https://www.theabr.org/diagnostic-radiology/initial-certification/alternate-pathways/international-medical-graduates Accessed November 21, 2022 26 Gamble DA Filipino nurse recruitment as a staffing strategy J Nursing Administration 32 4 2022 175 177 27 2021-22 Baldrige excellence framework (health care) 2022 28 Porath C Pearson C. The cost of bad behavior 2009 Penguin Group New York 29 Rawson JV Thomson T Sostre G Deitte L The cost of disruptive and unprofessional behaviors in health care Acad Radiol 20 2013 1074 1076 23931419 30 Chesbrough H Garman AR How open innovation can help you cope in lean times Harvard Business Rev 87 12 2009 68 76 31 Pereira SW, Fishman EK, Rowe SP, The future is now: how technology and entertainment are transforming education in the artificial intelligence era 2022 32 Allen LM Shechtel J Frederick-Dyer K Rapid response to acute iodinated contrast shortage during the COVID-19 pandemic: single instituion experience J Am Coll Radiol 19 2022 836 840 35598634 33 Salazar G Mossa-Basha M Kohi MP Short-term mitigation steps during the iohexol contrast shortage: a single instituion's approach J Am Coll Radiol 19 2022 841 845 35594951 34 HHS invests nearly $60 million to strengthen health care workforce and improve access to care in rural communities,https://www.hhs.gov/about/news/2022/08/08/hhs-invests-nearly-60-million-to-strengthen-health-care-workforce-and-improve-access-to-care-in-rural-communities.html, Accessed October 25, 2022

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==== Front Journal of Academic Librarianship 0099-1333 0099-1333 Elsevier Inc. S0099-1333(21)00151-8 10.1016/j.acalib.2021.102460 102460 Article College students' perceptions on sense of belonging and inclusion at the academic library during COVID-19 Scoulas Jung Mi ⁎ University Library, University of Illinois Chicago, Chicago, USA ⁎ Corresponding author at: University Library, University of Illinois Chicago, Chicago, IL 60607, USA. 12 10 2021 12 2021 12 10 2021 47 6 102460102460 9 8 2021 4 10 2021 5 10 2021 © 2021 Elsevier Inc. All rights reserved. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. This paper demonstrates how university students experienced and perceived inclusion in a public research university library context during COVID-19. Both quantitative (n = 3379) and qualitative data (n = 575) from the 2021 student survey were examined to explore students' library experiences and their perceptions of inclusion. The quantitative data revealed that students using both the physical and online library had the greatest sense of belonging, whereas students who never used any library resources had the least sense of belonging. The qualitative data further revealed that when students used the in-person library space they felt a sense of belonging, as well as feeling accepted and valued; on the other hand, it was hard for them to judge inclusion when they had not been in the library due to COVID-19. This finding suggests how academic libraries need to prepare for the hybrid environment (in-person and online) so that students using online resources and services feel connected to the library. Keywords Sense of belonging Inclusion COVID-19 Accommodation Strategic plan Student survey Academic library ==== Body pmcIntroduction As a federally designated Minority-Serving Institution, the University of Illinois Chicago (UIC) welcomes students, staff and faculty from a variety of racial, ethnic, and class backgrounds, gender identities, sexual orientations and abilities to cultivate a diverse learning community. In an effort to promote and strengthen the University Library's role as “the hub of intellectual activity” on campus, the University Library developed a new strategic plan for FY 19-21 including three major goals, as follows (University of Illinois Chicago (UIC) University Library, n.d.):1. Build seamless, comprehensive and consistent access to global collections, instruction and services, whether digital or physical. 2. Create and sustain an inclusive culture and a welcoming environment for all. 3. Expand integration of the Library into UIC faculty's and students' research life cycles. To accomplish all three major goals, the University Library outlined the detailed activities with measurable outcomes. To meet the second goal, “create and sustain an inclusive culture and a welcoming environment for all,” which is the focus of this paper, various activities at the organizational, departmental and individual level were specified. To create a welcoming environment for patrons who use the physical library spaces and interact with them in person or online, the University Library committed to train library employees, including student employees, to increase their cultural competency for all patrons' backgrounds by offering online curricula and in-person hands-on activities. To increase the accessibility to library resources and services online for all patrons, the University Library's Accessibility Committee collaborated with various stakeholders focusing on issues of physical access to library spaces and online resources and regularly evaluated library employees' competency regarding providing services to patrons with accessibility needs as addressed by the American with Disabilities Act. The University Library's Undergraduate Engagement Program focuses on enhancing undergraduate students' engagement in the library and has provided in-person programming such as relaxation stations (e.g., offering a massage chair), free coffee and snacks and a wall of encouragement (allowing students to express their emotions) during exam periods to help undergraduates reduce their anxiety and focus on studying within the library. Unexpectedly, due to the COVID-19 pandemic last year, the University Library buildings had to close and later reopen to the UIC community. With the pandemic and social unrest across the country, the University Library's priorities shifted, focusing on the institutional community's safety by implementing new health safety guidelines and monitoring compliance. In spite of the requirement to take immediate action within a limited time, the University Library demonstrated that it valued students' voices by collecting their feedback through focus groups on how they wanted the University Library to implement the rules and policies within the library (Scoulas et al., 2021a). Due to COVID-19, one drastic change was students' use of library space: the number of in-person visitors in Fall 2020 dropped to only 1% of the Fall 2019 visitors (pre-pandemic) (Scoulas et al., 2021b). COVID-19 also affected the major library services such as circulation of library books and in-person library workshops. Most library services had to convert to online with limited in-person interaction with patrons. The assessment plan was also affected by COVID-19. Originally, the University Library planned to conduct biennial surveys in 2020 for students to better understand their needs and use the findings to improve and measure the impact of the library's value on their academic success. Due to limited services and physical use, the plan was postponed to Spring 2021 and the survey questions were revised. The University Library determined to distribute the student biennial survey in Spring 2021 asking about experiences during the Fall 2020 semester. This paper reports whether the University Library met the strategic plan to “Create and sustain an inclusive culture and a welcoming environment for all.” It also aims to uncover how university students during the pandemic perceived their sense of belonging and inclusion in relation to the University Library as an institutional community and with respect to the library collections. In this paper, the sense of belonging within the library context can be conceptualized as students' perceptions of feeling valued and respected by library staff, and feeling accepted and a valued part of the university library through their access to and use of library spaces and collections, while their interactions can be affected by external environments (e.g., COVID-19), guided by Mahar et al. (2013). The findings will guide academic libraries to better understand why some students have a sense of belonging as part of the institutional community. Additionally, the findings can be used to further develop the University's strategic plan, determine future actions and measure their impact on students. Literature review In the research literature, sense of belonging is defined and conceptualized in various ways. For example, Tovar and Simon (2010) define this as “an individual's sense of identification or positioning in relation to a group or to the college community, which may yield an effective response” (p. 200). In a classroom context, Goodenow (1993) defined sense of belonging as “students' sense of being accepted, valued, included, and encouraged by others (teacher and peers) in the academic classroom setting and of feeling oneself to be an important part of the life and activity of the class. More than simple perceived liking or warmth, it also involves support and respect for personal autonomy and for the student as an individual.” (p. 25) However, the definitions of sense of belonging described above conceptualize one's feeling with another group or community and have some limitations of understanding how external factors or environment shape the individual's sense of belonging. Additionally, they emphasize individual's subjective feelings towards a group or community, but they overlook how the interactions between individuals and institutions are shaped or can be changed through institutional or community efforts to make them feel included or belonging. It has been pointed out that the definition of sense of belonging was used inconsistently across disciplines in the higher education. Mahar et al. (2013) conducted a systematic review of 40 articles that covered the concept of sense of belonging across multiple disciplines and identified five overarching themes to conceptualize sense of belonging. The five themes include: 1) subjectivity, referring to the individual being valued, respected and fitting in; 2) groundedness, indicating situating the individual to a referenced group, such as classrooms or the campus community; 3) reciprocity, meaning individuals sharing similar feelings, experiences or interests beyond the physical or behavioral characteristics; 4) dynamism, referring to external factors such as social and physical environments that affect their interactions; and 5) self-determination, indicating the individual's right to make decisions about belonging. Why should universities care about students' sense of belonging? There are numerous examples of research which show that students' sense of belonging has an impact not only on their academic outcomes but also on their psychological well-being: students who have a sense of belonging are likely to remain in university, because they feel accepted and valued by their peers and universities, whereas students who lack a sense of belonging are likely to experience loneliness and depression. Empirical research confirmed the relationship between students' sense of belonging and academic outcomes, such as retention or persistence with study (e.g., Stout & Wright, 2016), academic motivation (e.g., Sánchez et al., 2005), academic engagement and achievement (e.g., Zumbrunn et al., 2014) and academic self-efficacy (e.g., Holloway-Friesen, 2021); and psychological well-being, such as loneliness and depression (e.g., Fisher et al., 2015; Walton & Cohen, 2011). How do university students perceive their sense of belonging and inclusion in a university library context? Bodaghi and Zainab (2013) conducted interviews and focus groups to explore how visually impaired persons perceived and experienced sense of belonging through study carrels provided by a research university library to support their academic and social needs. The findings revealed that students perceived carrels as second homes where they could sit, feel safe and accepted, and considered carrels as a mechanism to feel a sense of belonging. In addition to feeling safe and accepted when using carrels, the university students also considered the carrels as social places where they could interact with others, including their peers. The authors concluded that “the carrels met their physical, academic, and social needs. In their second homes, these students felt safe and they believed their belongings were secure. They had privacy and experienced comfort” (Bodaghi & Zainab, 2013, p.50). Another study conducted by Griffen (2020) in a public library examined how young adults perceived a library space and its impact on their sense of belonging. The findings uncovered that young adults using the same library spaces felt belonging, independence and privacy, and library collections were important to young adults whose identity was connected to the library collections. Additionally, library staff and librarians were considered as having an important impact on patrons' sense of belonging. Bodaghi et al. (2017) interviewed visually impaired university students in Malaysia to understand how they perceived and experienced the support and behaviors of librarians. Bodaghi et al. found that participants considered librarians friendly and helpful because librarians helped them (e.g., finding books and answering questions) and the librarians' support contributed to “a feeling of being cared for, being included, and belonging to the library” (p.233). Conversely, the lack of librarians' support has a negative impact on students' attitudes towards the library and sense of belonging, such as students' being hesitant to seek help from the librarians. Librarians were also recognized as a “consult” because librarians spoke with students when they were dissatisfied with a situation or to discuss their needs and services. Students considered their consulting with librarians as being accepted and respected. At the same time, students suggested that librarians should have increased knowledge of disability awareness through various professional training for working with individuals with special needs because librarians' awareness of students' needs made them feel proud and welcomed in the library. Based on the five themes from Mahar et al. (2013) regarding the concept of sense of belonging in the context of the academic libraries, a sense of belonging can be conceptualized as students' perceptions of feeling valued and respected by library staff and feeling accepted and a valued part of the university library. At the same time, the unexpected factor, the pandemic, made the university students more isolated and resulted in less in-person interactions with their peers, professors and academic advisors. The five themes identified by Mahar et al. (2013) may guide the current uncertain and fluid context in conceptualizing the sense of belonging of university students at an urban context research university. As such, the author proposed the following research questions and covered the findings in this article. Research questions • How do students perceive sense of belonging, identity and representation in the collections in the UIC Library? • Is students' library use associated with their perceptions of sense of belonging, identity and collections in the UIC Library? • How do students perceive inclusion at their libraries? • What are the current levels of accommodation, challenges or issues? This paper is valuable to academic libraries because it reveals how university students perceive inclusion as part of the university community, in this case, the University Library, in their own words during the pandemic. Understanding how university students feel included as part of the university library and valued by library staff during the pandemic is critical to preparing for the hybrid environment and determining how the University Library reduces the gaps for students who feel a lack of being accepted or valued during this time. Methods Institutional setting UIC is a public research university consisting of 16 colleges, including health sciences colleges and Chicago's only public law school, and serves more than 31,000 students as of Spring 2021. The institution is well known as one of the most ethnically and culturally diverse universities in the United States. UIC is committed to “eliminating disparities in health, education, and economic opportunity,” and “increasing access to education, employment, programs and services for all and maintaining a barrier-free environment for individuals with disabilities” (University of Illinois Chicago (UIC), n.d.) The University Library consists of the main library, three regional health sciences libraries (Chicago, Peoria and Rockford), and a law library. Survey instrument and data collection This paper used data from the biennial student library experience survey that was conducted in Spring 2021 at UIC to examine the needs of university students, identify areas for improvement and decision making, and measure the impact of students' library use on their academic success. Five out of 13 questions were selected from the 2021 biennial students' library experience survey in this paper: a set of multiple choice questions related to students' perceptions on belonging, identity and representation in the collections at the library; frequency of library use (in-person and online); comments about inclusion using one open-ended question; and two questions concerning accommodation due to disability. The survey was distributed to the entire UIC student body of 31,332 students between February and March 2021, and a total of 3379 respondents completed the survey (response rate of 10.8%). For more information about the data collection process, please refer to Scoulas and De Groote (2021). Sense of belonging The measure of sense of belonging used in the current paper includes students' level of agreement using a five-point Likert scale from strongly agree to strongly disagree with the following items:• I feel like I belong at the UIC Library. • I feel that all aspects of my identity are respected at the UIC Library. • I feel that materials at the UIC Library reflect diverse cultural identities. Frequency of library use This question asks how often students visit the library in person and/or online from never (0) to daily (4). To examine how students' sense of belonging is associated with the types of library users, this set of questions was segmented into four groups: Group 1 (students who never visited the library in person nor used the online library); Group 2 (students who visited the library in person); Group 3 (students who used the online library); and Group 4 (students who visited the library in person and used the online library). Inclusion To measure how students perceive inclusion in the library, one open-ended question was used with the following item:• What comments do you have about inclusion in the library? Accommodation To examine whether the accommodations for students with disabilities (if needed) were met, one multiple choice question and follow up open-ended question were used.• If you required any accommodations due to a disability, were your needs met? 1) My needs were met; 2) My needs were not met; 3) I did not need any accommodations. • Please tell us more about any issues you encountered with respect to accommodations. The set of questions described above were new for the biennial student survey except for the frequency of library use and they were tested with several students to ensure the validity of the survey instrument. For more information about the procedures of survey development and full survey questions, please refer to Scoulas and De Groote (2021). Data analysis Descriptive statistics for demographics, level of agreement on the sense of belonging and crosstabs between students' library use group and their perceptions of sense of belonging were conducted in SPSS 27. Among a total of 3379 survey responses, there were 762 responses in the open-ended responses related to comments about inclusion. Any responses such as “no,” “none,” “nothing,” “no comments,” “N/A,” “not that I can think of” and “not applicable” were excluded. As a result, a total of 575 responses remained for the final analysis. Open-ended responses (students' perceptions of inclusion and accommodations) were analyzed using NVivo 12. The author reviewed open-ended responses as a whole a couple of times and then began coding using thematic analysis, examining repeated patterns and topics of meaning that appeared in the open-ended responses. Codes and themes were adjusted and revised several times in the process of reviewing. Codes and themes were reviewed by the Assessment Coordinator Advisory Committee and revised to address any unclear meanings. Final codes and themes are displayed in Table 2. Any comments related to issues and suggestions were separated and coded separately in order to share those findings with relevant stakeholders for improvement and decision-making. Results Participants Table 1 displays descriptive statistics based on the demographics of the entire university population (N = 31,332), survey respondents for all questions (n = 3379), and respondents who completed only the open-ended question related to the comments of inclusion (n = 575). This information indicates that the degree of survey samples (all survey respondents and qualitative respondents) represents the university population. Overall, the ratio of all survey participants and qualitative respondents were similar as the university population with the exceptions of class and gender. Both the survey participants (57%) and qualitative respondents (61%) are from three colleges: Liberal Arts and Sciences, Engineering and Business Administration. More than 30% of survey respondents and the qualitative respondents were White, followed by Hispanic (21% for survey respondents and 27% for qualitative respondents) and Asian (20% for survey respondents and 16% for qualitative respondents), and this ratio of race was similar to the university population. The majority of the survey respondents (92%) and qualitative respondents (92%) were commuters, which is the same percentage as the university population (92%). Regarding class, the percentage of qualitative respondents (61%) was similar to the university population (63%); however, slightly fewer undergraduate students (53%) participated in the survey. More female students completed both the survey (66%) and open-ended question related to inclusion (64%) compared to the university population (a difference of 10%). As such, survey respondents for all questions and the open-ended response, respectively, represent the university population.Table 1 Students' demographics: all survey respondents, respondents who answered “inclusion” in the open-ended question, and the institution's population Table 1College All survey responses n (%) (n = 3379) Qualitative Responses n (%) (n = 575) Population N (%) (N = 31,332) Liberal Arts & Sciences 1089 (32.2%) 218 (37.9%) 10,277 (32.8%) Engineering 517 (15.3%) 76 (13.2%) 5125 (16.4%) Business Administration 317 (9.4%) 58 (10.1%) 4005 (12.8%) College of Medicine 235 (7.0%) 23 (4.0%) 1475 (4.7%) Applied Health Sciences 178 (5.3%) 33 (5.7%) 2009 (6.4%) Nursing 167 (4.9%) 35 (6.1%) 1451 (4.6%) Architecture, Design,& the Arts 137 (4.1%) 32 (5.6%) 1244 (4.0%) Pharmacy 135 (4.0%) 13 (2.3%) 858 (2.7%) Education 131 (3.9%) 26 (4.5%) 1216 (3.9%) Law School 109 (3.1%) 13 (2.3%) 992 (3.2%) Dentistry 88 (2.6%) 10 (1.7%) 521 (1.7%) School of Public Health 82 (2.4%) 9 (1.6%) 813 (2.6%) Social Work 80 (2.4%) 11 (1.9%) 495 (1.6%) Urban Planning & Public Affairs 74 (2.2%) 12 (2.1%) 485 (1.5%) Graduate College & Extended Campus 40 (1.2%) 6 (1%) 365 (1.1%) Class Undergrad 1719 (53.0%) 348 (60.5%) 19,740 (63.0%) Grad 1483 (43.9%) 212 (36.9%) 10,559 (33.7%) Others 105 (3.1%) 15 (2.6%) 1033 (3.3%) Race White 1019 (32.8%) 173 (30.1%) 9793 (31.3%) Hispanic 714 (21.1%) 153 (26.6%) 8136 (26.0%) Asian 671 (19.9%) 93 (16.2%) 5673 (18.1%) Black/African American 233 (6.9%) 48 (8.3%) 2485 (7.9%) International 468 (13.9%) 74 (12.9%) 3525 (11.3%) Others 184 (5.4%) 34 (5.9%) 1720 (5.5%) Gender Female 2224 (65.8%) 369 (64.2%) 17,238 (55.0%) Male 1151 (34.1%) 206 (35.8%) 14,055 (44.9%) Residency Commuter 3107 (92.0%) 526 (91.5%) 28,992 (92.5%) Resident 184 (5.4%) 37 (6.4%) 1259 (4.0%) Online 88 (2.6%) 12 (2.1%) 1081 (3.5%) Pell status or transfer student Pell yes 823 (24.4%) 178 (31.0%) 9494 (30.3%) Transfer yes 60 (1.8%) 9 (1.6%) 652 (2.1%) First generation Yes 492 (14.6%) 106 (18.4%) 6250 (19.9%) Sense of belonging, identity and collection To measure the outcomes of the University Library Strategic plan of “demonstrating cultural competence in all aspects of Library services, policies, facilities and programs,” students were asked to rate the following three statements: 1) I feel like I belong at the UIC Library. 2) I feel that all aspects of my identity are respected at the UIC Library. 3) I feel that materials at the UIC Library reflect diverse cultural identities. While most of the respondents rated “agree” and “strongly agree” when asked about their feelings at the library, 22% or more of students rated “neutral” in all three areas. Among the three statements in Fig. 1 , most agreed that their identity was respected at the UIC Library. Only 2.7% of respondents rated “disagree” and “strongly disagree” in relation to being asked if materials at the UIC Library reflected diverse cultural identities.Fig. 1 Students' feeling at the libraries: Belonging, identity and library collections. Fig. 1 This response was further analyzed by race/ethnicity and library location. As shown in Fig. 2 , international and multi-race respondents were most likely to indicate that they feel that all aspects of their identity are respected at the UIC Library, whereas Black/African American respondents were the least likely to agree that library materials reflected diverse cultural identities. Among UIC libraries, students from the Library of the Health Sciences indicated the highest agreement in the area “I feel that all aspect of my identities are respected at the UIC Library,” whereas students from the law school which recently merged with John Marshall Law School indicated the lowest agreement with the statement “I feel like I belong at the UIC Library.”Fig. 2 Students' feeling at the libraries: Belonging, identity and library collections by race/ethnicity. Fig. 2 Students' library use and their perceptions on sense of belonging, identity and collection In response to the research question, “is students' library use associated with students' perceptions of sense of belonging, identities respected by their libraries and library materials reflected cultural identities?,” students' library user groups were used: Group 1 (students who never visited the library in person nor used the online library); Group 2 (students who visited the library in person); Group 3 (students who used the online library); and Group 4 (students who visited the library in person and used the online library). Fig. 3 displays the percentage of agreement level on the three areas of students' perceptions by their library use. The findings showed that Group 4 (students who visited the library in person and used the online library) were the most likely to agree on a feeling of belonging, their identities were respected by their libraries, and that collections reflected their cultural identities, followed by Group 2 (students who visited the library in person). Group 1 (students who never visited the library in person or used the online library) were the least likely to agree on a feeling of belonging, their identities were respected by their libraries, and that collections reflected their cultural identities. This finding suggests that students who actively use both the physical library building and the online library are likely to feel a sense of belonging, their identities are respected by their libraries, and that collections reflected their cultural identities.Fig. 3 Students' library use and their perceptions of belonging, identity and library collections. Note: The level of agreement in the three areas (I feel like I belong at the UIC Library, I feel that all aspects of my identity are respected at the UIC Library, I feel that materials at the UIC Library reflect diverse cultural identities) were abbreviated as “belonging,”, “identity,” and “collection.” Fig. 3 Students' perceptions on inclusion Respondents were asked an open-ended question, “what comments do you have about inclusion in the library?” A total of 575 respondents provided further feedback on this question. Four overarching themes relating to students' perceptions of inclusion at the UIC libraries were identified from the thematic analysis. Students' direct quotations with their demographics, such as race/ethnicity, gender, and program or college, were included in order to provide better context for the perceptions of students from diverse backgrounds. However, in some cases, programs were replaced by the broader designation colleges to protect the participants' confidentiality. Theme 1: library is a welcoming and inclusive environment First and foremost, a large number of the respondents commented that they felt welcomed, and the library provides an inclusive environment. For example, one White female junior who is an English major noted:“I think the UIC Library is very welcoming and inclusive. They try to make sure all students feel at home there and I appreciate that greatly. Being a part of such a large campus can be daunting but knowing I have a place where I feel I belong is comforting.” In addition to respondents feeling welcomed and included at their library, respondents also expressed other positive feelings towards the library such as “supportive,” “comfortable,” “friendly,” “safe,” “belonging,” and “respected.” For instance, one White male doctoral student who is from the College of Pharmacy noted: “The UIC Library offers a safe and inclusive environment for all students.” Due to COVID-19, some students thought they would not be allowed in the library buildings; however, they were able to enter library buildings, which enabled them to continue using the library space, and they felt welcomed. As an example, one Asian female who is a senior and major in Biological Sciences commented: “The library is a very welcoming place. Especially last semester, I thought I wouldn't be able to access the library as often I could but I was able. I always need a quiet space to study.” Among the 575 students who left their comments about inclusion, 71 respondents (12%) were freshman students. In spite of the fact that their first year experience was in the online environment and their in-person visits to the campus were limited, surprisingly, 55 respondents (77%) expressed that they felt included and comfortable. One Hispanic female freshman from the College of Liberal Arts and Sciences noted: “I feel like there is plenty of inclusion at the UIC Library to where I feel comfortable to be there and feel like I belong there.” Theme 2: COVID-19’s impact on students’ library experiences Respondents consistently expressed their experiences in the library before COVID-19 because they did not visit the library in Fall 2020 due to COVID-19. When they visited the library prior to COVID-19, they felt respected and included in the library. Students' perceptions of inclusion were mainly focused on their library experiences using the library spaces. Below are the examples of students who shared their library experiences before COVID-19.“I am currently a Senior year student at UIC, and past 3 year (before Pandemic) I use to spend most of the time studying at UIC library, it's a really quite place to study (fourth floor) and great place to collaborate too (first floor, commons ideas). I really miss being at library now since everything is online. But spending time at library will always be the most special time I spend on campus.” (male, senior, International, Engineering) “Before Covid I would go to the library often and I never felt uncomfortable no matter what. There were many different people there and the librarians were always nice and helpful so I never felt out of place or lost.” (female, sophomore, Hispanic, Engineering) “I found a prayer mat (I'm Muslim) in one corner of the library, which really surprised me, and I liked. It was also relatively easy to find specific books at the library once I asked the front desk for help. The first and fourth floors are very welcoming in being comfortable places to work and meet friends. The online database has also made it easy to find relevant articles for class. But I don't use the library's services very often, online or in-person because of the nature of my major” (female, senior, Asian, Architecture, Design and Sciences) While some respondents shared their library experiences before the COVID-19 pandemic, others also expressed that it is hard for them to comment on or judge inclusion because they did not visit the library during the Fall 2020 semester. For example, a female freshman who is from the College of Liberal Arts and Science said: “I feel as if I can't really say much due to the fact that I haven't visited the UIC Library in person.” However, due to the restrictions of the pandemic, some students felt “distant” from the library. For instance, a female Hispanic doctoral student who is from the College of Education explained how COVID-19 shaped her connection with the library: “I very much felt a part of the library prior to Covid. After Covid, the online shift has made my connection to UIC Library completely different and distant.” Also, some students expressed their hesitancy to visit the library due to their concerns of COVID-19. Others stated they want to visit or use the libraries in Fall 2021. Theme 3: factors influencing inclusion and belonging I: Diverse collections and services When expressing perspectives on inclusion, many respondents appreciated that the library provides diverse collections and services, such as online access materials and online help through Chat with a Librarian. Below are examples of quotes that describe how the library collections influence their perceptions of inclusion.“I think the library holdings reflect the variety of concerns, identities, and research topics that the UIC community members have.” (female, senior, Asian, anthropology) “I am honestly very surprised as to how inclusive the library is. I remember seeing book featured that represent marginalized groups, like LGBTQ+ and racial minorities. I felt seen and my identities were normalized. Very appreciative of all that.” (male, senior, Asian, psychology) “I really love the UIC library, it has tremendous amounts of electronic materials and easy to use after asking for librarians help.” (male, freshman, International, engineering) Some respondents found the online library services useful and made them feel included. For example: I really appreciate the IM/Online chat research help service. They always get me what I need. (female, doctoral degree, International, engineering) Never been there in person but the online seemed very friendly and inclusive. (female, freshman, White, Liberal Art and Sciences) Theme 4: factors influencing inclusion and belonging II: library staff and librarians Another important factor influencing students' sense of inclusion and belonging was library staff and librarians. In general, when they had questions, many students considered the library staff and librarians to be helpful in relation to their research or homework when they were in the library or via online chat. One Hispanic female junior student who is a finance major commented:“As a student, I feel like the library is one of the few places where librarians try their best efforts to help students succeed by going out of their way to help and make sure we are okay.” A White female doctoral student in history also expressed her genuine appreciation of the librarians as follows:“As a group, the librarians are the most consistently kind, patient and helpful people on campus.” Some respondents also acknowledged that their attitude towards the University Library had changed as a result of the librarians' instructions and workshops. One Asian female freshman student studying Psychology explained how her attitude towards the library had shifted:“At first I assumed the rules and the environment to be strict and cold since I am a freshman and college is a new experience. But after having a librarian come in and explain the UIC library to my class and I felt more welcomed and inclined to use it. To me, the library is now an inviting place that can help me with my school-related needs.” Library staff who ensured the library's safety during COVID-19 were also recognized as an important factor that influenced students' feeling welcomed and included. A Hispanic male sophomore student studying Architecture expressed his appreciation of the library staff: “Very helpful people, I want there once to ask questions about my computer program key and they helped me understand and have access to the software. they are very neat and give people lots of space and room which was good because I was afraid of Covid but the people at the UIC library made it a super safe environment.” As shown above, while most of the respondents expressed that they felt included as a part of the library, some students commented that they do not have any issues with inclusion because they have not been in the library. Some students also responded that, while the library cares about inclusion, they do not feel included because they have not been in the library or they do not have any interaction with others, while some students who did not answer that question directly did say that they appreciated being asked this question. However, a small number of respondents did not see why the library should care about inclusion. For example, one Black/African American female doctoral student who is from the College of Education commented that: “I do not view libraries as spaces needing to be inclusive as long as there is diverse media and literature.” Table 2, shown below, indicates the themes described above with examples of the codes used in the survey.Table 2 Themes of inclusion derived from the open-ended responses Table 2Themes Examples of code n Library is welcoming and inclusive environment Welcoming, supportive, inclusive, diverse, neutral, comfortable, friendly, safe, not feeling like an outsider, belonging, respect 153 Good, great, okay, positive, useful, helpful, adequate, appropriate 54 COVID-19’s impact on students' library experiences Library experience before COVID-19 56 Hard to comment or judge because I haven't visited library 36 COVID-19 impact on using library (challenges etc.) 28 Hope to visit the library soon 22 Factors influencing inclusion and belonging I: Diverse collections and services Collection and materials (good, various, diverse) 51 Online (website and chat) 24 Factors influencing inclusion and belonging II: Library staff and librarians Library, library staff and librarians, instructions, and workshops 55 Others No issue or neutral 21 Not feeling included or no inclusion 8 Why does it matter if the library is inclusive 7 Haven't thought about it or interesting to be asked 5 Issues and suggestions (n=118) When commenting on inclusion, more than 100 students (21%) addressed various issues they experienced prior to and during the pandemic and also provided some suggestions. The issues and suggestions are separated from the themes above because this allows the University Library to identify areas for improvement and decision making. Examples of codes were organized by categories and listed by frequencies: facilities, online access and website, collections, hours, staff, policies related to reservation systems and eating event services, communication and promotion, fees and tuition. Regarding facilities, respondents commented that a private room for those with children is needed, and about the slow elevator and outdated facilities. Some asked for more seating, suggesting that they may still think that the library is crowded during the COVID-19 pandemic. The second issue and suggestions were regarding online access and the library website, as students indicated that it was not easy to access and that it was hard to navigate the website even with a virtual tutorial. The third highest number of comments was about wanting more diverse books and collections related to minorities, health, history, and disability culture. Additionally, wanting longer library hours was also an issue. Only eight students commented that the Library/IT assessment (a per-semester fee all students pay) for library use is useless or wasted, that the library should reduce fees if students don't use the libraries and objected to paying the full tuition for printing privileges. Accommodations for disabilities In alignment with the UIC Library's vision of “a world of equal access to information and resources where everyone is inspired to achieve their goals,” the UIC libraries are committed to maximizing accessibility to all patrons. This new set of questions was added to identify whether the accommodations of students with disabilities (if needed) were met. As shown below in Fig. 4 , the majority of respondents (87%) across the libraries answered that they did not need any accommodations, followed by their needs were met (12%).Fig. 4 Accommodations due to disability. Fig. 4 The 43 respondents whose needs were not met were asked to provide additional feedback, and 16 students responded. To better understand their needs, their responses were categorized by areas of need: 6 responses were related to facilities (e.g., a distraction-free room was needed, they were unable to use the height-adjustable table, it was difficult to read signs in the elevator); 5 for services (e.g., hard to get answers through the online chat, receiving different answers from librarians, lack of discussion options for disabled students); and 3 for materials (e.g., physically accessing materials due to mobility issues, unable to convert print books to digital format due to COVID). Three of these issues occurred before the COVID pandemic, including difficulty finding seats or height-adjustable tables. Discussion In this paper, sense of belonging is defined as students' perceptions of feeling valued and respected by librarians, as well as feeling accepted and a valued part of the university library through their access to and use of library spaces and collections, while their interactions are influenced by external environments (e.g., COVID-19) in the library context, as guided by Mahar et al. (2013). This paper explored and measured students' perceptions on their sense of belonging and inclusion at their libraries during the COVID-19 pandemic through the online survey consisting of both multiple choice and open-ended questions. This assessment was a critical step for the University Library because this information indicates not only whether or not the University Library met the needs of students during this critical time, but also identified any gaps that hinder students' use of the library via physical library access, online library use, or interacting with library staff and librarians. When students were asked to rate their level of agreement regarding their feeling of belonging, their identities respected, and the collections are representative of diverse cultural identities, most of the students answered “agree” or “strongly agree” in all three areas. Overall, students' identity being respected by the library was the highest and students' feeling of belonging was the least likely to agree in comparison with other aspects of belonging. Among library locations, students using the law library were the least likely to agree with the sense of belonging. Given that the law library is part of a law school that recently merged with the current institution, it is possible that the library experiences of the law school students mainly remain the same; however, they may experience a lack of library “community” as part of the larger, merged institution's community. Students' sense of belonging was further analyzed by their library user groups. Interestingly, students who used both the physical and online library were the group who recorded the highest for the feeling of belonging, their identity respected, and the collections are representative of diverse cultural identities. This finding confirms that students felt belonging the most when they actively used both libraries (in-person and online). Moreover, students who only used the physical library are more likely to feel belonging than students who used only the online library. This finding implies that personal interaction with the physical library and staff has a greater impact than accessing library resources remotely via the library website. Not surprisingly, those who never visited the library or used the online library were the group that recorded the lowest sense of belonging compared to all of the other groups. While the findings above confirm that students' having a sense of belonging is related to their type(s) of library use, it is not clear whether their library use led to a sense of belonging or whether students who already felt they belonged were more likely to use its resources. Students' open-ended responses provided further insight. It is apparent that COVID-19 significantly impacted students' sense of inclusion. While many students felt welcomed and included in the library, their positive feelings occurred when they visited the library building or used the library spaces. This finding is supported by the previous study indicating that the library as a place contributed to students' feeling that it was a second home (e.g., Bodaghi & Zainab, 2013). However, the current findings revealed how external factors such as COVID-19 impacted their feeling of inclusion at their libraries. That is, some students expressed that it is hard to tell about their feeling of inclusion because they have not been in the library due to COVID-19. This finding implies that students' physical space use was an important factor that influenced students' feeling of inclusion and an external factor, in this case, COVID-19 was considered a significant hindrance to their feeling of inclusion. This finding can be explained by dynamism (e.g., social and physical environments affecting interactions), one of the themes identified by Mahar et al. (2013). COVID-19 hindered students visiting the library or using the library spaces due to safety concerns, which made students feel less connected or distant from the library. Also, students had little in-person interactions with library staff and librarians who usually were on the front line welcoming them and answering questions in the library, which resulted in their no longer feeling welcomed and included in the library when they were not using the library in-person. Due to COVID-19, most classes were transferred to the online learning environment which means students were not on campus and could no longer socialize and collaborate with their peers in library spaces; physical distancing requirements in the library also contributed to less student interaction. While students commented that they have not visited the library so they could not comment about inclusion, they also stated that they used library resources a lot and appreciated the librarians who answered their questions through the online chat. This finding indicates that, in spite of limited in-person access to the library building, they were still connected to library resources via the library website and services such as the online chat and virtual library instructions, which contributed to students' feeling supported, valued, and respected. This is valuable information because in spite of an external factor such as COVID-19 hampering students' use of library space during the pandemic, students still feel respected and valued through librarians' online support behind the scenes. This finding was supported by previous studies indicating that librarians played a significant role in creating students' sense of belonging (Bodaghi et al., 2017; Griffen, 2020). Another key finding through open-ended responses was that the university library provides diverse collections related to topics such as LGBTQ and race/ethnicity, which made them feel seen and appreciated. This finding was aligned with the findings of the study (Griffen, 2020) showing that library collections were important to young adults because they viewed their identity through the library collections including their race, culture and interests. In this study, respondents further suggested that they wanted more diverse books and collections related to minorities, health, history, and disability culture. Given that students' identity being reflected by library collections contributed to their sense of belonging (Griffen, 2020), this finding is critical to collection development for the University Library because the author's institution serves one of the most diverse student populations in the United States. Also, respondents' access to various library resources via the library website was a key factor that contributed to their feeling supported in the library. While many students commented positively about their experience using the library website to find online resources and services, such as the online chat, and felt included and supported, some students expressed that they had difficulty in accessing and navigating the website to find resources. This information is valuable for the University Library to address the website usability issue and has been shared with the Library Accessibility Working Group and Web Development Coordinator for further investigation. The results of whether the accommodations of students with disabilities (if needed) were met showed that the majority of respondents (86.6%) answered that they did not need any accommodations, and their needs were met (12%) when the respondents required accommodations. Only 1.4% (n = 43) of respondents responded that their needs were not met when they required accommodations. Based on the sixteen respondents who provided further feedback, most of them were related to using facilities (accessing tables or spaces for special needs) and services (different responses from library staff when asking questions), and three students identified issues that they encountered pre-COVID. This finding is very useful for the University Library for many reasons. Identifying issues related to accommodations is extremely valuable for the University Library to prepare for the upcoming academic year in order to meet the University Library's goal of “maximizing accessibility to all patrons.” Also, given that it is a challenge to target students with special needs and obtain their feedback, it is hard to measure and identify what concerns and issues students with disabilities have when using libraries. This information can be used as benchmarking data and set measurable outcomes for future strategic planning because it is difficult to know how we are doing and how much we should improve. In fact, this question was asked to students at the author's institution who only visited the library in-person during Fall 2020, indicating that 1% of respondents' needs were not met when they required accommodations; however, given that the previous data showed only students who visited the library, it is difficult to know whether the data represents the entire University population. For these reasons, the findings consisting of samples from all University populations (access to both the physical library and online library) are valuable and meaningful for decision-making and improvement. Last, but not least, while only a few students questioned why the library cares about inclusion, one should take into account how the efforts libraries invest to promote the library's role and its use are integral to their sense of belonging and inclusion. Previous research has shown that when students feel included, accepted, valued and respected, they are likely to persist with their studies (e.g., Stout & Wright, 2016), increase academic engagement and academic achievement (e.g., Zumbrunn et al., 2014), and feel less loneliness (e.g., Fisher et al., 2015). Implications and conclusion Exploring and measuring students' perceptions of their sense of belonging and inclusion at their libraries during the COVID-19 pandemic are more critical than ever for the University Library as it prepares to meet the needs of students and identified areas for future improvement. While there was limited access to print books and the hours of operation were shorter during the pandemic, the academic libraries served students' various needs from the physical library (e.g., using library spaces for coursework or homework, asking questions about where to find books or where to pick up books) to online resources (searching for journals and databases, requesting journals or books that are not available from the institution's library, asking questions via online chat services, and attending virtual instruction and workshops). As shown in the findings of the current study, in spite of a reduction in the use of library space due to the COVID-19 pandemic, students still perceived the library as a space where students feel welcomed, included and accepted. At the same time, due to COVID-19, students' learning environment was dramatically transformed to online and they had to adapt to attending online classes, participating in discussions without in-person interactions, and finding ways to complete homework, coursework and research by relying primarily on online resources such as the library website. The author shared students' feedback focusing on issues and suggestions with various stakeholders: The University Library's Leadership Team, the Undergraduate Engagement Program, the University Library's Accessibility Working Group, the Re-Engage working groups planning for Fall 2021, and the Collections Working Group. Given that the Library Accessibility Working Group includes representatives from the campus Disability Resource Center and the Disability Cultural Center, they would be our source to communicate directly with students with disabilities. Additionally, to better understand the specific needs of students according to library locations, the author conducted further data analysis and presented the findings to the regional locations (the health sciences libraries and law library) and discussed with them what they can prepare for each library location. This paper demonstrated how university students perceived their sense of belonging and inclusion during the pandemic and the findings revealed the areas for improving library resources and services. Given that academic libraries are preparing for the post-pandemic period, the current findings can guide them on identifying future priorities (e.g., developing and promoting programming for both physical and online library users); also, academic libraries must consider how to make students feel included when they are using online resources. Some online library users may not be familiar with the physical library building(s). For that reason, it would be helpful to provide users with more visualizations of physical spaces and the buildings when accessing library resources via the library website; this way, they will feel connected to the library. Students from the law school are familiar with their law school library's physical building and website. Since the law library does not report to the University Librarian and Dean of Libraries, however, they may not be familiar with the University Library's homepage and the physical library. To make the law students feel included, it is important to provide them with University Library tours of both the physical library and the website. Another suggestion for assisting online library users is to provide consistent, immediate and friendly responses to their questions submitted via email and online chat. The University Library provides online chat services, thereby offering longer hours to serve patrons anywhere in the world; this service was recognized as an essential library service for patrons during the pandemic, as supported by the current qualitative findings. If academic libraries already provide this service, their ongoing efforts should continue, including reviewing the chat transcripts, identifying areas where patrons encountered challenges, and offering regular training for reference librarians in order to assure quality service. With respect to Black/African American students' library experiences, the evidence from the current paper demonstrated that they were the least likely to agree that the library materials reflected diverse cultural identities. This evidence proved the importance of collections that represent Black/African American history and culture. As academic libraries increasingly experience budget limitations, however, expanding their collections could be challenging. In spite of this challenge, academic libraries should share these findings with student leadership committees and recommend expanding collections representing the Black community. If academic libraries already have diverse collections, it is important to display them more prominently and facilitate access to them. Another suggestion that makes Black/African Americans feel more included is to directly engage with the Black community through university student organizations and consider their feedback prior to implementing new programming and policies. The author's University Library values students' voices; students appreciated the University Library reaching out to them to seek their feedback in response to practices such as implementing new health safety guidelines during the pandemic (Scoulas et al., 2021a). The author's University Library is also beginning to develop a strategic plan for upcoming years, and these findings will be used for developing plans of action as well as for benchmarking data to set measurable outcomes for the strategic plan. Other academic libraries can also benefit from these findings when developing a strategic plan so their commitment to improve students' library experiences is documented and their progress is tracked through ongoing assessment. Overall, implementing the various ideas and suggestions that develop from the findings of this study may take time to put into action. Most importantly, academic libraries' persistent commitment to create a welcoming environment for all patrons is the key. CRediT authorship contribution statement Jung Mi Scoulas: Conceptualization, Methodology, Data curation, Formal Analysis, Investigation, Writing-Original draft preparation, Reviewing and Editing, Supervision, Project Administration, Visualization. Acknowledgements This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. This research was approved by the UIC Institutional Review Board (Research Protocol #:2019-1445). The author would like to acknowledge and thank her UIC Library Assessment Coordinator Advisory Committee Members for their continuing support in developing surveys and reviewing the preliminary findings. The author is especially grateful to her UIC Library colleagues, Linda Naru and Carl Lehnen, for reviewing the initial manuscript and providing their invaluable feedback, and Paula Dempsey for reviewing the revised manuscript and providing her strong support. ==== Refs References Bodaghi N.B. Cheong L.S. Zainab A.N. Riahikia M. Friendly librarians: The culture of caring and inclusion experiences of visually impaired students in an academic library Information Development 33 3 2017 229 242 10.1177/0266666916641178 Bodaghi N.B. Zainab A.N. My carrel, my second home: Inclusion and the sense of belonging among visually impaired students in an academic library Malaysian Journal of Library and Information Science 18 1 2013 39 54 Fisher L. Overholser J. Ridley J. Braden A. Rosoff C. From the outside looking in: Sense of belonging, depression, and suicide risk Psychiatry 78 1 2015 29 41 10.1080/00332747.2015.1015867 26168025 Goodenow C. Classroom belonging among early adolescent students: Relationships to motivation and achievement The Journal of Early Adolescence 13 1 1993 21 43 Griffen F.C. A space to belong: Space and a sense of belonging among teen and young adult patrons in the Fresno County public library system (Publication No. 28026009) Doctoral dissertation 2020 California State University ProQuest Dissertations and Theses Global Holloway-Friesen H. The role of mentoring on hispanic graduate students’ sense of belonging and academic self-efficacy Journal of Hispanic Higher Education 20 1 2021 46 58 10.1177/1538192718823716 Mahar A.L. Cobigo V. Stuart H. Conceptualizing belonging Disability and Rehabilitation 35 12 2013 1026 1032 10.3109/09638288.2012.717584 23020179 Sánchez B. Colón Y. Esparza P. The role of sense of school belonging and gender in the academic adjustment of latino adolescents Journal of Youth and Adolescence 34 6 2005 619 628 10.1007/s10964-005-8950-4 Scoulas J.M. Carrillo E. Naru L. Student voice in administrative decision-making: inclusive planning during the pandemic Journal of Library Administration 61 4 2021 458 475 10.1080/01930826.2021.1906554 Scoulas J.M. Carrillo E. Naru L. Assessing user experience: Incorporating student voice in libraries’ pandemic response Journal of Library Administration 61 6 2021 686 703 10.1080/01930826.2021.1947058 Scoulas J.M. De Groote S.L. University students’ library experience and its impact on their GPA during the pandemic Journal of Library Administration. 61 7 2021 813 837 10.1080/01930826.2021.1972730 Stout J.G. Wright H.M. Lesbian, gay, bisexual, transgender, and queer students sense of belonging in computing: An intersectional approach Computing in Science & Engineering 18 3 2016 24 30 10.1109/mcse.2016.45 Tovar E. Simon M.A. Factorial structure and invariance analysis of the sense of belonging scales Measurement and Evaluation in Counseling and Development 43 3 2010 199 217 10.1177/0748175610384811 University of Illinois Chicago (UIC). (n.d.). UIC about. https://www.uic.edu/about/. University of Illinois Chicago (UIC) University Library, (n.d.). UIC Library strategic plan. https://library.uic.edu/about/strategic-plan/. Walton G.M. Cohen G.L. A brief social-belonging intervention improves academic and health outcomes of minority students Science 331 6023 2011 1447 1451 10.1126/science.1198364 21415354 Zumbrunn S. McKim C. Buhs E. Hawley L.R. Support, belonging, motivation, and engagement in the college classroom: A mixed method study Instructional Science 42 5 2014 661 684 10.1007/s11251-014-9310-0

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(20)32174-7 10.1016/S0140-6736(20)32174-7 Comment Reimagining India's health system: a Lancet Citizens’ Commission Patel Vikram ab Mazumdar-Shaw Kiran c Kang Gagandeep d Das Pamela e Khanna Tarun f a Harvard Medical School and Harvard T H Chan School of Public Health, Boston, MA, USA b Sangath, Goa, India c Biocon Ltd, Bangalore, India d The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India e The Lancet, London, UK f Harvard Business School and Lakshmi Mittal and Family South Asia Institute, Harvard University, Cambridge, MA 02138, USA 10 12 2020 17-23 April 2021 10 12 2020 397 10283 14271430 © 2020 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe COVID-19 pandemic and response are having profound impacts on India's people, leading to myriad health-care challenges, a looming economic recession, and humanitarian crises.1 The long-standing need for universal health coverage (UHC) in India has been brought into sharp focus by the pandemic. The mission of the Lancet Citizens’ Commission on reimagining India's health system is to lay out the path to achieving UHC in India in the coming decade. A guiding principle for this Commission is that structural change towards UHC can only be attained through consultative and participatory engagement with the diverse sectors involved in health care and, most importantly, with India's citizenry. We expect that the Commission will formulate a roadmap for realising a resilient health system that offers comprehensive, accountable, accessible, inclusive, and affordable quality health care to all citizens in India. Although we recognise the important role that social determinants have in influencing health, the focus of the Commission will be on the architecture of India's health system. Health care in India was in dire need of reform long before the COVID-19 pandemic. Despite considerable progress across health indicators such as maternal and infant mortality, disease burden in India is disproportionately high, less than two-thirds of children were fully immunised in 2017–18,2 and malnutrition and other risk factors for disease and injury are widespread.3, 4 The pandemic has highlighted structural weaknesses in India's health system, ranging from inadequate medical supplies and insufficient numbers of health-care workers in public hospitals5 to irrational treatments and profiteering by private hospitals.6, 7 Out-of-pocket payments for health care in India continue to be among the leading causes of poverty for many households.8, 9 In a country with low public spending per capita on health care relative to its middle-income peers,10 the COVID-19 pandemic has further eroded an already fragmented health system.11 The situation is exacerbated by structural inequities of caste, class, gender, geography, and community in India that translate into health inequalities and are amplified by the state of the health system. Poor and marginalised populations, particularly children, adolescents, and older people, among others, are more likely to suffer than the wealthy when afflicted by the same health condition. An estimated 400 million people could fall deeper into poverty12 in the coming year as India's gross domestic product contracts by a projected 10·3%.13 The pandemic could worsen health disparities since much of the public health system has been redeployed in the COVID-19 response, disrupting routine health services. Data from India's National Health Mission showed there was a 64% decrease in child immunisation, a 50% drop in BCG vaccinations, and a 39% fall in oral polio immunisation in April, 2020, compared with January, 2020.14 At the heart of this crisis is the lack of accountability of the health system and a breakdown of trust between the public and the health system. A broad societal coalition is needed to remedy this trust deficit by working towards an adequately resourced and well governed system that responds to the health needs of all sections of India's population. Dating at least as far back as the 1943 Bhore Committee, many expert committees, a 2011 Series in The Lancet,15 a High-Level Expert Group on UHC constituted by the Indian Government, and government national health policies in 1983, 2002, and 2017 have wrestled with the challenges of delivering quality health care in India. Our Commission will build on this important body of work and is guided by four principles of UHC. First, UHC covers all health concerns. Second, it includes the prevention of mental and physical health problems and long-term care, not only clinical treatment. Third, financial protection must be in place for all health-care costs, beyond health insurance cover for hospitalisation for a section of the population. Fourth, the UHC vision aspires to a health system that can be accessed by all people who enjoy the same quality of care. Underpinning the Commission's work is a normative commitment to strengthening India's public health system in all its dimensions, including promotive, preventive, and curative care. The state must take a leadership role as provider, financier, regulator, and steward of the health system. But for the state to fulfil this role, it must grapple with the complex and fragmented architecture of India's health system. Key questions include: negotiating the intersections and complementarities between public and private health provision and the design of a regulatory structure that holds each component of the health system accountable; addressing the role of traditional systems of medicine;16 negotiating the federal dimensions and associated heterogeneity of health systems’ capacity across India's states to articulate the distinctive roles and responsibilities of the central, state, and local governments in delivering and regulating health care; and building health system capacity for enabling and regulating the use of technology in a way that supports and strengthens health delivery while protecting citizens’ rights. There are inherent tensions across these domains that need careful negotiation. The Commission will seek to unpack these tensions to identify the core principles of a health system that is inclusive, equitable, and accountable for the provision of quality health care. This Commission will base its recommendations on a consultative and participatory effort that brings together key stakeholders across India's health-care landscape. The Commissioners include leaders from diverse sectors, including academia, the scientific community, civil society, and the private health-care industry, with a strong representation of women. We also recognise it is necessary to go beyond the traditional boundaries of expertise to actively engage stakeholders whose voices have rarely been heard in previous reports: those who deliver health care and those who receive it. Thus, we frame our goal as a Citizens’ Commission that will invite and elicit the opinions of medical providers, hospital chiefs, front-line and primary health-care workers, and a wide cross-section of people from diverse socioeconomic backgrounds. The Commission will enable participatory public engagement to develop a citizens’ blueprint for the implementation of UHC. The work of the Commission could also serve as the foundation for propelling a citizens’ movement to demand the practical realisation of the aspiration of health as a fundamental right. To this end, we now launch the Lancet Citizens’ Commission website and invite any persons or organisations who wish to contribute or partner in this initiative to contact us through the website. While the COVID-19 pandemic has shown that health care is a crucially important investment for the economy, such an investment must be accompanied by a social compact that all Indians must have access to a similar quality of care without the risk of impoverishment. Health care cannot be viewed through the prism of charity for the poor and a commodity for the rich, but as an essential, fundamental element of sustainable development for the entire nation. The deep, historical, and structural problems that have afflicted health care in India must be addressed and the Lancet Citizens’ Commission aims to make recommendations that can improve the country's ranking among the world's health systems.17 Our Commission seeks to work with citizens, those who work in the health system, and the Indian Government to realise this aspiration. We aim to publish our Commission's report by Aug 15, 2022, when India will have completed its 75th year as an independent nation. VP is a founder of Librum, a mental health consulting firm, and co-founder of Sangath, India. KM-S is the Chairperson and Managing Director of the biopharmaceutical company Biocon. TK is a co-founder of Jana Care, a chronic disease diagnostics company but does not have any operating role or board stewardship role in the company. GK serves on the Boards of the Coalition for Epidemic Preparedness Innovations and Hilleman Laboratories Pvt Ltd. PD declares no competing interests. VP, KM-S, GK, and TK are the Co-Chairs of this Commission. We thank Shyamli Badgaiyan and Shubhangi Bhadada for their support in the launch of this Commission and help in the preparation of this Comment. Funders who have committed to support this Commission so far include the Azim Premji Foundation, Rohini Nilekani Philanthropies, Vikram Kirloskar, and The Lakshmi Mittal and Family South Asia Institute, Harvard University. The Commissioners of the Lancet Citizens’ Commission are: Yamini Aiyar (President and Chief Executive, Centre for Policy Research), Mirai Chatterjee (Director, Social Security Team, Self-Employed Women's Association [SEWA]), Armida Fernandez (retired professor of neonatology and Dean, Lokmanya Tilak Municipal Medical Hospital and College, Mumbai; Founder Trustee of SNEHA), Yogesh Jain (public health physician, Chhattisgarh), Gagandeep Kang (Co-Chair), Kiran Mazumdar-Shaw (Co-Chair), Nachiket Mor (visiting scientist, The Banyan Academy of Leadership in Mental Health), Poonam Muttreja (Executive Director, Population Foundation of India), Vikram Patel (Co-Chair), Bhushan Patwardhan (Distinguished Professor, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University; Vice Chairman, University Grants Commission; Chairman Additional Charge, Indian Council of Social Science Research, New Delhi), K Sujatha Rao (former Secretary of Health and Family Welfare, Government of India), K Srinath Reddy (President, Public Health Foundation of India), Sharad Sharma (Co-founder, iSPIRT Foundation), Devi Shetty (Chairman, Narayana Hrudayalaya Limited), S V Subramanian (Professor of Population Health and Geography, Harvard Center for Population and Development Studies and Department of Social and Behavioral Sciences, Harvard T H Chan School of Public Health), and Rajani Ved (former Executive Director, National Health Systems Resource Centre). ==== Refs References 1 The World Bank India development update, July 2020 2020 The World Bank Washington, DC 2 National Statistical OfficeMinistry of Statistics and Programme ImplementationGovernment of India NSS 75th Round (July 2017–June 2018) 2020 Ministry of Statistics and Programme Implementation New Delhi 3 Kurian OC Suri S Weighed down by the gains: India's twin double burdens of malnutrition and disease 2019 Observer Research Foundation New Delhi 4 Indian Council of Medical ResearchPublic Health Foundation of IndiaInstitute for Health Metrics and Evaluation India: health of the nation's states. The India State-Level Disease Burden Initiative 2017 Indian Council of Medical Research, Public Health Foundation of India, Institute for Health Metrics and Evaluation New Delhi 5 Balarajan Y Selvaraj S Subramanian SV Health care and equity in India Lancet 377 2011 505 515 21227492 6 Muraleedharan V Vaidyanathan G Sundararaman T Dash U Ranjan A Rajesh M What do NSSO 71st and 75th rounds say? Invest more in public healthcare facilities Econ Politic Wkly 55 2020 53 60 7 Kasturi A Challenges to healthcare in India—the five A's Indian J Commun Med 43 2018 141 143 8 Pandey A Ploubidis GB Clarke L Dandona L Trends in catastrophic health expenditure in India: 1993 to 2014 Bull World Health Organ 96 2018 18 29403097 9 Selvaraj S Farooqui HH Karan A Quantifying the financial burden of households' out-of-pocket payments on medicines in India: a repeated cross-sectional analysis of National Sample Survey data, 1994–2014 BMJ Open 8 2018 e018020 10 The World Bank Current health expenditure per capita https://data.worldbank.org/indicator/SH.XPD.CHEX.PC.CD 2020 11 Patel V Parikh R Nandraj S Assuring health coverage for all in India Lancet 386 2015 2422 2435 26700532 12 International Labour Organization ILO Monitor COVID-19 and the world of work. Updated estimates and analysis https://www.ilo.org/wcmsp5/groups/public/---dgreports/---dcomm/documents/briefingnote/wcms_740877.pdf April 7, 2020 13 International Monetary Fund World economic outlook update https://www.imf.org/en/Publications/WEO/Issues/2020/09/30/world-economic-outlook-october-2020 October 2020 14 Shukla A COVID-19 effect: massive disruption in routine health services; child immunisation, treatment for critical ailments worst-hit. CNBCTV18 https://www.cnbctv18.com/healthcare/covid-19-effect-massive-disruption-in-routine-health-services-child-immunisation-treatment-for-critical-ailments-worst-hit-6760031.htm Aug 28, 2020 15 Reddy KS Patel V Jha P Towards achievement of universal health care in India by 2020: a call to action Lancet 377 2011 760 768 21227489 16 Patwardhan B Tillu G Universal health coverage and AYUSH systems J Ayurveda Integrative Med 9 2018 1 17 Tandon A Murray CJ Lauer JA Evans DB Measuring overall health system performance for 191 countries 2000 World Health Organization Geneva

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==== Front Urology Urology Urology 0090-4295 1527-9995 Published by Elsevier Inc. S0090-4295(21)01202-4 10.1016/j.urology.2021.11.038 Article EDITORIAL COMMENT Javier-DesLoges Juan Monga Manoj Derweesh Ithaar ⁎ Department of Urology, UC San Diego School of Medicine, La Jolla, CA ⁎ Address correspondence to: Ithaar Derweesh, M.D., Department of Urology, Moores UCSD Cancer Center, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA 93093-0987. 27 5 2022 5 2022 27 5 2022 163 7980 18 6 2021 2 11 2021 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAs Williams and Talwar comment, policy surrounding telemedicine is forthcoming and needed. During the initial emergence of COVID-19 the Center for Medicare and Medicaid Services (CMS) temporarily expanded insurance coverage to include telemedicine.1 Similarly, most private insurances followed the path of CMS and expanded their coverage as well. CMS is finalizing their policy to extend telemedicine coverage into 2023 as many private insurances are doing the same. 1 While coverage is being extended, it remains unclear if this coverage will be permanent, and whether or not telemedicine will continue to offer fair and equitable reimbursements for services. 2 It is clear from our study that telemedicine can be effectively rolled out in a clinical setting and reach a broad population of patients, and while disparities exist, this should not deter providers from implementing telemedicine into their practice. While most of existing literature on telemedicine has focused on access and satisfaction, further study is needed into outcomes in urology. If future data can support that outcomes are equivalent to in-person visits, then this would further support legislative efforts to maintain telemedicine as a permanent fixture of the urologic care delivery pathway and reach at-risk patients. Financial Disclosure: The authors declare that they have no relevant financial interests. ==== Refs REFERENCES 1 CY 2022 medicare physician fee schedule final rule extends telehealth benefits. JD Supra. Accessed December 13, 2021.https://www.jdsupra.com/legalnews/cy-2022-medicare-physician-fee-schedule-2997542/ 2 Telehealth should be lasting care mode, not a temporary measure | American Medical Association. Accessed December 13, 2021.https://www.ama-assn.org/practice-management/digital/telehealth-should-be-lasting-care-mode-not-temporary-measure

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Urology. 2022 May 27; 163:79-80

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10.1016/j.urology.2021.11.038

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==== Front Rev Malad Respir Actual Rev Malad Respir Actual Revue Des Maladies Respiratoires Actualites 1877-1203 1877-122X SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS S1877-1203(22)00769-8 10.1016/S1877-1203(22)00769-8 Bpco et Maladies Respiratoires Obstructives BPCO et infection à SARS CoV2 Pontier-Marchandise S. 1* 1 Service de Pneumologie – Unité de Soins Intensifs Respiratoires et de Post-Urgences Respiratoires, Hôpital Larrey, CHU de Toulouse, Toulouse, France * Correspondance. Adresse e-mail : Pontier.S@chu-toulouse.fr (S. Pontier-Marchandise). 15 12 2022 12 2022 15 12 2022 14 2 2S4042S407 Copyright © 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS All rights reserved. 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIntroduction Depuis 2 ans, beaucoup de choses ont été écrites sur la pandémie à SARS CoV2. Nous commençons maintenant à avoir un peu plus de recul notamment sur l’impact de l’infection sur les maladies respiratoires chroniques, au premier rang desquelles la BPCO. Nous rapportons ici des données sur l’impact de l’infection chez les patients porteurs de BPCO. La BPCO est-elle un facteur de risque de gravité d’une pneumonie à SARS CoV2 ? Un temps évoquée, la susceptibilité particulière des patients porteurs de BPCO à être infectés par le SARS CoV2 reste une question en suspens. De même, le fait d’avoir une BPCO est souvent considéré comme un facteur de risque d’infection sévère ou, tout au moins, d’être hospitalisé. Là encore, les données sont discordantes, en grande partie en raison du caractère partiel et rétrospectif des nombreux travaux publiés [1]. Néanmoins, une vaste étude prospective de cohorte a montré une proportion loin d’être négligeable de BPCO (19 %) parmi les patients hospitalisés [2]. De même, une étude réalisée en soins primaires rapportait la BPCO comme un facteur de risque indépendant d’hospitalisation des patients COVID-19 [3]. Lors de cet ATS, Toppen et al. [4] ont rapporté une analyse rétrospective monocentrique dans laquelle les patients identifiés comme BPCO (122 patients sur 1 831 patients inclus dans la base) ne présentaient pas de pronostic plus défavorable (mortalité, hospitalisation en réanimation, recours à la ventilation mécanique) après ajustement sur l’âge, les comorbidités et le statut tabagique. Les seuls éléments significatifs étaient la consommation d’oxygène (odds-ratio (OR) = 3,62, p = 0,01) et la durée de séjour (12,5 ± 1,2 jours vs 9,6 ± 0,3 jours, p = 0,02). Myers et al. [5] ont réalisé une étude rétrospective portant sur des patients inscrits dans le système de santé de Californie du Nord (« Kaiser Permanente Northern California ») identifiés comme ayant une BPCO (2 codages BPCO sur les 3 dernières années) et une PCR positive pour le SARS CoV2. Sur plus de 19 000 patients de plus de 40 ans présentant une infection COVID-19, 697 (3,6 %) avaient une BPCO. Ils étaient plus âgés que les non BPCO (69 ans vs 53 ans, respectivement), plus souvent fumeurs ou ex-fumeurs (64,9 % vs 25,4 %) et présentaient plus fréquemment des comorbidités : diabète (58,5 % vs 26,1 %), hypertension artérielle (HTA) (59 % vs 23,1 %), obésité (24,8 % vs 9,3 %), insuffisance rénale (24,1 % vs 4,6 %). Les patients BPCO avaient plus souvent une pneumopathie (49 % vs 18,4 %), une dyspnée (71,1 % vs 20,5 %) et un apport en O2 dans l’année précédant l’infection (11,6 % vs 2 %). Ce travail présente un certain nombre de limites au 1er rang desquelles l’absence d’évaluation des stades de gravité de la BPCO et le flou entourant le diagnostic de BPCO (codage, pas de notion de fonction respiratoire). Il y avait parmi les patients hospitalisés, plus de patients BPCO (37,8 % vs 13,9 %) et plus de décès dans cette population (26,7 % vs 16,6 %). Mais, après ajustement sur l’âge et les comorbidités, il n’était plus retrouvé de différence en ce qui concerne les taux d’hospitalisation et de décès. La seule population dans laquelle une différence était maintenue était celle des patients sous oxygénothérapie de longue durée [5]. Un autre travail a pu retrouver un taux d’hospitalisation comparable pour les patients BPCO indépendamment de leur stade de gravité (uniquement apprécié sur l’utilisation des traitements inhalés, sans notion d’oxygénothérapie au long cours) [6]. Impact du COVID-19 sur la prise en charge de la BPCO Nous avons été nombreux à constater le faible nombre d’hospitalisations des patients porteurs de BPCO au moment des « vagues » de SARS CoV2 et plus spécifiquement lors des confinements. Les effets de la distanciation physique, de même probablement d’une moindre pollution atmosphérique ont été suggérés [7]. À partir d’une étude rétrospective, une équipe du Texas a pu montrer une diminution significative des exacerbations en général (645 pendant la période de confinement entre le 1er avril et le 1er juin 2020 vs 1 323 pendant la période de pré-quarantaine entre le 20 janvier et le 31 mars 2020), des exacerbations d’origine virale (0,6 % vs 8,2 %, p < 0,0001) [8]. Le travail détaille aussi la comparaison entre les patients hospitalisés entre avril et juin 2019 (période P1) et entre avril et juin 2020 (période P2) [8]. Deux cent vingt-deux patients durant P1 et 175 durant P2 ont été hospitalisés pour une exacerbation aiguë de BPCO (EA-BPCO). Les patients étaient discrètement plus jeunes durant P2 (60 ± 10,9 ans vs 70,9 ± 11,7 ans, p = 0,008), et plus souvent des noirs américains (20 % vs 9,5 %, p < 0,0001). La mortalité durant P2 était significativement plus élevée (4 % vs 2,7 %, p = 0,0023). Les auteurs rapportaient une diminution très nette des biomarqueurs viraux dans l’arbre bronchique (1,9 % vs 31,6 % durant P1, p < 0,0001) ainsi qu’une identification virale nettement moins importante (98,1 % de prélèvements négatifs lors de P2 vs 68,4 % durant P1, p < 0,0001). Ceci souligne bien l’impact positif de la distanciation physique dans cette population spécifique. Les patients porteurs de pathologies respiratoires (asthme ou BPCO) ont aussi reporté plus volontiers, voire renoncé à des soins en urgence en raison de la pandémie. Certaines de ces données sont rapportées dans le tableau 1 [[9], [10], [11], [12]]. Muellerova et al. [13] ont rapporté les résultats d’un travail ancillaire de l’étude « NOVELTY » [14], une étude prospective portant sur des patients asthmatiques ou porteurs de BPCO dans 18 pays. La comparaison entre les exacerbations diagnostiquées par les médecins (prescriptions de corticostéroïdes systémiques, d’antibiotiques ou hospitalisations) pendant la période 1 pré-COVID (janvier – décembre 2019) et la période 2 per-COVID (janvier – décembre 2020) est rapportée dans le tableau 2. Donnée intéressante, les évènements rapportés par les patients diminuaient également (sous-entendant ainsi un effet bénéfique de la distanciation physique) mais de façon moins importante (11 % en moyenne). Ceci souligne donc très probablement la réticence de ces patients à consulter durant la période pandémique.Tableau 1 Études rapportant des reports ou des annulations de consultations ou d’hospitalisations en rapport avec une exacerbation aiguë de BPCO durant la pandémie COVID-19. Tableau 1Fazio et al. [9] Étude déclarative sur les reports et annulations de consultations 31 568 patients ayant répondu à l’enquête dont 3 916 patients asthmatiques ou BPCO Retard (34,6 % vs 25,9 %, p < 0,001 ) ou renoncement à une consultation en urgence (24,3 % vs 15,4 %, p < 0,001) Kendzerska et al. [10] Descriptions des causes de décès, hospitalisation, consultation en urgence dans la période mars 2020–mars 2021 en comparaison avec les périodes similaires en 2016 – 2019 Diminution de toutes les consultations aux urgences pour asthme et BPCO Bogart et al. [11] Étude rétrospective sur 139 994 patients BPCO Comparaison avril 2020 vs avril 2019 Diminution des consultations (-43,8 %), admissions aux urgences (-46,9 %), des hospitalisations (-44,3 %) Fraughen et al. [12] Étude déclarative sur 184 patients porteurs d’un emphysème avec déficit ZZ en α1 anti-trypsine 114 sujets ont répondu Les hommes avaient une atteinte plus sévère (VEMS moyen 52,8 %) que les femmes (73,5 %) Hommes : 0,92 exacerbations vs 1,56 l’année précédente Femmes : pas de différence significative Pas de différence sur les hospitalisations (mais taux initial bas) Tableau 2 Évènements rapportés par les médecins pour exacerbations d’asthme et de BPCO entre les périodes pré et per-COVID-19. (d’après [9]). Tableau 2 Période 1 01/01/2019 – 31/12/2019 Période 2 01/01/2020 – 31/12/2020 Asthme (n = 3 855) Tous les évènements 0,36 0,18 Corticostéroïdes 0,24 0,12 Antibiotiques 0,46 0,22 Hospitalisation 0,08 0,03 BPCO (n = 2 397) Tous les évènements 0,45 0,25 Corticostéroïdes 0,31 0,17 Antibiotiques 0,32 0,17 Hospitalisation 0,10 0,05 Les chiffres représentent le nombre moyen d’évènements ou de prescriptions médicamenteuses par patient et par an. La fonction respiratoire après le COVID-19 De nombreux patients décrivent des symptômes respiratoires dans les suites d’une infection par le SARS CoV2. Plusieurs équipes ont essayé d’en faire la description et on retrouve fréquemment une atteinte de la DLCO aux explorations fonctionnelles respiratoires. Dans l’ensemble de ces travaux, il est cependant difficile de faire la part des choses entre une atteinte respiratoire préalable à l’infection et méconnue, les séquelles classiques et habituelles d’une pneumonie voire d’un SDRA de toute origine, et un retentissement propre au SARS CoV2. Nous rapportons ici les travaux de 2 équipes ayant porté sur des patients qui avaient déjà eu une évaluation respiratoire avant leur infection virale. Edmonds et al. [15] ont réalisé une étude portant sur 88 patients ayant déjà eu une exploration du souffle avant l’infection (en moyenne 208 jours avant (91–580)) puis ré-explorés après le COVID-19 (120 jours (69–168). Les patients étaient plus souvent des femmes (n = 57, 65 %), d’âge moyen 56,3 ans (44–66), avec un index de masse corporel (IMC) moyen de 29,5 kg/m2 (25–35). Les comorbidités principales étaient les suivantes : HTA (49 %), asthme (44 %), immunodépression (38 %), maladie interstitielle pulmonaire (35 %) et transplantation (23 %) sans que l’organe transplanté ne soit précisé. Soixante-sept patients (76 %) ont fait une infection légère à modérée, 21 (24 %) une infection sévère. L’hospitalisation a été nécessaire pour 34 (39 %) d’entre eux. Fait important, l’infection par le SARS CoV2, quel que soit son stade de gravité, n’a pas entrainé de modification de la fonction respiratoire (CVF, VEMS, VEMS/CVF, VR ou CPT). Par contre, était observée une altération significative de la DLCO (en moyenne –9,5 % [-14 % à –4,8 %], p = 0,0002), particulièrement chez les patients ayant fait une atteinte sévère (-19 %, [-30 % à –8 %], p = 0,0023). Les modifications les plus importantes de la DLCO étaient liées à la sévérité de l’infection (OR = 0,92, p = 0,015), à la nécessité d’une hospitalisation (OR = 0,093, p = 0,019), à la nécessité d’une oxygénothérapie au décours (OR = 0,93, p = 0,0112), à la nécessité d’un traitement par remdesivir (OR = 0,94, p = 0,036) ou par déxaméthasone (OR = 0,91, p = 0,0098) [11]. Il faut toutefois souligner le profil très spécifique des patients inclus qui pour la plupart présentaient une pathologie respiratoire (dont 35 % de pathologie interstitielle préalable) ou une immunosuppression. Sur une petite cohorte de 56 patients porteurs de pathologie respiratoire pré-existante (30 asthmatiques et 8 BPCO), Daouk et al. [16] ont réalisé des explorations fonctionnelles respiratoires 218 jours en moyenne après l’infection par le SARS CoV2. Il était retrouvé de façon surprenante une augmentation du VEMS de 3,1 % de la valeur prédite entre la période pré et post-COVID sans que cela ne soit significatif pour la population générale. Par contre, le VEMS augmentait davantage chez les patients BPCO que chez les autres (+ 4,7 % vs 2,8 %, p = 0,04). La DLCO diminuait de 7,6 % sans que cela ne soit significatif (p = 0,4). Il est néanmoins difficile de tirer des conclusions de ces résultats, étant donné le faible effectif de patients BPCO et l’absence d’évaluation précise de la sévérité de l’atteinte respiratoire. L’oxygénothérapie à domicile a, comme chacun le sait, connu un rebond de prescription durant la pandémie. Un certain nombre de patients a ainsi dû sortir d’hospitalisation avec de l’oxygène pour une durée plus ou moins importante. Kim et al. [17] ont ainsi mené une étude pour essayer de mieux caractériser cette population. Il s’agissait d’une étude rétrospective, menée entre octobre et décembre 2020, portant sur 210 patients hospitalisés pour COVID-19. Soixantequatre d’entre eux (30 %) sont donc sortis sous oxygène. Ces patients étaient plus souvent porteurs d’une BPCO (28 % vs 14 %) ; ils avaient de façon logique présenté une forme plus sévère de COVID-19 avec un recours plus fréquent à la ventilation mécanique ou aux stratégies d’oxygénation non invasives (39 % vs 11 %), aux corticostéroïdes (97 % vs 73 %) ou au remdesivir (63 % vs 35 %), et avaient eu une durée d’hospitalisation plus prolongée (6 jours vs 4 jours en moyenne, p < 0,01). L’oxygénothérapie n’a été arrêtée que chez 12 patients (23 %) dans les 60 jours suivant la sortie. Il faut surtout souligner, chez ces patients, un relatif « abandon » puisque 34 (65 %) d’entre eux étaient encore en attente de consultation (3 mois après) et que seuls 12 (33 %) avaient reçu le conseil de surveiller leur saturation en oxygène. Conclusion La pandémie à SARS CoV2 a soulevé de nombreuses difficultés dans les différents systèmes de santé. La prise en charge habituelle des maladies chroniques a été mise à mal. S’il est difficile d’affirmer que la BPCO est un facteur de risque de forme plus sévère de COVID-19, elle est néanmoins généralement associée à bon nombre de comorbidités rendant nos patients particulièrement fragiles. Ils sont logiquement considérés comme à risque et prioritaires lors des différentes campagnes vaccinales permettant au moins de limiter les formes graves et les hospitalisations en réanimation. La pandémie et les différents confinements qui en ont découlé ont montré une nette diminution des infections virales, et ainsi des exacerbations que nous connaissons régulièrement. Cela aura très probablement permis d’apprendre à nos patients (et peut-être aussi à nous-même) l’intérêt de la distanciation et des mesures d’hygiène (hygiène des mains, masque, distanciation physique) dans leur prévention. À nous pneumologues de les inciter à garder les « bonnes » habitudes permettant de limiter la diffusion virale ! À nous aussi de nous organiser pour garder le contact avec nos patients chroniques en cas de nouvelle pandémie… Liens d’intérêts S. Pontier-Marchandise déclare n’avoir aucun lien d’intérêt pour cet article. Cet article fait partie du numéro supplément Congrès annuel de l’American Thoracic Society 2022 réalisé grâce au soutien institutionnel apporté par GSK à la mission post ATS de la SPLF. ==== Refs Références 1 Halpin DMG Criner GJ Papi A Singh D Anzueto A Martinez FJ Agusti A Global initiative for the diagnosis, management, and prevention of chronic obstructive lung disease. The 2020 GOLD science committee report on COVID-19 and chronic obstructive pulmonary disease Am J Respir Crit Care Med 203 2021 24 36 33146552 2 Docherty AB Harrison EM Green CA Hardwick HE Pius R Norman L Holden KA Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study BMJ 369 2020 m1985 32444460 3 Hippisley-Cox J Young D Coupland C Channon KM Tan PS Harrison DA Rowan K Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people Heart 106 2020 1503 1511 32737124 4 Toppen W Ya P Markovic D Fulcher J Shover C Buhr R Tashkin DP Clinical outcomes in hospitalized COVID-19 patients suffering from COPD Am J Respir Crit Care Med 205 2022 A2782 5 Myers LC. Murray RK Donato B Liu V Kipnis P Shaikh A Helder J. Risk of hospitalization for coronavirus disease 2019 in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med 205 2022 A5097 6 Rothnie K Bancroft T Bogart M Gelwicks S Bengtson L Cole A Ismaila A Trends in COVID-19 incidence among patients with chronic obstructive pulmonary disease (COPD) in 2020: a population-based study in the United States Am J Respir Crit Care Med 205 2022 A3132 7 Alqahtani JS Oyelade T Aldhahir AM Mendes RG Alghamdi SM Miravitlles M Mandal S Reduction in hospitalised COPD exacerbations during COVID-19: A systematic review and metaanalysis PLoS One. 16 2021 e0255659 34343205 8 Subramanian A Acton T O’Connor S Mamawala M Ettlinger J Ghamande S Boethel C Impact of social distancing during the SARS-CoV-2 pandemic on the association between viral respiratory illness and COPD exacerbations Am J Respir Crit Care Med 205 2022 A1698 9 Fazio J C Buhr R. Delay and avoidance in care among asthma and COPD patients during the COVID-19 pandemic Am J Respir Crit Care Med 205 2022 A1068 10 Bogart M Han X Bengtson L Rothnie K Gelwicks S Bancroft T Cole A Impact of the COVID-19 pandemic on health care resource utilization (HCRU) and costs in chronic obstructive pulmonary disease (COPD) in the United States: a population-based study Am J Respir Crit Care Med 205 2022 A1304 11 Kendzerska T Fitzgerald JM Zhu DT Pugliese M Manuel D Sadatsafavi M Povitz M Longer term health system response to the COVID-19 pandemic on the management of respiratory conditions Am J Respir Crit Care Med 205 2022 A1066 12 Fraughen D McGoldrick K Carroll T Herron M Alhaddah L Casey M Murphy M The effect of cocooning on patient-reported pulmonary exacerbation frequency in A ZZ alpha-1 antitrypsin deficient Irish population Am J Respir Crit Care Med 205 2022 A1292 13 Muellerova H Hughes R Fenby B Keen Fredriksson C de Miquel G Emmas C Rapsomaniki E Impact of the COVID-19 pandemic on exacerbation rates in patients with asthma and/or chronic Obstructive Pulmonary Disease in the NOVELTY study Am J Respir Crit Care Med 205 2022 A5098 14 Reddel HK Vestbo J Agustí A Anderson GP Bansal AT Beasley R Bel EH Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort Eur Respir J 58 2021 2003927 33632799 15 Edmonds PJ Watchmaker J Kerchberger VE Sevin CM. Pulmonary function before and after COVID-19 in a mid-south US cohort Am J Respir Crit Care Med 205 2022 A3911 16 Daouk A Shammaa Y Chalhoub M n. Effect of COVID-19 on pulmonary function testing among adult survivors with pre-existing lung disease Am J Respir Crit Care Med 205 2022 A3910 17 Kim YJ Ziauddin L Delisa JA Krishnan JA Alvi S Chung YC Kaul M Oxygen status following hospitalization with coronavirus disease 2019 (OXFORD) Am J Respir Crit Care Med 205 2022 A2688

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Rev Malad Respir Actual. 2022 Dec 15; 14(2):2S404-2S407

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==== Front Journal of Academic Librarianship 0099-1333 0099-1333 Elsevier Inc. S0099-1333(21)00140-3 10.1016/j.acalib.2021.102449 102449 Article Love Data Week in the time of COVID-19: A content analysis of Love Data Week 2021 events Rod Alisa B. a⁎ Isuster Marcela Y. b Chandler Martin c a McGill University Library, 550 Sherbrooke Street West, West Tower, 6th floor, Montreal, Quebec H3A 1B9, Canada b McGill University Library, 3459 McTavish Street, Montreal, Quebec H3A 0C9, Canada c Cape Breton University Library, 1250 Grand Lake Road, Sydney, Nova Scotia B1M 1A2 ⁎ Corresponding author. 8 9 2021 12 2021 8 9 2021 47 6 102449102449 23 7 2021 27 8 2021 27 8 2021 © 2021 Elsevier Inc. All rights reserved. 2021 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. A primary role for data-focused librarians is building community through traditional and novel modes of in-person outreach, including consultations, training, and themed events such as Love Data Week. Unfortunately, the COVID-19 pandemic rendered in-person events impossible. However, Love Data Week 2021 persisted in an online format, allowing data-focused librarians a unique chance to initiate outreach to geographically dispersed constituents. In this study, the authors investigate the nature and context of Love Data Week 2021 events to gain insight into current research data services trends, as impacted by the global COVID-19 pandemic. The authors collected qualitative information about 242 Love Data Week 2021 events across 37 organizations and coded the information using manual content analysis. This paper reports on descriptive results from the content analysis, including the dominant topics across events (software or digital tools, research data management, and service or product awareness) and the primary mode of events (workshops). The authors discuss implications for future research on Love Data Week and themed weeks in general as successful modes of outreach, community-building, and as venues for tracking emerging trends in the context of research data services. Keywords Love data week Research data Data librarianship Research data services ==== Body pmcIntroduction Love Data Week is an annual international celebration dedicated to raising data awareness and building a community interested in issues related to data, such as research data management, data sharing, preservation, reuse, dissemination, and library-based research data services. Love Data Week is usually hosted by academic libraries and research centers, but it is not limited to those organizations. Love Data Week 2021, which was held between February 8th and 12th in 2021, presented an interesting challenge for hosts as the COVID-19 pandemic made in person events less feasible. However, hosts rose to the challenge and offered a variety of engaging virtual events. As the authors were organizing their own Loved Data Week events, they became curious about how other institutions were celebrating Love Data Week under the current circumstances. This article reports on a descriptive content analysis of Love Data Week 2021 events, guided by the following novel research questions:1. What were the common themes, methodologies, and tools discussed and taught during Love Data Week 2021? 2. What types of events were hosted for Love Data Week 2021 by different organizers? 3. How were the Love Data Week 2021 events distributed geographically and by sector? Background At major research universities, the library's role in providing data and research data management (RDM) services is increasingly recognized (Dai, 2020; Kim, 2020; Oliver et al., 2019; Wong & Chan, 2021). Over the past decade or two, librarians working in data-related capacities have built awareness among researchers of these services and have shared successful approaches within the broader scholarly community of information professionals via conference presentations and publications. Data-focused librarians, including data services, data science, and RDM librarians or specialists, have generally implemented two types of approaches to generate awareness of services among researchers. First, data-focused librarians have implemented conventional marketing and outreach strategies tied to traditional modes of data literacy and technical instruction, including campus or library newsletters/email lists, LibGuides, swag, and social media announcements, to promote regularly offered workshops or trainings (Chaput & Walsh, 2019; Oliver et al., 2019; Read et al., 2019). A second strategy focuses on the development and marketing of novel community-building events such as hackathons and datathons, themed weeks, and multi-institution/international grassroots campaigns related to promoting the library's data services or data products (Barnett et al., 2018; Cross & Davis, 2016; Fritz et al., 2020; Gao et al., 2019). Hackathons and datathons have mostly been implemented at single institutions or through collaborative funding initiatives to generate awareness on specific topics. For example, the “Archives Unleashed” project, funded by the Andrew W. Mellon Foundation, grew out of a series of datathons designed to build community around archived web content as data (Milligan et al., 2019). Themed weeks have also allowed for grassroots community-building related to emerging trends in data practices. For example, data-focused librarians and units have piggybacked on Open Access Week, held annually in October, for years to offer open data events as part of an international community (Johnson, 2014; Jones et al., 2010). The success of Open Access Week has sparked others to coordinate international events related to a specific theme, such as GIS day, Endangered Data Week, the International Open Data Day, and Love Data Week (Carruthers, 2014; Koivisto, 2019; Weimer et al., 2012; Wissel & DeLuca, 2018). Love Data Week began at Indiana University–Purdue University Indianapolis (IUPUI) in 2016 as a Valentine's Day (week) initiative spearheaded by a planning committee, coordinated by IUPUI Digital Scholarship and Data Management Librarian Heather Coates (Wissel & DeLuca, 2018). The planning committee maintained a website and announced an annual theme, including “Data Quality” in 2017, “Data Stories” in 2018, and “Data in Everyday Life” in 2019. A key component of Love Data Week is social media engagement using coordinated hashtags on Twitter. In 2016, 30 institutions participated and listed their events on the collective website. Over the next couple of years, the event grew to include more than 100 participating organizations and institutions (Wissel & DeLuca, 2018). After the 2020 event, the original planning committee announced they would archive the website as events were occurring in a more decentralized manner (Coates et al., 2020). In late 2020, several data-focused librarians initiated discussions through listservs, notably the IASSIST and the CANLIB-DATA listservs, to determine if there would be any central organization of Love Data Week 2021, including a theme or a single site to list events. As a result of these discussions, the University of Michigan's Inter-university Consortium for Political and Social Research (ICPSR) volunteered to host a list of global events, choose a theme (“Data: Delivering a Better Future”), and serve as a central organizing location going forward. Due to the pandemic, most Love Data Week 2021 events were exclusively online and there were fewer participating institutions. However, this presented an opportunity to study a cross-section of unique Love Data Week events in order to understand what data-focused librarians did to pivot community-building strategies to a virtual setting. In this paper, the authors focus specifically on Love Data Week 2021 to gain insight into current trends, as impacted by the global COVID-19 pandemic, related to training and community events as a major component of outreach for library's data-related services, products, and capacities. Methodology The organizations and events analyzed in this study were identified through three different methods. First, the authors mined ICPSR's Love Data Week website. From 2021, ICPSR became the official home of International Love Data Week. The website lists some of the week's events. However, it relies on institutions self-reporting. To account for this, the authors searched emails in data and library listservs (e.g. IASSIST listserv and CANLIB-Data) for mentions of additional events. Finally, internet searches for “Love Data Week” and “Love Your Data Week” as well as those terms combined with country identifiers were performed and results were explored for up to 20 pages per search. While the authors acknowledge that these searches could potentially exclude non-English or non-Latin alphabet sites, the goal was to identify institutions and events that specifically used the Love Data Week branding. Once the organizations and events had been identified, the authors visited the corresponding webpages to collect the relevant information. Using a spreadsheet tabular format, all identified participating organizations were assigned a tab where all their events were listed. For each event the following information was collected: title, type of event, description, organizer (library/other), speaker/facilitator, and language. Originally the authors also intended to include information on whether events were open to those outside the host organization, since events were almost exclusively virtual, but such information proved difficult to obtain. A notes field for each event was available in case the data collector had any useful information about the event that did not fit the previous categories. Following the data collection, the authors (a data services librarian, a subject librarian, and a research data management specialist) conducted a content analysis of the event titles and descriptions in order to determine high level topics emerging within and across institutions. Content analysis is a systematic method of coding, analyzing, and inferring meaning from qualitative data types, including unstructured text such as the event descriptions (Bernard et al., 2016; Krippendorff, 2018; Stemler, 2000). The process of content analysis involves categorizing a corpus of data to identify variations and comparisons among the observations, which in this case were the events (Ryan & Bernard, 2003). Content analysis can be conducted by human coders or by machines (e.g. software or algorithms). Although many researchers rely on software, which is more efficient at identifying themes in large datasets, there is also research showing that human coders are reliably better than machines at coding for nuanced or sophisticated concepts (Conway, 2006). Thus, since the dataset was not unmanageably large and covered specialized technical topics, the authors decided to code the dataset manually. Generally, there are two levels or units of analysis that can be coded using content analysis, including words or word counts (e.g. “data”, “R”, “cybersecurity”, etc.) and concepts (e.g. “data science”, “open science”, references to ideas about the relationship between social justice and data, etc.). Based on the nature of our dataset, the authors employed an approach that accounted for coding a set of specific words and concepts in general. The process of content analysis is highly iterative and involved multiple independent coders (the three authors) in order to ensure internal validity (Fonteyn et al., 2008; Kurasaki, 2000). First, the authors familiarized themselves with the dataset by each reading through a different sample of event descriptions from 3 to 5 institutions. A preliminary codebook was then constructed by developing a list of categories based on the research questions. For example, each author independently noticed at least one mention of COVID-19 or the pandemic, which was then included in the codebook. The total institutions were then divided into three samples with 10 or 11 institutions in each sub-sample. Authors each coded two of the three sub-samples using the preliminary codebook (i.e. two coders reviewed each sub-sample). Following the initial round of coding, the authors reconvened to discuss discrepancies in the codebook and disagreements among the coders and to clarify terms or concepts. For example, codes for data infrastructure or cybersecurity were not originally included, but it became clear during the initial round of coding that these concepts were central to at least a few events. In the process of content analysis, data coding can begin after the creation of a refined and final codebook (Erlingsson & Brysiewicz, 2017). However, there are three additional decisions to first reconcile regarding the process of coding the data. First, coders must determine if content can be coded into more than one category (Krippendorff, 2018; Kurasaki, 2000). In many cases, for this dataset, the Love Data Week 2021 events covered more than one topic or theme. Thus, due to the nature of this dataset, the categories included in the codebook were not mutually exclusive. For example, several events focused on teaching R as a tool for data visualization and creating maps. In this case, events were coded for a data tool (e.g. R, Tableau, Excel, Python, etc.), data visualization, and GIS/mapping, resulting in three codes for each of these events. The second decision related to coding is to finalize the unit of analysis (Krippendorff, 2018; Stemler, 2000). With qualitative data, it may not always be apparent how to organize the data until after an initial coding round. In this case, because the research questions relate to describing the events, including the context of each event, the unit of analysis for this study is the full event description. The third decision relates to the number of coders for each observation in the dataset. For manual content analysis involving human coders, including at least two coders per observation improves the level of rigor of the overall study (DeCuir-Gunby et al., 2011). For efficiency, the authors opted to again each code two-thirds of the dataset, resulting in each observation coded twice independently. For the second round of coding, each author coded independently, meaning first round codes for each event were masked. Following the second round of coding, two coders' results were compiled for all events to compare agreement or disagreement. Determining inter-coder reliability is more complex when multiple codes are assigned to each event. Overall, there was agreement on fewer than 50% of the codes, which is an unacceptable level. Generally, 80% agreement is considered high enough to ensure reliability (Franklin et al., 2010). However, in manual content analysis of complex unstructured data, this is neither uncommon nor unexpected (Kurasaki, 2000). The remedy is to review the codebook and discuss the disagreements and then re-code the dataset again. This process is repeated until near total agreement is reached among the coders. Upon discussion, the authors discovered many instances of disagreement stemmed from similar sources of differences in interpretation and their position in the library and research ecosystems. For example, the subject librarian author coded the concept of citing data as an ethical issue, whereas the RDM specialist author, who has a background in applied survey research methodology as opposed to library and information science, initially did not. The subject librarian convinced the RDM specialist that citations are directly related to the ethical use of information. Additional disagreements involved the categorization of complex or nuanced concepts. For example, a set of events about the effects of algorithmic biases on marginalized populations, one coder was applying a code for data ethics and another for social justice. Although ethics and social justice are not mutually exclusive, it was decided that social justice was the more applicable category in this case due to the context of the event descriptions. Thus, it was agreed to consistently apply the social justice code to events about the effects of algorithmic biases, whereas events about the biases themselves would be coded with the ethics category. This example also highlights the high degree of contextual nuance of the event descriptions. Following a review of all disagreements within the coding, the data was re-coded a third time and resulted in close to 99% agreement (see Appendix A for final version of codebook). Since many events corresponded to multiple codes, the descriptive results depict non-unique aggregations except for the event type. Data Availability Statement The data that support the findings of this study are openly available in Scholars Portal Dataverse at https://doi.org/10.5683/SP3/LZ1GYN (Rod et al., 2021). Results A total of 37 organizations hosting 242 events were identified. The majority of these organizations (30) were universities hosting these events through their libraries or research data services departments. Of the remaining, five (5) were information-related organizations (e.g. ICPSR. National Library of Medicine, and UK Data Service) and two (2) were vendors (LabArchives and Springer Nature). Organizations were mostly based in the United States (26), five (5) were in Canada and six (6) others were in Europe (France, Germany, Ireland, Switzerland, and the United Kingdom). Most organizations offered between 4 and 12 events during Love Data Week 2021. However, three institutions offered over 20 events: The University of California System (29) – comprising UC Davis, UC Irvine, UCLA, UC Merced, UC Riverside, UC San Diego, UC San Francisco, UC Santa Barbara, and UC Santa Cruz, Brown University (28), and New York University (21). Regarding the types of events, workshops were the most popular format accounting for 57.9% (140) of all events. Lectures, panels, and talks represented 19% (46) of all events followed by informational webinars, which made up 11.2% (27) of all activities. Other less popular events were discussions (4.5%), drop-in sessions or office hours (4.1%), and immersive experiences (3.3%). The latter included events such as a data escape room, a data haiku contest, and a datathon (see Fig. 1 ). Speakers and facilitators included librarians, representatives from university departments (e.g. IT, research funding), graduate students, external and internal researchers, and professors.Fig. 1 Love Data Week 2021 events by type. Breakdowns of the types of events offered during Love Data Week 2021. Each event was coded once for type, thus percentages depicted in this figure represent unique cases proportionally out of the total number of cases. Fig. 1 Given that three organizations hosted almost a third of the events, the authors also looked at the event type distribution omitting those three organizations. The results were not substantially different from the aggregated results including the full dataset. While there were slight increases in workshops (4.3%), discussions (2.2%), drop-in sessions or office hours (0.8%) and immersive experiences (0.4%), lectures/panels/talks and informational webinars experienced slight decreases of 5.6% and 2.2% respectively. However, the overall distribution of the data did not shift. Regarding topics, events focusing on tools, including scripting/programming, data analysis, or other digital tools or software, were the most prevalent with tools or software mentioned or featured 138 times across the 242 events analyzed. Tools for programming/statistics/computational analysis and those for data analysis were the most popular being present in 15.3% (37) and 14.9% (36) of events, respectively. Of the 41 explicitly named tools identified in this analysis, R was the most prevalent having been discussed or taught in 12 events (see Appendix B for a complete list of tools). Research data management (RDM) and its subcategories (data-sharing and data management plans) were also very popular with a combined 85 related events. The overarching RDM category was incorporated in 19.8% (48) of all events. Events raising awareness of products or services were prominently featured by institutions. They account for 22.7% (55) of all events and highlighted services and products such as data sets from ICPSR and the US Census as well as library or institutional services such as access to LabArchives, institutional data repositories, and data librarians/specialists. On a related note, sessions on finding data were also popular, accounting for 12.4% (30) of all events. Data visualization was present in 15.3% (37) of the sessions. These ranged from workshops on how to produce data visualizations to more theoretical approaches including sessions on data visualization best practices as well as critical approaches to the topic (e.g. how data visualizations can perpetuate structural oppression). Tableau was the most popular data visualization tool, represented in seven (7) workshops. Lectures, panels, and talks featuring data case studies made up 10.7% (26) of all events and included speakers from a variety of disciplines including medicine, linguistics, dance, epidemiology, art, economics, public policy, etc., and academic statuses including graduate students, researchers, and professors. The topic of social justice and equity, diversity, and inclusion (EDI) was present in 9.1% (22) of the events and included themes such as data feminism (3), data for Black lives (2), and Indigenous data (2). One interesting finding about this topic was that social justice and EDI was weaved into a variety of topics and events spanning almost the entire research data cycle including the use of data tools, data case studies, finding data, data-sharing, data ethics, and data science among others. Similarly, sessions mentioning COVID-19 accounted for 6.6% of events and included titles such as “Finding COVID-19 Data” or “Research Integrity in the Era of COVID-19.” Remaining topics included data science, qualitative data, open data, open science, and data ethics among others. See Fig. 2 for a complete list of topics and their prevalence throughout all the events.Fig. 2 Love Data Week 2021 events by topic (non-unique). This figure depicts a horizontal bar chart of Love Data Week 2021 event topics, sorted from high to low based on frequency. This figure represents non-unique frequencies, meaning that some events covered more than one topic. Fig. 2 Discussion The COVID-19 pandemic presented challenges for academic libraries around the world and generated a shift to online services and virtual events (Fritz et al., 2020; Jaskowska, 2020: Martzoukou, 2020; Walsh & Rana, 2020; Harris, 2021). Love Data Week, which at many institutions used to mainly be an in-person event (Berkeley Research Data Management, 2019; EPFL Library, 2019; Maynooth University, 2019; University of Notre Dame, 2019; Maynooth University, 2020; UC San Diego Library, 2020; University of Notre Dame, 2020; University of Chicago Library, 2020; Seton Hall University Libraries, 2021), was no exception and the shift to a virtual event was present in all the organizations reviewed for this analysis. The topics for Love Data Week 2021 showed the breadth and depth of the interests and opportunities that fall under the umbrella of the data community. It would appear, indeed, that many do “love data”, and of those who love it, they love it quite a lot. With 242 total events among 37 different organizations, Love Data Week delved deep into the many aspects of data present in the research community, and broadly highlighted the move of libraries from early data providers to a more mature data and research data support role. While libraries comprised the majority of the organizers of Love Data Week 2021 events, it is worth noting that they often collaborated with other departments and units within their organizations. Examples of these collaborations included the Vice-President's/Vice-Principal's Office for Research, IT services, funding offices, and research/academic integrity units. This could be indicative of a move toward a more collaborative research ecosystem where skills and knowledge are less siloed within individual departments. There is currently a paucity of literature on the topic of Love Data Week, which makes it difficult to assess the impact of COVID-19 on the event in terms of activities and organizations. This was further complicated by a potential issue of endogeneity due to the dissolution of the original Love Data Week team and central organizing website in 2020 (pre-COVID-19), which was followed by a more grassroots-style organization of the 2021 event. However, archived documentation shows that 55 organizations participated in the 2019 edition of Love Data Week compared with 37 in 2021 (Coates et al., 2020). Although fewer institutions participated in 2021 when compared with 2019, it would be difficult to isolate the primary causal factor. The dissolution of the original organizing team may have led to a leadership vacuum that caused Love Data Week to lose momentum. It is worth noting, however, that while many institutions chose not to organize Love Data Week events in 2021, many others celebrated it for the first time, for example, McGill University. The 2021 edition showed a clear preference for workshops, with 57.9% of all events being a workshop of some form. In addition, only 7 of the 140 workshop descriptions explicitly described or mentioned theoretical aspects of data. This suggests that the ongoing view of data within libraries is one of practicality, i.e. the how of data, rather than more theoretical or conceptual aspects, i.e. the why of data. This can be viewed as a part of that ongoing maturity, as libraries move toward data literacy as a separate topic (Beauchamp & Murray, 2016) rather than a subfield of information literacy, and thus create more data literacy-specific workshops rather than folding them into general information literacy. Indeed, the development of events such as Love Data Week, GIS Day, and International Open Data Day would improve this awareness among librarians. Further study on this move to data literacy would benefit the field and could lead to an exploration of the praxis potential in critical data literacy, as a mirror to critical information literacy (Downey, 2016). A comparison of the event type distribution between the full dataset and a dataset excluding the three top organizations offering almost a third of the events, showed no substantial differences. However, institutions offering fewer events tended to offer more interactive events such discussions, drop-in sessions, and immersive experiences. Alternatively, the top three organizations offered more lectures/panels/talks. It is interesting to note the results showing an even spread of events relating to data across the research lifecycle. Data finding, analysis, visualization, and sharing each represented between 10% and 16% of the events. RDM was represented in almost 20% of the events, reflecting the status of RDM as something of a “hot topic” within the data librarianship world currently, as funding agencies focus on RDM best practices (Bill & Melinda Gates Foundation, 2021; Canada, 2021; National Institutes of Health, 2020). Tool workshops tended toward a classical view of data, with tools such as R and Excel having a combined 16 events. Tableau's data visualization software was featured in six (7) events, and geospatial data tools of QGIS and ArcGIS showed up in three (3) events each. The ongoing tension between geospatial data as a separate field or subfield, then, was present, though this may be attributable to geospatial librarians' own GIS Day. It is perhaps also indicative of the culture of data librarianship that open or free tools were more prevalent than commercial applications. While the authors were able to identify a “love” for data, this analysis suggests there is no common definition of data among the different organizations. While some organizations only offered events focusing on traditional data tools and methodologies, others widened their definition of data to include workshops on citation management, web design, and general research ethics. While this may have been caused by organizations choosing to include prescheduled workshops in their Love Data Week calendar, it may represent a shift in how organizations define and contextualize “data” as a concept or field. Topics in the current cultural zeitgeist featured strongly, with events containing elements of data ethics or social justice, or COVID-19, or (in some cases) both. While a cynic could suggest a desire to leverage these topics for user engagement, or simple virtue signaling, one could conversely argue an awareness among data librarians of the need for change, and a willingness to undertake some part of this work. The use of data as an agent of change, though, is one bearing discussion – perhaps as a topic for next year's Love Data Week. From an organizer's perspective, the disagreements between the authors regarding the coding of events highlight the importance of collaboration between different areas of the library to ensure a well-rounded approach to data. The discussions in the third round of data coding fostered better understanding of how different groups may interpret and take advantage of Love Data Week offerings. For example, events involving ethics and/or social justice did not typically explicitly mention ethics or social justice. These codes were mostly inferred by the authors based on the entire description of the event and following intense scrutiny and discussion. One event focusing on Institutional Review Board (IRB) inter-institution collaborative agreements did not mention ethics, human participants, or the purpose of IRBs in the title or description of the workshop. However, two authors of this study have previously submitted proposals to similar review boards for research ethics and one author works closely with the staff at McGill University's research ethics board to facilitate inter-institutional collaborative research projects. Thus, following discussion, the authors' prior knowledge of the role of IRBs, and the reasonable expectation that researchers who work with human or animal participants would associate the concept of ethics with IRBs, led to coding this event as relating to ethics. Having these types of conversations as events are organized may result in events that are both more responsive to the organization's needs and better attended. For example, events promoting specific research-related procedures, such as inter-institution collaborative agreements or data use agreements, should be explicit about the connection with research integrity and the ethical and legal implications for these practices. Therefore, organizers may benefit from having a diverse group of library staff in planning Love Data Week events in the future. Ultimately, the Love Data Week results offer insights into current and ongoing issues in data librarianship. This current research is based on a cross-sectional study design, and further investigation is needed to examine trends and shifts in the needs of researchers over time. However, despite the analysis of just one year, the authors' perspective is that this study is a major contribution of original research. Since this project is novel and there are few existing studies on Love Data Week, the contribution of a new codebook and an analysis of the implementation of that codebook will enable future research in this area to develop. In addition, from a methodological perspective, it is not possible to confirm that all previous Love Data Week events still have a digital presence, thus it would be likely that any datasets of previous years would be missing potentially significant amounts of data. It may be possible to put together a dataset of past events that were registered with the previous central organizers at IUPUI, though our current methodology includes the centrally registered events (at ICPSR) in addition to events that were advertised elsewhere (e.g. solely on listservs, internally on their institutional communications channels, or solely via social media). For this current study, a comprehensive overview of all events can be included since data collection occurred in real-time before, during, and after 2021 Love Data Week. Conclusion Love Data Week 2021 presented unique challenges for hosts. Despite the limitations imposed by COVID-19, organizations in North America and Europe were able to offer a combined 242 workshops, lectures, talks, immersive experiences, and more. The wealth of events and event types highlighted creativity within the community and a desire to expand conceptions of what constitutes cutting-edge research data services and data librarianship. At a high-level, the enthusiasm to host Love Data Week 2021 events among organizations demonstrates the perceived usefulness of themed weeks in generating or maintaining community. In this study, the authors demonstrated that data-related library programming, at least in the context of a relevant themed week, is incorporating more global trends regarding the ways that researchers are engaging technologically and critically with data. For example, the digital tool that was most widely taught during Love Data Week 2021 was R, an open-source statistical programming language. This reflects shifts in both industry and academia toward the adoption of open-source tools more generally (Kross & Guo, 2019, p. 7; Spinellis & Giannikas, 2012). The collection of this “meta” data could be interesting to investigate from a time series perspective. Future avenues for research could include comparing the 2021 events to those taking place once organizations re-establish their pre-pandemic services. Tracking these events over time could reveal emerging trends related to data services within libraries and could illuminate causal factors driving change. Another potential route for future research could involve surveying Love Data Week organizers to better understand their experiences at their respective organizations and to collect information about attendance levels and event-level feedback from local attendees. A third possible line of inquiry could involve comparing the events of Love Data Week to other themed weeks to further investigate the overall utility of such outreach methods in building community or awareness among researchers. Love Data Week 2021 occurred during an unprecedented time in which organizations and individual data-related librarians were grappling with profound uncertainty and were highly resource constrained. These circumstances provided the ultimate test for the ability of a themed week to serve its fundamental purpose in fostering community. Based on the analysis of this study, Love Data Week 2021 persevered to provide a sufficient level of outreach and community-building opportunities across a virtual landscape to warrant the continuation of the event in 2022 (Inter-university Consortium for Political and Social Research, 2021). CRediT authorship contribution statement Alisa B. Rod: conceptualization (supporting); data curation (lead); formal analysis (equal); investigation (supporting); methodology (equal); visualization; writing – original draft preparation (equal); writing – review & editing (equal). Marcela Y. Isuster: conceptualization (lead); data curation (supporting); formal analysis (equal); investigation (lead); methodology (equal); writing – original draft preparation (equal); writing – review & editing (equal). Martin Chandler: conceptualization (supporting); data curation (supporting); investigation (supporting); writing – original draft preparation (equal); writing – review & editing (equal). Appendix A Codebook 1. Digital tools/software (explicit or implied)1.1. Data analysis1.1.1. Data cleaning 1.1.2. Data mining 1.2. GIS 1.3. Computational/technical/programming/machine learning/scripting/statistics 1.4. Project management 2. Type of event2.1. Workshop 2.2. Lecture/talk/panel 2.3. Informational webinar 2.4. Immersive experience 2.5. Drop-in session/office hours 2.6. Discussion 3. Methods3.1. Qualitative – text analysis/etc. 3.2. Geographical data 3.3. Numerical data 4. Domain Topic4.1. Open Science4.1.1. Open data 4.1.2. Open access 4.2. COVID-19 4.3. Ethics/ethical use of data 4.4. Social justice/EDI4.4.1. Data feminism 4.4.2. Data for Black Lives 4.4.3. Indigenous data 4.4.4. Data and Disability 4.5. Digital humanities 4.6. Data science 4.7. Theory 4.8. Service/product awareness 4.9. Data case study 4.10. Data infrastructure4.10.1. Advanced Research Computing/High Performance Computing 4.10.2. Cybersecurity 5. Finding data 6. Research Data Management6.1. Data sharing/publishing 6.2. Data management plan (DMP) 7. Data visualization 8. Web design Appendix B Complete list of tools APIs – ArcGIS – Atlas.ti – Dataverse – DMP Assistant – DMP Tool – EndNote – Excel – Gale Digital Scholar Lab – GitHub – GitHub Pages – Glitch Art – HathiTrust Research Center – Jekyll – Jupyter Notebooks – LabArchives – MATLAB – MaxQDA – MDClone – NVivo – Open Science Framework – OpenRefine – Power BI – PSPP– Python – QGIS – Qualtrics – R – R Markdown – RedCap – SAS – Social Explorer – SQL – Survey123 – Tableau – Taguette – TDM Studio – Twarc – Unix – VOSviewer – VoyantTools – Xpath ==== Refs References Barnett L. Brackett A. Grimshaw A. Nyhan K. The future comes one week at a time: Data outreach at Cushing/Whitney Medical Library University of Massachusetts and New England Area Librarian e-Science Symposium 2018 10.13028/ytzx-ye72 Bernard H.R. Wutich A. Ryan G.W. Analyzing qualitative data: Systematic approaches 2016 Sage Publications Beauchamp A. Murray C. Teaching foundational data skills in the library Kellam L.M. Thompson K. Databrarianship: The academic data librarian in theory and practice 2016 Association of College and Research Libraries, a division of the American Library Association Chaput J. Walsh R. Opening doors to research success: Data management programming and outreach. [Poster session] 2019 ACRL NEC Annual Conference Portland, ME, United States https://scholarworks.umass.edu/acrl_nec_conf/2019/posters/9/ Berkeley Research Data Management Love Data Week 2019 | Research Data Management https://researchdata.berkeley.edu/events/love-data-week-2019 2019 Bill & Melinda Gates Foundation Open access policy https://www.gatesfoundation.org/about/policies-and-resources/open-access-policy 2021 Canada Tri-Agency research data management policy Retrieved July 20, 2021, from https://www.science.gc.ca/eic/site/063.nsf/eng/h_97610.html 2021 Carruthers A. Open data day hackathon 2014 at Edmonton public library Partnership: The Canadian Journal of Library and Information Practice and Research 9 2 2014 10.21083/partnership.v9i2.3121 Coates H.L. Atwood T. Bass M. Condon P. Foster E.D. Graebner C. Adamus T. Love Data Week website 2016–2020 Retrieved July 19, 2021, from https://scholarworks.iupui.edu/handle/1805/23785 2020 Conway M. The subjective precision of computers: A methodological comparison with human coding in content analysis Journalism & Mass Communication Quarterly 83 1 2006 186 200 https://doi-org.proxy3.library.mcgill.ca/10.1177/107769900608300112 Cross W.M. Davis H.M. Where do we go from here: Choosing a framework for assessing research data services and training Proceedings of the Charleston Library conference 2016 10.5703/1288284316312 Dai Y. How many ways can we teach data literacy? IASSIST Quarterly 43 4 2020 1 11 10.29173/iq963 DeCuir-Gunby J.T. Marshall P.L. McCulloch A.W. Developing and using a codebook for the analysis of interview data: an example from a professional development research project Field Methods 23 2 2011 136 155 10.1177/1525822X10388468 Downey A. Critical information literacy: Foundations, inspiration, and ideas 2016 Library Juice Press Erlingsson C. Brysiewicz P. A hands-on guide to doing content analysis African Journal of Emergency Medicine 7 3 2017 93 99 30456117 Library E.P.F.L. Love data week 2019 at EPFL https://memento.epfl.ch/event/love-data-week-2019-at-epfl/ 2019 Fonteyn M.E. Vettese M. Lancaster D.R. Bauer-Wu S. Developing a codebook to guide content analysis of expressive writing transcripts Applied Nursing Research 21 3 2008 165 168 10.1016/j.afjem.2017.08.001 18684411 Franklin C. Cody P. Ballan M. Reliability and validity in qualitative research The handbook of social work research methods 2010 Sage Publications 355 374 Fritz S. Milligan I. Ruest N. Lin J. Building community at distance: A datathon during COVID-19 2020 Digital Library Perspectives 10.1108/DLP-04-2020-0024 Gao W. Malone A. Simons A. Love Data@ UH: Collaborating with campus partners to promote data services Collaborative Librarianship 11 3 2019 4 https://digitalcommons.du.edu/collaborativelibrarianship/vol11/iss3/4 Harris S.Y. Covid-19 impact on the Caribbean academic library: Jamaica's preliminary response to people, place, product and services Library Management 42 6–7 2021 340 361 10.1108/LM-10-2020-0144 Inter-university Consortium of Political and Social Research Love Data Week with ICPSR https://www.icpsr.umich.edu/web/about/cms/1576 2021, February 7 Jaskowska B. Management of Academic Libraries in Poland during the COVID-19 lockdown Zagadnienia Informacji Naukowej-Studia Informacyjne 58 2A (116A) 2020 29 43 https://www.ceeol.com/search/article-detail?id=923746 Kim J. Academic library's leadership and stakeholder involvement in research data services Proceedings of the Association for Information Science and Technology 57 1 2020 e304 10.1002/pra2.304 Koivisto J. What if you could save the data?: Endangered Data Week & how libraries can protect public data. [Conference presentation] 2019 Maryland Library Association Annual Conference http://hdl.handle.net/1903/22254 Krippendorff K. Content analysis: An introduction to its methodology 2018 Sage Publications Kross S. Guo P.J. Practitioners teaching data science in industry and academia: Expectations, workflows, and challenges Proceedings of the 2019 CHI conference on human factors in computing systems 2019 1 14 10.1145/3290605.3300493 Kurasaki K.S. Intercoder reliability for validating conclusions drawn from open-ended interview data Field Methods 12 3 2000 179 194 10.1177/1525822X0001200301 Johnson P.C. International open access week at small to medium US academic libraries: The first five years The Journal of Academic Librarianship 40 6 2014 626 631 10.1016/j.acalib.2014.07.011 Jones J. Waller A. McLennan J. Open Access Week; library strategies for advancing change Research Library Issues: A Bimonthly Report from ARL, CNI, and SPARC 270 2010 21 26 http://www.arl.org/resources/pubs/rli/archive/rli270.shtml Martzoukou K. Academic libraries in COVID-19: A renewed mission for digital literacy Library Management 42 4/5 2020 266 276 10.1108/LM-09-2020-0131 Maynooth University Love Data Week 2019 | Maynooth University Retrieved August 25, 2021, from https://www.maynoothuniversity.ie/news-events/love-data-week-2019 2019 Maynooth University Love Data Week 2020 | Maynooth University https://www.maynoothuniversity.ie/news-events/love-data-week-2020 2020 Milligan Ian Casemajor Nathalie Fritz Samantha Lin Jimmy Ruest Nick Weber Matthew Worby Nicholas Building Community and Tools for Analyzing Web Archives Through Datathons 2019 ACM/IEEE Joint Conference on Digital Libraries (JCDL) 2019 265 268 10.1109/JCDL.2019.00044 National Institutes of Health NOT-OD-21-013: Final NIH policy for data management and sharing https://grants.nih.gov/grants/guide/notice-files/NOT-OD-21-013.html 2020 Oliver J.C. Kollen C. Hickson B. Rios F. Data science support at the academic library Journal of Library Administration 59 3 2019 241 257 10.1080/01930826.2019.1583015 Read K.B. Koos J. Miller R.S. Miller C.F. Phillips G.A. Scheinfeld L. Surkis A. A model for initiating research data management services at academic libraries Journal of the Medical Library Association: JMLA 107 3 2019 432 10.5195/jmla.2019.545 31258450 Rod Alisa Beth Isuster Marcela Y. Chandler Martin Replication Data for: Love Data Week in the time of COVID-19: A content analysis of Love Data Week 2021 events Scholars Portal Dataverse 2021 V1 10.5683/SP3/LZ1GYN Ryan G.W. Bernard H.R. Techniques to identify themes Field Methods 15 1 2003 85 109 10.1177/1525822X02239569 Seton Hall University Libraries Love Data Week – University Libraries https://blogs.shu.edu/libraries/category/love-data-week/ 2021 Spinellis D. Giannikas V. Organizational adoption of open source software Journal of Systems and Software 85 3 2012 666 682 10.1016/j.jss.2011.09.037 Stemler S. An overview of content analysis Practical Assessment, Research, and Evaluation 7 1 2000 17 10.7275/z6fm-2e34 UC San Diego Library Love Data Week 2020 Kicks off Next Week https://library.ucsd.edu/news-events/love-data-week-2020-kicks-off-next-week/ 2020 University of Chicago Library Celebrate Love Data Week with the Library's data specialists https://www.lib.uchicago.edu/about/news/celebrate-love-data-week-with-the-librarys-data-specialists/ 2020 University of Notre Dame Love Data Week 2019 // Notre Dame Events // University of Notre Dame https://events.nd.edu/events/2019/02/12/love-data-week-2019/ 2019 University of Notre Dame Love Data Week 20202 // Notre Dame Events // University of Notre Dame https://events.nd.edu/events/2020/02/12/love-data-week-2020/ 2020 Walsh B. Rana H. Continuity of academic library services during the pandemic the University of Toronto Libraries' response Journal of Scholarly Publishing 51 4 2020 237 245 10.3138/jsp.51.4.04 Weimer K.H. Olivares M. Bedenbaugh R.A. GIS Day and web promotion: Retrospective analysis of U.S. ARL libraries' involvement Journal of Map & Geography Libraries 8 1 2012 39 57 10.1080/15420353.2011.629402 Wissel K. DeLuca L. Learning to love data (week): Creating data services awareness on campus College & Research Libraries News 79 9 2018 490 Wong G.K. Chan D.L. Designing library-based research data management services from bottom-up Baker I.D. Ellis L. Future directions in digital information 2021 Chandos Publishing 55 68 10.1016/B978-0-12-822144-0.00004-5

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==== Front Rev Malad Respir Actual Rev Malad Respir Actual Revue Des Maladies Respiratoires Actualites 1877-1203 1877-122X SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS S1877-1203(22)00785-6 10.1016/S1877-1203(22)00785-6 Soins Intensifs Respiratoires et Réanimation COVID-19 et insuffisance respiratoire aiguë : particularités de la prise en charge ventilatoire Girault C. 1* 1 Service de Médecine Intensive et Réanimation, Normandie Univ, UNIROUEN, UR-3830, CHU de Rouen, Rouen, France * Correspondance. Adresse e-mail : Christophe.Girault@chu-rouen.fr (C. Girault). 15 12 2022 12 2022 15 12 2022 14 2 2S4832S491 Copyright © 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS All rights reserved. 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIntroduction Depuis les premiers cas chinois de COVID-19 en décembre 2019 [1], la pandémie mondiale n’a fait que contribuer au développement de la prise en charge ventilatoire de l’insuffisance respiratoire aiguë (IRA) sévère. En effet, lors de la première vague, 15 à 20 % des patients COVID-19 devaient être hospitalisés, parmi lesquels 5 à 10 % nécessitaient d’être admis en réanimation pour IRA hypoxémique, et plus de 50 % d’entre-eux pouvaient développer un syndrome de détresse respiratoire aiguë (SDRA) [2]. Rappelons qu’en raison du risque d’aérosolisation de particules virales et donc de contamination potentielle du personnel soignant, les stratégies ventilatoires non invasives (ventilation non invasive (VNI), oxygénothérapie à haut débit (OHD)) n’étaient pas recommandées [3,4] et donc peu utilisées au début de la pandémie. En conséquence, bon nombre de patients COVID-19 en IRA hypoxémique ont pu être intubés-ventilés (trop) rapidement, selon les centres, lors des premières vagues de la pandémie [2]. Cette ventilation mécanique invasive (VMI), malgré des modalités protectrices utilisées comparables à celles des patients non COVID-19, semble par ailleurs pouvoir exposer les patients COVID-19 à un risque plus élevé de barotraumatisme (pneumothorax et/ou pneumomédiastin), avec une incidence de l’ordre de 10 % à 15 % selon les études, et donc d’aggravation potentielle de leur morbi-mortalité [5]. D’autre part, en raison des différents mécanismes physiopathologiques impliqués dans l’hypoxémie des patients COVID-19, le clinicien doit garder à l’esprit qu’ils peuvent être profondément hypoxémiques tout en étant peu ou pas tachypnéïques et/ou dyspnéïques [6]. Cette hypoxémie « silencieuse » ou « joyeuse », constatée tout particulièrement à la phase initiale de l’IRA à COVID-19, peut donc s’avérer tout à fait trompeuse et déconcertante pour le clinicien [6,7]. Plusieurs sessions ont donc été consacrées au COVID-19 lors de cet ATS 2022. Sans souci d’exhaustivité, nous en rapportons ici les principaux aspects nous paraissant utiles et pertinents pour le clinicien. Stratégies ventilatoires non invasives et COVID-19 Malgré les réserves initiales émises quant au recours à l’assistance respiratoire non invasive (ARNI), intégrant l’OHD, la VNI et la CPAP (« continuous positive airway pressure »), pour la prise en charge de l’IRA hypoxémique sévère des patients COVID-19 en termes de risque infectieux viral et de lésions pulmonaires induites par l’excès d’effort respiratoire spontané (« patient-self inflited injury » ou P-SILI) [3,4], les cliniciens du monde entier ont très vite eu recours à ces stratégies d’ARNI en raison du manque de ventilateurs et de lits de réanimation, tout en observant le port du masque et un habillage de protection rigoureux pour les soignants. Globalement, les données disponibles jusqu’à maintenant dans l’IRA hypoxémique des patients COVID-19, ont démontré que [8] : l’OHD pouvait être efficace pour éviter l’intubation et le recours aux soins critiques sans augmenter la mortalité dans les formes légères à modérées d’IRA (rapport PaO2/FiO2 ≥ 200 mmHg) ; la VNI, utilisée en première intention ou en sauvetage après échec de l’OHD, exposait à des taux de succès variables selon l’interface utilisée, les réglages et protocoles appliqués, le lieu de mise en œuvre (soins critiques versus services conventionnels), avec un risque d’échec pouvant atteindre 40 % à 80 % dans les formes d’IRA les plus sévères ; la CPAP, qui a le mérite de pouvoir être appliquée plus facilement en dehors des soins critiques, exposait, elle aussi, à des taux d’échec variables, de 20 % à 40 %, selon l’interface utilisée, la sévérité de l’hypoxémie mais pourrait s’avérer comparable aux autres ARNI, voire à l’oxygénothérapie standard (O2), en termes d’intubation et de mortalité. Lors de la session « Clinical Year in Review » (session D1), KS Mathews (New York, USA) a donc présenté et discuté les dernières grandes études prospectives ayant évalué les stratégies d’ARNI dans l’IRA hypoxémique à COVID-19. Une équipe colombienne a mené, d’Août à Janvier 2021, la première étude prospective randomisée ayant comparé l’OHD (n = 109) à l’O2 (n = 111) chez 220 patients COVID-19 avec hypoxémie modérée à sévère (PaO2/FiO2 < 200 mmHg) [9]. Les deux co-critères principaux de jugement étaient représentés par le recours à l’intubation et le délai de récupération clinique évaluée selon 7 critères d’autonomie et de besoins en soins dans les 28 jours après la randomisation (allant de la sortie au domicile avec reprise d’une activité normale au décès). Les principaux résultats sont reproduits dans la figure 1. L’OHD diminuait donc le recours à l’intubation (34,3 % vs 51 % respectivement : hazard ratio (HR) = 0,62, intervalle de confiance (IC) 95% : 0,39-0,96 ; p = 0,03) et le délai de récupération (11 (interquartile range (IQR) : 9-14) vs 14 (11-19) jours : HR = 1,39, IC95% : 1,00-1,92 ; p = 0,047) comparativement à l’O2 standard.Figure 1 Probabilité d’intubation et de récupération clinique selon la stratégie d’oxygénation (d’après [9]). Figure 1 Fort du bénéfice potentiel de la VNI appliquée via un casque (VNI-Helmet) au cours du SDRA hors COVID-19, comparativement au masque standard, pour diminuer le taux d’intubation et la mortalité) [10], et devant le recours de plus en plus important à l’OHD avec la pandémie COVID-19 [8], il était donc logique, comme l’a aussi souligné L. Munshi (Toronto, Canada) lors d’une session orale consacrée au SDRA (session B4), de comparer la VNI-Helmet à l’OHD dans cette situation. Dans une étude prospective randomisée, menée dans quatre services de réanimation italiens d’octobre à décembre 2020, Grieco et al. [11] ont donc comparé l’impact de ces deux stratégies non invasives sur le nombre de jours sans assistance respiratoire (OHD, VNI, VMI) dans les 28 jours post-randomisation. Pour les 109/110 patients analysés avec une hypoxémie modérée à sévère (PaO2/FiO2 < 200 mmHg), le nombre médian de jours sans assistance respiratoire à J28 était respectivement de 20 (IQR : 0-25) versus 18 (0-22) jours entre le groupe VNI-helmet (n = 54) et le groupe OHD (n = 55), sans différence significative (différence médiane = 2 jours, IC95% : -2 à 6 ; p = 0,26). Parmi les critères secondaires de jugement, le taux d’intubation était moindre (30 % versus 51 % respectivement ; p = 0,03) ( Fig. 2) et le nombre médian de jours sans VMI à J28 plus élevé (28 (13-28] versus 25 (4-28) jours ; p = 0,04) pour le groupe VNI-helmet. Cependant, la mortalité intra-hospitalière n’était pas retrouvée différente entre les deux stratégies (24 % versus 25 % ; p > 0,99).Figure 2 Probabilité d’intubation selon la stratégie d’oxygénation (d’après [11]). Figure 2 Comme nous l’avons vu plus haut, la place de la CPAP et de l’OHD reste discutée dans la prise en charge de l’IRA hypoxémique liée au COVID-19 [8]. Une vaste étude prospective, menée d’avril 2020 à mai 2021 dans 48 centres anglais, a donc randomisé 1 273 patients COVID-19 avec IRA hypoxémique entre le recours à la CPAP (n = 380), l’OHD (n = 418) ou l’O2 standard (n = 475) [12]. Le critère principal d’évaluation était un critère composite associant le recours à l’intubation ou la mortalité dans les 30 jours après la randomisation, avec ajustement selon les centres et les évolutions thérapeutiques des différentes vagues (dexaméthasone et tocilizumab notamment). L’étude a été interrompue prématurément par défaut de recrutement de patients COVID-19 en Angleterre avec par ailleurs un chevauchement important (17 %) entre les différentes stratégies pour la population globale (15 % pour le groupe CPAP, 11,5 % pour le groupe OHD et jusqu’à près de 24 % pour le groupe O2). Le critère composite à J30 était retrouvé significativement plus bas avec la CPAP qu’avec l’O2 (36,3 % versus 44,4 % respectivement ; p = 0,03) en rapport cependant avec un bénéfice sur l’intubation (p = 0,02) mais pas sur la mortalité (p = 0,65). Ce critère composite n’était par contre pas retrouvé différent entre l’OHD et l’O2 (44,3 % versus 45,1 % respectivement ; p = 0,83). À noter que la CPAP générait davantage d’évènements indésirables (34,2 %) que l’OHD (20,6 %) et l’O2 (13,9 %). Enfin, une analyse comparative post-hoc entre CPAP et OHD, ayant inclus 570 patients, a montré que le critère composite était retrouvé significativement plus bas avec la CPAP qu’avec l’OHD (34,6 % versus 44,3 % respectivement ; p = 0,02). Ces résultats, pour intéressants qu’ils soient, doivent être interprétés avec prudence en raison de certaines limites de l’étude : effectif planifié non atteint par arrêt prématuré de l’étude ce qui peut avoir réduit sa puissance pour pouvoir détecter une différence minime mais cliniquement pertinente pour la comparaison entre OHD et O2 ; nombreux chevauchement des stratégies ventilatoires utilisées entre les groupes ce qui peut contribuer à lisser les résultats en diminuant l’importance de l’effet observé d’un traitement potentiellement bénéfique ; recours au décubitus ventral non négligeable avec chacune des trois stratégies (> 60 %), plus important dans le groupe OHD (71 %), cette technique étant largement utilisée et potentiellement bénéfique dans l’IRA hypoxémique du patient COVID-19 [13]. Ce que l’on peut retenir actuellement de ces dernières études contrôlées, c’est que l’OHD, la CPAP et la VNI-helmet font respectivement probablement mieux que l’O2 pour éviter l’intubation dans la prise en charge de l’IRA hypoxémique liée au COVID-19 de gravité plutôt modérée (100 < PaO2/FiO2 ≤ 200 mmHg) sans impact formellement démontré sur la mortalité. À l’instar de ce qui a pu être proposé par L. Munshi (New York, USA) pour la prise en charge du SDRA non COVID-19 (session B4), il est probable que la CPAP et la VNI-helmet puisse s’adresser à des patients plus sévères nécessitant des niveaux de pression expiratoire positive externe (PEPe) importants (obésité, œdème aigu pulmonaire associé, importantes condensations des bases). En attendant des études randomisées complémentaires pour juger au mieux du devenir des patients (intubation, durées de séjour, mortalité) avec ces différentes stratégies d’oxygénation, le challenge pour le clinicien reste avant tout, face à l’hypoxémie « trompeuse » du COVID-19 [6,7], de ne pas retarder une intubation qui s’impose sous l’effet d’une stratégie non invasive susceptible d’aggraver les lésions pulmonaires sous-jacentes en raison d’efforts inspiratoires excessifs (« patient-self inflicted lung injury » ou P-SILI), et donc de grever le pronostic vital des patients [14]. Deux études présentées lors de cet ATS ont ainsi évalué l’impact du délai d’intubation sur le devenir des patients [15,16]. La première, rétrospective chez 203 patients COVID-19 avec IRA hypoxémique, a montré que la durée d’OHD ou de VNI préalable à l’intubation était étroitement corrélée à la mortalité en réanimation (odds-ratio (OR) = 1,36, IC95% : 1,1-1,68 ; p = 0,004) [15]. La seconde, à partir d’une cohorte prospective de 205 patients COVID-19 intubés-ventilés, a montré qu’une intubation tardive (> 48 h après l’initiation du premier support respiratoire) était non seulement corrélée à la mortalité intra-hospitalière (OR = 2,45, IC95% : 1,29-4,65 ; p = 0,006) mais aussi à un plus grand risque de séquelles pulmonaires radiologiques et fonctionnelles respiratoires (DLCO) [16]. Décubitus ventral et COVID-19 La pandémie COVID-19 a été l’occasion d’un développement important du recours au décubitus ventral (DV), passant de moins de 20 % au cours du SDRA avant la pandémie [17] jusqu’à 60 à 70 % des patients COVID-19 intubés-ventilés [18,19]. En raison d’un afflux important d’IRA hypoxémiques à COVID-19 devant être prises en charge en dehors des services de soins critiques, le DV appliqué aux patients non intubés, dont la faisabilité et la sécurité avaient pu être démontrées avant la pandémie [20], s’est aussi très largement développé avec celle-ci [[21], [22], [23]]. De fait, une nouvelle terminologie s’est parallèlement imposée chez ces patients en ventilation spontanée : « awake prone position or self-proning » en anglo-saxon ou « décubitus ventral vigil » (DVV) en français. En deux ans de pandémie, si de nombreux travaux ont été publiés dans ce domaine, il est difficile de se faire une idée sur le réel bénéfice du DVV au cours de l’IRA hypoxémique du patient COVID-19 [13,24]. En effet, les principales limites sont les suivantes : il s’agit d’études essentiellement observationnelles et rétrospectives ; elles n’utilisent pas de définition claire et homogène pour les patients dits « répondeurs » au DVV ; il existe par ailleurs, entre ces études, une grande hétérogénéité dans la pratique du DVV (critères d’initiation et durée notamment) dont la tolérance et la compliance à la technique peuvent être aussi très variablement appréciées. De plus, les dernières revues systématiques ou méta-analyses rapportent des résultats discordants. La première suggère que, comparativement au décubitus dorsal (DD), le DVV diminuerait le recours à l’intubation seulement quand il est utilisé en dehors des services de réanimation alors qu’il ne réduirait la mortalité qu’appliqué dans ces derniers [13]. La seconde conclue, à partir de 10 études randomisées (1 985 patients) que le DVV réduirait le recours à l’intubation seulement chez les patients pris en charge en réanimation et relevant d’une ARNI (OHD ou VNI), contrairement à ceux traités hors réanimation ou seulement sous O2 [24]. Par contre, cette dernière méta-analyse ne retrouvait pas de bénéfice du DVV sur la mortalité. Des études complémentaires étaient donc attendues. La dernière étude randomisée dans ce domaine a donc été présentée par W. Alhazzani (Hamilton, Canada), et publiée « online » en même temps [25], lors de l’une des fameuses sessions « opposant » les éditeurs du « JAMA » et du « New England Journal of Medicine » (session A84). Cet essai multicentrique international (21 centres répartis entre Canada, Koweit, Arabie Saoudite, USA), mené de mai 2020 à mai 2021, a donc randomisé 400 patients COVID-19, non intubés mais avec IRA hypoxémique nécessitant une oxygénothérapie (FiO2 ≥ 40 %) ou une ventilation non invasive, entre soins standards avec (n = 205) ou sans DVV (n = 195) [25]. La durée médiane du DVV dans les quatre premiers jours, était de 4,8 h/j (IQR : 1,8 à 8,0 h/j) pour le groupe concerné. Le recours à l’intubation à J30 post-randomisation, critère principal de jugement, n’était pas significativement différent entre les deux groupes DVV et sans DVV (contrôle) : 70/205 patients (34,1 %) versus 79/195 patients (40,5 %) respectivement (HR = 0,81, IC95% : 0,59 to 1,12], p = 0,20 ( Fig. 3). Le DVV ne réduisait pas la mortalité à J60 (HR = 0,93, IC95% : 0,62-1,40 ; p = 0,72) (Fig. 3) et aucune différence n’était retrouvée entre les deux groupes pour les autres critères secondaires ( Tableau 1). À noter que, contrairement au groupe contrôle, 10 % des patients du groupe DVV rapportaient des effets secondaires à type de douleurs musculaires et d’inconfort principalement (6,34 %). Par ailleurs, les analyses de sous-groupes préétablies selon la sévérité de l’hypoxémie (PaO2/FiO2 > ou ≤ 150 mmHg) ou selon l’ARNI utilisée avant l’inclusion (O2, OHD ou VNI) n’objectivaient pas non plus de différence (DVV versus contrôle) pour le taux d’intubation à J30.Figure 3 Probabilité d’intubation et de mortalité selon la stratégie de prise en charge avec ou sans décubitus ventral vigile (d’après [25]). Figure 3 Tableau 1 Critères secondaires de devenir selon la stratégie de prise en charge avec ou sans décubitus ventral vigile (d’après [25]). Tableau 1 Décubitus ventral vigile (n = 205) Groupe contrôle (n = 195) Différence moyenne (IC95%) p Nombre de jours sans VMI ou VNI à J30 21,4 ± 12,7 19,4 13,2 2,04 (-0,50 à 4,59) 0,12 Nombre de jours sans VMI à J30 21,6 ± 12,4 19,6 13,1 2,03 (-0,47 à 4,54) 0,11 Nombre de jours hors réanimation à J60 38,6 ±23,6 34,5 24,6 4,07 (-0,67 à 8,81) 0,09 Nombre de jours hors hôpital à J60 34,4 ± 22,9 30,8 23,5 3,52 (-1,05 à 8,08) 0,13 Résultats exprimés sous forme de moyenne ± SD ; IC : intervalle de confiance ; VMI : ventilation mécanique invasive ; VNI : ventilation non invasive Bien que les auteurs aient allégué une ampleur de l’effet observé sur l’intubation potentiellement sous-estimée [25], ces résultats, qui seront certainement très discutés, mettent quelque peu à mal les espoirs des cliniciens dans le DVV chez les patients COVID-19 [13,23]. En attendant les résultats d’autres études à venir sur le sujet, il est probable que cette stratégie de DVV, dont la durée optimale n’est pas connue (≥ 6 heures ?), puisse, de façon pragmatique, être proposée mais non imposée aux patients au risque de masquer une aggravation nécessitant l’intubation. Sinon, la position assise selon le « Penseur de Rodin » pourrait aussi constituer une alternative intéressante au DVV, notamment chez les patients ne tolérant pas ce dernier ( Fig. 4) [26].Figure 4 Faisabilité de la position assise selon le « Penseur de Rodin » (d’après [26]). A : Statue « Le Penseur » d’Auguste Rodin (1840-1917) ; Reproduction de la position du « Penseur » en position assise, thorax appuyé sur un plan dur (B : lit ou C : table). Position réalisable en ventilation spontanée sous oxygénothérapie standard ou à haut débit (B), voire sous ventilation non invasive, avec un casque « helmet » notamment (C). Figure 4 Assistance respiratoire extra-corporelle et COVID-19 Comme l’a rappelé E. Fan (Toronto, Canada) lors d’une session consacrée au SDRA (session B4), le SDRA lié au COVID-19, peut relever des mêmes principes de prise en charge que le SDRA non COVID-19 en termes de stratégies ventilatoires et thérapeutiques adjuvantes. Des patients COVID-19 sélectionnés peuvent donc justifier d’une assistance respiratoire extracorporelle (AREC) ou « veno-venous extracorporeal membrane oxygenation » (ECMO-VV) en cas de SDRA sévère ne permettant pas d’assurer des échanges gazeux suffisants malgré l’optimisation d’une ventilation mécanique protectrice et le recours au DV. Des centres experts « ECMO-VV » se sont donc rapidement développés au cours des deux années de pandémie, en particulier aux USA, en raison de l’afflux massif de patients COVID-19 avec SDRA sévère [27]. Discutées lors de la session « Clinical Year in Review » (session D4) par KS. Mathews (New York, USA), plusieurs méta-analyses ou revues systématiques ont donc rapporté un bénéfice de l’ECMO-VV chez les patients COVID-19 avec un taux global de mortalité intra-hospitalière de seulement 37 % (22 études observationnelles ; 1 896 patients) [28] à 39 % (134 études observationnelles incluant 3 études prospectives, 82 rétrospectives et 49 cas cliniques ou séries de cas ; 4 044 patients [29]. Sous l’effet de la VMI protectrice et de l’ECMO-VV, on peut donc espérer, au cours du SDRA à COVID-19, une récupération pulmonaire chez 50 à 60 % des patients [30]. Le DV faisant partie intégrante de la prise en charge ventilatoire du SDRA et l’ECMO-VV représentant encore une stratégie de sauvetage dans les formes les plus sévères, il peut-être néanmoins intéressant d’évaluer la faisabilité et l’intérêt de la combinaison des deux stratégies (ECMO-VV + DV) dans ces situations. Une récente méta-analyse a ainsi montré, sur 11 études observationnelles (640 patients), dont 10 rétrospectives et seulement 3 multicentriques, que le DV combiné à l’ECMO-VV constituait, au cours du SDRA hors COVID-19, une technique faisable et sécuritaire sans complication majeure, associée à un taux de survie cumulative de 57 %, aux dépends cependant de durées d’ECMO-VV et de séjour en réanimation plus prolongées [31]. Il était donc logique d’évaluer la pertinence d’une telle combinaison thérapeutique (ECMO-VV + DV) au cours du SDRA lié au COVID-19. Une première étude observationnelle multicentrique internationale, menée de février à octobre 2020, a pu montrer chez 67/232 SDRA COVID-19 positionné en DV sous ECMO-VV que le DV pouvait améliorer la survie intra-hopitalière comparativement au 165/232 patients maintenus en DD sous ECMO-VV : 33 % versus 22 %, HR = 0,31, IC95% : 0,14-0,68) [32]. Lors de cet ATS, à partir du registre « ECMOSARS » représentant à l’échelon national 77 % des consoles d’ECMO pour 47 centres français, l’analyse d’une large cohorte multicentrique a également eu pour objectif d’évaluer l’impact du DV utilisé en association à l’ECMO-VV chez des patients, adultes ou enfants, atteints de SDRA sévère lié au COVID-19 [33]. Le critère principal de jugement était la mortalité hospitalière. Sur les 647 patients du registre lors de l’extraction des données, 517 ont été analysés. L’âge médian était de 55 ans [IQR : 47-61), 78 % étaient des hommes et la plupart des patients (82 %) ont été inclus au printemps 2020. Les valeurs médianes de l’IGSII et du « Sequential Organ Failure Assessment » (SOFA) score étaient respectivement de 35 (24-52) et 9 (I7-12) au moment de la canulation pour ECMO-VV. Quatre-vingt-dix-huit pourcents des patients répondaient à la définition du SDRA selon les critères de Berlin et 95 % ont bénéficié du DV avant la canulation pour ECMO-VV. Après canulation, 364 patients (70 %) ont eu du DV, tandis que 153 (30 %) sont restés maintenus en DD pendant toute la durée de l’ECMO-VV. La mortalité a concerné 194/364 patients (53 %) pour le groupe DV contre 92/153 (60 %) pour le groupe DD. Le DV sous ECMO-VV était retrouvé indépendamment associé à la survie hospitalière (HR = 0,76, IC95% : 0,58-0,98 ; p < 0,033). Par la suite, pour limiter l’impact des facteurs confondants pouvant affecter à la fois la possibilité d’être mis en DV et la mortalité, seuls les patients vivants à la décanulation ont été pris en compte. Dans ce sous-groupe, les patients mis en DV ont été appariés avec des patients maintenus en DD en fonction de la probabilité de pouvoir bénéficier du DV. Dans cette analyse, l’effet protecteur indépendant du DV à l’égard de la mortalité hospitalière était maintenu (HR = 0,48, IC95% : 0,27-0,86 ; p < 0,013). Le DV associé à l’ECMO-VV semble donc potentiellement bénéfique chez les patients pris en charge pour SDRA sévère lié au COVID-19. Si le DV peut être encouragé dans ces conditions, ces données cliniques observationnelles mériteront néanmoins d’être confirmées par des études prospectives randomisées. De plus, il faut garder à l’esprit que ces deux stratégies combinées nécessitent un personnel nombreux et expérimenté, les complications potentielles des deux techniques n’étant par ailleurs pas rapportées ici [33]. Enfin, il faudra pouvoir déterminer, non seulement le rôle du DV pré-ECMO sur le bénéfice du DV per ECMO-VV, mais aussi les critères et la durée de mise en DV sous ECMO-VV. Transplantation pulmonaire et COVID-19 Contrairement à certaines pathologies respiratoires chroniques évoluées (fibrose pulmonaire, mucoviscidose, bronchoemphysème, hypertension pulmonaire), le SDRA n’a, avant la pandémie à COVID-19, que rarement été considéré comme une indication à la transplantation pulmonaire (TP) [34]. Un consortium international composé de plusieurs centres experts en transplantation (USA, Italie, Australie, Inde) a cependant récemment montré la faisabilité chirurgicale et le bénéfice sur la survie à court terme de la transplantation bi-pulmonaire dans une cohorte de 12 patients sélectionnés atteints d’un SDRA à COVID-19 réfractaire, « insevrable » de la VMI et/ou de l’ECMO-VV [35]. Ce travail préliminaire a par ailleurs conduit à proposer des critères précis pour sélectionner au mieux les patients SDRA COVID-19 les plus sévères et susceptibles de bénéficier d’une TP. Lors de l’une des sessions ayant confronté les éditeurs des revues du « JAMA » et du « New England Journal of Medicine » (session A2), Kurihara et al. [36] ont donc présenté l’expérience de leur centre en TP au cours d’une période de la pandémie allant de janvier 2020 à décembre 2021. Sur 102 TP, 72 ont concerné des pathologies respiratoires chroniques à un stade terminal et 30 des patients COVID-19 avec SDRA considéré comme réfractaire après au moins 4 à 6 semaines d’évolution depuis le début des symptômes. Pour les 30 patients COVID-19, comparativement aux 72 non COVID-19, 29 patients étaient sous VMI protectrice et 1 sous VNI avant la TP, 56,7 % bénéficiaient d’une ECMO-VV pré-TP contre 1,4 % respectivement, et la durée médiane d’inscription sur la liste de TP était de 11,5 jours versus 15 jours. En post-opératoire, le taux de dysfonction primaire du greffon dans les 72 heures était de 70 % contre 20,8 % respectivement, les durées médianes de VMI de 6,5 jours versus 2,0 jours, de séjour en réanimation de 18 jours versus 9 jours, et d’hospitalisation post-TP de 28,5 versus 16 jours. Aucun patient COVID-19 n’a présenté de rejet humoral post-greffe contre 12,5 % chez les greffés non-COVID-19. Au 15 novembre 2021, date de fin de suivi pour l’étude, 100 % (30/30) des patients SDRA COVID-19 transplantés étaient vivants (durée médiane de suivi : 351 jours, IQR : 176-555) contre 83,3 % (60/72) pour la cohorte non COVID-19 (durée médiane de suivi : 488 jours, IQR : 368-570) ( Fig. 5). Malgré le faible effectif de la cohorte COVID-19 et le caractère monocentrique de l’étude, ces résultats apparaissent très impressionnants et mériterons, bien qu’on ne le souhaite pas vraiment (…), d’être confortés par d’autres équipes. Quoi qu’il en soit, l’orateur, C. Kurihara (Chicago, USA) (session A2) insistait tout particulièrement sur la nécessité d’une sélection rigoureuse des patients [35], et d’une prise en charge pré et post-greffe multidisciplinaire impérative (infectiologues, réanimateurs, pneumologues, chirurgiens thoraciques) dans des centres à forte expertise à la fois dans la prise en charge du SDRA et en TP [35,36].Figure 5 Survie post-transplantation pulmonaire selon les cohortes (d’après [36]). Figure 5 Liens d’intérêts Au cours des 5 dernières années, C. Girault a perçu des honoraires ou financements pour participation à des congrès, communications, actions de formation et travaux de recherche de la part des laboratoires Fischer & Paykel Healthcare, Resmed, Lowenstein Medical et Kernel Médical. 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Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: A randomized clinical trial JAMA 315 2016 2435 2441 27179847 11 Grieco DL Menga LS Cesarano M Rosà T Spadaro S Bitondo MM Montomoli J Effect of helmet noninvasive ventilation vs high-flow nasal oxygen on days free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure: The HENIVOT randomized clinical trial JAMA 325 2021 1731 1743 33764378 12 Perkins GD Ji C Connolly BA Couper K Lall R Baillie JK Bradley JM Effect of noninvasive respiratory strategies on intubation or mortality among patients with acute hypoxemic respiratory failure and COVID-19: The RECOVERY-RS randomized clinical trial JAMA 327 2022 546 558 35072713 13 Kharat A Simon M Guérin C. Prone position in COVID-19 associated acute respiratory failure Curr Opin Crit Care 28 2022 57 65 34750322 14 Battaglini D Robba C Ball L Silva PL Cruz FF Pelosi P Rocco PRM. Noninvasive respiratory support and patient self-inflicted lung injury in COVID-19: a narrative review Br J Anaesth 127 2021 353 364 34217468 15 Raia SA Wittrock E Khatiwada A Strand M Lockhart GC. An examination of early intubation versus initial trial of non-invasive ventilation on outcomes in COVID-19 pneumonia Am J Respir Crit Care Med 205 2022 A4277 16 Gonzalez J Benítez I de Gonzalo-Calvo D Torres G de Batlle J Gómez S Moncusí-Moix A Impact of time to intubation on mortality and pulmonary sequelae in critically ill COVID-19 patients: A prospective cohort Am J Respir Crit Care Med 205 2022 A3139 17 Guérin C Beuret P Constantin JM Bellani G Garcia-Olivares P Roca O Meertens JH A prospective international observational prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone Position Network) study Intensive Care Med 44 2018 22 37 29218379 18 Langer T Brioni M Guzzardella A Carlesso E Cabrini L Castelli G Dalla Corte F Prone position in intubated, mechanically ventilated patients with COVID-19: A multi-centric study of more than 1000 patients Crit Care 25 2021 128 33823862 19 Le Terrier C Sigaud F Lebbah S Desmedt L Hajage D Guérin C Pugin J Early prone positioning in acute respiratory distress syndrome related to COVID-19: a propensity score analysis from the multicentric cohort COVID-ICU network-the ProneCOVID study Crit Care 26 2022 71 35331332 20 Scaravilli V Grasselli G Castagna L Zanella A Isgrò S Lucchini A Patroniti N Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study J Crit Care 30 2015 1390 1394 26271685 21 Elharrar X Trigui Y Dols AM Touchon F Martinez S Prud’homme E Papazian L. Use of prone positioning in nonintubated patients with COVID-19 and hypoxemic acute respiratory failure JAMA 323 2020 2336 2338 32412581 22 Coppo A Bellani G Winterton D Di Pierro M Soria A Faverio P Cairo M Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study Lancet Respir Med 8 2020 765 774 32569585 23 Hochberg C Psoter KJ Eakin MN Hager DN. Factors associated with increased use of early prone positioning for moderate-to-severe ARDS during COVID-19 Am J Respir Crit Care Med 205 2022 A5083 24 Li J Luo J Pavlov I Perez Y Tan W Roca O Tavernier E Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure: a systematic review and meta-analysis Lancet Respir Med 10 2022 573 583 35305308 25 Alhazzani W Parhar KKS Weatherald J Al Duhailib Z Alshahrani M Al-Fares A Buabbas S Effect of awake prone positioning on endotracheal intubation in patients with COVID-19 and acute respiratory failure: A randomized clinical trial JAMA 327 2022 2104 2113 35569448 26 Coppo A Winterton D Benini A Monzani A Aletti G Cadore B Isgrò S Rodin’s Thinker: An alternative position in awake patients with COVID-19 Am J Respir Crit Care Med 204 2021 728 730 34242143 27 Farooqi M Amin F Owen J Ainsworth C Belley-Cote E Sharma S Centofanti JE Development and implementation of an extracorporeal membrane oxygenation (ECMO) program during the COVID-19 pandemic: A single-center experience Am J Respir Crit Care Med 205 2022 A2918 28 Ramanathan K Shekar K Ling RR Barbaro RP Wong SN Tan CS Rochwerg B Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis Crit Care 25 2021 211 34127027 29 Bertini P Guarracino F Falcone M Nardelli P Landoni G Nocci M Paternoster GJ ECMO in COVID-19 Patients: a systematic review and meta-analysis Cardiothorac Vasc Anesth 36 2021 2700 2706 30 Barbaro RP MacLaren G Boonstra PS Combes A Agerstrand C Annich G Diaz R Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry Lancet 398 2021 1230 1238 34599878 31 Poon WH Ramanathan K Ling RR Yang IX Tan CS Schmidt M Shekar K. Prone positioning during venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis Crit Care 25 2021 292 34384475 32 Zaaqoq AM Barnett AG Griffee MJ MacLaren G Jacobs JP Heinsar S Suen JY Beneficial effect of prone positioning during veno-venous extracorporeal oxygenation for coronavirus disease 19 Crit Care Med 50 2022 275 285 34582415 33 Nesseler N Guervilly C Mansour A Porto A Flécher E Esvan M Fougerou-Leurent C Prone position is beneficial in COVID-19 patients on veno-venous extracorporeal membrane oxygenation for respiratory failure Am J Respir Crit Care Med 205 2022 A3537 34 van der Mark SC Hoek RAS Hellemons ME. Developments in lung transplantation over the past decade Eur Respir Rev 29 2020 190132 32699023 35 Bharat A Machuca TN Querrey M Kurihara C Garza-Castillon R Jr Kim S Manerikar A Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries Lancet Respir Med 9 2021 487 497 33811829 36 Kurihara C Manerikar A Querrey M Felicelli C Yeldandi A Garza-Castillon R Jr Lung K Clinical characteristics and outcomes of patients with COVID-19-associated acute respiratory distress syndrome who underwent lung transplant JAMA 327 2022 652 661 35085383

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Rev Malad Respir Actual. 2022 Dec 15; 14(2):2S483-2S491

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Rev Malad Respir Actual

10.1016/S1877-1203(22)00785-6

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==== Front Med Clin (Engl Ed) Med Clin (Engl Ed) Medicina Clinica (English Ed.) 2387-0206 The Author(s). Published by Elsevier España, S.L.U. S2387-0206(22)00556-3 10.1016/j.medcle.2022.02.029 Original Article Impact of dexamethasone and tocilizumab on hematological parameters in COVID-19 patients with chronic disease Impacto del tratamiento combinado de dexametasona y tocilizumab sobre parámetros hematológicos en pacientes con enfermedad crónica COVID-19Qutob Haitham M.H. ab⁎ Saad Ramadan A. bc Bali Hamza d Osailan Abdulaziz d Jaber Jumana d Alzahrani Emad d Alyami Jamilah d Elsayed Hani be Alserihi Raed fg Shaikhomar Osama A. h a Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Rabigh, 25732, Saudi Arabia b Medical Laboratory Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia c Physiology Department, Faculty of Medicine, Ainshams University, Cairo, Egypt d Internal Medicine Department, Dr Soliman Fakeeh Hospital, Jeddah, Saudi Arabia e Physics Department, Faculty of Science, Mansoura University, Mansoura, Egypt f Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia g 3D Bioprinting Unit, Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia h Department of Physiology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia ⁎ Corresponding author. 15 12 2022 23 12 2022 15 12 2022 159 12 569574 11 10 2021 23 2 2022 © 2022 The Author(s) 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background and aim The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers. Materials and methods This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients’ lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab. Results The WBC and neutrophil counts were increased significantly in group 3 upon the treatment when they were compared with patients in group 1 (p = 0.004 and p = 0.001, respectively). The comparison of C-reactive Protein (CRP) level at admission was higher in group 3 than in group 1 with p = 0.030. After 10 days of treatment, CRP level was decreased in all groups, but in group 3 it was statistically significant (p = 0.002). Conclusion The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases. Antecedentes y objetivo La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio. Materiales y métodos Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab. Resultados Los recuentos de glóbulos blancos y neutrófilos aumentaron significativamente en el grupo 3 tras el tratamiento cuando se compararon con los pacientes del grupo 1 (p = 0,004 y p = 0,001, respectivamente). La comparación del nivel de proteína C reactiva (CRP) al ingreso fue mayor en el grupo 3 que en el grupo 1, con p = 0,030. Después de 10 días de tratamiento, el nivel de CRP disminuyó en todos los grupos, pero en el grupo 3 fue estadísticamente significativo (p = 0,002). Conclusión El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas. Abbreviations COVID-19, coronavirus disease 2019 SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ARDS, severe acute respiratory distress syndrome CBC, complete blood count CRP, C-reactive protein Keywords COVID-19 WBCs Neutrophils Lymphocytes CRP Dexamethasone Tocilizumab Palabras clave COVID-19 Leucocitos Neutrófilos Linfocitos CRP Dexametasona Tocilizumab ==== Body pmcIntroduction Coronavirus disease 2019 (COVID-19) is a serious pneumonia infection that was identified in Wuhan, Hubei Province, China, in late December 2019 and subsequently spread worldwide.1, 2 The causative virus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the Coronaviridae family.3 Currently, the number of people worldwide who have been infected with the virus has reached 194 million with approximately 4 million deaths; in Saudi Arabia, the total number of COVID-19 cases is 515,000 with 8141 deaths. The clinical characteristics of patients with COVID-19 vary from asymptomatic to the development of severe acute respiratory distress syndrome (ARDS), which can cause mortality in infected patients.4 The study of the pathophysiological process of COVID-19 has revealed the involvement of the host immune response. It has been found that inflammatory molecules, primarily interleukin (IL)-1, IL-6, and tumor necrosis factor, are elevated in patients with COVID-19.5, 6 These substances bind to host tissue, causing the development of ARDS, which is a serious causative factor in morbidity and organ dysfunction.5, 7 In patients with severe COVID-19 disease, it has been found that inflammatory factors such as C-reactive protein (CRP), ferritin, IL-1, and IL-6 are higher than in patients with mild disease.7, 8 Thus, it is suggested that elevated inflammatory markers are an indication of disease severity. COVID-19 patients with chronic diseases such as diabetes mellitus, hypertension, and obesity are at high risk of developing severe ARDS and experiencing morbidity and mortality.9 Studies in China have found that the patients with COVID-19 most likely to require hospitalization and have high mortality rates are individuals with cardiovascular disease, diabetes, and chronic respiratory diseases, with the ratio 10, 7, 6, and 6, respectively.10, 11, 12 Moreover, the complications from COVID-19 associated with mortality were more often seen in patients suffering from hypertension, diabetes, ischemic heart disease, and chronic renal failure.11, 12, 13 Several therapeutic studies have been conducted with the goal of reducing the severity of the disease by targeting the inflammatory elements. Introducing treatment with corticosteroids such as Dexamethasone or hydrocortisone has shown a reduction in both inflammatory activity and mortality rate in severe patients.14 Studies on the effect of such anti-inflammatory drugs have shown promising results in patients with COVID-19 who were on either mechanical oxygen support or noninvasive oxygen supplement.15 Administration of Tocilizumab as an anti–IL-6 agent has shown a significant reduction in mortality and need for respiratory support.16, 17 In addition, patients who underwent treatment comprising a combination of steroids and Tocilizumab had a higher survival rate than patients treated with Tocilizumab or steroids alone (29%).18 The aim of our study was to evaluate the effect of steroid and Tocilizumab treatment on hematological and other laboratory results of COVID-19 patients with chronic diseases to establish predictive parameters for response to treatment protocols and expedite progress in the treatment of the disease. Methods Patients The study was reviewed and approved by the institutional review board (IRB) at Fakeeh College for Medical Sciences and Dr. Soliman Fakeeh Hospital. The data of 68 patients with COVID-19 who were admitted to Dr. Soliman Fakeeh Hospital (DSFH) between April 24, 2020, and June 30, 2020 were collected following IRB waived the written informed consent for this retrospective data analysis. During this time, the Ministry of Health in Saudi Arabia published a treatment protocol that included steroid and/or Tocilizumab administration for patients with COVID-19 in moderate, severe, or critical conditions based on the World Health Organization disease severity classification as mild, moderate, severe, or critical illness (Table 1 ).19 Table 1 COVID-19 disease severity classification according to World Health Organization guidelines. Table 1Mild illness Moderate illness Severe illness Critical illness Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging. Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level. Individuals who have SpO2 < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mmHg, respiratory frequency >30 breaths/min, or lung infiltrates >50%. Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction. COVID-19 detection test The diagnosis of COVID-19 was confirmed by the presence of SARS-CoV-2 RNA in a nasopharyngeal swab. The RNA was extracted using the TANBead Nucleic Acid Extraction Kit and assayed using the PowerChek 2019-nCOV Real-Time PCR Kit. Treatment protocols The patients were categorized into the following four groups based on the treatment protocol: control group corresponded to the lab results of the patients at admission, before the treatment protocol was applied; group 1 comprised patients who were treated with the standard protocol of an anticoagulant (low molecular weight heparin – Enoxaparin) which was used as a prophylactic (40 mg subcutaneous once daily) or therapeutic (1 mg/kg twice daily), Hydroxychloroquine 400 mg/12 h on day one then followed with 200 mg/12 h for the next four days, and antibiotics in patients at high risk of developing an infection was as follow Ceftriaxone 2 g IV once daily for seven to ten days and Azithromycin 500 mg IV/PO once daily for three days; group 2 consisted of patients receiving Dexamethasone, and group 3 comprised patients receiving steroid and Tocilizumab (a monoclonal antibody against the IL-6 receptor) treatment. The dosages were as follows: 20 mg/day of Dexamethasone for groups 2 and 3 and 4–8 mg/kg of IV Tocilizumab by two consecutive IVs 12 h apart for group 3. Identifying laboratory results Laboratory result data at admission and after 10 days of treatment were collected retrospectively. The laboratory results investigated included red blood cell count, white blood cell (WBC) count, neutrophils, monocytes, platelets, and CRP. Coagulation profile and d-dimer tests were excluded because of the administration of anticoagulant therapeutics as part of the treatment protocol. Statistical analysis The statistical electronic platform SPSS version (v23) was used for data analysis comparing patient outcomes based on WBCs, neutrophils, monocytes, and lymphocytes. paired and unpaired t-test were used in the analysis. A p value <0.05 was considered statistically significant. Results There were 68 patients with COVID-19 and a history of chronic disease enrolled in the study. The distribution of chronic diseases and COVID-19 severity is summarized in Table 2 . Among the patients, 64.6% were male and 35.4% were female, the mean age was 59.4 years (standard deviation = 14.1), and the median age was 61 years.Table 2 Distribution of patients with COVID-19 based on disease severity and history of chronic disease. Table 2Type of chronic disease Sample COVID-19 disease severity Mild Moderate Severe Critical Diabetes mellitus 14 5 2 3 4 Diabetes mellitus and other chronic diseasesa 4 1 2 0 1 Hypertension 6 2 0 3 1 Hypertension and other chronic diseasesa 5 0 1 4 0 Diabetes mellitus and hypertension 15 4 1 8 2 Diabetes mellitus, hypertension, and other chronic diseasesa 13 4 0 6 3 Other chronic diseasesa 8 2 1 4 1 Total 65 18 7 28 12 a Other chronic diseases include any disease other than diabetes mellitus and hypertension, such as obesity, chronic lung disease, hypothyroidism, bronchial asthma, and chronic kidney disease. Severe and critical cases made up 38.5% (10/26) of group 1, 53.3% (8/15) of group 2, and 88% (22/25) of group 3. The mortality rate was 8% (1/26) in group 1, 6.7% (1/15) in group 2, and 21% (5/24) in group 3. The development of ARDS and acute kidney injury with or without septic shock was observed in patients with multiple preexisting chronic diseases such as hypertension and diabetes mellitus with chronic kidney disease or cardiopathy. A comparison of hematological laboratory results showed a significant increase in WBC and platelet counts and a reduction in CRP in group 3 patients when compared with the laboratory results at admission, represented as control group (p  < 0.05; Table 3 ). When group 1, treated with the standard protocol, and group 2, treated with Dexamethasone, were compared, the WBC count at admission for both groups was around 6.5 × 103/μL; WBC count increased in group 2 to 8.67 × 103/μL after 10 days of treatment with Dexamethasone, though the difference between the two groups was nonsignificant (p  = 0.234; Table 4 ). The neutrophil count in group 2 were higher than in group 1 after 10 days of treatment. In group 2, the neutrophil count increased to 6.79 × 103/μL, while the lymphocyte count slightly decreased to 1.85 × 103/μL. However, there were no significant differences between the groups in neutrophil count at admission or after 10 days of treatment (p  = 0.529 and p  = 0.178, respectively). Between-group comparisons of other hematological laboratory data showed nonsignificant results (Table 4).Table 3 a comparison of laboratory results at admission in control group and 10 days after treatment in group 1, 2, and 3. Table 3CBC markers Control Group vs Group 1 Control Group vs Group 2 Control Group vs Group 3 Mean at admission (SD) Mean after 10 days (SD) p value Mean at admission (SD) Mean after 10 days (SD) p value Mean at admission (SD) Mean after 10 days (SD) p value RBC count ×106/μL 4.82 (0.75) 5.27 (0.88) 0.219 4.82 (0.75) 4.89 (0.59) 0.759 4.82 (0.75) 4.45 (0.65) 0.071 WBC count ×103/μL 7.26 (3.61) 6.66 (2.13) 0.464 7.26 (3.61) 8.66 (3.78) 0.220 7.26 (3.61) 10.47 (4.79) 0.004* Neutrophils ×103/μL 5.58 (5.94) 3.94 (7.81) 0.180 5.58 (5.94) 6.36 (2.87) 0.645 5.58 (5.94) 7.59 (4.59) 0.184 Monocytes ×103/μL 0.87 (1.84) 0.66 (0.20) 0.575 0.87 (1.84) 0.94 (3.63) 0.893 0.87 (1.84) 0.56 (0.35) 0.472 Lymphocytes ×103/μL 1.55 (1.12) 1.93 (1.04) 0.253 1.55 (1.12) 1.85 (1.57) 0.423 1.55 (1.12) 1.44 (0.67) 0.707 Platelet count ×103/μL 235.98 (75.96) 264.29 (83.73) 0.197 235.98 (75.96) 275.86 (89.01) 0.143 235.98 (75.96) 316.28 (54.59) 0.001* C-reactive protein mg/L 97.13 (86.89) 19.6 (23.93) 0.063 97.13 (86.89) 75 (74.14) 0.622 97.13 (86.89) 23.85 (156.58) 0.024* The p value represents the statistical significance between the mean values of the two groups. * p value is statistically significance (< 0.05). Table 4 Laboratory data of the three groups at admission and after 10 days of treatment. Table 4Lab Parameters Group 1 (Standard Protocol) Group 2 (Steroid) Group 3 (Steroid + Tocilizumab) Sample Mean at admission (SD) Mean after 10 days (SD) p value Sample Mean at admission (SD) Mean after 10 days (SD) p value Sample Mean at admission (SD) Mean after 10 days (SD) p value RBC count ×106/μL 26 4.96 (0.88) 5.27 (2.56) 0.562 15 4.85 (0.59) 4.89 (0.90) 0.875 24 4.62 (0.65) 4.45 (0.83) 0.479 WBC count ×103/μL 26 6.64 (2.13) 6.66 (2.74) 0.970 15 6.84 (3.78) 8.66 (4.47) 0.257 24 8.39 (4.79) 10.47 (5.37) 0.216 Neutrophils ×103/μL 26 5.56 (7.81) 3.94 (1.73) 0.316 15 4.03 (2.87) 6.36 (4.16) 0.097 24 6.75 (4.59) 7.59 (4.64) 0.580 Monocytes ×103/μL 26 0.66 (0.20) 0.66 (0.73) 0.693 15 1.88 (3.63) 0.94 (1.62) 0.387 24 0.49 (0.35) 0.56 (0.42) 0.571 Lymphocytes ×103/μL 26 1.65 (1.042) 1.93 (1.81) 0.508 15 1.96 (1.57) 1.85 (1.66) 0.851 24 1.12 (0.67) 1.44 (1.02) 0.254 Platelet count ×103/μL 26 226.44 (83.73) 264.29 (116.71) 0.197 15 243.5 (89.01) 275.86 (136.86) 0.465 24 243.00 (54.59) 316.28 (112.68) 0.016* C-reactive protein 5 37.31 (30.32) 19.6 (35.71) 0.280 5 96.2 (114.37) 75 (93.69) 0.757 9 130.89 (80.41) 23.85 (29.48) 0.002* The p value represents the statistical significance between the mean values of the two groups. * p value is statistically significance (< 0.05). Regarding group 3, which received both Tocilizumab and Dexamethasone as part of the therapeutic strategy, laboratory data revealed an improvement in WBC, neutrophil, and monocyte counts (Table 4). A similar pattern was observed in group 2 for WBCs and neutrophils, though monocytes and lymphocytes showed a slight reduction; all laboratory results were, however, within the normal range (Table 4). When comparing groups 1 and 3 before and after 10 days of treatment, only WBC and neutrophil counts showed significant differences. WBC and neutrophil counts increased by approximately 36.39% and 26%, respectively, after treatment, leading to a significant difference between groups 1 and 3 after treatment (p  = 0.004 and p  = 0.001, respectively; Table 5 ). Lymphocyte count was higher in group 1 than in group 3 at admission, though increased in both groups, by 12.8% in group 1 and 15.9% in group 3, after 10 days of treatment. The laboratory results of group 2 and group 3 showed nonsignificant differences after 10 days of treatment.Table 5 Comparison of the different therapeutic strategies after 10 days of treatment. Table 5Lab parameters Group 1 vs Group 2 Group 1 vs Group 3 Group 2 vs Group 3 Sample Group 1 mean after 10 days (SD) Group 2 mean after 10 days (SD) p value Sample Group 1 mean after 10 days (SD) Group 3 mean after 10 days (SD) p value Sample Group 2 mean after 10 days (SD) Group 3 mean after 10 days (SD) p value RBC count ×106/μL 26 5.27 (2.56) 4.89 (0.90) 0.594 15 5.27 (2.56) 4.45 (0.83) 0.184 24 4.89 (0.90) 4.45 (0.83) 0.152 WBC count ×103/μL 26 6.66 (2.74) 8.66 (4.47) 0.092 15 6.66 (2.74) 10.47 (5.37) 0.004* 24 8.66 (4.47) 10.47 (5.37) 0.313 Neutrophils ×103/μL 26 3.94 (1.73) 6.36 (4.16) 0.015* 15 3.94 (1.73) 7.59 (4.64) 0.001* 24 6.36 (4.16) 7.59 (4.64) 0.439 Monocytes ×103/μL 26 0.66 (0.73) 0.94 (1.62) 0.449 15 0.66 (0.73) 0.56 (0.42) 0.617 24 0.94 (1.62) 0.56 (0.42) 0.331 Lymphocytes ×103/μL 26 1.93 (1.81) 1.85 (1.66) 0.895 15 1.93 (1.81) 1.44 (1.02) 0.300 24 1.85 (1.66) 1.44 (1.02) 0.389 Platelet count ×103/μL 26 264.29 (116.71) 275.86 (136.86) 0.784 15 264.29 (116.71) 316.28 (112.68) 0.155 24 275.86 (136.86) 316.28 (112.68) 0.367 The p value represents the statistical significance between the mean values of the two groups. * p value is statistically significance (< 0.05). Furthermore, CRP levels in all groups were higher than the normal range. In group 3 patients, mean CRP level at admission was 130 mg/L (standard deviation = 80.42; Table 4). Comparison of CRP levels between groups 1 and 3 showed a significant difference (p  = 0.030), while with group 2, the difference was non-significant (p  = 0.298). After 10 days of treatment, CRP levels were reduced in all groups, though a significant difference was only seen in group 3 (p  = 0.002). Discussion In this retrospective study, the characteristics of hematological laboratory results were assessed in patients with COVID-19 with a history of chronic disease. We observed that WBC count, platelet count, and CRP level in patients in group 3 were significantly improved after treatment with Dexamethasone and Tocilizumab. In addition, WBC and neutrophil counts were higher in the patients administered Dexamethasone and Tocilizumab as well as patients treated with only Dexamethasone when compared to the patients treated with the standard treatment protocol. These parameters increased after administration of Dexamethasone alone or in combination with Tocilizumab. This result indicates that patients with COVID-19 and a history of chronic disease are more likely to benefit from treatment protocols that include Dexamethasone and Tocilizumab. In addition, the lymphocyte count in all groups was just above the lower cutoff while the inflammatory marker CRP was markedly high, which is consistent with other observations of COVID-19 cases at high risk of hospitalization.20, 21 In our study, WBCs, neutrophils, and lymphocytes increased after steroid and Tocilizumab treatment but the level of lymphocytes is lower than the level observed in patients treated with the standardized protocol. Based on this, it is proposed that adding Tocilizumab, an IL-6 inhibitor, to the treatment may minimize the side effects associated with the administration of Dexamethasone by reducing the release of cytokines associated with chimeric antigen receptors redirecting T cells.22 IL-6 levels have been identified in other studies and are used to monitor disease severity and progression during treatment.20, 23, 17, 24 IL-6 accumulates in the serum temporarily after Tocilizumab infusion before decreasing due to the inhibition of inflammatory activity, leading to an improvement in patients’ clinical manifestation.23, 25 On the other hand, while an increase in platelet count was seen in all groups after treatment, the increase was only significant in group 3; this could be explained by the interaction of IL-6 with hematopoietic stem cells to enhance megakaryocyte production and release into the circulation. In addition, the over activation of hemostasis and related pathways is a hallmark in severe COVID-19 cases.26 Thus, regulation of platelet adhesion, aggregation, and coagulation pathways during treatment leads to a reduction in platelet consumption, thus preserving platelet count. Introducing Dexamethasone and Tocilizumab into the treatment of patients with COVID-19 elicited clinical improvements in patients with severe and critical conditions. Patients whose COVID-19 treatment protocol included Dexamethasone and Tocilizumab have been shown to have a 10.7% higher survival rate than patients not administered these therapeutics.24 Furthermore, significant differences have been found between patients on steroid treatment and those without steroid treatment in oxygen support need (p  = 0.04) as well as in mortality rate, with decreased mortality among patients undergoing steroid treatment (p  < 0.001).27, 28 In another study performed on 100 patients treated with Tocilizumab, 58% of patients had improved clinical presentations and 37% were stabilized, and at day 10, the improvement in symptoms was 77%.29 Our study has some limitations that could reflect negatively on our conclusions regarding administering Tocilizumab with Dexamethasone to patients with COVID-19 and chronic disease. The primary limitations are the number of patients involved in the study and their laboratory results, such as lactate dehydrogenase, d-dimer, and ferritin. In addition, our patients’ data were collected from a single tertiary hospital in the region. Increasing the number of patients and involving additional tertiary hospitals would strengthen our observation of the effectiveness of Dexamethasone and Tocilizumab in patients with COVID-19 and chronic disease. Moreover, IL-6 level was not reported in our study due to it not being tested at the time of diagnosis or during treatment. Thus, it is recommended to consider testing IL-6 levels in routine laboratory tests to aid in categorizing disease severity, determining appropriate treatment protocols, and monitoring treatment progress. Conclusion An increase in CRP level and low lymphocyte count in patients with COVID-19 and a history of chronic disease could be a positive indication for the use of Dexamethasone with Tocilizumab as therapeutic strategies to improve clinical outcomes and prevent disease progression. Ethics approval The proposal of study was approved by IRB at DSFH. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contribution Haitham MH. Qutob: Study plan, Methodology, data validation, and Writing – original draft. Ramadan A. Saad: Study plan, and Writing – original draft. Hamza Bali, Abdulaziz Osailan, Jumana Jaber, Emad Alzahrani, and Jamilah Alyami: Patients’ data collection. Hani Elsayed: Data analysis, Raed Alserihi, and Osama A. Shaikhomar: Manuscript review and editing. Consent for publication I confirm that the study was carried out in accordance with relevant guidelines and regulations. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments I would like to thank Dr. Ziyad Alharbi, Director of Academic & Training Affairs at DSFH and Vice Dean for Clinical Affairs at FCMS, for his support and coordination in collecting the data. ==== Refs References 1 Li Q. Guan X. Wu P. Wang X. Zhou L. Tong Y. Early transmission dynamics in Wuhan China, of novel coronavirus–inected pneumonia. N Engl J Med. 382 2020 1199 1207 31995857 2 Guo Y.R. Cao Q.D. Hong Z.S. Tan Y.Y. Chen S.D. Jin H.J. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status Mil Med Res. 7 2020 11 32169119 3 Shereen M.A. Khan S. Kazmi A. Bashir N. Siddique R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses J Adv Res 24 2020 91 98 32257431 4 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England). 2020;395:497-506. 5 Channappanavar R. Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Paper presented at: Seminars in immunopathology 2017 6 Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir Med. 8 2020 420 422 32085846 7 Costanzo G. Cordeddu W. Chessa L. Del Giacco S. Firinu D. COVID-19: considerations about immune suppression and biologicals at the time of SARS-CoV-2 pandemic World J Clin Cases 9 2021 5352 5357 34307589 8 Fan Y. Wang Y. Yu S. Chang J. Yan Y. Wang Y. Natural products provide a new perspective for anti-complement treatment of severe COVID-19: a review Chin Med. 16 2021 67 34321065 9 Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy JAMA 323 2020 1775 1776 32203977 10 Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. MedRxiv. 2020.04.08.20057794. 11 Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan China: a single-centered, retrospective, observational study. Lancet Respir Med. 8 2020 475 481 12 Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan China: a retrospective cohort study. Lancet. 395 2020 1054 1062 13 Zhang J.J. Dong X. Cao Y.Y. Yuan Y.D. Yang Y.B. Yan Y.Q. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan China. Allergy. 75 2020 1730 1741 32077115 14 Lee N. Allen Chan K.C. Hui D.S. Ng E.K. Wu A. Chiu R.W. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients J Clin Virol. 31 2004 304 309 15494274 15 Angus D.C. Derde L. Al-Beidh F. Annane D. Arabi Y. Beane A. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial Jama. 324 2020 1317 1329 32876697 16 Fu B. Xu X. Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 18 2020 1 5 31900168 17 Xu X. Han M. Li T. Sun W. Wang D. Fu B. Effective treatment of severe COVID-19 patients with tocilizumab Proceedings of the National Academy of Sciences. 117 2020 10970-5 18 Ruiz-Antorán B. Sancho-López A. Torres F. Moreno-Torres V. de Pablo-López I. García-López P. Combination of tocilizumab and steroids to improve mortality in patients with severe COVID-19 infection: a Spanish, multicenter, cohort study Infect Dis Ther. 10 2021 347 362 33280066 19 World Health Organization Clinical management of COVID-19: interim guidance, 27 May 2020 2020 World Health Organization Geneva 20 Toniati P. Piva S. Cattalini M. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia Italy Autoimmun Rev 19 2020 102568 32376398 21 Muñoz-Rodríguez J.R. Gómez-Romero F.J. Pérez-Ortiz J.M. López-Juárez P. Santiago J.L. Serrano-Oviedo L. Characteristics and Risk Factors Associated With Mortality in a Multicenter Spanish Cohort of Patients With COVID-19 Pneumonia Arch Bronconeumol. 57 Suppl 2 2021 34 41 34629641 22 Kotch C. Barrett D. Teachey D.T. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome Expert Rev Clin Immunol 15 2019 813 822 31219357 23 Luo P. Liu Y. Qiu L. Liu X. Liu D. Li J. Tocilizumab treatment in COVID-19: a single center experience J Med Virol 92 2020 814 818 32253759 24 Mikulska M. Nicolini L.A. Signori A. Di Biagio A. Sepulcri C. Russo C. Tocilizumab and steroid treatment in patients with COVID-19 pneumonia PLoS One. 15 2020 e0237831 25 Nishimoto N. Terao K. Mima T. Nakahara H. Takagi N. Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease Blood 112 2008 3959 3964 18784373 26 Qu R. Ling Y. Zhang Y.H. Wei L.Y. Chen X. Li X.M. Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19 J Med Virol. 92 2020 1533 1541 32181903 27 Dequin P.F. Heming N. Meziani F. Plantefève G. Voiriot G. Badié J. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial JAMA. 324 2020 1298 1306 32876689 28 Bauchner H. Fontanarosa P.B. Randomized clinical trials and COVID-19: managing expectations JAMA 323 2020 2262 2263 32364561 29 Toniati P. Piva S. Cattalini M. Garrafa E. Regola F. Castelli F. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia Italy. Autoimmun Rev. 19 2020 102568

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Med Clin (Engl Ed). 2022 Dec 23; 159(12):569-574

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Med Clin (Engl Ed)

10.1016/j.medcle.2022.02.029

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==== Front Med Clin (Engl Ed) Med Clin (Engl Ed) Medicina Clinica (English Ed.) 2387-0206 Elsevier España, S.L.U. S2387-0206(22)00558-7 10.1016/j.medcle.2022.03.020 Original Article Effectiveness of corticosteroids to treat coronavirus disease 2019 symptoms: A meta-analysis Eficacia de los glucocorticoides en el tratamiento de los síntomas de la enfermedad por coronavirus 2019: un metaanálisisZeng Yiqian a1 Zeng Weizhong a1 Yang Bihui b Liu Zhao a⁎ a Department of Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou, Hunan, China b Department of Hematology, Zhuzhou Central Hospital, Zhuzhou, Hunan, China ⁎ Corresponding author. 1 These authors contributed equally to this work. 15 12 2022 23 12 2022 15 12 2022 159 12 575583 7 9 2021 9 3 2022 © 2022 Elsevier España, S.L.U. All rights reserved. 2022 Elsevier España, S.L.U. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objective Currently, corticosteroids are widely used to treat coronavirus disease 2019 (COVID-19) symptoms. However, the therapeutic role of corticosteroids remains highly controversial. To that end, we aimed to assess the efficacy of corticosteroids in treating COVID-19 patients. Method We searched PubMed, Embase, and Cochrane Library to select suitable studies. Our primary study endpoint was all-cause mortality. The secondary study endpoint was the length of hospital stay. Results A total of 9 randomized controlled trials (RCTs) with 7907 patients were assessed. The pooled result indicated that corticosteroids treatment could significantly reduce all-cause mortality in patients with COVID-19 (RR = 0.88, 95% CI [0.82, 0.95], P = 0.002). When subgroup analyses were performed, we found that corticosteroids were associated with decreased all-cause mortality in severe COVID-19 patients (RR = 0.77, 95% CI [0.68, 0.88], P < 0.0001), however no obvious difference was observed in all-cause mortality of non-severe COVID-19 patients between the corticosteroid and control group (RR = 0.96, 95% CI [0.86, 1.06], P = 0.41), meanwhile, a low dose (RR = 0.89, 95% CI [0.82, 0.97], P = 0.007) of dexamethasone (RR = 0.9, 95% CI [0.83, 0.98], P = 0.01) with a long treatment course (RR = 0.89, 95% CI [0.82, 0.98], P = 0.02) was beneficial for all-cause mortality in COVID-19 patients. Additionally, we found that corticosteroids might be associated with a longer length of hospital stay in non-severe COVID-19 patients (MD = 3.83, 95% CI [1.11, 6.56], P = 0.006). Conclusion Our results showed that corticosteroid therapy was related to a reduction in all-cause mortality in severe COVID-19 patients. However, in patients with non-severe COVID-19, the use of corticosteroids did not decrease all-cause mortality and may prolong the duration of hospital stay. In addition, we revealed that a low dose of dexamethasone with a long treatment course could reduce all-cause mortality in COVID-19 patients. Objetivo Actualmente, los glucocorticoides se utilizan ampliamente para tratar los síntomas de la enfermedad por coronavirus 2019 (COVID-19). Sin embargo, el papel terapéutico de los glucocorticoides sigue siendo muy controvertido, por ello, nos propusimos evaluar su eficacia en el tratamiento de los pacientes con COVID-19. Método Se realizaron búsquedas en PubMed, Embase y Cochrane Library para seleccionar los estudios adecuados. El criterio de valoración principal del estudio fue la mortalidad por todas las causas. El criterio de valoración secundario del estudio fue la duración de la estancia en el hospital. Resultados Se evaluó un total de 9 ensayos controlados aleatorizados con 7.907 pacientes. En general, el tratamiento con glucocorticoides redujo la mortalidad por todas las causas en los pacientes con COVID-19 (RR = 0,88, IC 95% [0,82; 0,95], p = 0,002). Al realizar análisis de subgrupos, se observó que los glucocorticoides se asociaban a una disminución de la mortalidad por todas las causas en los pacientes con COVID-19 grave (RR = 0,77, IC 95% [0,68; 0,88], p < 0,0001), sin embargo no se observaron diferencias evidentes en la mortalidad por todas las causas de los pacientes con COVID-19 no grave entre el grupo de glucocorticoides y el de control (RR = 0,96, IC 95% [0,86; 1,06], p = 0,41), mientras que una dosis baja (RR = 0,89, IC 95% [0,82; 0,97], p = 0,007) de dexametasona (RR = 0,9, IC 95% [0,83; 0,98], p = 0,01) con un curso de tratamiento largo (RR = 0,89, IC 95% [0,82; 0,98], p = 0,02) fue beneficiosa para la mortalidad por todas las causas en los pacientes con COVID-19. Además, encontramos que los glucocorticoides podrían estar asociados con una mayor duración de la estancia hospitalaria en los pacientes con COVID-19 no grave (DM = 3,83, IC 95% [1,11; 6,56], p = 0,006). Conclusión Nuestros resultados mostraron que el tratamiento con glucocorticoides estaba relacionado con una reducción de la mortalidad por todas las causas en los pacientes con COVID-19 grave. Sin embargo, en los pacientes con COVID-19 no grave, el uso de glucocorticoides no disminuyó la mortalidad por todas las causas y puede prolongar la duración de la estancia hospitalaria. Además, descubrimos que una dosis baja de dexametasona con un curso de tratamiento largo podría reducir la mortalidad por todas las causas en los pacientes con COVID-19. Keywords Coronavirus disease 2019 Corticosteroids Meta-analysis Palabras clave Enfermedad por coronavirus 2019 Glucocorticoides Metaanálisis ==== Body pmcIntroduction The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared at the end of December 2019 and has since brought about an unprecedented challenge to public health worldwide.1 Reportedly, 20% of COVID-19 patients will progress to severe respiratory failure requiring intensive care.2, 3 Severe cytokine and chemokine storms are believed to be involved in respiratory and multi-organ failure. Thus, immunosuppressive drugs such as corticosteroids have been widely used in the treatment of COVID-19 patients. Nevertheless, the role of corticosteroids in the management of COVID-19 remains a subject of controversy. Recently, the RECOVERY trial reported a notable survival benefit of a daily low dosage of dexamethasone for up to 10 days in subjects with COVID-19 who were receiving oxygen therapy or mechanical ventilation.4 However, other clinical studies showed different results. The Metcovid trial found no benefit in the 28-day mortality of a low methylprednisolone dosage for 5 days in COVID-19 patients.5 Similarly, in the CAPE COD trial,6 compared with the placebo group, using low-dose hydrocortisone for 10 days or 8 days could not reduce mortality or the requirement for respiratory support. Additionally, a study by Jamaati et al.7 suggested that a 10-day high dosage of dexamethasone did not decrease mortality in patients with non-severe COVID-19 compared to the control group. Previous meta-analyses of several RCTs mainly focused on the effect of corticosteroids treatment on severe COVID-19 patients. In this meta-analysis, we included more valuable RCTs to evaluate the efficacy of corticosteroids among not only severe but also non-severe COVID-19 patients. Materials and methods Search strategy and data sources The present study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Eligible RCTs were identified through a systematic search of PubMed, Embase and Cochrane Library from December 31, 2019 to March 31, 2021. The following search terms were used: (adrenal cortex hormone or corticosteroid or glucocorticoid or corticoid or steroid) and (COVID-19 or 2019 nCoV or coronavirus disease-19 or 2019 novel coronavirus disease or 2019-nCoV disease or coronavirus disease 2019 or SARS CoV-2 or nCov 2019). In addition, the references were manually searched to make the results more comprehensive. The work was done independently by two authors. A third investigator resolved all encountered disagreements. Inclusion and exclusion criteria Studies that met all of the following criteria were selected: (1) patients in each study were adults with laboratory-confirmed or clinically suspected COVID-19. (2) The participants were assigned to a corticosteroid group using corticosteroids plus standard care, and the control group received standard care without corticosteroids. We excluded conference abstracts, case reports, articles not in English and studies without full text or missing important data. Our primary study endpoint was the all-cause mortality rate at the longest follow-up available. The secondary study endpoint was the length of stay in the hospital. Data extraction Two reviewers independently extracted data from the included studies. If there was any dispute, it was discussed or resolved by the third author. The following data were collected: first author, year of publication, study region, study design, inclusion criteria, type, dose, and duration of corticosteroid use, control intervention, outcome in each study, as well as the longest follow-up. Quality assessment The quality of each study was independently evaluated by two authors using the Cochrane Collaboration risk of bias, consisting of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Statistical analysis The meta-analyses were performed using RevMan 5.4 software (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Dichotomous data were analyzed as the pooled relative risk (RR) with its 95% confidence interval (CI), while for continuous data, we calculated the mean difference (MD) and the 95% CI. A P-value of <0.05 was considered statistically significant. Statistical heterogeneity between studies was estimated using statistic I 2. A random-effects model was used when either P  < 0.1 or I 2  > 50% defined significant heterogeneity; otherwise, the fixed-effects model was used. For the primary study endpoint, subgroup analyses were carried out according to the severity of disease, corticosteroids dosage, type and treatment time. Severe COVID-19 patients were defined as those patients admitted to the Intensive Care Unit (ICU), and the remaining were non-severe. A low or high dosage was defined based on the cutoff values: dexamethasone 15 mg/day, hydrocortisone 400 mg/day, or equivalent methylprednisolone 80 mg/day.8 Besides, treatment duration was classified as short (≤7 days) or long course (>7 days). Results Study selection A total of 696 articles were obtained from our database search, 188 in PubMed, 297 in Embase, 211 in the Cochrane Library. After removing 151 duplicates and another 533 records by screening the title and abstract, there were 12 remaining full-text articles, among which 3 studies were removed due to non-randomized controlled trials. Ultimately, 9 trials4, 5, 6, 7, 9, 10, 11, 12, 13 were included. The literature screening workflow is shown in Fig. 1 .Fig. 1 Flow diagram of literature search and study selection. Study characteristics The characteristics of included studies are summarized in Table 1 . In total, 7907 patients from 9 studies were analyzed. Of the 9 studies, 2940 patients were treated with corticosteroids and 4967 were treated without corticosteroids. There were 54, 5, 6, 9, 10 articles describing the use of corticosteroids in severe patients and another 54, 7, 11, 12, 13 in non-severe patients. The corticosteroids utilized in the studies included hydrocortisone,6, 9 dexamethasone,4, 7, 10 and methylprednisolone.5, 11, 12, 13 Table 1 Characteristics of trials. Table 1Study Study region Study design Inclusion criteria Dosage and duration of corticosteroids (n) Control intervention (n) Primary outcome Longest follow-up Angus 2020 REMAP-CAP Australia, Canada, France, Ireland, the Netherlands, New Zealand, the UK, the USA Multicenter Open-label RCT Aged at least 18 years confirmed or suspected COVID-19 admitted to ICU receiving respiratory or cardiovascular support A fixed 7-day course of intravenous hydrocortisone (50 or 100 mg every 6 h) (n = 137) OR A shock-dependent course (50 mg every 6 h up to 28 d for shock patients) (n = 141) Standard care (n = 101) Respiratory and cardiovascular organ support-free days up to day 21 21 days Jeronimo 2020 Metcovid Brazil Single center RCT Aged at least 18 years confirmed or suspected COVID-19 in use of oxygen therapy or under invasive mechanical ventilation Methylprednisolone 1 mg/kg/d for 5 d (n = 194) Standard care (n = 194) 28-day mortality 28 days Dequin 2020 CAPE COD France Multicenter Double-blind RCT Aged at least 18 years confirmed or suspected COVID-19 admitted to ICU with acute respiratory failure Hydrocortisone 200 mg/d for 7 d, then 100 mg/d for 4 d and 50 mg/d for 3 d; if symptoms improved by day 4, then followed with hydrocortisone 100 mg/d for 2 d and 50 mg/d for 2 d (n = 76) Standard care (n = 73) Death or persistent respiratory support on 21 d 21 days Edalatifard 2020 Iran Multicenter Single-blind RCT Aged at least 18 years confirmed COVID-19 receiving oxygen therapy but not intubation or ventilation Methylprednisolone 250 mg/d for 3 d (n = 34) Standard care (n = 28) Time to clinical improvement and hospital discharge or death Until clinical improvement and hospital discharge or death Tomazini 2020 CoDEX Brazil Multicenter Open-label RCT Aged at least 18 years confirmed or suspected COVID-19 receiving mechanical ventilation for ARDS Dexamethasone 20 mg/d for 5 d, then 10 mg/d for 5 d or until ICU discharge (n = 151) Standard care (n = 148) Ventilator-free days at 28 d 28 days Corral 2021 GLUCOCOVID Spain Multicenter Open-label RCT Aged at least 18 years confirmed COVID-19, not intubated or ventilated Methylprednisolone 80 mg/d for 3 d, then 40 mg/d for 3 d (n = 35) Standard care (n = 29) A composite of death, ICU admission, or requirement of noninvasive ventilation Until composite endpoint happened Horby 2021 RECOVERY UK Multicenter Open-label RCT Confirmed or suspected COVID-19 Oral or intravenous dexamethasone 6 mg/d for up to 10 d (or until hospital discharge if sooner) (n = 2104) Standard care (n = 4321) All-cause mortality within 28 d after randomization 28 days Tang 2021 China Multicenter Single-blind RCT Aged at least 18 years confirmed COVID-19 admitted to general wards less than 72 h Methylprednisolone 1 mg/kg/d for 7 d (n = 43) Standard care (n = 43) Incidence of clinical deterioration 14 days after randomization. 14 days Jamaati 2021 Iran Single center RCT Aged at least 18 years confirmed COVID-19 (PaO2/FiO2) between 100 and 300 mmHg Dexamethasone 20 mg/d for 5 d, then 10 mg/d for 5 d (n = 25) Standard care (n = 25) Need for invasive mechanical ventilation and death rate 28 days Risk of bias Results of the methodological quality assessment of included studies are presented in Fig. 2 . As indicated, two trials5, 7 have a low risk of bias, while the other seven trials4, 6, 9, 10, 11, 12, 13 were judged to have a high risk of bias.Fig. 2 Methodological quality evaluation of the randomized controlled trials. All-cause mortality All 9 trials reported data on all-cause mortality. There were 753 deaths among the 2940 patients in the corticosteroid group (25.6%) and 1363 deaths among the 4967 patients in the control group (27.4%). The pooled result indicated that corticosteroids treatment could significantly reduce all-cause mortality in patients with COVID-19 (RR = 0.88, 95% CI [0.82, 0.95], P  = 0.002, I 2  = 28%) (Fig. 3 ). When subgroup analyses were performed, we found that corticosteroid use was associated with decreased all-cause mortality in severe COVID-19 (RR = 0.77, 95% CI [0.68, 0.88], P  < 0.0001, I 2  = 45%) (Fig. 4 ). However, no obvious difference was observed in all-cause mortality of non-severe COVID-19 between the corticosteroid and control group (RR = 0.96, 95% CI [0.86, 1.06], P  = 0.41, I 2  = 0%) (Fig. 4). Interestingly, a low dose (RR = 0.89, 95% CI [0.82, 0.97], P  = 0.007, I 2  = 0%) of dexamethasone (RR = 0.9, 95% CI [0.83, 0.98], P  = 0.01, I 2  = 0%) with a long treatment course (RR = 0.89, 95% CI [0.82, 0.98], P  = 0.02, I 2  = 5%) could reduce all-cause mortality in COVID-19 patients (Fig. 5, Fig. 6, Fig. 7 ).Fig. 3 Forest plot showing the all-cause mortality in COVID-19 patients. Fig. 4 Subgroup analysis for all-cause mortality according to the severity of COVID-19. Fig. 5 Subgroup analysis for all-cause mortality according to the corticosteroid dosage. Fig. 6 Subgroup analysis for all-cause mortality according to the corticosteroid type. Fig. 7 Subgroup analysis for all-cause mortality according to the corticosteroid treatment duration. Duration of hospitalization Two studies evaluated the length of hospital stay of non-severe COVID-19 patients; Data from the studies were pooled, and meta-analysis showed that corticosteroid use was significantly associated with longer length of hospital stay (MD = 3.83, 95% CI [1.11, 6.56], P  = 0.006, I 2  = 0%) (Fig. 8 ).Fig. 8 Forest plot showing the length of hospital stay in non-severe COVID-19. Discussion SARS-CoV-2 is a highly transmissible virus that caused the greatest pandemic of the century. At present, we are looking for effective treatments to control this deadly and evolving disease. In this meta-analysis, we have assessed the effect of corticosteroids in COVID-19 patients. Corticosteroids therapy could significantly reduce all-cause mortality in patients with COVID-19. When subgroup analysis was performed according to disease severity, we found that corticosteroid use was associated with a decreased all-cause mortality in severe COVID-19, but not in patients with non-severe COVID-19. Moreover, we performed other subgroup analyses according to the dosage, type and treatment duration of corticosteroids. The pooled results suggested that a low dosage and long-term use of dexamethasone could reduce all-cause mortality in COVID-19 patients. Finally, we also concluded that corticosteroid use might be associated with a longer length of hospital stay in non-severe COVID-19 patients. COVID-19-related respiratory or multi-organ failure might be due to an excessive immune response that damages pulmonary alveoli, leading to severe cytokine and chemokine storms with systemic effects.14 To dampen the inflammatory dysfunction, the administration of corticosteroids has attracted significant attention. In the past, corticosteroids have been used extensively in acute respiratory distress syndrome (ARDS), caused by SARS-CoV or Middle East respiratory syndrome (MERS)-CoV.15, 16 Nevertheless, there is no consensus that corticosteroid administration is helpful for COVID-19 patients, considering the possibility of delayed viral clearance, increased secondary infections or severe adverse events. Previous meta-analytical studies have evaluated the role of corticosteroids in COVID-19 patients and reached mixed conclusions. A meta-analysis written by Lu et al.17 addressing the impact of corticosteroids in adults and children with coronavirus diseases (MERS, SARS, and COVID-19) included five studies available for COVID-19 indicating that corticosteroid use did not reduce mortality and might instead prolong the duration of hospital stay in adults with COVID-19. Similarly, another meta-analysis18 reviewed 5249 patients from 1 randomized clinical trial and 10 cohort involving coronavirus-related diseases caused by SARS-CoV-2, SARS-CoV, and MERS-CoV. Of the 5249 patients, 1426 were COVID-19 patients. Taking everything into account, corticosteroids use in patients affected by coronavirus diseases delayed virus clearing, failed to improve survival. Notably, SARS, MERS and COVID-19 are phenotypically heterogeneous despite their close virus phylogeny19 and may pose significant selection bias, collectively reducing the quality of the conclusion. Contrary to previous results, a prospective meta-analysis20 published in JAMA concluded that corticosteroids were associated with lower 28-day all-cause mortality in critically ill patients with COVID-19. Subsequently, Ma et al.,21 conducted a meta-analysis of 7 RCTs that showed decreased all-cause mortality in severe COVID-19 patients following corticosteroid treatment. These two meta-analyses mainly focused on the effect of corticosteroid treatment on severe COVID-19 patients only and did not include non-severe COVID-19 patients. The results of our meta-analysis show that corticosteroids could reduce all-cause mortality in COVID-19 patients. Subsequently, subgroup analyses for mortality stratified by severity of disease, corticosteroids dosage, type and treatment duration were performed in this meta-analysis. Corticosteroid use was associated with decreased all-cause mortality in severe COVID-19 (RR = 0.77, 95% CI [0.68, 0.88], P  < 0.0001, I 2  = 45%), but not in non-severe COVID-19 patients (RR = 0.96, 95% CI [0.86, 1.06], P  = 0.41, I 2  = 0%). Survival benefit was observed with a low dosage (RR = 0.89, 95% CI [0.82, 0.97], P  = 0.007, I 2  = 0%) and long treatment course (RR = 0.89, 95% CI [0.82, 0.98], P  = 0.02, I 2  = 5%) of dexamethasone (RR = 0.9, 95% CI [0.83, 0.98], P  = 0.01, I 2  = 0%) in COVID-19 patients. Furthermore, our findings showed that corticosteroid use in non-severe COVID-19 patients might be related to a lengthier hospital stay (MD = 3.83, 95% CI [1.11, 6.56], P  = 0.006, I 2  = 0%). In non-severe COVID-19 people, an effective immune response with neutralizing antibodies promotes viral clearance and a short-lived inflammatory response.22 However, the immune response in patients with severe SARS-CoV-2 infection is quite strong, often resulting in ARDS or multi-organ dysfunction.23 Corticosteroids can reduce capillary dilation, inflammatory cell exudation, leukocyte infiltration, and phagocytosis in the early phase of inflammation, and also inhibit the excessive proliferation of capillaries and fibroblasts in the late stage.24 In conjunction with our results, treatment with corticosteroids appeared to be more beneficial in severe COVID-19. Moreover, the most effective type of corticosteroid treatment is another concern that needs to be addressed. In our study, dexamethasone could reduce all-cause mortality in COVID-19 patients, while a recent RCT demonstrated that methylprednisolone treatment was more beneficial than dexamethasone in COVID-19 treatment.25 Therefore, there is an urgent need for more RCTs to confirm and validate previous findings. Limitations Nevertheless, this meta-analysis has several limitations. Firstly, the study contained some high-quality RCTs, but the sample size of patients was dominated by the RECOVERY trial. Secondly, both severe and non-severe COVID-19 patients were included in our research, which might increase the overall heterogeneity. Thirdly, there was no unified standard for the type, time and dosage of corticosteroids used in the various studies. Fourthly, due to the limited data, we could not provide a meta-analysis on other outcomes such as organ support-free days, length of ICU stay, or duration of virus shedding. Lastly, some studies presented the data for continuous variables as the median and interquartile range (IQR), and we had to convert to mean and standard deviation. Conclusions The present meta-analysis revealed that corticosteroid therapy was related to reduced all-cause mortality in severe COVID-19 patients. However, in patients with non-severe COVID-19, the use of corticosteroids did not decrease the all-cause mortality and might instead prolong the duration of hospital stay. More importantly, we uncovered that extended use of low-dose dexamethasone could reduce all-cause mortality in COVID-19 patients. Nevertheless, more RCTs are needed to substantiate our conclusions. Author contributions YQZ, WZZ, and BHY searched databases and performed analysis. YQZ and WZZ wrote the manuscript. ZL and BHY designed the study and revised the manuscript. All authors read and approved the final manuscript. Funding This research received no external funding. Conflicts of interest The authors declare no conflict of interest. ==== Refs References 1 Phelan A.L. Katz R. Gostin L.O. The novel coronavirus originating in Wuhan, China: challenges for global health governance JAMA 323 2020 709 710 31999307 2 Chen G. Wu D. Guo W. Cao Y. Huang D. Wang H. Clinical and immunological features of severe and moderate coronavirus disease 2019 J Clin Invest 130 2020 2620 2629 32217835 3 Zhang W. Zhao Y. Zhang F. Wang Q. Li T. Liu Z. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China Clin Immunol 214 2020 108393 32222466 4 Horby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. Linsell L. Dexamethasone in hospitalized patients with Covid-19 N Engl J Med 384 2021 693 704 32678530 5 Jeronimo C.M.P. Farias M.E.L. Val F.F.A. Sampaio V.S. Alexandre M.A.A. Melo G.C. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): a randomized, double-blind, phase IIb. Placebo-controlled trial Clin Infect Dis 72 2021 e373 e381 32785710 6 Dequin P.F. Heming N. Meziani F. Plantefève G. Voiriot G. Badié J. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial JAMA 324 2020 1298 1306 32876689 7 Jamaati H. Hashemian S.M. Farzanegan B. Malekmohammad M. Tabarsi P. Marjani M. No clinical benefit of high dose corticosteroid administration in patients with COVID-19: a preliminary report of a randomized clinical trial Eur J Pharmacol 897 2021 173947 33607104 8 Annane D. Pastores S.M. Rochwerg B. Arlt W. Balk R.A. Beishuizen A. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Intensive Care Med 43 2017 1751 1763 28940011 9 Angus D.C. Derde L. Al-Beidh F. Annane D. Arabi Y. Beane A. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial JAMA 324 2020 1317 1329 32876697 10 Tomazini B.M. Maia I.S. Cavalcanti A.B. Berwanger O. Rosa R.G. Veiga V.C. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial JAMA 324 2020 1307 1316 32876695 11 Corral-Gudino L. Bahamonde A. Arnaiz-Revillas F. Gómez-Barquero J. Abadía-Otero J. García-Ibarbia C. Methylprednisolone in adults hospitalized with COVID-19 pneumonia: an open-label randomized trial (GLUCOCOVID) Wien Klin Wochenschr 133 2021 303 311 33534047 12 Edalatifard M. Akhtari M. Salehi M. Naderi Z. Jamshidi A. Mostafaei S. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial Eur Respir J 2020 56 13 Tang X. Feng Y.M. Ni J.X. Zhang J.Y. Liu L.M. Hu K. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind randomized control trial Respiration 100 2021 116 126 33486496 14 Solinas C. Perra L. Aiello M. Migliori E. Petrosillo N. A critical evaluation of glucocorticoids in the management of severe COVID-19 Cytokine Growth Factor Rev 54 2020 8 23 32616381 15 Arabi Y.M. Mandourah Y. Al-Hameed F. Sindi A.A. Almekhlafi G.A. Hussein M.A. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome Am J Respir Crit Care Med 197 2018 757 767 29161116 16 Stockman L.J. Bellamy R. Garner P. SARS: systematic review of treatment effects PLoS Med 3 2006 e343 16968120 17 Lu S. Zhou Q. Huang L. Shi Q. Zhao S. Wang Z. Effectiveness and safety of glucocorticoids to treat COVID-19: a rapid review and meta-analysis Ann Transl Med 8 2020 627 32566564 18 Li H. Chen C. Hu F. Wang J. Zhao Q. Gale R.P. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2 SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis Leukemia 34 2020 1503 1511 32372026 19 Petrosillo N. Viceconte G. Ergonul O. Ippolito G. Petersen E. COVID-19 SARS and MERS: are they closely related? Clin Microbiol Infect 26 2020 729 734 32234451 20 Sterne J.A.C. Murthy S. Diaz J.V. Slutsky A.S. Villar J. Angus D.C. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis JAMA 324 2020 1330 1341 32876694 21 Ma S. Xu C. Liu S. Sun X. Li R. Mao M. Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials Signal Transduct Target Ther 6 2021 83 33612824 22 Azkur A.K. Akdis M. Azkur D. Sokolowska M. van de Veen W. Brüggen M.C. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19 Allergy 75 2020 1564 1581 32396996 23 Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention Nat Rev Immunol 20 2020 363 374 32346093 24 Cruz-Topete D. Cidlowski J.A. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids Neuroimmunomodulation 22 2015 20 32 25227506 25 Ranjbar K. Moghadami M. Mirahmadizadeh A. Fallahi M.J. Khaloo V. Shahriarirad R. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial BMC Infect Dis 21 2021 337 33838657

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Med Clin (Engl Ed). 2022 Dec 23; 159(12):575-583

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Med Clin (Engl Ed)

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==== Front Med Clin (Engl Ed) Med Clin (Engl Ed) Medicina Clinica (English Ed.) 2387-0206 Elsevier España, S.L.U. S2387-0206(22)00555-1 10.1016/j.medcle.2022.02.028 Original Article Predicting the response to methylprednisolone pulses in patients with SARS-COV-2 infection Predicción de la respuesta a pulsos de metilprednisolona en pacientes con infección por SARS-COV-2Sarriá-Landete Antonio J. a⁎ Crespo-Matas José A. a Domínguez-Quesada Inmaculada a Castellanos-Monedero Jesús J. a Marte-Acosta Dinés b Arias-Arias Ángel J. c a Departamento de Medicina Interna, Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real, Spain b Departamento de Neumología, Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real, Spain c Departamento de Investigación, Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real, Spain ⁎ Corresponding author. 15 12 2022 23 12 2022 15 12 2022 159 12 557562 11 7 2021 23 2 2022 © 2022 Elsevier España, S.L.U. All rights reserved. 2022 Elsevier España, S.L.U. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Introduction Treating systemic inflammation caused by SARS-COV 2 (COVID-19) has become a challenge for the clinician. Corticosteroids have been the turning point in the treatment of this disease. Preliminary data from Recovery clinical trial raises hope by showing that treatment with dexamethasone at doses of 6 mg/day shows a reduction on morbidity in patients requiring added oxygen therapy. However, both the start day or what kind of corticosteroid, are still questions to be clarified. Since the pandemic beginning, we have observed large differences in the type of corticosteroid, dose and initiation of treatment. Our objective is to assess the predictive capacity of the characteristics of patients treated with methylprednisolone pulses to predict hospital discharge. Materials and methods We presented a one-center observational study of a retrospective cohort. We included all patients admitted between 03/06/2020 and 05/15/2020 because of COVID-19. We have a total number of 1469 patients, of whom 322 received pulses of methylprednisolone. Previous analytical, radiographic, previous disease data were analyzed on these patients. The univariant analysis was performed using Chi-squared and the T test of Student according to the qualitative or quantitative nature of the variables respectively. For multivariate analysis, we have used binary logistic regression and ROC curves. Results The analysis resulted statistically significant in dyspnea, high blood pressure, dyslipidemia, stroke, ischemic heart disease, cognitive impairment, solid tumor, C-reactive protein (CRP), lymphopenia and d-dimer within 5 days of admission. Radiological progression and FIO2 input are factors that are associated with a worst prognosis in COVID-19 that receive pulses of methylprednisolone. Multivariate analysis shows that age, dyspnea and C-reactive protein are markers of hospital discharge with an area below the curve of 0.816. Conclusions In patients with methylprednisolone pulses, the capacity of the predictive model for hospital discharge including variables collected at 5 days was (area under the curve) 0.816. Introducción Tratar la inflamación sistémica producida por el SARS-COV 2 (COVID-19) se ha convertido en un reto para el clínico. Los corticoides han sido el punto de inflexión en el tratamiento de esta enfermedad. Los datos preliminares del ensayo clínico Recovery alentan esperanza mostrando que con el tratamiento con dexametasona a dosis de 6 mg/día hay una disminución de la morbimortalidad en pacientes que requieren oxigenoterapia añadida. Sin embargo, tanto el día de inicio, o qué tipo de corticosteroide, son todavía preguntas por aclarar. Desde el inicio de la pandemia hemos observado grandes diferencias en cuanto al tipo de corticoide, dosis e inicio de tratamiento. Nuestro objetivo es valorar la capacidad predictiva de las características de los pacientes tratados con bolos de metilprednisolona para predecir el alta hospitalaria. Materiales y métodos Presentamos un estudio unicéntrico observacional de cohorte retrospectiva. Incluimos a todos los pacientes ingresados entre el 06/03/2020 y el 15/05/2020 por COVID-19. Contamos con un número total de 1469 pacientes, de los cuales 322 recibieron pulsos de metilprednisolona. De estos pacientes se analizaron los datos clínicos, analíticos, radiográficos, enfermedades previas. El análisis univariante se realizó mediante Chi cuadrado y el test t de Student según la naturaleza cualitativa o cuantitativa de las variables respectivamente. Para el análisis multivariante hemos empleado la regresión logística binaria y las curvas ROC. Resultados En el análisis resultó estadísticamente significativo la disnea, hipertensión arterial, dislipemia, accidente cerebrovascular, cardiopatía isquémica, deterioro cognitivo, tumor sólido, la proteína C reactiva (PCR), linfopenia y d-dímero a los 5 días de ingreso. La progresión radiológica y de aporte de FIO2 son factores que se asocian a peor pronóstico en la COVID-19 que reciben pulsos de metilprednisolona. En el análisis multivariante se observa que la edad, disnea y la proteína C reactiva son marcadores de alta hospitalaria con un área bajo la curva de 0,816. Conclusión En pacientes con bolos de metilprednisolona, la capacidad del modelo predictivo del alta hospitalaria incluyendo variables recogidas a los 5 días ha sido (Área Bajo la Curva) de 0.816. Keywords COVID-19 virus infection Corticosteroids Methylprednisolone Predictive model Treatment Internal medicine SARS-CoV-2 Palabras clave Infección por COVID-19 Corticoesteroides Metilprednisolona Modelo predictivo Tratamiento Medicina interna SARS-CoV-2 ==== Body pmcIntroduction At the end of December 2019, the first cases of severe viral pneumonia of unknown etiology were reported in China and weeks later it was confirmed that it was a new coronavirus, called SARS-CoV-2.1 Coronaviruses receive their name by crown-shaped microscopic morphology on their surface, and there are four main subgroups of coronavirus known as alpha, beta, gamma, and delta. SARS-CoV-2 belongs to the beta group and is one of the seven coronaviruses that infect humans.2 SARS-CoV-2 shares many genetic characteristics with other similar viruses, such as SARS-CoV and MERS-CoV. As they are peer viruses, they also have shared clinical characteristics in terms of their behavior.1, 3 Due to this genetic and clinical similarity between SARS-CoV-2, SARS-CoV and MERS-CoV, and the absence of scientific evidence on the benefits of glucocorticoid use in the treatment of viral pneumonia, this therapy was initially not recommended for its management.4, 5, 6 In addition, some studies defend that the use of corticosteroids could delay viral clearance and even increase mortality.1, 4, 7, 8 Over time we have gained more knowledge about SARS-COV2, both in pathological behavior and clinical spectrum. Currently, two main phases have been defined in the pathogenesis of the disease, the first, in which direct damage by the virus predominates, and the second due to the hyper-inflammatory response of the host. These phases are usually overlaid for a few days, in which the patient may develop an intermediate phase that has a pulmonary commitment to or without hypoxia and slightly elevated analytical inflammation markers.9, 10, 11 In the second phase of the disease, there is extrapulmonary systemic hyperinflammation in which there is a decrease in T-cell count and a storm of inflammatory cytokines that overshadow the prognosis of the disease. Cytokine storm is a very serious complication in SARS-CoV-2 infection by in many cases committing the lives of patients.12 Several articles have been published on the beneficial use of glucocorticoids, including the randomized recovery (Randomized Evaluation of COVID-19 therapy), which was initiated in March 2020 to approve potential treatments for COVID-19 in a total of 176 hospitals in the UK, which has shown that the use of dexamethasone at doses of 6 mg/day reduces mortality, the need for mechanical ventilation and oxygen therapy.13 The doses of corticosteroids used have been very varied. The study made by Callejas R et al. used pulses of methylprednisolone doses of 2 mg/kg/d, 250 mg/d or 500 mg/d for 3 days in patients meeting cytokine release syndrome (FTA) criteria defined as an elevation of IL6 > 40 pg/ml and/or 2 of the following: ferritin > 300 μg/l, d-dimer > 1 mg/l, triglycerides > 300 mg/dl. This study found that pulses of methylprednisolone could decrease the outcome of intubation or death.14 The poor prognostic risk factors present in the different patients admitted because of SARS-COV-2 pneumonia such as age, diabetes, hypertension and tobacco, together with the variability of response to hospital treatment makes it essential to find which factors are associated with a better pharmacological response.15 The clear benefit of corticosteroids in SARS-COV-2 disease, as well as in viruses counterpart to it, is likely to be based on three fundamental pillars: the dose, when to start and the patient's profile better corticoid responder. The objective of our study was to analyze the factors that influence the response to methylprednisolone pulses and determine whether there is a mathematical model to predict that response. Methods This is an observational retrospective cohort study in which patients admitted to the La Mancha Centro General Hospital (HGMC) in Alcázar de San Juan with a diagnosis of respiratory infection or SARS-CoV-2 pneumonia were included between 03/06/2020 and 05/15/2020. A total of 1469 patients were collected from these receiving pulses of methylprednisolone 322. In all patients, the diagnosis of COVID-19 was confirmed by nucleic acid detection amplification test (RT-PCR) or by a rapid antigenic test with nasopharyngeal swabs. Patients were treated at doses of 250 mg/24 h/3 days or 500 mg/24 h/3 days according to the hospital protocol that allowed these doses to be used, all patients have been grouped for statistical analysis. The characteristics have been explored by grouping patients into hospital discharge and deceased. Demographic characteristics, personal history such as cardiovascular risk factors (arterial hypertension, diabetes, dyslipidemia, tobacco), lung diseases (chronic obstructive pulmonary disease (COPD) asthma), stroke, ischemic heart disease, cognitive impairment, solid tumor, autoimmune diseases, as well as previous treatments were collected. In addition, we analyzed the clinical characteristics of the disease (such as symptoms, start date, progressive oxygen therapy needs). Analytical data at admission, at five days of stay and discharge, including hemoglobin levels, absolute lymphocytes, creatinine, transaminases, C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase (LDH) and Interleukin 6 (IL6). We checked for differences in the degree of pulmonary involvement, based on X-ray findings using chest X-rays upon entry and discharge. As a radiological criterion for assessing the degree of pulmonary involvement by COVID-19, we used the scale proposed by Warren et al. called RALE score (Radiographic Assessment of lung), used for radiographic evaluation in pulmonary edema. A score of 0–4 was assigned for each lung depending on the affected lobes, with 0-normal and 4 being an affectation greater than 75%.16 Statistical analysis Qualitative variables were analyzed using the Chi-square test and the quantitative variables Student's T test. To compare which variables were independently associated with the final result of our study (hospital discharge), a binary logistic regression analysis was performed, with those variables that were statistically significant from the univariate analysis previously performed with a p  < 0.05. Using the ROC curve, we analyzed the sensitivity and specificity of the equation generated by logistic regression. The statistical analysis was performed with the SPSS version 21.0 program. Results 1469 patients were admitted in Hospital General Mancha Centro during the study period. Of these, 322 received pulses of methylprednisolone and were included in our study. Finally, 247 patients (76.7%) were discharged and 75 died (23.3%). The main clinical and demographic characteristics of the patients included are presented in Table 1 . Briefly, the mean age was 68.4 ± 15.2 years (rank 1–99). Patients who died were older (mean [SD] age, 76.5 [11.1] years vs. 65.9 [15.4] years; p  < 0.001) than patients who survived. In our study, we have not observed significant differences in sex in patients where corticosteroid bolus was used (50.9% were male and 49.1% were female) neither in their mortality rates.Table 1 Demographic, baseline comorbidities and clinical characteristics at admission of patients with COVID-19, and differences between patients who survived and dead. COPD: chronic obstructive pulmonary disease. Table 1 Overall (n = 322) Dead (n = 75) Discharged (n = 247) p Mean age at admission, years (SD; rank) 68.4 (15.2; 1–99) 76.5 (11.1; 47–99) 65.9 (15.4; 1–96) <0.001 Sex  Male, n (%) 164 (50.9%) 43 (57.3%) 121 (49%) 0.205  Female; n (%) 158 (49.1%) 32 (42.7%) 126 (51%) Smoker  No; n (%) 138 (61.1%) 27 (46.6%) 111 (66.1%) 0.019  Yes; n (%) 19 (8.4%) 5 (8.6%) 14 (8.3%)  Former; n (%) 69 (30.5%) 26 (44.8%) 43 (25.6%)  No data; n (%) 96 (29.8%) 17 (22.7%) 79 (32%) – Arterial hypertension; n (%) 194 (60.2%) 60 (80%) 134 (54.3%) <0.001 Dyslipidemia; n (%) 107 (33.2%) 32 (42.7%) 75 (30.4%) 0.048 Diabetes; n (%) 102 (31.7%) 29 (38.7%) 73 (29.6%) 0.137 Obesity; n (%) 63 (19.6%) 16 (21.3%) 47 (19%) 0.659 COPD; n (%) 30 (9.3%) 10 (13.3%) 20 (8.1%) 0.172 Asthma; n (%) 17 (5.3%) 3 (4%) 14 (5.7%) 0.771 Cerebrovascular accident; n (%) 19 (5.9%) 8 (10.7%) 11 (4.5%) 0.048 Ischemic heart disease; n (%) 35 (10.9%) 14 (18.7%) 21 (8.5%) 0.013 Venous thromboembolic disease; n (%) 14 (4.3%) 4 (5.3%) 10 (4%) 0.746 Cognitive impairment; n (%) 30 (9.3%) 12 (16%) 18 (7.3%) 0.023 Peripheral vascular disease; n (%) 10 (3.1%) 1 (1.3%) 9 (3.6%) 0.312 Chronic kidney disease; n (%) 28 (8.7%) 9 (12%) 19 (7.7%) 0.246 Autoimmune disease; n (%) 15 (4.7%) 2 (2.7%) 13 (5.3%) 0.543 Solid tumor; n (%) 41 (12.7%) 15 (20%) 26 (10.5%) 0.031 Leukemia; n (%) 7 (2.2%) 3 (4%) 4 (1.6%) 0.360 Symptoms  Cough; n (%) 193 (59.9%) 45 (60%) 148 (59.9%) 0.990  Fever; n (%) 199 (61.8%) 50 (66.7%) 149 (60.3%) 0.322  Dyspnea; n (%) 205 (63.7%) 61 (81.3%) 144 (58.3%) <0.001  Chest pain; n (%) 22 (6.8%) 5 (6.7%) 17 (6.9%) 0.948  Ageusia; n (%) 11 (3.4%) 2 (2.7%) 9 (3.6%) 0.999  Anosmia; n (%) 11 (3.4%) 0 11 (4.5%) 0.074  Diarrhea; n (%) 41 (12.7%) 8 (10.7%) 33 (13.4%) 0.540  Vomiting; n (%) 20 (6.2%) 6 (8%) 14 (5.7%) 0.426  Syncope; n (%) 6 (1.9%) 1 (1.35) 5 (2%) 0.999 The most common comorbidities in our patients were hypertension (60.2%), dyslipidemia (33.2%), diabetes (31.7%), and obesity (19.6%). A significant higher frequency of hypertension (80% vs. 54.3%; p  < 0.001), dyslipidemia (42.7% vs. 30.4%; p  = 0.048), cerebrovascular accident (10.7% vs. 4.5%; p  = 0.048), ischemic heart disease (18.7% vs. 8.5%; p  = 0.013), venous thromboembolic disease (16% vs. 7.3%; p  = 0.023) and solid tumors (20% vs. 10.5%; p  = 0.031) was observed among those patients who died compared to those who survived. The main symptoms were dyspnea, fever and cough (in 60% of patients), although only dyspnea was higher in patients who died compared to survivors (81.3% vs. 58.3%; p  < 0.001). Less frequently, the patients experienced chest pain, ageusia, anosmia, diarrhea, nausea and vomiting or syncope (Table 1). Laboratory findings at admission and at 5-days are presented in Table 2 . Patients with methylprednisolone pulses who died from COVID-19 infection had a elevation of lymphopenia, creatinine, D-dimer, AST and CRP values in comparison with discharged patients, both on admission and after 5 days (p  < 0.05). Parameters such as ferritin, hemoglobin, and ALT were not significant in our study.Table 2 Laboratory values, expressed as median ± interquartile range, at admission and 5 days of patients with COVID-19 overall, and in those who survived or died. Table 2 Overall Dead Discharged p Admission  Radiography at admission   Normal (0 points) 27 (8.6%) 1 (1.3%) 26 (10.9%) <0.001   Mild (1–2 points) 72 (23%) 11 (14.7%) 61 (25.6%)   Moderate (3–6 points) 151 (48.2%) 36 (48%) 115 (48.3%)   Severe (>6 points) 63 (20.1%) 27 (36%) 36 (15.1%)  Hemoglobin, g/dL 13 ± 2.6 13 ± 3 13 ± 2.5 0.899  Lymphocytes, 103/μL 0.9 ± 0.7 0.6 ± 0.75 1 ± 0.6 <0.001  Creatinine, mg/dL 0.8 ± 0.4 1.1± 0.5 0.9 ± 0.4 <0.001  D-dimer, ng/mL 1.1 ± 1.3 2.1 ± 2.5 0.9 ± 1 <0.001  Ferritin, ng/mL 584 ± 686 576.5 ± 881 584 ± 661 0.733  AST, U/L 29 ± 24.2 39 ± 33 27 ± 23 0.003  ALT, U/L 26 ± 29 27 ± 27 25 ± 29 0.756  C-reactive protein, mg/L 6.5 ± 12.2 16 ± 21.4 6 ± 9 <0.001 5 days  Hemoglobin, g/dL 12.6 ± 2.8 12.3 ± 3 12.7 ± 2.9 0.904  Lymphocytes, 103/μL 0.9 ± 07 0.55 ± 0.6 1 ± 2.4 0.007  Creatinine, mg/dL 0.8 ± 0.3 1 ± 0.6 0.8 ± 0.4 0.022  D-dimer, ng/mL 1 ± 2.1 2.5 ± 5.3 0.9 ± 2 0.025  Ferritin, ng/mL 650 ± 1187 563 ± 1300 669 ± 1206 0.999  AST, U/L 28 ± 24 38 ± 62.5 27 ± 21 0.038  ALT, U/L 28.5 ± 40 41 ± 40.8 28 ± 40 0.300  C-reactive protein, mg/L 3.3 ± 6 11.1 ± 19.3 3.1 ± 5 0.034 We also see in Table 2, patients with the greatest involvement in chest X-ray during admission had a higher probability to death. However, patients with normal or mild chest X-ray at the onset of the disease were more likely to be hospital discharged (p  < 0.001). In this sense, patients who needed a progressive increase in oxygen therapy during admission had a higher probability of dying (58.7% vs. 27.1%; p  < 0.001). Finally, a binary logistic regression was performed, obtaining a predictive model in which those patients with lower age (OR: 0.933 [95%CI: 0.902–0.965]), less elevated PCR at admission (OR: 0.916 [0.886–0.948]) and not suffer from dyspnea (OR: 0.383 [0.164–0.894]) have a higher rate of hospital discharge (Table 3 ).Table 3 Binary logistic regression model to predict hospital discharge. Table 3 Estimated parameter (B) Standard error OR (95% CI) p Age −0.069 0.017 0.933 (0.902–0.965) <0.001 CRP at admission −0.087 0.017 0.916 (0.886–0.948) <0.001 Dyspnea −0.959 0.432 0.383 (0.164–0.894) 0.026 Constant 8.202 1.400 – – The resulting equation for determining the good response to corticosteroid bowling is Hospital discharge is 8202 + (Age* − 0.069) + (CRP* − 0.087) + (Dyspnea* − 0.959). To establish sensitivity and specificity for the use of our equation we make an ROC curve, resulting in an area under the curve of 0.816 (Fig. 1 ) with a confidence interval (95% CI: 0.751–0.880).Fig. 1 ROC curve: area under the curve of 0.816 with a confidence interval (95% CI: 0.751–0.880). Discussion The benefit of corticosteroids in SARS-COV-2 infection could be defined based on three factors: the dose, the day of initiation and the profile of the responding patient to these. In our study, we try to find the patient profile best responding to pulses of methylprednisolone as a treatment for SARS-CoV-2 infection. We have observed with high sensitivity and specificity that, at a lower age and lower value of the C-reactive protein (CRP) at admission and not suffer from dyspnea, better response to corticosteroid pulses, understood as a result of hospital discharge. Ripe old age presents an increased risk of serious illness or even death in COVID-19, this could be related to immunosenescence. Immunosenescence results in a decrease in CD3+ T cell generation and a loss of CD8+ T cells resulting in an inversion of the usual CD4/CD8 ratio. In addition, there is an increase in regulatory T cells and a decrease in B lymphocytes. Wu et al. in their retrospective cohort study observed how elderly patients had an increased risk of acute respiratory distress syndrome and death and people who survived in their cohort had higher levels of CD8 T cells significantly.17, 18 Fan Wang et a establishes in his study a high CD4/CD8 ratio, as immunosenescence has been linked to greater severity in SARS-CoV-2 infection. In addition, it identified the decrease or loss of T CD8+ as an independent factor of gravity by COVID-19. Therefore, lymphocyte dysregulation could be the point of similarity of poor prognosis between elderly patients and patients severely ill with COVID-19.19 One of the main mechanisms by which corticosteroids suppresses inflammation is to prevent access of lymphocytes and macrophages to the inflammatory site, causing transient lymphopenia after treatment and may contribute to this lymphocyte dysregulation.20, 21 In Sterne's meta-analysis22 which includes up to 55 studies, the association between corticosteroids and mortality, OR was 0.69 (95% CI, 0.51–0.93) among 880 patients over 60 years of age, OR was 0.67 (95% CI, 0.48–0.94) among 821 patients 60 years of age or younger (OR ratio, 1.02 [95% CI, 0.63–1.65], p  × 0.94). According to this meta-analysis, corticosteroid treatment in patients between 60 years of age or younger does not affect mortality as its OR value is close to 1. For patients over 60 years old, the effect of corticosteroid therapy has a protective effect since the value of OR was 0.67. However, these results must be interpreted considering their confidence interval. In our study the meaning is aimed at young patients, it can largely be because the epidemiological characteristics of our environment tend to an average age of about 66 years which is in line with the results of this study. In the RECOVERY study (with an average age of 66 years with a 15-year-old ID), shows that the use of dexamethasone for up to 10 days among patients hospitalized by COVID-19 showed a reduction in mortality to 28 days. Age-related outcomes were divided into three age groups whose results were RR close to one for patients between 70 and 80 years, indicating that there is association. Corticosteroid therapy is a protective factor for patients with COVID under 70 years of age, which is in the same trend as our study with an RR of 0.64. C-reactive protein (CRP) is a marker that reflects systemic inflammation, as well as being a poor prognosis factor in SARS-COV-2 acute inflammatory response syndrome. We have observed that at lower CRP within 5 days of admission better corticoid response and a greater likelihood of receiving hospital discharge. Li Yan et al. establish in their study a rapidly used gravity model for the first emergency assessment of the patient with SARS-CoV-2 infection from 3 analytic parameters: CRP, LDH and lymphopenia.23 Other predictive models such as Allenbach et al.24 define as a high-risk group both age and CRP, lymphopenia, IL-6 levels and radiological impact. It also defines as independent factors that are associated with poor prognosis >60 age and elevated CRP levels. In our study the lymphopenia at admission was not significant but it did show differences within 5 days of admission darkening the prognosis of patients with a higher rate of death. We continue to collect data in this regard to optimize the predictive model. Dong Ji et al.25 establishes a predictive risk model called CALL (Comorbidity, Age, Lymphocyte and LDH), where it predicts with a ROC area of 0.91 that patients with comorbidity (hypertension, diabetes, cardiovascular disease, liver disease, asthma, chronic lung disease, HIV infections and malignancy for at least 6 months), elderly (>60 years), lymphopenia (<1000) and increased Lactate Dehydrogenase (LDH) (>500 U/l) predict a poor evolution of the disease. Ze Chen et al.26 develop the latest available predictive gravity model, called OURMAPCN score based on baseline data on entry. This predictive model was created from 6415 patients from a Wuhan cohort and validated with two patient cohorts one Italian and one from independent sites in China. Ze Chen et al. tried to facilitate the use of their tool by dichotomizing their 8 variables used. These variables included age >60 and CRP > Upper Mortality Limit (LSM) as severity criteria. As for autoimmune diseases (EI) and their association with good response to corticosteroid pulses in our study was not significant. Published articles state that patients with autoimmune diseases are at a lower risk of entering an ICU and needing VMNI. This could be because in this study most patients were undergoing treatment based on corticotherapy and classic (non-biological) disease-modifying rheumatologically drugs.12, 27 Therefore, most predictive models state that both age and CRP are 2 of the fundamental parameters that change the prognosis of the disease. In our study, we have used pulses of methylprednisolone and tried to find the main characteristics of the responding patient. In our study age and CRP and not suffer from dyspnea are related to an increased likelihood of hospital discharge. As a major limitation of our study, the days of symptoms for the initiation of treatment have not been considered. It would be interesting to optimize the predictive model to assess the use of corticosteroids from the 7 days of symptoms, as assessed in the preliminary recovery study in which the response improved. In addition, the integral number of patients studied with pulses of methylprednisolone bolus is somewhat limited, with 322. These two limitations will try to correct them with our new updated patient cohort pending publication, as well as improve and validate our predictive corticosteroid pulse response model. Another important limitation of the study is that other simultaneous use treatments such as tocilizumab (anti-interleukin 6) have not been considered. Conclusion Due to the enormous interpersonal variability of corticoid response during the COVID-19 pandemic, it has become essential to find the characteristics that allow us to know the prognosis and evolution of patients starting with the treatment. In our study, we reveal an equation with the area under the curve of 0.816 that allows us to determine the response to pulses of methylprednisolone measured as hospital discharge. C-reactive protein at admission, age and dyspnea are easy parameters to obtain and allow us to know in advance the prognosis after methylprednisolone pulses. Conflict of interest The authors declare that they have no conflict of interest. ==== Refs References 1 Gobierno de España-Ministerio de Sanidad. Manejo clínico del COVID-19: Tratamiento médico. Minist Sanid [Internet]. 2020;1–23. Available from: https://fundacionio.com/wp-content/uploads/2020/03/Protocolo_manejo_clinico_tto_COVID-19.pdf. 2 Wu R. Wang L. Kuo H.C.D. Shannar A. Peter R. Chou P.J. An update on current therapeutic drugs treating COVID-19 Curr Pharmacol Rep 6 2020 56 70 32395418 3 Li H. Chen C. Hu F. Wang J. Zhao Q. Gale R.P. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2 SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis Leukemia 34 2020 1503 1511 32372026 4 Zhou W. Liu Y. Tian D. Wang C. Wang S. Cheng J. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia Signal Transduct Target Ther 5 2020 1 7 32296011 5 Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Lancet 395 2020 473 475 32043983 6 Ye Z. Wang Y. Colunga-Lozano L.E. Prasad M. Tangamornsuksan W. Rochwerg B. Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis CMAJ 192 2020 E755 E767 7 Ni Y.N. Chen G. Sun J. Liang B.M. Liang Z.A. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis Crit Care 23 2019 1 18 30606235 8 Stockman L.J. Bellamy R. Garner P. SARS: systematic review of treatment effects PLoS Med 3 2006 1525 1531 9 Siddiqi H.K. Mehra M.R. COVID-19 illness in native and immunosuppressed states: a clinical–therapeutic staging proposal J Heart Lung Transplant 39 2020 405 407 32362390 10 To K.K.W. Tsang O.T.Y. Leung W.S. Tam A.R. Wu T.C. Lung D.C. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study Lancet Infect Dis 20 2020 565 574 10.1016/S1473-3099(20)30196-1 32213337 11 Majmundar M. Kansara T. Lenik J.M. Park H. Ghosh K. Doshi R. Efficacy of corticosteroids in non-intensive care unit patients with COVID-19 pneumonia from the New York Metropolitan region PLoS ONE 15 2020 1 18 12 Bhaskar S. Sinha A. Banach M. Mittoo S. Weissert R. Kass J.S. Cytokine storm in COVID-19 – immunopathological mechanisms clinical considerations, and therapeutic approaches: the REPROGRAM consortium position paper Front Immunol 11 2020 1 31 32038653 13 RECOVERY Collaborative GroupHorby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. Dexamethasone in hospitalized patients with Covid-19 N Engl J Med 384 2021 693 704 10.1056/NEJMoa2021436 Epub 2020 July 17. PMID: 32678530; PMCID: PMC7383595 32678530 14 Callejas Rubio J.L. de Luna del Castillo J. de la Hera Fernández J. Guirao Arrabal E. Colmenero Ruiz M. Ortego Centeno N. Eficacia de los pulsos de corticoides en pacientes con síndrome de liberación de citocinas inducido por infección por SARS-CoV-2 Med Clin (Barc) 155 2020 159 161 15 Figliozzi S. Masci P.G. Ahmadi N. Tondi L. Koutli E. Aimo A. Predictors of adverse prognosis in COVID-19: a systematic review and meta-analysis Eur J Clin Invest 50 2020 1 15 16 Wong H.Y.F. Lam H.Y.S. Fong A.H.T. Leung S.T. Chin T.W.Y. Lo C.S.Y. Frequency and distribution of chest radiographic findings in patients positive for COVID-19 Radiology 296 2020 E72 E78 32216717 17 Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA Intern Med 180 2020 934 943 32167524 18 Chen Y. Klein S.L. Garibaldi B.T. Li H. Wu C. Osevala N.M. Aging in COVID-19: vulnerability, immunity and intervention Ageing Res Rev 65 2021 1 30 19 Pallotto C. Suardi L.R. Esperti S. Tarquini R. Grifoni E. Meini S. Increased CD4/CD8 ratio as a risk factor for critical illness in coronavirus disease 2019 (COVID-19): a retrospective multicentre study. Vol. 52. Infectious diseases 2020 Taylor and Francis Ltd. 675 677 20 Fauci A.S. Dale D.C. Balow J.E. Glucocorticosteroid therapy: mechanisms of action and clinical considerations Ann Intern Med 84 1976 304 315 769625 21 Fan P.T. Yu D.T. Clements P.J. Fowlston S. Eisman J. Bluestone R. Effect of corticosteroids on the human immune response: comparison of one and three daily 1 gm intravenous pulses of methylprednisolone J Lab Clin Med 91 1978 625 634 76667 22 Sterne J.A.C. Diaz J. Villar J. Murthy S. Slutsky A.S. Perner A. Corticosteroid therapy for critically ill patients with COVID-19: a structured summary of a study protocol for a prospective meta-analysis of randomized trials Trials 21 2020 23 Yan L. Zhang H.-T. Goncalves J. Xiao Y. Wang M. Guo Y. An interpretable mortality prediction model for COVID-19 patients Nat Mach Intell 2 2020 283 288 10.1038/s42256-020-0180-7 24 Allenbach Y. Desarrollo de un modelo de predicción multivariable de transferencia de unidades de cuidados intensivos o muerte: Un estudio prospectivo francés de cohortes de pacientes hospitalizados con COVID-19 2020 4 11 25 Ji D. Zhang D. Xu J. Chen Z. Yang T. Zhao P. Prediction for progression risk in patients with COVID-19 pneumonia: the CALL score Clin Infect Dis 71 2020 1393 1399 32271369 26 Chen Z. Chen J. Zhou J. Lei F. Zhou F. Qin J.J. A risk score based on baseline risk factors for predicting mortality in COVID-19 patients Curr Med Res Opin 37 2021 917 927 10.1080/03007995.2021.1904862 33729889 27 Sarmiento-Monroy J.C. Espinosa G. Londoño M.C. Meira F. Caballol B. Llufriu S. Immunocovid clinic. A multidisciplinary registry of patients with autoimmune and immune-mediated diseases with symptomatic COVID-19 from a single center J Autoimmun 117 2021 102580 10.1016/j.jaut.2020.102580 Epub 2020 November 30. PMID: 33338707; PMCID: PMC7836738 33338707

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==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 34952937 10.1038/s41390-021-01879-8 nihpa1758478 Article Mechanisms and Modulation of Sepsis-Induced Immune Dysfunction in Children Mithal Leena B. MD MSCI 1 Arshad Mehreen MD 1 Swigart Lindsey R. APN 2 Khanolkar Aaruni MBBS PhD 3 Ahmed Aisha MD 4 Coates Bria MD 2 1 Department of Pediatrics, Division of Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago; Northwestern University Feinberg School of Medicine 2 Department of Pediatrics, Division of Critical Care, Ann & Robert H. Lurie Children’s Hospital of Chicago; Northwestern University Feinberg School of Medicine 3 Department of Pathology, Division of Pediatric Pathology, Ann & Robert H. Lurie Children’s Hospital of Chicago; Northwestern University Feinberg School of Medicine 4 Department of Pediatrics, Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago; Northwestern University Feinberg School of Medicine Author contributions: All co-authors included on this manuscript have contributed to the conception, content, review of manuscript, and agree to the submitted version of this review article. Correspondence and requests for materials should be addressed to Leena B. Mithal, MD MSCI at lmithal@luriechildrens.org or Bria Coates, MD at bcoates@luriechildrens.org. Address: Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Avenue, Chicago IL, 60611 23 11 2021 1 2022 24 12 2021 15 12 2022 91 2 447453 Reprints and permissions information is available at www.nature.com/reprints. Summary paragraph/Abstract Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells. Dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression that can result in immunoparalysis. In this review, we discuss components of immune dysregulation in sepsis, biomarkers and functional immune assays to aid in immunophenotyping patients, and evolving immunomodulatory therapies. Important research gaps for the future include: 1) Defining how age, host factors including prior exposures, and genetics impact the trajectory of sepsis in children, 2) Developing tools for rapid assessment of immune function in sepsis, and 3) Assessing how evolving pediatric sepsis endotypes respond differently to immunomodulation. Although multiple promising immunomodulatory agents exist or are in development, access to rapid immunophenotyping will be needed to identify which children are most likely to benefit from which therapy. Advancements in the ability to perform multidimensional endotyping will be key to developing a personalized approach to children with sepsis. ==== Body pmcIntroduction According to the international consensus guidelines, sepsis is defined as a life-threatening state of organ dysfunction that is caused by a dysregulated host response to a pathogen1. Globally, sepsis contributes to more than 20% of all deaths in the pediatric age group, with children <5 years of age being particularly vulnerable2. Mortality in severe sepsis varies widely by geographical region, and can be as high as: 21% in North America, 29% in Europe, 32% in Australia/New Zealand, 40% in Asia, 11% in South America, and 40% in Africa3. The majority of pediatric patients (67%) present with multi-organ dysfunction syndrome (MODS) at the onset of sepsis, with a further 30% also developing MODS in the first 7 days of sepsis. Among survivors across all age groups, up to 28% may have mild disability, and 17% may have moderate disability at the time of hospital discharge3. Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Immune cell activation and inflammatory responses can result in a spectrum of immune dysregulation characterized by excess inflammation, compensatory immune suppression, and immune-mediated organ damage. Although the immune system matures significantly throughout childhood4,5, our understanding of how this underlying immunologic maturation impacts the features and outcomes of sepsis in children is evolving6. In this review we discuss the key components of immune dysregulation in sepsis, biomarkers to aid in immunophenotyping patients during acute illness and recovery, and evolving immunomodulatory therapies. Immune dysregulation in sepsis Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells7 (Figure 1). The initial stages of sepsis are marked by a pro-inflammatory state with activation of the innate immune system7. Invading pathogens are recognized by the host immune system through pattern recognition receptors (PRRs) on innate immune cells (monocytes and neutrophils) and somatic tissues8. Invading microbes, both commensal and pathogenic, express pathogen-associated molecular patterns (PAMPs), which are recognized by PRRs, including toll-like receptors (TLRs), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs). Similarly, host tissue components that are released after cell damage and breakdown are recognized as damage-associated molecular patterns (DAMPs)7,9. Overall, activation of innate immune cells through these mechanisms results in release of pro-inflammatory cytokines including IL-1, IL-2, IL-6, IFN-gamma, and TNF-α8. There is additional activation of the complement system that together with the cytokine storm can result in further damage to host tissue and worsening multi-organ failure10. If this initial phase of sepsis does not resolve promptly, overactivation of the immune system can be accompanied by an excessive anti-inflammatory and potentially immunosuppressive response that can result in an increased risk of secondary infections11. Multiple cells of both the innate and adaptive immune system have been found to be dysfunctional during sepsis. Neutrophils, which play a key role in host defense against bacterial pathogens, have been shown to have altered chemotaxis and recruitment to the site of infection, impaired phagocytic activity, defects in the production of reactive oxygen species (ROS), and altered secretion of pro-inflammatory cytokines12. Each of these alterations in neutrophil function may contribute to failure to control the initial infection. Concurrently, exaggerated production of neutrophil extracellular traps (NETs), a chromatin mesh that serves to contain pathogens, may stimulate autoinflammation and exacerbate end-organ damage13. Reduced expression of monocyte human leukocyte antigen (HLA)-DR, an important antigen-presenting molecule on innate immune cells, often correlates with decreased responsiveness to ex vivo stimulation with bacterial endotoxin and may increase the risk of secondary infection in patients with sepsis. In addition, increased apoptosis of antigen presenting cells (APCs) has been demonstrated in septic patients with secondary infections and may play a role in T-cell anergy7,14. CD4+ T-cells, key components of the adaptive immune system, are significantly reduced in non-survivors of sepsis due to apoptosis and splenic removal15. Among remaining CD4+ cells, cytokine production in both T helper 1 (Th1) and T helper 2 (Th2) subpopulations is diminished. T-regulatory cells (Treg), a potentially immunosuppressive subset of CD4+ T cells, may play a role in suppressing excessive inflammation in sepsis. However, evidence suggests that Tregs may be more resistant to sepsis-related apoptosis than other T-cell populations and may therefore contribute to immunoparalysis16. Still, the role of Treg cells in perpetuating sepsis-induced immune suppression has not been as clearly established in children as it has in adults. Similar to CD4+ T-cells, depletion of B-cells, especially the CD5+ B1a-type cells, is also associated with worse outcomes in septic patients17. Deletion of innate response activator (IRA) B cells is associated with hypercytokinemia and delayed clearance of pathogenic bacteria18. The timeline of these changes, based on adult data, has been recently reviewed by Martin et al.19 In brief, there is leukocytosis (increase in neutrophil and monocyte populations) in the first days after sepsis onset followed by a state of lymphopenia with decreased numbers of both adaptive and innate immune cells. Even when cell counts recover, there can be lasting immunoparalysis characterized by reduced functionality of immune cells that increases the risk of secondary infections and death15,19,20. There are developmental differences in host innate and adaptive immune responses from the neonatal period to adulthood that may impact how sepsis affects children6. For example, an imbalance in the inflammatory and compensatory anti-inflammatory responses may play a greater role in septic shock and MODS in children compared to adults21. Inflammatory response is attenuated in neonatal mice with sepsis22, and while macrophages from young children produce greater amounts of both pro-inflammatory TNF-α and anti-inflammatory IL-10 compared to adults, the resulting IL-10/TNF ratio is higher in children23. Multiple studies have demonstrated that adaptive and innate immune suppression in children within the first 2 days of septic shock is associated with adverse outcomes24,25. And similar to adults, clinical studies have demonstrated that higher initial pro-inflammatory responses in children are associated with impairment of innate immunity, represented by decreased monocyte HLA-DR expression, and adverse infection-related outcomes26. In summary, dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression. This heterogeneity in sepsis phenotypes is likely responsible for the failure of multiple immunomodulatory therapies trialed in patients with sepsis. Precise and rapid characterization of the unique disturbances in the immune response in children with sepsis may promote personalized therapy and improved outcomes. Biomarkers and functional immunologic assays In order to characterize sepsis phenotypes in children and develop a personalized treatment plan, biomarkers and immunologic assays to assess the degree of immune dysregulation are needed. The goal of testing would be to diagnose and quantify impaired immunologic function (i.e., hyperinflammation and immunoparalysis) and identify which patients would benefit from immunomodulatory treatments. To date, however, no one specific marker of immune activation or suppression has been consistently associated with risk of poor outcome. Single cytokine levels can be measured or tracked in the setting of sepsis, although a lag in availability of results hinders clinical applicability. Following trends in IL-6 or TNF levels may help determine the likelihood of recovery, with decreasing IL-6 levels associated with improved prognosis in septic adults27 28. An overproduction of anti-inflammatory cytokines, such as IL-10 or a high IL-10/TNF ratio, may be a predictor of severity and fatal outcome29. Lymphopenia, a low circulating absolute number of lymphocytes, has been observed in patients following sepsis and may be secondary to apoptosis and/or decreased bone marrow production30,31. The degree and duration of lymphopenia is correlated with delayed hospital-acquired infections and death32. Lymphopenia is relatively easy to follow with peripheral blood count testing and may help to identify patients for whom immunostimulatory therapies could be useful33. In children with septic shock, infectious complications were associated with lower lymphocyte counts and reduced ability of lymphocytes to respond to stimulation24. Functional immune testing, however, remains the gold standard for lymphocyte assessment because it directly measures the capacity of a cell population to respond to an immune challenge34. T-cell anergy or lack of proliferation can be assessed by mitogen stimulation. However, assays require time for incubation and access to flow cytometry with fluorescent probes, limiting their clinical use in rapidly evolving diseases such as sepsis. Quantification of co-inhibitory receptor expression, such as programmed cell death 1 (PD-1), may be an alternate and more accessible way to assess lymphocyte anergy in sepsis35. Overexpression of PD-1 and its ligand PDL-1 has been associated with decreased lymphocyte proliferation capacity, late infectious complications, and mortality36. The antigen presenting molecule HLA-DR should be expressed on the surface of the vast majority of circulating monocytes. This can be quantified by flow cytometry as a percentage of circulating cells or molecules of HLA-DR per cell. Low HLA-DR is considered a hallmark of sepsis-induced immunosuppression37,38. In adults, HLA-DR <30% or <8,000 molecules/cell is associated with increased risk for nosocomial infection and mortality. The threshold of HLA-DR expression associated with adverse outcomes in children with sepsis is likely similar, though less clear due to limited data26. The trajectory of HLA-DR expression may be more important than an absolute threshold, with lack of improvement in a low initial HLA-DR expression over the first week after sepsis onset being predictive of mortality, including in a study of children39. Unfortunately, monocyte HLA-DR lacks standardization across individual laboratories and is subject to inconsistencies if processing is delayed. In addition, although a marker of immunologic state, it is not directly a functional assay. HLA-DR expression correlates with TNF-α secretion after ex vivo endotoxin challenge, a potentially more functional assessment of monocyte responsiveness. Whole blood is incubated with lipopolysaccharide (LPS) and TNF-α production is measured. Marked reduction in TNF-α production indicates a decreased innate immune response capacity and has been associated with nosocomial infection, prolonged organ dysfunction, and mortality in children25,40,41. However, care must be taken when performing this assay, as monocytes are prone to rapid adaptation to changes in their microenvironment, such as ex vivo testing conditions42. The discussed measures of immune status and function are somewhat accessible, albeit to different degrees, and have been associated individually with outcomes, most with some study in children. Many of these assays link to immunomodulatory therapeutic agents addressed next. Further innovative approaches including gene expression profiling and complex endotyping are discussed under precision approaches to come. Immunomodulatory Therapies in Sepsis Since the 1960s, sepsis-induced inflammation has been a major therapeutic target. Initial anti-inflammatory therapies included high dose corticosteroids, antagonists to pro-inflammatory cytokines and endotoxins, TLR blockers, and platelet activating factor inhibitors43–45. However, in the past two decades, numerous studies have shown that specifically targeting the sepsis induced pro-inflammatory response has not led to clear improvement in outcomes. This may be because the hyperinflammatory phase in sepsis confers some benefit, including initiating broad-based and timely immune activation46, or because these therapies were given non-selectively to heterogeneous populations with different sepsis phenotypes. Additionally, our knowledge of the immunoparalysis phase of sepsis as well as the molecular signature of sepsis-induced immune dysregulation has greatly expanded. Utilizing an evidence-based, directed therapy approach to specifically target the major mechanism of immune dysregulation may improve outcomes. We focus herein on the current evidence and available immunomodulatory therapies (Figure 3), while acknowledging the advancements to come in precision endotyping and need for utilization of these subtypes in therapeutic trials and analyses. Immunosuppressive therapies Given that sepsis is essentially a dysregulated immune response mediated by both pro- and anti-inflammatory cytokines, a large body of literature has developed surrounding the use of generalized and individual cytokine-directed therapies. CytoSorb® (CytoSorbents Corporation, New Jersey, USA) is a potential anti-cytokine therapy that has demonstrated utility in a pilot study47. The concept of using hemoperfusion to remove damaging immune mediators is not novel. Polymyxin B hemoperfusion (PMX-HP) directed at removing LPS has been studied extensively. Since endotoxin mediated tissue injury and resultant hyperinflammation is a major source of sepsis related mortality, LPS is a seemingly important target. However, a recent metanalysis confirmed findings from smaller studies that found there was no significant difference in mortality among those who received PMX-HP and those who received standard therapy48. The trial of PMX-HP set a precedent for consideration of other immune-filtration modalities as possible treatment options in sepsis. CytoSorb® is an extracorporeal device with a high-flow, low-resistance cytokine adsorbent, containing specially developed polymer beads with a huge adsorption surface and adsorption spectrum between 5 and 60 kDa49. In a proof of concept pilot study, extracorporeal cytokine removal was applied for 24 hours in the early stage of septic shock. The trial met safety endpoints and the authors reported that even with a single treatment there were statistically significant reductions in vasopressor requirements, serum procalcitonin, and big-endothelin 1 (BigET-1), compared to controls47. However, additional studies are needed to determine how these short-term clinical and biochemical improvements may impact outcomes and whether extracorporal cytokine removal has any benefit in pediatric sepsis. There is more literature available surrounding the use of cytokine-directed therapy including TNF and IL-1 blockade, as well as IL-7, IL-15 and IFN-γ agonists. As mentioned previously, blockade of pro-inflammatory cytokines such as TNF and IL-1 in heterogeneous populations of patients with sepsis has not led to clear improvement in outcomes50,51. However, in a post-hoc analysis of a subset of adult patients with sepsis and features of macrophage activation syndrome, treatment with IL-1 receptor antagonist significantly decreased mortality52. This suggests that improved phenotyping prior to immunomodulation is necessary to identify patients most likely to benefit from cytokine-directed therapies. Immunostimulatory therapies Immunostimulatory therapies to counter the immunoparalysis stage of sepsis, which is associated with significant late-stage mortality53, are receiving increasing attention. As outlined above, immunoparalysis is characterized by dysfunction and apoptosis of numerous immune cells including lymphocytes, monocytes, and macrophages54. To protect against fatal opportunistic infections associated with T cell lymphopenia, treatment with IL-7 has been proposed. Interleukin-7 is antiapoptotic and is necessary for lymphocyte survival and expansion. In addition, it induces proliferation of both CD4+ and CD8+ T cells. The IRIS-7 trial was a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. The study suggested that CYT107 was safe and well tolerated. Treatment with CYT107 resulted in a 3- to 4-fold increase in the absolute lymphocyte count and in circulating CD4+ and CD8+ T cells, but there was no improvement in 28-day mortality55. Interleukin-15 is important for natural killer (NK) cell, NKT cell, and memory CD8+ T-cell development and function, and has therefore been proposed for use as an immunostimulatory therapy in sepsis-induced immunoparalysis56. The use of IL-15 in sepsis has only been studied in the mouse model57, though clinical trials have demonstrated safety and efficacy in cancer patients58. Guo et al reported that mice treated with high-dose IL-15 immediately following the onset of sepsis had worse outcomes, but the study did not test its impact later in disease when immunoparalysis may be expected57. Given these mixed results, further clinical trials need to be performed with close attention to safety outcomes surrounding the use of IL-15. A recent case series, which included two pediatric patients, demonstrated that IFN-γ therapy was well-tolerated and improved immune host defense in sepsis-induced immunosuppression, as measured by HLA-DR expression in monocytes59. A larger, multicenter placebo-controlled trial assessing the effect of IFN-γ therapy on immune function in patients with sepsis has been completed, though results have not yet been published (NCT01649921). Results from such studies will shed further light on the efficacy of IFN-γ therapy in sepsis. Due to the potential role of T-cell exhaustion in sepsis-induced immunosuppression, antagonizing inhibitory immune checkpoints, which limit T-cell function, has been proposed. Immune checkpoint inhibitors are currently approved and in use for treatment of multiple cancers. As previously mentioned, increased PD-1 and PDL-1 have been documented in septic patients compared to healthy controls and in sepsis non-survivors compared to sepsis survivors15,60. Preclinical data supports the use of immune checkpoint inhibitors to improve survival from secondary fungal infections following recovery from polymicrobial sepsis, but inconsistent protection is reported when they are used in primary polymicrobial sepsis61. A phase 1b study of anti-PDL-1 in 24 patients with sepsis suggested it was safe, did not lead to hypercytokinemia, and resulted in a dose-dependent increase in monocyte HLA-DR expression62, but further clinical trials have yet to be performed. Impaired function of APCs has also been implicated in sepsis-induced immunosuppression. Tolerance to endotoxin and reduced antigen presentation capacity in peripheral blood mononuclear cells (PBMCs), defined by ex vivo stimulation or HLA-DR expression, has been documented in children and adults with sepsis63. Reduced HLA-DR has been associated with impaired monocyte function, increased secondary infections, and increased mortality in adults with sepsis64. Consequently, granulocyte-macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor that impacts the survival, proliferation, and activation of neutrophils and monocytes as well as numerous other immune cells, has been promoted as a potential therapy to restore antigen presentation and reduce immunoparalysis in sepsis. In a small, randomized trial of septic neonates with neutropenia (n=60), GM-CSF therapy increased neutrophil, monocyte, lymphocyte, and platelet counts and was associated with decreased mortality65. A trial in septic children with MODS with severe reduction in TNF response who were treated with GM-CSF had fewer nosocomial infections40. However, trials in children and adults that did not attempt to select for participants with immunoparalysis did not show similar benefits64,66. A multicenter trial in children with sepsis and endotoxin tolerance is currently enrolling (NCT03769844). Precision approaches to pediatric sepsis care Sepsis is complex and heterogenous at the individual level, and to move the needle in development of effective therapeutics, we need to stratify patients into clearer endotypes based on biological features (host factors, comorbidities, genetics)67. Beyond single biomarkers, cell counts, and specific functional assays, broad screening and omics approaches have been used to identify and endotype patients with sepsis. Several investigators have published leukocyte derived mRNA transcriptomic gene expression and discovery-based biomarker studies utilizing modeling to identify subgroups of children with sepsis who have immunologic abnormalities in similar pathways and/or are at risk for particular outcomes68,69,70. Sweeney et al pooled pediatric/neonatal transcriptomic sepsis datasets and noted three clusters: inflammopathic, adaptive, and coagulopathic71. However, the therapeutic implications of these endotypes remain unclear and warrant further study. Additional considerations for endotyping critically-ill children with sepsis include the potential utility of sampling local inflammatory environments (e.g., the upper airway and lung in acute respiratory distress syndrome)72; linking immunologic and other system (e.g., coagulation, hepatobiliary) abnormalities; and prediction of disease trajectories73. Advanced consensus endotype definitions and multi-center cohorts are needed to solidify models for 1) development of rapid platforms/multiplex assays in a clinically actionable timeline and 2) interventional trials to tailor therapeutics in a precision medicine approach to clinical care for children with sepsis. To this point, accessibility and turnaround time of immune profiling and functional assays remains a limitation to applying results to clinical care. Newer technologies are being developed that utilize microfluidic platforms, single cell proteomics (e.g., Olink®, IsoPlexis©), or rapid transcriptomic patterns that may provide more rapid results that can be used in clinical decision-making, monitoring patients over time, and/or assessing response to therapy. Conclusion Sepsis is a disorder of immune dysregulation triggered by infection1. Although accumulation of environmental and infectious exposures modifies the immune system throughout childhood, little is known about how differences in innate and adaptive immunity based on age, comorbidities, prior exposures, and genetics impact the pathophysiology of pediatric sepsis and this remains an area for advancement. Accurate phenotyping of immune function during sepsis and endotyping of disease subtypes may be particularly important in children. Caution must be taken when extrapolating results from adult trials and animal models. To advance effective therapeutics for pediatric sepsis, we must move from undifferentiated immunomodulatory therapies (i.e., a one size fits all) to individual immune phenotyping and directed therapy. Advancements in the ability to perform multidimensional endotyping at the bedside will be central to developing a personalized approach to children with sepsis diagnosis and management. Acknowledgements: We would like to thank the Program in Inflammation, Immunity and the Microbiome (PrIIMe) team and acknowledge the Lurie Children’s Immunology Lab. The following authors are supported by National Institutes of Health awards: NHLBI K08HL143127 (Coates), NIAID K08AI123524 (Arshad), and NIAID K23AI139337 (Mithal). Figure 1: Pathways of immune dysfunction associated with sepsis. The illustration depicts the dysregulation at the levels of the innate immune response (complement, neutrophils, monocytes-macrophages) as well as the adaptive immune response (T cells and B cells) that characterizes the immunopathology observed in the setting of sepsis. Figure 2: Representative monocyte HLA-DR expression before and after GM-CSF treatment in sepsis. This is an example of polychromatic flow-cytometry utilized to assess monocyte-associated HLA-DR expression pre and post GM-CSF treatment in a sepsis patient. Briefly, whole blood samples from a patient and commercially available flow-cytometry control samples (Streck, Omaha, NE) were stained with fluorochrome-conjugated monoclonal antibodies targeting the CD45, CD3 and HLA-DR surface markers, and hierarchical gating was utilized to evaluate HLA-DR expression on monocytes. Monocytes were identified based on CD45 expression and light scatter characteristics (side-scatter [SSC]) (left panel). Surface expression of HLA-DR on monocytes is demonstrated by utilizing the stacked histogram plot (right panel). The numerical values in the plot depict the frequency of monocytes expressing HLA-DR and response post GM-CSF therapy. Laboratory assays done under IRB-approved protocol at Lurie Children’s. Figure 3: Targeted immunomodulatory therapies in sepsis. Schematic depicting therapies trialed to target specific areas of immune dysregulation in sepsis. Treg: regulatory T cell, HLA-DR: human leukocyte antigen-DR, IFN: interferon, TNF: tumor necrosis factor, IL: interleukin, PD: programmed cell death, PDL: programmed cell death ligand. Impact bullet points: Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. The resulting spectrum of immunoparalysis that can occur due to sepsis can increase morbidity and mortality in children and adults. This narrative review summarizes the current literature surrounding biomarkers and functional immunologic assays for immune dysregulation in sepsis, with a focus on immunomodulatory therapies that have been evaluated in sepsis. A precision approach toward diagnostic endotyping and therapeutics including gene expression will allow for optimal clinical trials to evaluate efficacy of individualized and targeted treatments for pediatric sepsis. Competing interest declaration: The authors have no competing interests to disclose. ==== Refs References: 1 Singer M The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama 315 , 801–810, doi:10.1001/jama.2016.0287 (2016).26903338 2 Fleischmann-Struzek C The global burden of paediatric and neonatal sepsis: a systematic review. The Lancet. 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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00680-2 10.1016/S0140-6736(21)00680-2 Correspondence Leveraging data and new digital tools to prepare for the next pandemic Davies Sally C a Audi Hala b Cuddihy Mitch b a Trinity College, University of Cambridge, Cambridge, UK b The Trinity Challenge, Cambridge CB2 1TQ, UK 1 4 2021 10-16 April 2021 1 4 2021 397 10282 13491350 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe COVID-19 pandemic has accelerated the pace of digital innovation, in part thanks to unprecedented private–public and private–private collaborations. The pandemic has promoted collaboration between inventive and influential companies, universities, and public organisations. These institutions have worked together in vaccine development, in forecasting the spread of infection, and in sharing technology to build public health apps for general use. We must now build on this ability to work across boundaries to deliver results, not return to old silos. As a society, we can change how we prepare for future health emergencies in a way that is more effective, less expensive, and equitably benefits more people and communities globally New perspectives can be encouraged by hosting competitive public challenges to incentivise and reward the best ideas in digital and data analytics from anyone, anywhere; by fostering collaboration among our coalition of cross-sectoral leaders in technology and health to address tough global health questions; and by promoting a better data ecosystem—one that can contribute to long-term health and economic benefits. There are emergent and powerful digital and analytical tools that can advance both access to health care and the quality of care received. Yet the wider adoption of these tools is too slow. We need new datasets that are more broad than those typically held in the public sector, including data on knowledge, attitudes, and behaviours, and new models that encourage cross-sector collaborations with research, business, the social sector, and governments. We fear that attention from leaders in government and business will wane when the moment of crisis passes. We must act fast to embed the changes we need while pandemic preparedness remains on top of everybody's agenda. In 2020, motivated by these challenges in the midst of the COVID-19 pandemic, the Trinity Challenge was established by a committed coalition of more than 20 founding members from academia, business, and philanthropy. The initiative works to improve how the world identifies, responds to, and recovers from health emergencies by uniting different data sources, new digital tools, public health, and science. It is a call to action for the world's best and brightest minds to contribute ideas and solutions towards achieving this aim. With awards of up to £2 million, from the total prize fund of up to £10 million, the Trinity Challenge is seeking digitally focused ideas on how the world can identify, respond, and recover from health emergencies. © 2021 Gorodenkoff Productions/Science Photo Library 2021 We declare no competing interests.

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Lancet. 2021 Apr 1 10-16 April; 397(10282):1349-1350

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00680-2 10.1016/S0140-6736(21)00680-2 Correspondence Leveraging data and new digital tools to prepare for the next pandemic Davies Sally C a Audi Hala b Cuddihy Mitch b a Trinity College, University of Cambridge, Cambridge, UK b The Trinity Challenge, Cambridge CB2 1TQ, UK 1 4 2021 10-16 April 2021 1 4 2021 397 10282 13491350 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe COVID-19 pandemic has accelerated the pace of digital innovation, in part thanks to unprecedented private–public and private–private collaborations. The pandemic has promoted collaboration between inventive and influential companies, universities, and public organisations. These institutions have worked together in vaccine development, in forecasting the spread of infection, and in sharing technology to build public health apps for general use. We must now build on this ability to work across boundaries to deliver results, not return to old silos. As a society, we can change how we prepare for future health emergencies in a way that is more effective, less expensive, and equitably benefits more people and communities globally New perspectives can be encouraged by hosting competitive public challenges to incentivise and reward the best ideas in digital and data analytics from anyone, anywhere; by fostering collaboration among our coalition of cross-sectoral leaders in technology and health to address tough global health questions; and by promoting a better data ecosystem—one that can contribute to long-term health and economic benefits. There are emergent and powerful digital and analytical tools that can advance both access to health care and the quality of care received. Yet the wider adoption of these tools is too slow. We need new datasets that are more broad than those typically held in the public sector, including data on knowledge, attitudes, and behaviours, and new models that encourage cross-sector collaborations with research, business, the social sector, and governments. We fear that attention from leaders in government and business will wane when the moment of crisis passes. We must act fast to embed the changes we need while pandemic preparedness remains on top of everybody's agenda. In 2020, motivated by these challenges in the midst of the COVID-19 pandemic, the Trinity Challenge was established by a committed coalition of more than 20 founding members from academia, business, and philanthropy. The initiative works to improve how the world identifies, responds to, and recovers from health emergencies by uniting different data sources, new digital tools, public health, and science. It is a call to action for the world's best and brightest minds to contribute ideas and solutions towards achieving this aim. With awards of up to £2 million, from the total prize fund of up to £10 million, the Trinity Challenge is seeking digitally focused ideas on how the world can identify, respond, and recover from health emergencies. © 2021 Gorodenkoff Productions/Science Photo Library 2021 We declare no competing interests.

33639086

PMC9752209

NO-CC CODE

2022-12-16 23:25:21

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Lancet. 2021 Feb 24 6-12 March; 397(10277):878-879

latin-1

Lancet

10.1016/S0140-6736(21)00376-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(20)32513-7 10.1016/S0140-6736(20)32513-7 Comment Adopting an intersectionality framework to address power and equity in medicine Samra Rajvinder a Hankivsky Olena b a School of Health, Wellbeing and Social Care, The Open University, Milton Keynes MK7 6AA, UK b Centre for Health Equity, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia 23 12 2020 6-12 March 2021 23 12 2020 397 10277 857859 © 2020 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcResponses to police brutality and the disproportionate effects of COVID-19 among ethnic minority populations have widened realisations about racism, and social and health inequities.1 Typically, medical institutions such as the Association of American Medical Colleges outline their position against racism1 separately from their mission for achieving gender equity.2 However, in western settings, the downstream effects of medical education on doctors and patients is shaped by patriarchal and colonial histories and values.3, 4 Patriarchal cultures in medicine constrain women doctors’ career choices and progression internationally.5 Medical textbooks reinforce norms based on Whiteness by under-representing racial and ethnic minorities—eg, different presentations and clinical signs for patients with darker skin tones.6 Exporting western biomedical knowledge to other global settings reinforces inequality.3 Dismantling the power structures in medicine, however, requires complex thinking that goes beyond focusing on one dimension at a time—eg, patriarchy or racism. This requirement is also relevant to the decolonising global health movement. Medical institutions need to turn their lens towards intersectionality—the inextricable way that factors such as race, class, gender, disability, and sexuality intersect to shape each other within broader structures and processes of power.7 Intersectionality has its roots in Black feminist scholarship8 and its transformative potential has been recognised in the context of global health7 and in medicine.4 However, as Sharma has argued: “to be truly transformative, any intersectional approach must grapple with the issue of power and privilege within medicine itself”.4 There is a need to scrutinise how medical institutions, which are increasingly working abroad in global health activities as well as at home, constrain or enable the critique of power structures and whether individuals working within those spaces analyse their own privileges, practices, and pedagogy to advance social justice.4 Recognition of systemic, intersecting inequities in professional medical culture begins by examining exclusion and discrimination in medical education, training, and workplace experiences. Western medicine is embedded with power structures3 that favour those racialised as White9 and cisgender and heterosexual men.4, 10 But experiences of marginalisation cannot be dissected, one social category at a time. For example, a White woman may experience relative advantage over a Black man during medical selection and training, despite the prevailing gender inequity in medicine. But it is also true that neither White women nor Black men are homogeneous in their experiences of advantage or disadvantage. Intersectionality points to other factors that shape inequities within groups—eg, disability, socioeconomic status, migration status, or sexuality. Challenging medical cultural norms and the system inequities they produce and reproduce starts with rejecting the idea that one system of inequality is more important than any other. Different inequities are intertwined and experienced simultaneously. During medical training, implicit and explicit biases based on social stereotyping shape the identification, cultivation, and selection of individuals chosen for programmes and internships.11 However few studies have examined the role of such biases on the relative lack of diversity in medicine, or how they operate through medical culture.10 Unconscious bias can contribute to systematic underestimation of the capabilities of qualified women and ethnic minority and internationally trained applicants. Importantly, medical education requires learning associations contingent on schemas (knowledge based on patterns) and can inadvertently teach stereotypes relating to social identity categories.10 Unconscious bias training will not address discrimination that results from explicit and intentional bias, but can increase awareness of how inequities are reproduced, without deliberate action challenging the broader structures and systemic practices that go beyond individuals.11 Social diversity in medical recruitment panels and faculty composition can promote inclusion for historically marginalised individuals10 and lead to rethinking the skills and competencies of medical professionals. Recruiting from under-represented groups can help reduce health disparities in these communities.10 Key actors within institutions must engage in practices of cultural humility,10 including qualitatively examining experiences of marginalisation to recognise and address inequities. Visual audits of building and room names and the images in workplaces and websites can indicate the institutional messages about power and privilege being signalled to patients and doctors. © 2021 Shapecharge/Getty Images 2021 The reinforcement of Whiteness norms and patriarchal practices in medicine should be recognised and challenged, from the medical simulation manikins used in teaching5 to the clinical handbooks used in practice.6 Including examples of patients’ intersectionality in medical curricula educates students on how experiences are shaped by the intersection of race, gender, class, and disability, which can create health inequities that are amplified by medical care.12 The use of an intersectionality framework can improve diagnostic accuracy and protect against systematic biases that disproportionately affect marginalised patients.13 Biological and racial essentialism are embedded in medical research and education but are not rooted in scientific evidence5, 9 and can be challenged through use of an intersectionality framework. Importantly, intersectionality education and reflexivity skills training for medical students and doctors can make them aware of how their own social positions, values, and experiences shape their professional identities and approaches to patient care.12 Positioning intersectionality into medical curricula signals institutional legitimisation of this approach and empowers individuals by recognising and confronting marginalisation. Intersectionality can also inform multilevel analysis of inequality outcomes— eg, generating more precise information about medical recruitment, retention, and doctors’ career progression.7 Such analysis identifies how inclusionary and exclusionary practices in medical culture shape individuals’ lives and at which intersections. Such fine-grained evidence will demonstrate each institution's commitment to dismantling intersecting power structures that impede the achievement of equity. We declare no competing interests. ==== Refs References 1 Association of American Medical Colleges AAMC statement on police brutality and racism in America and their impact on health https://www.aamc.org/news-insights/press-releases/aamc-statement-police-brutality-and-racism-america-and-their-impact-health June, 2020 2 Association of American Medical Colleges AAMC statement on gender equity https://www.aamc.org/what-we-do/mission-areas/diversity-inclusion/aamc-statement-gender-equity January, 2020 3 Verdonk P Abma T Intersectionality and reflexivity in medical education research Med Educ 47 2013 754 756 23837419 4 Sharma M Applying feminist theory to medical education Lancet 393 2019 570 578 30739692 5 Bleakley A Gender matters in medical education Med Educ 47 2013 59 70 23278826 6 Page S A medical student couldn't find how symptoms look on darker skin. He decided to publish a book about it The Washington Post July 22, 2020 https://www.washingtonpost.com/lifestyle/2020/07/22/malone-mukwende-medical-handbook/ 7 Kapilashrami A Hankivsky O Intersectionality and why it matters to global health Lancet 391 2018 2589 2591 30070211 8 Crenshaw KW Mapping the margins: intersectionality, identity politics, and violence against women of color Stanford Law Rev 43 1991 1241 1299 9 Braun L Theorizing race and racism: preliminary reflections on the medical curriculum Am J Law Med 43 2017 239 256 29254464 10 Marcelin JR Siraj DS Victor R Kotadia S Maldonado YA The impact of unconscious bias in healthcare: how to recognize and mitigate it J Infect Dis 220 suppl 2 2019 S62 S73 31430386 11 Pritlove C Juando-Prats C Ala-Leppilampi K Parsons JA The good, the bad, and the ugly of implicit bias Lancet 393 2019 502 504 30739671 12 Muntinga ME Krajenbrink VQ Peerdeman SM Croiset G Verdonk P Toward diversity-responsive medical education: taking an intersectionality-based approach to a curriculum evaluation Adv Health Sci Educ Theory Pract 21 2016 541 559 26603884 13 Cho HL Can intersectionality help lead to more accurate diagnosis? Am J Bioethics 19 2019 37 39

33357466

PMC9752210

NO-CC CODE

2022-12-16 23:25:21

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Lancet. 2021 Dec 23 6-12 March; 397(10277):857-859

utf-8

Lancet

10.1016/S0140-6736(20)32513-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00561-4 10.1016/S0140-6736(21)00561-4 World Report Medical oxygen crisis: a belated COVID-19 response Usher Ann Danaiya 4 3 2021 6-12 March 2021 4 3 2021 397 10277 868869 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcMore than a year into the pandemic, global health agencies have set up a taskforce to address the vast unmet demand for medical oxygen. Ann Danaiya Usher reports. Wellcome Trust, Unitaid, and WHO have established a COVID-19 Oxygen Emergency Taskforce and say that US$90 million is needed to fund an “immediate emergency response”. This response would initially target patients with COVID-19 in up to 20 low-income and middle-income countries (LMICs), including Malawi, Nigeria, and Afghanistan. $1·6 billion will be needed to make medical oxygen available more widely over the coming year. In a press release, the agencies said that more than half a million patients with COVID-19 in LMICs need oxygen every day and shortages are causing preventable deaths. This figure does not include the millions of patients, including newborn babies and children with pneumonia, malaria, and other ailments, who also require medical oxygen therapy each year. “COVID-19 has put huge pressure on health systems, with hospitals in many LMICs running out of oxygen…This is a global emergency that needs a truly global response, both from international organisations and donors. Many of the countries seeing this demand struggled before the pandemic to meet their daily oxygen needs”, Philippe Duneton, executive director of Unitaid said. He urged countries to assess their overall needs and to put forward concrete funding propositions to global health agencies, as well as to the World Bank, to ensure that oxygen is prioritised. The global pandemic response mechanism, the Access to COVID-19 Tools Accelerator (ACT-A), has been slow to take up the issue. During the first year of the pandemic, ACT-A and its donors have concentrated overwhelmingly on developing new vaccines. Other tools like oxygen and personal protective equipment failed to generate the same level of interest and engagement. A spate of recent media reports about oxygen shortages in sub-Saharan Africa, Nigeria, Egypt, Brazil, Mexico, and Peru has documented an increasingly desperate situation for hospitals, and patients and their families. Last week's announcement by Wellcome and Unitaid follows repeated calls from health charities and researchers for ACT-A to deal more seriously with the oxygen crisis. The new ACT-A taskforce includes the Every Breath Counts pneumonia coalition, Save the Children, the Clinton Health Access Initiative, and PATH, groups that have been sounding the alarm about oxygen shortages in LMICs. Leith Greenslade, coordinator of Every Breath Counts, welcomed the announcement as “a major step that recognises the critical status of oxygen as an essential medicine and a vital therapy”. But she urged agencies to “move quickly in the weeks ahead” to make bulk liquid oxygen, oxygen cylinders, and oxygen concentrators available. Kevin Watkins, CEO of Save the Children, has previously accused the international community of “sitting on its hands” in the face of this growing humanitarian emergency. Now he is cautiously optimistic. “This crisis has been unfolding in full view for weeks and months. The international response has been way too slow to the point of complacency. This initiative is the wake-up call”, he told The Lancet. When ACT-A was launched in April, 2020, it had three focal points: vaccines, therapeutics, and diagnostics. Oxygen was introduced in November when a fourth pillar on health systems was added with a fundraising target of $1·6 billion. While the requests for the first three ACT-A pillars were based on detailed costing and a clear target to reach 20% of people with the new tools, the health system pillar contained no such details. Only a small proportion of donor support to ACT-A ended up being earmarked for the fourth pillar. The first indication that oxygen was being given higher priority came on Feb 9, 2021, when ACT-A presented a new budget and strategy. Oxygen was moved out of the health system pillar and into the therapeutics pillar, under the responsibility of the Wellcome Trust and UNITAID. Speaking on condition of anonymity, sources closely involved with ACT-A told The Lancet that this was a way of lifting the attention on oxygen. The move was also a recognition of the fact that it was more logical for a therapy that WHO categorises as an essential medicine to be included with other treatments. One of the few drugs shown to be effective against COVID-19, dexamethasone, works more efficiently when combined with medical oxygen. The slow roll-out of vaccines in LMICs added urgency. Richard Mihigo at the WHO Africa regional office estimates that Africa is likely to vaccinate only about a third of the total population of 1·3 people billion by the end of 2021. The ambition is to extend this to 60% by 2023, according to John Nkengasong, director of the Africa Centres for Disease Control and Prevention. Speaking to The Independent, he said he believes that the shortage of oxygen is a main reason that patients with COVID-19 in Africa are more likely to die there during a surge of cases. “This is a rapidly escalating crisis and oxygen is the only thing keeping people alive as countries wait for vaccines”, says Watkins. In November, as SARS-CoV-2 infection rates in LMICs rose and many countries faced a double burden of pneumonia and COVID-19—two respiratory illnesses that require oxygen treatment—the Every Breath Counts coalition and PATH launched a COVID-19 Oxygen Needs Tracker, to raise awareness about the surge in daily oxygen requirements. The ACT-A oxygen initiative draws heavily on this work: both the $90 million request and the assertion that 500 000 patients with COVID-19 in LMICs need medical oxygen each day are taken directly from the tracker. However, the numbers generated by the tracker give only a partial picture, for two main reasons. First, the numbers only include COVID-19 cases confirmed by testing, not taking into account the low levels of testing in LMICs, and second, the numbers do not include the oxygen needs of patients without COVID-19, who vastly outnumber people with COVID-19. PATH, which hosts the tracker, describes it as an “advocacy tool”, which “underestimates the total oxygen needs of health systems in LMICs and is not intended to be used for planning or procurement purposes”. How many patients then—with COVID-19 and other ailments—died last year because they needed medical oxygen but did not have access to it? Hamish Graham, a clinician scientist specialising in oxygen therapy at the Murdoch Children's Research Institute in Melbourne, Australia, often encounters this question. He estimates that approximately 38 million patients in LMICs were admitted to hospitals with hypoxaemia last year. Of these, 8 million were patients with COVID-19. Most of the others were children, including 6 million newborns and 5 million children up to 15 years old who had pneumonia, as well as 11 million adults. Non-hospital patients are not included, he said. © 2021 Edgard Garrido/Reuters 2021 According to Graham, before the pandemic, nine in ten hospitals in LMICs lacked access to pulse oximetry and oxygen therapy and only 20% of those patients who needed medical oxygen received it. Graham cannot confirm a direct correlation between increased oxygen use by COVID-19 patients and lack of access by others. He says child mortality probably increased in the past year, but this increase is due to many factors, including disruption of immunisation programmes, parents not being able to take their children to care due to fear of COVID-19, and economic reasons. “The massive pressure on oxygen systems that has hit the news is mainly in the big hospitals that already had oxygen, whereas the majority of sick kids tend to be cared for in smaller, rural facilities”, he said. However, the dramatic increase in the price of oxygen sparked by the pandemic is probably affecting smaller facilities that are dependent on filling their oxygen cylinders at a particular point. “That would potentially have a huge spillover effect”, Graham said. Graham underlines that oxygen should not be seen as an intervention, but rather as a core part of health-facility infrastructure. He warns against merely delivering equipment to hospitals. “You can spend as much as you want on equipment and it will only last for the lifetime of the equipment. Unless you have substantially changed the system—the biomedical, maintenance, distribution, and the economic purchasing system—you will be back in the same situation in 5 years”, he said. After years of neglect, campaigners and health officials hope that the focus on oxygen triggered by COVID-19 will lead to wider availability of medical oxygen, which can be used when the pandemic is over to help patients with pneumonia, malaria, sepsis, and other ailments that require oxygen therapy. Commenting on the ACT-A request for $1·6 billion for oxygen, Watkins says this amount will, if financed, enable countries to deal with “some of the worst aspects of the crisis while putting in place some of the infrastructure that can serve as a foundation for more sustainable and equitable oxygen systems”.

33676621

PMC9752211

NO-CC CODE

2022-12-16 23:25:21

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Lancet. 2021 Mar 4 6-12 March; 397(10277):868-869

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Lancet

10.1016/S0140-6736(21)00561-4

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00523-7 10.1016/S0140-6736(21)00523-7 Correspondence The ultra-connected generation would like to disconnect now Cassan Julie a Claude Agathe a de Hillerin Mariuca a Fontaine Audrey a Goodwin Paige a Halstead Emily a Lama Maya-Lhanze a M'zali Yanis a Paulin Kim a Raimbault Leonard a Tocqueville-Perrier Robin a Verma Riya a Villaret Chloe a a Sciences Po, School of Public Affairs, Paris 75007, France 8 4 2021 10-16 April 2021 8 4 2021 397 10282 13501350 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcJohn Donne warned, “No man is an island.”1 The COVID-19 pandemic is a reminder not only of the interconnectedness of humans to each other, but also to their environment. Guided by the short-term imperatives of a globalised system, growth and productivity have been prioritised at the expense of animals' natural habitats. As a result, human–animal interactions are more frequent and zoonotic viruses, such as SARS-CoV-2, are more likely to contaminate humans. Undoubtedly, societies will have to integrate a One Health perspective into policy design: environmental issues and animal health should be part of the approach to future health policies. Just as humans exist in an ecosystem, they also coexist in a social network. A year ago, societies implemented drastic measures to flatten the curve (of the spread of COVID-19), and individuals put aside freedoms for the common good. These changes were a great feat of solidarity. But as time passed, these new rules sparked moral dilemmas in daily choices. The current young generation faces constant conflict between contributing to the economy, enjoying their youth, and risking their own and others' health. This moral fatigue is just one of the new psychological challenges posed by the pandemic. Although digitalisation has thankfully allowed the continuation of life with minor alterations, the sustainability of a virtually based society is not evident. The overdose of screen time and social media might ultimately lead to a shift in behaviour. Now, more than ever, there is an awareness of what can be accomplished remotely, and what cannot. It is our hope that the digital generation does not soon forget the struggles of the pandemic and places great importance on real relationships, and that it does not take for granted the opportunity to be present in the real world. This generation, already more digitalised than any other before it, is now being forced into further reliance on technology for daily activities. Red eyes, sore backs, and migraines: the ultra-connected generation would like to disconnect now. But there is no cure for so-called Zoom fatigue when even the doctor is behind a screen. As the prevalence of depression and anxiety rises in all populations, students are among the most affected.2 The crisis in mental health has been a long time coming. Addressing the challenges ahead will require long-term efforts, not just crisis management. Building on existing strategies to include health considerations in policy making across all sectors, the next logical step is to integrate mental health. As the post-pandemic world gets closer, humanity will only face more challenges posed by an increasingly digitalised society. It is necessary to learn from the mistakes of the pandemic. Policies should consider the interconnectedness of humans, animals, the natural environment, social wellbeing, and mental health. More than a cry for help, this is a call to action. We declare no competing interests. All authors contributed equally. ==== Refs References 1 Donne J Devotions upon emergent occasions 1987 Oxford University Press Oxford 2 Santé Publique France Coviprev: une enquête pour suivre l'évolution des comportements et de la santé mentale pendant l'épidémie de COVID-19 https://www.santepubliquefrance.fr/etudes-et-enquetes/coviprev-une-enquete-pour-suivre-l-evolution-des-comportements-et-de-la-sante-mentale-pendant-l-epidemie-de-covid-19 Feb 26, 2021

33838755

PMC9752213

NO-CC CODE

2022-12-16 23:25:21

no

Lancet. 2021 Apr 8 10-16 April; 397(10282):1350

utf-8

Lancet

10.1016/S0140-6736(21)00523-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00571-7 10.1016/S0140-6736(21)00571-7 Comment Offline: It's time to ask questions and learn lessons Horton Richard 4 3 2021 6-12 March 2021 4 3 2021 397 10277 865865 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmc1 year on from WHO's assessment, on March 11, 2020, that its Public Health Emergency of International Concern (PHEIC) had evolved into a full blown coronavirus pandemic, what can we conclude? Many governments have decided not to conclude anything. They argue that it is still too soon to learn lessons. With over 2·5 million deaths worldwide, and 1 million more predicted by June 1, this political deflection is no longer sustainable. Indeed, it is unconscionable. While governments resist accountability, countries are seeing unofficial inquiries spring up to fill the vacuum. In the UK, Keep Our NHS Public last week held the first evidence session of its People's Covid Inquiry. Chaired by human rights lawyer Michael Mansfield, five witnesses gave testimony. Jo Goodman's father died on April 2, 2020. He received a letter from the government advising him to shield 9 days after his death. His daughter believes he likely became infected while sitting in a crowded hospital waiting room. Staff did not have personal protective equipment (PPE). Her experience led her to join with others who had lost relatives to create Covid-19 Bereaved Families for Justice UK, which has called for an independent, judge-led statutory public inquiry. They have repeatedly asked to meet Prime Minister Boris Johnson. He has repeatedly declined their requests. © 2021 Richard Horton 2021 The lessons of the pandemic are not hard to discern, although they are politically inconvenient for governments anxious to retain control of the political narrative. Johnson hopes to claw back some integrity through a manifestly successful national vaccination programme. But, as Professor Sir Michael Marmot told Mansfield, the UK's poor performance had several possible explanations that deserved further investigation. First, there was a political class distracted by Brexit and that had refused to put wellbeing and equity at the heart of its policies. Second, deepening socioeconomic inequalities had made certain groups especially vulnerable to infection. Third, long-standing disinvestment in the public sector left the health system, and especially the public health system and social care, in particular jeopardy. And finally, poor population health meant that many communities were poorly protected against a new and dangerous virus. Holly Turner, a learning disability nurse, described how the care sector had been fatally weakened after years of neglect. Professor Gabriel Scally explained how the public health system had been “decimated” by a decade of austerity. And John Lister described how those policies had put intolerable pressures on the National Health Service (NHS). The People's Covid Inquiry aims to learn lessons to rebuild the NHS. It will be taking evidence until June. © 2021 Richard Horton 2021 The COVID-19 Genomics UK Consortium has done more than any other organisation to anatomise the severity of those early pandemic months. Well over 1000 separate importation events seeded virus across the country, first from China but later from Spain, France, and Italy. Over 80% of virus importations took place between Feb 27 and March 30, 2020. The consortium concluded that to get ahead of the virus “rapid or preemptive interventions” were needed. The UK Government had 4 crucial weeks after WHO's declaration of a PHEIC to prepare—building testing capacity, securing national borders, delivering PPE to front-line services, readying the NHS, protecting care homes, and pooling knowledge with other countries to ensure a coordinated global response. But the Johnson administration did little during those crucial few weeks. His government's paralysis allowed the country to become overwhelmed by coronavirus. The COVID-19 Genomics UK Consortium found that the largest viral lineages were already in the country by the time of the first lockdown on March 23. Instead of acting decisively, the government deluded itself with a set of comforting myths—that herd immunity would save us, that flattening the epidemic curve (“squashing the sombrero” in Johnson's words) would be sufficient, and that there had to be a trade-off between health and the economy. Western governments, such as Johnson's, were too slow and too indecisive. They didn't follow the science. They displayed erratic leadership. They were consistently unwilling to do what was needed to drive the virus out of communities. And they lost the trust of their publics. Saying sorry is necessary, but it isn't enough. If democracy means anything, those ministers who presided over this human catastrophe must be willing to subject themselves to independent scrutiny. And, if necessary, make way for more competent political leaders. © 2021 Richard Horton 2021

33676619

PMC9752214

NO-CC CODE

2022-12-16 23:25:21

no

Lancet. 2021 Mar 4 6-12 March; 397(10277):865

utf-8

Lancet

10.1016/S0140-6736(21)00571-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00459-1 10.1016/S0140-6736(21)00459-1 Comment Thank you to The Lancet's reviewers of 2020 The Editors of The Lancet a a The Lancet, London EC2Y 5AS, UK 4 3 2021 6-12 March 2021 4 3 2021 397 10277 864864 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIn 2021, many of us are still looking back to 2020 and trying to make sense of the impacts of the COVID-19 pandemic. For those working in medicine and science, 2020 was unusual and difficult. The rapid research advances made to understand SARS-CoV-2, to describe the clinical course and long-term consequences of COVID-19, and to develop treatments and vaccines are incomparable. This incredible progress is a testament to the hard work and dedication of countless researchers and clinicians worldwide. But the pace of scientific research has been driven not only by the researchers whose names appear on the papers, but also by the commitment and drive of the peer reviewers. In 2020, peer reviewers (appendix) at The Lancet reviewed more papers than ever before, many of these on rapid timelines. The expert input and incisive comments of reviewers who, despite time pressures and no doubt difficult personal and professional circumstances, are of the utmost value. Last year reviewers delivered thoughtful evaluations and constructive feedback for vital and time-sensitive papers that have helped shape the global public health response to COVID-19, which makes their contributions an essential part of advancing medical research. We are extremely grateful. 2020 was also a year that was marked by global condemnation and dismay to the police killings of George Floyd, Breonna Taylor, and other Black people in the USA, and by increased visibility to unacceptable racial inequities around the world. Building on the Lancet Group's Diversity Pledge devoted to increasing representation in research and publishing, the Lancet's Group for Racial Equality (GRacE) is working to review policies and processes of the Lancet journals for inviting peer reviewers to ensure that we improve inclusion of experts from racial and ethnic minorities.1 This work builds on The Lancet's work to advance gender equity. In 2019, The Lancet committed to track and report the progress to diversifying our pool of peer reviewers. In 2020, 30% of our peer reviewers were women, which is an improvement from 22% in 2017, but not an increase from 30% in 2019. A disproportionate burden of caring responsibilities has fallen to female academics during the COVID-19 pandemic.2 Enabling and campaigning for women's equal participation and recognition in research and publishing are vital to The Lancet. We aim for higher figures. The Lancet will redouble its efforts and editors are working to ensure a more diverse pool of reviewers. To all The Lancet's reviewers of 2020, thank you. Supplementary Material Supplementary appendix We declare no competing interests. ==== Refs References 1 Das P Aujla M Racial and ethnic equality—time for concrete action Lancet 396 2020 1055 1056 33038952 2 Gabster BP van Daalen K Dhatt R Barry M Challenges for the female academic during the COVID-19 pandemic Lancet 395 2020 1968 1970

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Lancet. 2021 Mar 4 6-12 March; 397(10277):864

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10.1016/S0140-6736(21)00459-1

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==== Front Urology Urology Urology 0090-4295 1527-9995 Published by Elsevier Inc. S0090-4295(21)00595-1 10.1016/j.urology.2021.06.025 Education CASE-based and Guidelines-based Lectures are the Most Preferred Form of Online Webinar Education: Results from the Urology Collaborative Online Video Didactics Series (COViD) Li Yi MD Calle Claire de la MD Chu Carissa MD Baussan Caitlin MD Hampson Lindsay A. MD, MAS ⁎ 1 Department of Urology, San Francisco, University of California, 400 Parnassus Ave A610, San Francisco, CA 94143 ⁎ Address correspondence to: Dr. Lindsay Hampson, MD, MAS, Department of Urology, San Francisco, University of California, 400 Parnassus Avenue, Box 0738, San Francisco, CA 94143 3 7 2021 12 2021 3 7 2021 158 5256 16 1 2021 15 6 2021 © 2021 Published by Elsevier Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objective To evaluate the most preferred style of online didactic lectures. The COVID-19 pandemic has had a significant impact on surgical resident education, instigating a major shift towards online webinar didactics as a major of resident teaching. We hypothesize that a case-based format of online didactics are the most preferred format for this style of lecture. Study Design We analyzed viewer evaluations following 82 online hour-long lectures in the Urology Collaborative Online Video Didactics Lecture Series. We categorized each lecture as case-based, guidelines-based, practice updates, or surgical technique-based and assessed viewer responses to survey questions regarding subject area relevance, lecturer knowledgeability, lecturer effectiveness, and usefulness to learning. We performed logistic regression to control for viewer level, instructor level, and lecture topic, and using surgical technique-based lectures as the baseline variable. Results 2176 evaluations were analyzed. Case-based, guidelines-based and practice updates were all scored significantly higher than surgical technique for subject area relevance. Case-based and guideline-based lectures scored significantly higher for usefulness to learning. Case-based lectures scored significantly higher for lecturer effectiveness. There was no significant difference in scoring between any lecture style when rated on lecturer knowledgeability. Conclusion When preparing online webinar based didactics for surgical resident education, case-based lecturers appear to be the most preferred and well received lecture style, followed closely by guidelines-based lectures. Practice updates and surgical technique-based lectures are less preferred formats for this teaching modality. ==== Body pmcThe 2019-2020 coronavirus pandemic has had a significant impact on all aspects of healthcare. One major shift has been an acceleration of the trend towards telehealth and remote meetings.1 Surgical residency training programs likewise have moved towards web-based learning, surgical simulators, and remote clinics.2 Otolaryngology and urology academic programs were among the first in the country to utilize these e-tools to optimize resident education via online didactic series as a response to the slowdown in resident education3 , 4 Collaborative webinar series for both general resident education (i.e. Collaborative Multi-Institutional Otolaryngology Residency Education Program3, Urology Collaborative Online Video Didactics Lecture Series, EMPIRE Lecture Series), and subspecialty specific topics (i.e. Peds UROFLO, SMILES Series) were quickly developed and well received.5 While these programs were borne out of a need to supplement resident education, they have shown themselves to be a beneficial resource, allowing trainees access to experts in the field across the country, and bringing the academic urology community closer together. With the success of these webinar lecture series and the ongoing nature of the pandemic, it appears that video didactics will be here to stay for the foreseeable future. Video didactics that have been recorded and remain free to access in various formats (Youtube, podcasts, etc.) can serve as an invaluable resource as they are maintained online for future trainees and learners. Given this trend, we aimed to identify if there are specific lecture styles that are better received by the viewers and trainees in this format. The Urology Collaborative Online Video Didactic (COViD) lecture series has broadcasted 98 lectures to date and has collected thousands of viewer evaluations. Lectures have varied both in content and in presentation style: focusing on guidelines and basics, case scenarios, practice updates, and surgical techniques. We hypothesize that webinar lectures that focus on guidelines/basics, and case-based lectures will be rated higher than practice updates and surgical technique-based lectures by the viewers. METHODS Post-lecture online evaluations were offered to viewers after both live and recorded viewings. Lectures were evaluated on a Likert scale (1 = Poor, 2 = Below Average, 3 = Average, 4 = Above Average, 5 = Excellent). Viewers responded to questions worded as follows: 1) Subject area was relevant, 2) Instructor was knowledgeable in the content area, 3) Instructor's effectiveness in teaching the material, and 4) Didactic session was useful to my learning and education. Evaluations were collected and analyzed after the first two months of lectures, from 3/30/2020 to 5/30/2020. Lecture style was categorized into guidelines/basics, case-based, practice updates, or surgical techniques based on the majority of the lecture content. Guidelines-based or basic lectures were categorized as such when the focus of the speaker was primarily on either American Urological Association/European Association of Urology (AUA/EUA) guidelines, or the most basic level of subject knowledge when guidelines were not available. Lectures were categorized as case-based if the majority of the lecture was centered around case scenarios or index patients. Practice update style lectures were categorized as such when the majority of the lecture focused on new clinical and research updates in the field. Lectures were categorized as surgical technique if the majority of the lecture focused on surgical techniques, including videos, outcomes, and complications. This categorization was made by three PGY5 urology residents at the University of California, San Francisco independently, and then compared. Instructor faculty level, lecture topic category, and viewer training level data were collected and evaluated. Instructor levels were categorized as assistant, associate, full professor or other. Lecture topic was broken down to general, oncology, reconstructive/transgender, pediatric, minimally invasive/stone, female/neuro-urology, and andrology/infertility. Viewer level was categorized as medical student, junior resident (PGY1-PGY3), senior resident (PGY4-PGY7), fellow, and practicing provider (physicians and advanced practice providers). Univariate analysis was performed using one-way analysis of variance to evaluate the association between lecture style and lecture rating for each rating category. Multivariable analysis using ordinal logistic regression was performed to evaluate the association between lecture style (with surgical technique as the reference group) and lecture rating for each category, controlling for lecture topic, instructor level and viewer level. Stata/SE 16.0 software was used for analysis with a p-value < 0.05 deemed statistically significant. Biostatistical consultation was utilized through the UCSF Clinical and Translational Science Institute. This study was evaluated by the institutional review board at the University of California, San Francisco and approved as exempt due to the educational nature and minimal risk of this study. RESULTS A total of 2176 post lecture evaluations were collected for the 82 COViD lectures broadcast between 3/30/2020 and 5/30/2020. 1595 evaluations were done after watching the lecture in real time, and 565 after watching the video recording. 96 evaluations were completed by medical students, 799 by junior residents, 516 by senior residents, 70 by fellows, and 290 by practicing providers (Fig. 1 ).Figure 1 Percent breakdown of self-reported education level of viewers who submitted post-lecture evaluations in the COViD lecture series following the first two months of lectures. (Color version available online.) Unlabelled image Of the 82 lectures broadcast by the end of May 2020, 33 were by assistant professors, 17 by associate professors and 23 by full professors. Ten lectures were categorized as general urology, 18 as oncology, 10 as reconstructive/transgender, 18 as pediatric, 7 as minimally invasive surgery/stone, 10 as female/neuro-urology, and 9 as andrology/infertility. Of the lectures, 37 were categorized as guidelines/basics, 12 were case based, 24 were practice updates, and 9 were surgical technique-based (Fig. 2 ). Out of the 82 lectures categorized by the three residents, only 2 lectures were not unanimously categorized by all three reviewers. The two lectures were categorized via majority consensus.Figure 2 Breakdown of the 82 Urology COViD Series lectures by lecturer level, lecture category, and lecture style. (Color version available online.) Figure 2 On univariate analysis, lecture style was found to be significantly associated with ratings for subject area relevance (P = 0.001), instructor effectiveness (P = 0.007), and usefulness to learning (P = 0.001) but was not significantly associated with instructor knowledgeability. Overall, guidelines-based and case-based lectures received higher ratings than practice updates and surgical technique lectures across all rating categories (Fig. 3 ).Figure 3 Average viewer evaluation results by lecture style. Error bars indicate standard deviation. Asterix indicates statistically significant differences between the lecture styles on bivariate analysis. (Color version available online.) Figure 3 In multivariate analysis of subject relevance ratings by lecture style, guidelines-based (OR 3.89, CI 2.31-6.56), case-based (OR 3.58, CI 1.71-7.49), and practice updates (OR 2.42, CI 1.31-4.49) all scored significantly higher than surgical techniques. For lecturer effectiveness ratings, only case-based lectures (OR 2.81, CI 1.26-6.26) scored significantly higher than surgical technique. For usefulness to learning, both guidelines-based (OR 1.81, CI 1.08-3.05) and case-based lectures (OR 4.96, CI 2.21-11.14) scored significantly higher than surgical technique. There was no significant association between lecturer knowledgeability scores and lecture styles (Table 1 ).Table 1 Multivariate analysis of varying lecture styles by each survey category controlling for lecture topic, viewer level, and lecturer level. Surgical Technique scores used as reference group for analysis. Table 1Table 1 Guidelines Based Case Based Practice Updates OR 95% CI OR 95% CI OR 95% CI Subject Area Relevance 3.89 2.31-6.56 3.58 1.71-7.49 2.42 1.31-4.49 Lecturer Knowledgeability 1.09 0.51-2.35 1.63 0.55-4.87 0.94 0.39-2.27 Lecturer Effectiveness 1.43 0.82-2.49 2.81 1.26-6.26 0.99 0.53-1.88 Usefulness to Learning 1.81 1.08-3.05 4.96 2.21-11.14 1.19 0.65-2.17 DISCUSSION In recent decades, there has been a shift towards utilizing the virtual classroom and “new media” in resident education.6, 7, 8 In undergraduate medical education, there has been a well-documented major shift towards watching recorded lectures instead of attending live lectures.9 The COVID-19 pandemic drastically hastened the transition to virtual classrooms and collaborative video didactics in surgical residency training, and online and video learning appears to be here to stay for the foreseeable future.10 The difficulties presented by online didactics include the limited attention span of passive learners11, variability in lecture styles that may not suit each learner, and variation in level of information.12 The COViD Lecture Series was one of the earliest programs to adopt streaming webinar format for resident education nationwide and as such offers us a chance to understand how to best present virtual education in the future. Case-based lectures overall scored highly in all categories. Decades of medical education research have outlined the effectiveness of both problem-based curricula13 and the utilization of media and discussion beyond the conventional lecture format.14 While webinar lecture series are limited in being able to incorporate small group discussions and multi-modal learning, case-based scenarios and case-based lectures are the closest they can get to the “flipped classroom” model. Therefore, it is unsurprising that the case-based style of lecture was rated significantly higher than the other lecture styles in terms of subject relevance, lecturer effectiveness, and usefulness to learning. Prior survey studies have shown that trainees feel case-based learning in urology is effective for improving both clinical care and knowledge base.15 In the COViD series, lectures utilized case scenarios to teach both guidelines and basics in the “index patient” model, as well as to create a more interactive learning environment. Guidelines-based or basic lectures also scored well overall and were found to have significantly higher ratings in terms of subject relevance and usefulness to learning compared to surgical techniques. While graduate level medical education has seen a shift away from this model of lecture, it remains the staple format for most didactics and junior trainee level learning.16 As an educational resource primarily directed towards resident-level education, and with the majority of viewers self-reporting to be junior residents (Fig. 1), a format that focuses on basics and guidelines understandably rates well in terms of subject area relevance and usefulness to learning. While this style of lecture does not utilize the “flipped classroom” model, it can remain interactive with use of poll questions, videos, and discussion to engage learners and provide “active” learning opportunities. Practice update style lectures are similar in concept to plenary sessions at region and national meetings, often focusing on more advanced information. The style may assume a level of baseline knowledge by the viewer. For example, the Urology COViD lecture on prostate cancer screening discussed the latest epidemiology of prostate cancer, trends in racial disparities, and details on the newest genomic testing. This lecture was categorized as a practice update as it assumed baseline knowledge of PSA testing and early detection guidelines. In our analysis, practice update lectures scored better than surgical technique in terms of subject relevance, but in terms of lecturer effectiveness and usefulness to learning it did not score any higher. Previous studies have noted that lectures where the information is too abundant or advanced were more difficult for learners to appreciate.12 Practice update lectures may have fallen into this pitfall, where the assumption of basic understanding of the viewer was overestimated. While viewer level was controlled for in this analysis, 80% of the viewers were resident level or below. Lectures focusing on practice updates and new studies should take care to know the audience and explain basic principles that are necessary to understanding the new findings being discussed. Finally, surgical technique lectures overall fared the poorest and were the lowest rated in each evaluation category. Only 9 out of the 82 lectures during the study period were categorized as surgical technique, and the majority focused on techniques and surgeries that were either not commonly performed at all residency programs, or were rarely seen, such as transgender surgery or pediatric robotic surgery. The fact that these topics are less routine in nature and more uncommon in practice may explain the decreased rating for “subject area relevance” even when controlling for overall lecture topic. This may be an implicit deficiency in this style of lecture, as speakers are less likely to present surgical technique lectures for the more common urologic surgery experiences. Surgical training programs have explored using virtual and e-learning to teach surgical technique, specifically utilizing robot and laparoscopic simulators.17 However, surgical technique education in a webinar format does not give the learning, the feedback and physical experience that a simulator can provide.18 There is still likely a significant gap in learner experience between virtual surgery simulation and the operating room setting. Limitations to our study include the categorization process of lectures. We attempted to mitigate this by having three residents categorize them independently, but there was no way to blind the resident to the lecture topic or speaker in this process. However, there was a high level of concordance between the raters. While we were able to categorize the lectures, we did not report on the “interactiveness” of lectures that may underlie ratings. Case based lectures are inherently interactive, but other lecture formats can increase learner engagement by utilizing polling questions, discussions, and other techniques. There were no significant differences noted when we compared evaluations between live lecture viewers (who could interact with poll questions and chat) and viewers who watched the recording. This is something that can be further investigated in future studies. Additionally, the surveys distributed were created with quality improvement in mind, and not specifically for the purposes of this study. Wording and validation of the survey could have been improved during study design. We did not evaluate the efficacy of the lectures styles with regard to learner knowledge retention, i.e. pre and post testing. Thus, the effectiveness of the lectures were evaluated via subjective viewer feedback, which may be subject to bias from multiple sources. Finally, while we do find statistical significance on univariate and multivariate analysis, the actual difference in average scores between the four lecture styles remains less than have a point for each question (Figure 3). This is likely due to the overall positive reception of this lecture series as a whole.10 Therefore, the clinical significance of these findings remain open to interpretation. Readers should not interpret from this study that practice update lectures or surgical technique-based lectures are not beneficial styles of webinar lecture, but rather utilize this data to better incorporate multiple lecture styles and techniques to improve the effectiveness and usefulness of these webinars. There will be lecture topics that are better suited to various styles and learners, and the end goal should be the produce the most effective and palatable learning experience for the viewer as possible. In this new era of shared learning and webinar-based didactics, incorporating guidelines and basic knowledge into a case-based format seems to be the highest yield for resident learners, though further analysis of the most effective ways to teach urologic content will be an integral aspect of the progression of academic urology into the future. CONCLUSION In the new era of online web-based learning for surgical resident education, understanding the most effective way to deliver online lectures to large resident audiences has gained increased importance. Our study shows that case-based and guidelines-based styles of lectures are the best received by viewers in this format when controlling for lecture topic, speaker, and viewer. Lecture styles will inevitably be influenced by lecture topic and lecturer preference. However, lecturers should take into account these viewer-reported preferences when preparing for resident-based webinar lecturers. Funding support : N/A – UCSF , Department of Urology internal departmental funding. ==== Refs References 1 Gadzinski AJ Gore JL Ellimoottil C Implementing Telemedicine in Response to the COVID-19 Pandemic J. Urol. 204 2020 14 16 Available at: https://pubmed-ncbi-nlm-nih-gov.ucsf.idm.oclc.org/32249678/ accessed July 9, 2020 32249678 2 Kogan M Klein SE Hannon CP Orthopaedic Education During the COVID-19 Pandemic J. Am. Acad. Orthop. Surg. 28 2020 e456 e464 Available at https://pubmed-ncbi-nlm-nih-gov.ucsf.idm.oclc.org/32282439/ accessed July 9, 2020 32282439 3 Anon Otolaryngology offers free residency education program | Keck School of Medicine of USC 2020 Available at: https://keck.usc.edu/otolaryngology-offers-free-residency-education-program/ accessed September 3 4 Porpiglia F Checcucci E Amparore D Slowdown of urology residents’ learning curve during the COVID-19 emergency BJU Int 125 2020 E15 E17 10.1111/bju.15076 accessed July 11, 2020 32274879 5 Li Y Chu C de la Calle CM Multi-Institutional Collaborative Resident Education in the Era of COVID-19 Urol. Pract. 7 2020 425 433 10.1097/UPJ.0000000000000158 accessed September 3, 2020 6 Salem J Borgmann H MacNeily A New Media for Educating Urology Residents: An Interview Study in Canada and Germany J. Surg. Educ. 74 2017 495 502 28017704 7 Buxton E Burns E pharmaceutical JDM-A journal of: Professional development webinars for pharmacists 2020 ajpe.org. Available at: https://www.ajpe.org/content/76/8/155.abstract accessed July 9 8 Shaffer K Small JE Blended learning in medical education: use of an integrated approach with web-based small group modules and didactic instruction for teaching radiologic anatomy Acad. Radiol. 11 2004 1059 1070 Available at: http://www.ncbi.nlm.nih.gov/pubmed/15350588 accessed July 9, 2020 15350588 9 Gupta A Saks NS Exploring medical student decisions regarding attending live lectures and using recorded lectures Med. Teach. 35 2013 767 771 10.3109/0142159X.2013.801940 accessed July 19, 2020 23869431 10 Li Y Chu C de la Calle CM Multi-institutional Collaborative Resident Education in the Era of COVID-19 Urol. Pract. 2020 11 Mustafa T, Farooq Z, Asad Z, et al: Lectures in medical education: what students think?; 2013. Available at: http://www.ayubmed.edu.pk/JAMC/26-1/Zerwa.pdf, accessed July 19, 2020. 12 Jen A Webb EM Ahearn B Lecture Evaluations by Medical Students: Concepts That Correlate with Scores J. Am. Coll. Radiol. 13 2016 72 76 26314795 13 Neville AJ Problem-Based Learning and Medical Education Forty Years On A Review of Its Effects on Knowledge and Clinical Performance A Brief History of Problem-Based Learning in Medical Education Princ Pr 18 2009 1 9 Available at: www.karger.comwww.karger.com/mpp accessed July 19, 2020 14 Sadeghi R Sedaghat MM Sha Ahmadi F Comparison of the effect of lecture and blended teaching methods on students’ learning and satisfaction J. Adv. Med. Educ. Prof. 2 2014 146 150 Available at http://www.ncbi.nlm.nih.gov/pubmed/25512938 accessed July 19, 2020 25512938 15 Mishra K Snow-Lisy DC Ross J Evaluation of a case-based urology learning program Urology 82 2013 1207 1210 24295241 16 Ounounou E Aydin A Brunckhorst O Nontechnical Skills in Surgery: A Systematic Review of Current Training Modalities J. Surg. Educ. 76 2019 14 24 Available at: https://pubmed-ncbi-nlm-nih-gov.laneproxy.stanford.edu/30122636/ accessed July 10, 2020 30122636 17 Mota P Carvalho N Carvalho-Dias E Video-Based Surgical Learning: Improving Trainee Education and Preparation for Surgery J. Surg. Educ. 75 2018 828 835 Available at: https://pubmed-ncbi-nlm-nih-gov.laneproxy.stanford.edu/29031522/ accessed July 10, 2020 29031522 18 Nataraja RM Webb N Lopez PJ Simulation in paediatric urology and surgery, part 2: An overview of simulation modalities and their applications J. Pediatr. Urol. 14 2018 125 131 Available at: https://pubmed-ncbi-nlm-nih-gov.laneproxy.stanford.edu/29456118/ accessed July 9, 2020 29456118

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Urology. 2021 Dec 3; 158:52-56

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10.1016/j.urology.2021.06.025

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==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Published by Elsevier B.V. S0048-9697(21)07490-8 10.1016/j.scitotenv.2021.152412 152412 Article Evidence of Covid-19 lockdown effects on riverine dissolved organic matter dynamics provides a proof-of-concept for needed regulations of anthropogenic emissions Retelletti Brogi S. a⁎ Cossarini G. b Bachi G. a Balestra C. b Camatti E. ac Casotti R. d Checcucci G. a Colella S. e Evangelista V. a Falcini F. e Francocci F. f Giorgino T. g Margiotta F. d Ribera d'Alcalà M. df Sprovieri M. h Vestri S. a Santinelli C. a⁎ a Istituto di Biofisica, CNR, Pisa, Italy b Istituto Nazionale di Oceanografia e Geofisica Sperimentale. Sgonico (TS), Italy c Istituto di Scienze Marine, CNR, Venezia, Italy d Stazione Zoologica Anton Dohrn, Napoli, Italy e Istituto di Scienze Marine, CNR, Roma, Italy f Istituto per lo studio degli impatti Antropici e Sostenibilità in ambiente marino, CNR, Roma, Italy g Istituto di Biofisica, CNR. Milano, Italy h Istituto per lo studio degli impatti Antropici e Sostenibilità in ambiente marino, CNR. Campobello di Mazara (TP), Italy ⁎ Corresponding authors. 16 12 2021 15 3 2022 16 12 2021 812 152412152412 5 10 2021 9 12 2021 10 12 2021 © 2021 Published by Elsevier B.V. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The fast spread of SARS-CoV-2 virus in Italy resulted in a 3-months lockdown of the entire country. During this period, the effect of the relieved anthropogenic activities on the environment was plainly clear all over the country. Herein, we provide the first evidence of the lockdown effects on riverine dissolved organic matter (DOM) dynamics. The strong reduction in anthropogenic activities resulted in a marked decrease in dissolved organic carbon (DOC) concentration in the Arno River (−44%) and the coastal area affected by its input (−15%), compared to previous conditions. The DOM optical properties (absorption and fluorescence) showed a change in its quality, with a shift toward smaller and less aromatic molecules during the lockdown. The reduced human activity and the consequent change in DOM dynamics affected the abundance and annual dynamics of heterotrophic prokaryotes. The results of this study highlight the extent to which DOM dynamics in small rivers is affected by secondary and tertiary human activities as well as the quite short time scales to return to the impacted conditions. Our work also supports the importance of long-term research to disentangle the effects of casual events from the natural variability. Graphical abstract Unlabelled Image Keywords Lockdown DOM Carbon cycle Riverine inputs Arno River Editor: Ouyang Wei ==== Body pmc1 Introduction Rivers connect a large portion of Earth's land surface to the ocean; their input of a large amount of organic matter and nutrients stimulates biological activity in coastal areas, contributing to making them one of the most productive ecosystems on the Earth. Riverine inputs therefore have a profound impact on the biogeochemistry of the world's oceans, playing a crucial role in the global biogeochemical cycles (Aufdenkampe et al., 2011). Because of its importance, riverine water quality is monitored worldwide, and several parameters (e.g. oxygen, inorganic nutrients, pH, bacterial load, heavy metals, contaminants) are measured in order to evaluate the ecosystem status. Monitoring programs do not take into account dissolved organic matter (DOM), even if it has been demonstrated that human-related activities have induced changes in the quantity and quality of DOM in rivers (Stanley et al., 2012; Xenopoulos et al., 2021). Through the years, anthropogenic activities have increased the input of DOM to the aquatic environment, and since anthropogenic DOM is different from the natural one, being either more recalcitrant (e.g. the black carbon produced by combustion), or more labile (e.g. DOM from wastewaters or urban sewage) (Xenopoulos et al., 2021), it can impact the functioning of riverine ecosystems and the CO2 fluxes from the rivers to the atmosphere. Being the main source of energy for heterotrophic prokaryotes, DOM fuels the microbial loop (Carlson and Hansell, 2015), whose proper functioning regulates the dynamics of the whole food web, channeling energy toward the higher trophic levels (Williams et al., 2019). DOM also screens aquatic organisms from harmful UV radiation (Stedmon and Nelson, 2015) and directly influences the bioavailability of pollutants (Aiken et al., 2011). Modification of DOM natural dynamics can therefore strongly affect the wellbeing of riverine ecosystems, and consequently of the coastal areas impacted by riverine inputs. For instance, an excess of DOM can limit the light available to primary producers (Thrane et al., 2014; Wikner and Andersson, 2012) or can be associated with eutrophication, leading to a shift toward a net heterotrophy of the ecosystem (Deininger and Frigstad, 2019; Wikner and Andersson, 2012). DOM concentration and dynamics in rivers is the result of the interplay among the inputs from natural (e.g. in-situ production, soil leaching of plant root exudates) and anthropic (e.g. industries, agriculture, oil combustion, water treatment plant) processes, and the physico-chemical and biological re-elaboration and removal of these inputs within the soil and the river itself. It can be therefore considered as a synthetic ecosystem descriptor and, as such, a very good proxy for aquatic ecosystems' health (Deininger and Frigstad, 2019). But what happens if the anthropogenic pressure is relieved or significantly reduced? How will DOM dynamics respond in rivers and coastal areas? What timeframe is needed to observe a response? The lockdown due to the COVID-19 pandemic represented an unprecedented opportunity to answer these questions. In different parts of the world, the relief of anthropic activities due to the COVID-19 control policies had a strong impact on the quality of both air and surface waters. Indeed, the marked reduction of the monitored atmospheric pollutants (e.g. CO, CO2, NOx, SOx, PM2.5, PM10, hydrocarbons, etc.) (Elsaid et al., 2021, and references therein) was observed. In over polluted rivers, an improvement of the Water Quality Indexes (Dutta et al., 2020; Patel et al., 2020), the decrease of heavy metal loads (Shukla et al., 2021), and the restoration of natural bacterial communities (Jani et al., 2021) were also reported. Since DOM dynamics is driven by the interaction of several factors, it shows a non-linear response to changes in environmental forcing and human pressure. As a consequence, DOM cannot be considered in the same way as a pollutant and a decrease in its concentration cannot be considered a necessary effect of the lockdown. Yet, taking into consideration the impact of human activities on riverine DOM, it is reasonable to hypothesize that the shut-down of a significant fraction of human activities would result in a change in DOM dynamics. In this paper, we show the first evidences and quantification of the lockdown effects on riverine DOM dynamics in the Arno River (Tuscany, Italy). This river (average discharge 86 m3 sec −1, drainage basin 8228 Km2) is characterized by a torrential hydrological regime (Retelletti Brogi et al., 2020), high Dissolved Organic Carbon (DOC) concentration (Retelletti Brogi et al., 2015, Retelletti Brogi et al., 2020; Santinelli, 2015), a medium-high anthropogenic impact (Fig. 1 ), and it can be considered as a case study for DOM dynamics in small Mediterranean rivers with similar characteristics and human impact (Retelletti Brogi et al., 2020). The high-resolution record of DOM concentration and optical properties (absorption and fluorescence) available for 2014 and 2015, years with contrasting riverine discharge covering a wide spectrum of river variability (Retelletti Brogi et al., 2020), offers a unique chance to compare the data collected in the COVID era with the pre-lockdown regime.Fig. 1 Arno River basin’s land coverage. Data from Copernicus Land Monitoring Service (CLC2018). The map is realized by using QGIS software (v. 3.12). The numbers refer to the location of the sampling stations along the river. The tributary between stations 2 and 3 is the Canale della Chiana; the tributary between stations 7 and 8 is the Ombrone Pistoiese; the tributary between stations 10 and 11 is the Usciana. The map on the left bottom corner shows the location of the coastal stations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 1 2 Methods 2.1 Samples collection and treatment In order to evaluate the effect of the lockdown on riverine DOM, samples were collected (1) from the spring to the mouth of the river; (2) in the lower part of the river, with a high temporal resolution; (3) in the coastal area in front of the river mouth.(1) On March 5th, 2021, samples were collected at 14 stations along the river, upstream and downstream of the main tributaries, cities, and industrial areas (Fig. 1). This period was chosen since previous data showed the lowest DOM concentration in March, with a main terrestrial origin, coincident with the lowest autotrophic activity (Retelletti Brogi et al., 2020). (2) From April 2020 to May 2021, surface river samples were collected two times a week in the lower part of the river in Pisa (station 14, Fig. 1), at the same location where samples were collected from January 2014 to December 2015 (Retelletti Brogi et al., 2020). A high temporal resolution sampling, whose importance is often underestimated, is necessary to be able to discriminate between the effect of a temporary relieve of anthropic pressure, such as the COVID-19 lockdown, and the effect of other disturbance events (e.g. floods or drought) that can have short-time effects (i.e. day or week). (3) On May 5th 2020, 15 surface samples were collected within 12 miles from the coast and 7 miles northward and southward of the Arno River estuary. All samples were collected into 2 l HCl-cleaned polycarbonate bottles (Nalgene), rinsed 3 times with the sample before filling, and kept refrigerated and in the dark until filtration, within a few hours from the sampling (1 h for the weekly samples). The samples were filtered by using a pre-washed 0.2 μm pore size Polycap filter (Whatman Polycap, 6705–3602 capsules) into HCl-cleaned 60 ml polycarbonate bottles (Nalgene), rinsed 3 times with the filtrate before filling, and measured immediately after filtration. 2.2 Analytical measurements Dissolved organic carbon (DOC) concentration was measured to obtain quantitative information on DOM concentration. DOC was measured with an analytical precision of ±1 μM by using a Shimadzu Total Organic Carbon analyzer (TOC-Vcsn), following the method described in Santinelli et al. (2015). DOC Reference Material (Hansell, 2005) was used to verify the instrument performance (CRM Batch #19 nominal concentration of 40–43 μM; measured concentration 41.5 ± 1.1 μM, n = 81). Absorbance spectra were measured in a 10 cm quartz cuvette using a Jasco UV–visible spectrophotometer (Mod-7850) according to Retelletti Brogi et al. (2020). The absorption coefficient at 254 nm (a254) and the spectral slope between 275 and 295 nm (S275 – 295) were calculated by using the ASFit tool (Omanović et al., 2019). Since primary CDOM absorption is caused by conjugated systems present in organic compounds having the peak of absorption near 254 nm, a254 can be used to have quantitative information on CDOM (Del Vecchio and Blough, 2004). The S275 – 295 was calculated to obtain information on the change in the DOM properties since its values are inversely related to the average molecular weight and aromaticity of the molecules. Fluorescence excitation-emission Matrixes (EEMs) were obtained using the Aqualog spectrofluorometer (Horiba) according to Retelletti Brogi et al. (2020). The EEMs were elaborated using the TreatEEM software (Omanović Dario, TreatEEM—program for treatment of fluorescence excitation-emission matrices, https://sites.google.com/site/daromasoft/home/treateem). A blank EEM (Milli-Q water) was subtracted from each EEM and they were corrected for inner-filter effect (Lakowicz, 2006). The Rayleigh and Raman scatter peaks were removed by using a shape-preserving monotone cubic interpolation (Carlson and Fritsch, 1989). PARAFAC analysis (drEEM Toolbox, Murphy et al., 2013) was carried out on the EEMs, by merging the 2020–2021 dataset with the data from 2014 to 2015 (533 EEMs total). The validation of the PARAFAC model was performed by (i) analyzing the sum of squared error for different models (Fig. S1); (ii) visual inspection of the residuals between different models (Fig. S2); (iii) core consistency results (Fig. S3); (iv) split-half analysis results (Fig. S4); and (v) percentage of explained variance (99.6%, Fig. S5). The analysis resulted in the validation (Fig. S5) of a 6-component model (Fig. S6 and S7, Table S1). The emission and excitation spectra of the components (Fig. S6) were compared with those published by using the OpenFluor database (Murphy et al., 2014) and characterized as follows, component 1: microbial humic-like compounds (C1mh); component 2: terrestrial humic-like compounds (C2th); components 3 and 5: fulvic-like compounds (C3f, C5f); component 4: protein-like compounds (C4p); component 6: polycyclic aromatic hydrocarbons (C6pah) (see Table S1 for further information and Retelletti Brogi et al., 2020 for details on components identification). For each sample, the total fluorescence was calculated as the sum of the 6 components and normalized by the DOC concentration in order to evaluate the changes in fluorescence regardless of the variation in concentration. One ml samples for Heterotrophic Prokaryotes (HP) Abundance (HPA) were fixed for 10 min with glutaraldehyde (GL, 0.05% final concentration) and stored at −80 °C until the analysis. After thawing, samples were stained with SYBR Green (Invitrogen Milan, Italy) 10−3 dilution of stock solution for 15 min at room temperature. Cell concentrations were assessed using a FACSVerse flow cytometer (BD BioSciences Inc., Frankyn Lakes, USA) equipped with a 488 nm Ar laser and a standard set of optical filters, at the Flow Cytometry Facility of the Stazione Zoologica Anton Dohrn of Naples, Italy. FCS Express software was used for analyzing the data and HP were discriminated from other particles based on scattering and green fluorescence from SYBR Green (Balestra et al., 2011). 2.3 Environmental conditions Temperature and conductivity were measured with a portable multiparameter probe (Hanna HI98194). Daily average river discharge, precipitation, and air temperature were downloaded from the Regional Hydrological Service (www.sir.toscana.it). Precipitation data for 122 meteorological stations since 2004 were averaged in order to reconstruct the climatology. 2.4 Socio-economic data Data and information on the anthropic activities within the Arno River basin affected by the lockdown were gathered from regional and national databases. Industrial activity is expressed as an index of regional industrial production at the provincial-sectorial level in Tuscany (IRIP). The IRIP indicator is elaborated by the Regional Institute for economic planning of Tuscany (IRPET) and describes the evolution of industrial production within the Tuscany region. Data on the arrival of foreign tourists, as well as the movement of local people for tourism, were obtained from the statistics division of the Tuscany Region (https://www.regione.toscana.it/statistiche/dati-statistici/turismo); these data are publicly available on an annual basis. Data on transportation were gathered from, (i) the Italian Civil Aviation Authority (ENAC), which provides information about the airplane's movements (in or out) from each Italian airport on an annual basis, and (ii) the Google community mobility report, which provides the percentage of variation inland transportation, categorized according to the purpose of the movement, related to a baseline (calculated as the median value, for the corresponding day of the week, during the 5 weeks Jan 3–Feb 6, 2020; https://www.google.com/covid19/mobility/). 2.5 Statistical analyses For all the parameters, the significance of the differences between the years (2014, 2015, 2020–2021) was tested by using the Kruskal–Wallis test (Origin software). Differences were considered significant at the threshold of p < 0.05. A principal component analysis (PCA, Legendre and Legendre, 2012) was applied to the data of the 6 FDOM components after standardization of the variables. PCA was performed using the R software (Team R Development Core, 2018). A stepwise regression approach (Draper and Harry, 1998) was used to analyze DOC temporal variability versus some explanatory variables that track sources and processes driving DOC evolution in the river. At each step of the regression analysis, independent variables were chosen if their contribution to the model was significant. Among the explanatory variables, the water temperature represents a proxy of the autochthonous DOC production, while bacteria abundance is a proxy for the potential decomposition rate of DOC. River discharge is used to describe the soil leaching and transport of DOC during flood events. Given that the flood duration can last from 1 to several days and the sampling could not catch the exact moment of the highest correlation value between DOC concentration and runoff (Retelletti Brogi et al., 2020), we tested the 1, 2 and 3 days discharge averages before the sampling. Additionally, since drought periods enhance the accumulation of organic matter in the soil that can be leached and transported by a flood event, we included in the model the discharge averages for the 30, 60, 90, 120 days before the sampling. Finally, we chose to add some dummy variables (i.e., variables assuming the values of 1 in a specific period and 0 otherwise) to indicate the presence (1) or absence (0) of the COVID-19 lockdown impacts on human activities (e.g., tourism, transport, industry, agriculture). Thus, we tested the hypothesis that allochthonous DOC production and transport into the river have been impacted by the reduction of human activities during the lockdown. Since the timing of the reduction of human activities during 2020 cannot be identified precisely (i.e., there have been possible mismatches between Italian restriction regulations and the effective reductions of human activities) we build several dummy variables and let the stepwise regression analysis select the most statistically relevant lockdown period. The analysis was performed with the stepwise fit Matlab statistical toolbox that uses an initial constant model and takes forward steps to include new variables based on their statistical significance (F-statistics at p-level or 0.025). 2.6 Remote sensing analysis Weekly data from 2016 to 2019 were used to obtain the weekly climatology, which is then used as a reference for the analysis. The analysis of Chlorophyll-a (Chl-a) concentration was based on the Sentinel-3 OLCI (Ocean and Land Colour Instrument) full spatial resolution imagery, which properly captures the fine-scale variability associated with the coastal environment. We collected the full-time series (May 2016 – to present) of OLCI Level-2 full resolution (300 m) data from the EUMETSAT (European operational satellite agency for monitoring weather, climate and the environment from space) data center. Level-2 products were then extracted and remapped over a regular equirectangular grid off the Arno River mouth. We applied the CMEMS (Copernicus Marine Environment Monitoring Service) operational regional algorithms for phytoplankton chlorophyll retrieval (Volpe et al., 2019), adapted to OLCI bands, and implemented daily. The OLCI daily time series is then turned into a weekly time series by averaging on a pixel-by-pixel basis. For each pixel, the average and standard deviation are computed from a data cube of 3 pixels × 3 pixels × 7 days. This averaging reduces the impact of possible noise, common at these small scales, and increases spatial coverage mined by lack of data mostly due to clouds. The climatology has the same spatial resolution as the weekly data to which it is compared (nominally 300 m). Finally, we consider the difference between the 2020 weekly observations and the weekly climatology at the scale of the pixel, expressed as weekly mean anomalies (WMA):WMA=WeeklyObservations2020−WeeklyClimatology2016−2019WeeklyClimatology2016−2019 3 Results 3.1 Allochthonous sources of DOM to the Arno River The samples, collected from the spring to the mouth of the river in March 2020 (sampling 1 in the methods), allowed for the identification of the main DOM enrichment areas within the river drainage basin and therefore for the primary allochthonous sources of DOM to the Arno River. A 125 μM DOC total enrichment was observed from the spring (50 μM) to the mouth of the river (175 μM) (Fig. 2 ), approximately 0.5 μM DOC per km. The increase is not linear and point source effects were observed along the river path. The highest increase in DOC (+ 130 μM) was observed downstream station 2 (after the Canale della Chiana tributary, Fig. 1) although the 43% of DOC enrichment was removed after the input of this tributary (Fig. 2) suggesting its labile form. Surprisingly, after Florence (station 6, Fig. 1), the biggest city along the river, a slight decrease in DOC was observed (Fig. 2). The Ombrone Pistoiese (discharging between stations 7 and 8, Fig. 1), and the Usciana (discharging between stations 10 and 11, Fig. 1) tributaries determined a 28 and 59 μM DOC enrichment, respectively (Fig. 2). Downstream station 12 no change in DOC was observed (Fig. 2). Specifically, the Canale della Chiana tributary (between stations 2 and 3, Fig. 1) drains an area mostly used as agricultural land, and passes through a gold processing industrial area; the Ombrone Pistoiese tributary (between stations 7 and 8, Fig. 1) drains a region that is characterized by a large portion of agricultural land, with a large number of greenhouses, and by the presence of textile industries; the Usciana tributary (between stations 10 and 11, Fig. 1) receives the wastewater from many tanneries and paper-mills. All these anthropic activities may represent an important source of DOM to the Arno River, although, due to the large spatial coverage of agriculture areas (Fig. 1), the main input is expected to come from the intensive agriculture activities. The unexpected lack of DOC enrichment after the city of Florence, and the many small cities located along the river, is due to the high biological lability of the DOM pool within the urban wastewaters (Regnier et al., 2013), allowing its rapid removal by the microbial community. This observation is further supported by the evidence of enhanced chemical oxygen demand measured after the Florence settlement (Cortecci et al., 2009).Fig. 2 DOC concentration from the spring to the mouth of the Arno River. The numbers refer to the sampling stations (their location on the basin is shown in Fig. 1). Fig. 2 3.2 How the lockdown affected the anthropogenic activities in Tuscany Tuscany was one of the Italian regions most affected by the lockdown. During (March–May 2020) and immediately after (June 2020) the lockdown, the decrease in industrial production (−21.9%) was higher than the national one (−18.6%; IRPET, 2020). This depends on the industrial sectorial composition of Tuscany that is specialized in those sectors that more than all the others were affected by the lockdown restrictions. A drastic reduction of all the industrial activities (−50%) was observed in April 2020, with values slowly going back to the pre-lockdown values since August 2020 (Fig. S8a). Compared to the average between 2012 and 2019, in 2020, a 57% reduction in the total tourist arrivals (−7.5 million people), 79% if considering only the foreign tourist, was registered in Tuscany (Fig. S8b). These data are available only on a yearly time scale, implying that these percentages would have been much more relevant if only the months of the lockdown would have been taken into account. The reduction of tourists, as well as the restrictions to travel, was also reflected in a 54% decrease in air traffic (i.e. 67,574 less airplane movements) in the two major airports in Tuscany (Pisa and Florence), compared to the average between 2014 and 2019 (Fig. S8c). A drastic reduction in inland transportation was also observed. The 2020 Google community mobility report shows a decrease of up to −97% between February and May 2020 (Fig. S8d). Regarding the food compartment, the publicly available data from the Tuscany Region database suggest that in 2020 agriculture was not significantly affected by the lockdown restrictions. The total cultivated agricultural land was 9.63·1016, 9.78·1016, and 9.63·1016 Ha in 2018, 2019, and 2020, respectively. Yet, it is not possible to exclude an effect on specific cultivation type (i.e. change in cultivated crops) or harvest, both factors being able to influence soil composition and its organic matter content. It was not possible to gather data on flowers cultivation and livestock, which have been significantly affected by lockdown restrictions according to the Regional Institute for economic planning of Tuscany (http://www.irpet.it). 3.3 The lockdown impact on DOC concentration In order to test our hypothesis that the removal of a significant fraction of human activities affected DOM dynamics, the data collected in 2020 and 2021 (sampling 2 in the methods) have been compared with those measured in 2014 and 2015 (Retelletti Brogi et al., 2020). The published data on DOC and DOM optical properties (absorption and fluorescence) represent a reference point for DOM dynamics in the river in “normal” conditions, which includes contrasting hydrological conditions. Their comparison with the data collected in 2020–2021 therefore allows to identify changes mostly ascribable to the lockdown. DOM dynamics in 2020–2021, similarly to 2014 and 2015 (Retelletti Brogi et al., 2020), showed a clear seasonality with the lowest DOC values in winter and a marked increase in spring, in correspondence with the increase in temperature, to reach its maximum in summer (Fig. 3 ). During the lockdown (April 24th to May 12th, 2020) DOC values (189 ± 8 μM) were significantly lower (−27%) than those observed in 2014 and 2015 during the same period (258 ± 17 μM, and 261 ± 21 μM, respectively; Fig. 3). This difference slightly increased in summer (June and July) reaching −30% of DOC concentration with respect to 2014 and 2015. From August, the difference with the previous years was less marked, although a 21% reduction in DOC concentration was still observed between October and December 2020 (Fig. 3), when a partial lockdown was again established. These results clearly show an offset in DOC concentration between April and December 2020 with respect to previous years, even if the cycle followed the expected seasonal variability. Since December 2020, DOC values were comparable to the pre-lockdown ones (Fig. 3).Fig. 3 Arno River DOC concentration in 2014, 2015, 2020, and 2021, bars represent the standard deviation (n = 3). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 3 A stepwise regression was carried out to test whether the observed decrease in DOC concentration was a consequence of the human activity reduction following the lockdown. This analysis identified 7 factors that explain the variability of DOC in the Arno River (Table S2). Among the selected factors, the average discharge of the 90 days before the sampling is the most significant variable followed by a dummy variable for the period March–July 2021 (p-value in Table S2). These two terms have both a negative impact on DOC concentration (coefficient of the regression model in Table S2). The next two most important variables are the water temperature and the 2-day run-off that represent the positive factors associated with autochthonous DOC production and flood events, respectively. Two other variables, the 30-day run-off average and a second dummy variable for the Aug-Nov 2020 period, contribute negatively to the reconstruction of the DOC variability even if with a lower effect than the other variables. Finally, the degradation of DOC due to the HP has a low marginal effect, indeed the HPA is the last variable to be included in the regression model. Other variables have been excluded from the final regression model given their low level of significance (p-values>0.05; Table S2). The final regression model reconstructs remarkably well the DOC time series (Fig. 4 ), reproducing the interannual, seasonal, and most of the high-frequency variability with an error of ≈39 μM.Fig. 4 Time series of DOC observations (black) and values reconstructed by using the stepwise regression model (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 4 3.4 Effects on DOM quality In agreement with DOC, the absorption coefficient at 254 nm (a254), showed a significant reduction (−26%) during the lockdown (April 24th to May 12th, Fig. S9). During the rest of the year, this difference was reduced, except for July and August when a reduction of 11-16% was still observed with respect to 2014 and 2015. Compared to the previous years, the CDOM spectral slope, S275 – 295, indicates a change in the average molecular weight and aromaticity of the molecules in the CDOM pool. In particular, between April and December 2020, S275 – 295 was higher than in 2014 (on average + 14%) and 2015 (on average + 8%) (Fig. 5 ). The higher values of S275 – 295 suggest the predominance in the DOM pool of molecules that are smaller and less aromatic in 2020 than in 2014 and 2015. Moreover, the observed S275 – 295 decrease between June and July 2020 suggests a change in DOM molecular properties. Since December 2020, S275 – 295 re-aligns to the values observed in 2014 and 2015, as observed for DOC.Fig. 5 Arno River CDOM spectral slope (S275–295) in 2014, 2015, 2020, and 2021 (left panel), error bars represent the standard deviation (n=3); Arno River DOC normalized total fluorescence in 2014, 2015, 2020, and 2021 (right panel). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 5 Fluorescence data further support the change in DOM quality. The total fluorescence normalized by DOC showed values lower in 2020 and at the beginning of 2021 than in 2014 and 2015; from March 2021 the values are comparable to those observed in 2015 (Fig. 5). The largest difference (−41 to –46%) was observed between May and August 2020. To better evaluate changes in FDOM, a PCA analysis was carried out on the 6 fluorescent components (Fig. 6 ).Fig. 6 Results of the PCA carried out on fluorescence data. Red lines and dots refer to loadings and scores of the first two principal components. The colors of the symbols identify the sampling year. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 6 The score of the first two principal components, which explain up to 76% of the total variances, show a marked difference in the fluorescence properties of DOM in 2020–2021 compared to 2014–2015. The 2020–2021 data are grouped in an opposite quadrant with respect to 2014–2015 data (Fig. 6). The first component (PC1) is a positive combination of all fluorescent components except C5f, while the second component (PC2) is a positive combination of C1mh, C4p, and C5f with a lower and negative contribution from C2th, C3f, C6pah (Fig. 6). Thus, it emerges that C1mh and C4p, contribute equally to PC1 and PC2, having no particular influence on the distribution of the samples. On the other hand, C2th, C3f, and C6pah, in opposition with C5f, drive the observed separation of the 2014–2015 and 2020–2021 samples in the first two components projection. The distribution of the samples is also reflected in the annual dynamics of these components in 2020–2021 (Fig. S10). Both components C3f and C5f can be identified as fulvic-like, having only a small shift in excitation and emission maxima (Fig. S6, Table S1). The small blue shift in excitation and emission maxima of C5f with respect to C3f suggests that C5f fluorophores are on average smaller and less aromatic than C3f fluorophores. These two components have an opposite behavior in 2020–2021 with respect to 2014–2015; C3f fluorescence is strongly reduced in 2020–2021 with respect to 2014–2015, whereas C5f was markedly higher in 2020-2021 than in 2014–2015, when it showed a very low fluorescence (Fig. S10). These data suggest that the fulvic-like compounds present in 2014–2015 were replaced by similar but smaller and less aromatic compounds in 2020. These results are in agreement with the high values of S275 – 295 observed in 2020. Component C6pah, attributed to polycyclic aromatic hydrocarbons-like molecules, showed one of the biggest differences among years, being reduced by 72 to 92% in 2020 with respect to 2014 and 2015, respectively. 3.5 The change in DOM dynamics affected the microbial loop Since HP are the main consumers of DOM, their abundance was used to evaluate if and how changes in DOM dynamics affected the microbial loop, also inferring a potential impact on the higher trophic levels. In 2014 and 2015, HPA gradually increased from May (Fig. 7 ), showing a linear correlation with water temperature (Retelletti Brogi et al., 2020). Differently, in 2020, HPA did not increase until the end of June, when a sudden, sharp increase was observed in a very short time (Fig. 7). This HPA maximum persisted for 1 month and coincided with the change in S275 – 295 (Fig. 5). Both C1mh and C4p components increased in correspondence with the peak in HPA (Fig. S10). This observation suggests that the low HPA values, measured before July 2020, may have been caused by the presence of a qualitatively different DOM, which is also reflected in a coincident relative increase in the High Nucleic Acid (HNA) subpopulation (Santos et al., 2019), indicating a shift in the prokaryotic community composition (Fig. S11). Before July, the HPA lower in 2020 than in 2014 and 2015 may therefore have determined a reduced transfer of energy to the higher trophic levels, whereas between July and Octber 2020, HPA was markedly higher than in previous years.Fig. 7 Annual trend of the heterotrophic prokaryotes abundance (HPA) in 2014, 2015, 2020, and 2021. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 7 3.6 Impact of the lockdown on the coastal area The marked reduction in DOC, observed in the river between April and August 2020, resulted in a decrease in the total DOC flux to the coastal area. The average daily DOC flux during this period (5.9 · 106 g DOC day−1) was indeed 58% less than in 2014 (1.4 · 107 g DOC day−1), with average daily water discharg 43% lower. The impact was much more striking with respect to 2015 (8.6 · 106 g DOC day−1) when a 31% reduction of DOC flux was observed despite a reduction of the average daily water discharg of only 16%. The observed DOC reduction in the Arno River is also mirrored by the very low DOC concentration in front of the river mouth (Fig. S12) during the lockdown. DOC concentration, measured in 15 stations within 12 miles from the coast (Fig. 1), was 58 ± 3 μM (range = 48–62 μM; Fig. S12). These values are 15% lower than data collected in the same area between 1998 and 2015, showing an average DOC concentration of 68 ± 5 μM over different seasons (Retelletti Brogi et al., 2015). Satellite images show a marked reduction in the Chl-a concentration, with respect to the 2016–2019 climatology (Fig. 8 ). In particular, it is evident a consistent decrease in the weekly Chl-a concentration anomaly from 1 April to 12 May 2020. It is noteworthy that the most marked anomaly (dark area in Fig. 8) is coherent with the main path of the Arno River plume (moving northward the estuary). This clearly indicates that the coastal pattern of Chl-a concentration during the lockdown was strongly controlled by the coastal plume dynamic, which connects inland water inputs with the coastal marine environment. The low DOC concentration in the coastal area could be a combination of a low input by the Arno River and a low in-situ production, probably due to a low riverine input of nutrients.Fig. 8 Weekly Chlorophyll-a concentration anomaly in the area in front of the Arno River mouth. The week 22–28 April and the week 6–12 May correspond to the week before and the week after the sampling. Data from the sampling week are not available due to cloud cover. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 8 4 Discussion 4.1 How do human activities impact the riverine DOM dynamics? The 125 μM DOC enrichment, observed from the spring to the mouth of the Arno River in March 2021, can be mostly attributed to allochthonous sources, being in-situ production at its minimum (Retelletti Brogi et al., 2020). Being riverine DOM an integrated result of natural and anthropic inputs and the physico-chemical and biological re-elaboration of these inputs within the soil, the river itself and the processes occurring in the watershed, its potential sources can be only determined indirectly. In addition, within the soil the transformation mechanisms affecting the concentration and properties of the DOM finally transferred into the rivers are poorly known, and a chemical characterization of DOM both in the soil and in the water is still missing. For all these reasons, it is not possible to quantify the anthropogenic inputs and so far there is no way to disentangle the contribution of the different sources to riverine DOM. The interruption of a large number of human activities during the lockdown, in particular industries and transportations (Fig. S8), is therefore expected to influence DOC dynamics in the river. Indeed, the comparison of our data with those collected in 2014–2015, combined with the stepwise analysis, provides a robust evidence that the restriction to the human activities significantly reduced the DOC concentration in the river (Fig. 3, Fig. 4) and changed its optical properties (Fig. 5, Fig. 6, S9, and S10). The stepwise analysis allowed to quantify a riverine DOC reduction of 130 and 20 μM, corresponding to 44% and 7% of the mean annual concentration, in 2 periods. The first period is between April and July 2020, corresponding to the almost complete restriction to human activities during the first phase of the COVID-19 pandemic and their partial relief in the following 2 months; the second period is between August and November 2020, corresponding to the recovery of some activities, but with still many restrictions, especially for tourism and transportation, as shown from the mobility data (Fig. S8d). It is, therefore, reasonable to state that at least 130 μM of DOC in the river (those reduced during the strong lockdown) are due to anthropic activities. The link between DOC reduction and lockdown is further supported by the “recovery” of the system to its pre-lockdown conditions since December 2020, when most of the restrictions were relieved, as also shown by the rejection of the other dummy variables (Table S2). It is important to stress that, from a climatic point of view, 2020 was not significantly different from the average conditions (i.e., 2004–2021 climatology, Figs. S13, and S14), thus excluding environmental factors as drivers of the observed changes in DOM dynamics. One of the main effects of the marked reduction in industrial activities and transportations was a noticeable improvement in air quality (Elsaid et al., 2021). Industrial activities, as well as rail, road, and air traffic, contribute to organic carbon through particulate matter (PM) emission into the atmosphere (Chow et al., 2011). The improvement of the air quality could have therefore had an important role in the observed reduction of riverine DOC, being the atmospheric deposition an important and overlooked source of DOC to the Mediterranean area (Galletti et al., 2020). Atmospheric organic carbon can reach the riverine water both directly by atmospheric deposition on the water and indirectly by the deposition on land and vegetation which can be then flushed to the river by the rain or by an increase in the water level. In order to roughly estimate the contribution of atmospheric deposition to the DOC pool in the Arno River before the lockdown, we assume that the range of its concentration in atmospheric deposition reported in the literature over the Mediterranean area (59–153 m mol C m−2 yr−1; de Vicente et al., 2012; Djaoudi et al., 2018; Galletti et al., 2020; Pulido-Villena et al., 2008) is valid for the Arno River drainage basin (8.23·109 m2). This calculation indicates a flux ranging between 16 and 41·106 g C day−1 (5.8 and 15.1·109 g C yr−1). These values are very similar to the total DOC flux from the Arno River to the Mediterranean Sea (5.1–12.9 · 109 g C yr−1) (Retelletti Brogi et al., 2020). To the best of our knowledge, there is no information about the percentage of atmospheric organic carbon deposited over the river drainage basin reaching riverine water. It would be crucial to quantify the amount of atmospheric DOC that reaches the river since, even if we assume that only 10% will reach the river, this input would increase riverine DOC concentration by 17–46 μM, supporting the relevance of this source. It is important to stress that these values are probably underestimated since the data reported in the literature mostly refer to remote sites, whereas the river drainage basin is highly affected by anthropic activities. A reduction of 45% of atmospheric black carbon (i.e. the carbon produced by incomplete combustion) due to the lockdown was observed in Spain (Tobías et al., 2020). Assuming a reduction of atmospheric OC similar to that observed in Spain, the lockdown could have caused a 6–16·106 g C day−1reduction in atmospheric deposition to the river drainage basin. The reduced input of anthropogenic DOM from the atmosphere is also supported by the marked reduction in C6pah (Fig. S10); this component is attributed to the presence of PAHs, commonly found in rivers worldwide because of anthropogenic activities (Mojiri et al., 2019). As PHAs are big aromatic compounds, a decrease in their abundance is also supported by the decrease in the average aromaticity of the molecules indicated by the increase in S275 – 295. The marked reduction in industrial activities in Tuscany (Fig. S8a) may also have a direct effect on DOM in the river due to the reduced wastewater discharge. Most of the industries have wastewater treatment plants; data about the amount and the kind of compounds discharged into the river are not available, making very difficult to quantify these inputs and their reduction due to the COVID-19 lockdown. Nevertheless, it is known that the most water-polluting industries, in terms of organic contamination, are those dealing with organic raw materials (UNWWAP, 2003) (e.g. food, drinks, paper, and textile industries), which are abundant in the Arno River basin. The observed shift toward a smaller and less aromatic DOM pool (i.e. higher spectral slope, Fig. 5), the decrease in total fluorescence (Fig. 5), and the changes in the fulvic and PAH-like components (Fig. S10) are difficult to compare with other studies. Human activities can have contrasting effects on riverine DOM, they can either increase or decrease the average molecular weight and aromaticity, and these effects are highly context-dependent and variable on a local and regional scale, according to the characteristics of the watershed (Xenopoulos et al., 2021). The effect of human disturbance on DOM properties is indeed influenced by several factors, such as soil structure, lithology, climate, vegetation cover, population density, crops type, industrial activity (Lambert et al., 2017; Xenopoulos et al., 2021). Tourism may have had a direct effect on riverine DOM through the decrease in sewage organic load ascribable to the presence of fewer people over a certain area with respect to previous years. The effect of this reduced sewage input on DOC concentration is probably not visible since sewage mostly brings labile DOM (Regnier et al., 2013). It is therefore probable that this contribution is not measurable since it is rapidly removed, as it can be observed from the lack of DOC enrichment after the city of Florence (Fig. 2). It is possible to hypothesize that the reduction of labile DOM may have contributed to the low HPA until July since HP had less labile DOM to use for their growth. Tourism can also have important indirect effects on DOM reduction by influencing both traffic and agriculture; fewer tourists mean less transportation as well as reduced food needs. 4.2 Changed DOM dynamics: implication for the riverine and coastal ecosystems Considering that DOC in Mediterranean rivers ranges between 92 and 500 μM (Retelletti Brogi et al., 2020; Santinelli, 2015), and between 36 and 90 μM in both the Mediterranean Sea and the global ocean (Roshan and DeVries, 2017; Santinelli, 2015), the observed decrease in the Arno River (up to 130 μM) is highly significant. Due to its complex nature (i.e. numerous sources and transformation processes) and its multiple interaction within the aquatic environment, it cannot be stated weather this marked reduction in DOC had an overall positive or a negative effect on the riverine ecosystem and the coastal area. Yet some positive effects can be highlighted, with the support of the results shown in previous studies.1. In the river, the reduced DOM concentration and the different quality impacted the microbial loop:a. The reduced HPA until July and the delay in the HP growth in 2020 with respect to the previous years, might result in a reduction of microbial respiration rates, reducing the CO2 released into the atmosphere. This is further supported by the shift in HNA bacteria within the community (Fig. S11). Taking into account the decrease in DOC and the lower HPA observed between April and July 2020 than in 2014–2015, one can estimate the decrease in CO2. Assuming that all the missing DOC was labile (and therefore consumed by the HP community in a relatively short time), and taking into account the HP growth efficiency (HPGE) calculated for the Arno River estuary (Retelletti Brogi et al., 2021), it is possible to estimate a 2.4–7.6 · 106 g C day−1 decrease in the CO2 released into the atmosphere in 2020 compared to 2014 and 2015. This calculation may however overestimate the reduction in CO2 fluxes, due to the assumption that all the missing DOC is labile and therefore entirely uptaken by the HP. Another way to estimate the “missing CO2 production” is to use the HPA abundance and indirectly retrieve the HP carbon demand (HPCD) by using the Arno HPGE (Retelletti Brogi et al., 2021). These calculations indicate a reduction of the CO2 flux to the atmosphere of 0.5–3.0 · 106 g C day−1 compared to 2014–2015. b. Between July and October 2020, a much higher HPA, together with a longer persistence of its maximum (i.e. almost 2 months), was observed with respect to 2014 and 2015 (Fig. 7). An increased biomass when the resources (i.e. DOM, Fig. 3) are reduced is surprising. The explanations can be several and would need further investigation, but with the available data, it was possible to observe a change in DOM quality in 2020. This suggests that a higher fraction of the 2020 DOM was used to build biomass instead of being used for respiration, leading to a possible increase in the energy transfer to the higher trophic levels; 2. The reduction in DOM together with its different quality could increase microbial diversity in both the river and the estuary. It has indeed been observed that the composition of the microbial community and its functioning vary according to the composition of the DOM pool (Logue et al., 2016; Osterholz et al., 2016; Xenopoulos et al., 2021). DOM composition has been also demonstrated to affect primary production (Creed et al., 2018; Kelly et al., 2018; Xenopoulos et al., 2021) and alter ecosystem respiration rates and metabolism (Jane and Rose, 2018). The satellite analysis, indeed, revealed that the anomalous pattern of Chl-a concentration along the coastal area was significantly affected by the buoyancy Arno River plume (Fig. 8), which showed a coherent alongshore dynamic. Anomalies of Chl-a concentration, which represents the most direct indicator of phytoplankton biomass in coastal environments, were likely connected to riverine inputs (Colella et al., 2016). An increase in bacterial diversity due to the lockdown restrictions has been observed also in the Godavari River (India, Jani et al., 2021). 3. In both the riverine and coastal environment, a reduction of DOM, in particular of humic-like substances, will reduce the ability of DOM to complex pollutants and metals, leading to lower bioavailability of these substances. It has indeed been observed that the increase in DOC concentration is correlated to a higher bioavailability of metals and pollutants to both bacteria (Aiken et al., 2011; Chiasson-Gould et al., 2014; Pothier et al., 2020) and bigger organisms (Bourdineaud et al., 2019), and to a higher production of toxic compounds such as methylmercury (Bravo and Cosio, 2020), favoring their bioaccumulation in the higher trophic levels and posing a threat to human health. 4. The complexation between DOM and metals is also an important issue in those regions where riverine water is the source for drinking water production (Matilainen et al., 2011). DOM concentration is correlated with the production of toxic disinfection by-products (DBPs) during chlorination (Zhang et al., 2020), a fundamental step in water treatment plants. A decrease in DOM concentration would therefore simplify the drinking water treatment, increasing the efficiency and reducing the cost. A 31–58% reduction in DOC flux from the river could be highly beneficial for the coastal area. It has indeed been shown that a high load of terrestrial DOM might advantage heterotrophs (Andersson et al., 2013; Wikner and Andersson, 2012), causing a shift in the composition of the biological community, that can ultimately lead to a net heterotrophy of the system (Deininger and Frigstad, 2019). This condition (i.e., increase in respiration and decrease in oxygen production) can increase the release of greenhouse gases and favor processes such as (i) hypoxia (Andersson et al., 2013; Lapierre et al., 2013; Wikner and Andersson, 2012), (ii) changes in benthic and pelagic community composition (Deininger et al., 2017; Jessen et al., 2015; Moy and Christie, 2012), and (iii) reduced efficiency in energy transfer to higher trophic levels (Deininger and Frigstad, 2019). 5 Conclusions and perspectives The unfortunate circumstances of the lockdown due to the COVID-19 pandemic allowed to observe a period of strongly reduced anthropogenic pressure. For the first time, it was possible to grab a snapshot of an almost background condition which provided an estimate of the real impact that human activities can have on the riverine and coastal environments. Our data not only show the first evidence of the impact of the lockdown on DOM dynamics in rivers, but also allowed to quantify for the first time that at least 44% of DOM in the Arno River is ascribable to human-related activities, mostly from secondary and tertiary sectors, stopped during the lockdown. This percentage is astounding and indicates that a very large fraction of DOM in this small river does not come from ‘natural’ processes, but from anthropic activities. This percentage is probably higher because it does not include the reduction of sewage (mostly biological labile DOC) due to the much lower number of tourists. The high temporal resolution sampling (two times per week) together with the detailed, parallel analysis of the climate components (i.e. discharge, precipitation, temperature) as well as of the biomass indicator (chlorophyll-a in the coastal area), allowed us to discriminate the effect of the lockdown from single disturbance events that could affect the DOM dynamics on the short temporal scale. Moreover, our study gives insights into the impact of lockdown to the ecosystem, bringing evidences that the change in both DOM concentration and quality affected the abundance and trend of heterotrophic prokaryotes, that are a key component of the riverine ecosystem, starting the microbial loop. Finally, by covering up to 1 year after the lockdown (from April 2020 to May 2021), our results show the return of the system to pre-lockdown conditions, supporting on one hand the link between the observed changes and the temporary stop of the anthropogenic activities, on the other hand the short-time effect that the lockdown had on the ecosystem (i.e. approximately 6 months to go back to pre-lockdown conditions). Even though further studies, aimed at a better quantification of the external inputs and their effects on the riverine biological community, are surely needed, it is evident that many of the putative anthropogenic sources that contribute to riverine DOM could be kept under tighter control even after a back-to-normal of human activities. The observed short time needed to the riverine DOM to return to pre-lockdown conditions even with a not full relaunch of the activities, highlights that such a strong reduction of anthropogenic pressure for a short period can give very limited beneficial effects to the riverine ecosystem. This suggests that different, even small yet constant, practices can be suggested in order to reduce the impact of human activities on the river. For instance, exhaust can be filtered, DOM in industrial wastewater could be better treated, anthropogenic DOM release in the atmosphere could be better controlled. All the above would drive small rivers toward a status likely closer to a sustainable regime than that regularly observed before the lockdown. Thanks to their rapid response to environmental changes, small rivers can be considered as sentinels and used to investigate the effects of restorations actions as well as the effect of global changes and human activities. Our work also stresses the importance of long-term research on key areas in order to disentangle the effects of casual events from natural variability. CRediT authorship contribution statement S. Retelletti Brogi: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Data curation, Writing – original draft. G. Cossarini: Formal analysis, Investigation, Data curation, Visualization, Writing – review & editing. G. Bachi: Investigation, Writing – review & editing. C. Balestra: Formal analysis, Investigation, Writing – review & editing. E. Camatti: Investigation, Writing – review & editing. R. Casotti: Formal analysis, Investigation, Resources, Data curation, Writing – review & editing. G. Checcucci: Investigation, Writing – review & editing. S. Colella: Formal analysis, Visualization, Investigation, Writing – review & editing. V. Evangelista: Investigation. F. Falcini: Investigation, Visualization, Writing – review & editing. F. Francocci: Formal analysis, Data curation. T. Giorgino: Formal analysis, Data curation, Writing – review & editing. F. Margiotta: Investigation, Resources, Data curation, Writing – review & editing. M. Ribera d'Alcalà: Conceptualization, Writing – review & editing. M. Sprovieri: Conceptualization, Writing – review & editing, Project administration. S. Vestri: Investigation. C. Santinelli: Conceptualization, Investigation, Data curation, Formal analysis, Methodology, Resources, Writing – review & editing, Project administration, Funding acquisition. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data Supplementary material Image 1 Acknowledgment This research was supported by the SNAPSHOT (Synoptic Assessment of Human Pressures on key Mediterranean Hot Spots) project, funded by the Department of Earth System Science and Environmental Technologies, CNR (Italy). We thank Nunzia Antonicelli, Marco Carloni, Claudia Tropea and Silvia Valsecchi for their support in the Arno river weekly sampling and samples filtration and analyses. We are grateful to Margherita Gonnelli for her scientific support. We further thank Davide Pellegrini for his help with GIS data, and Tommaso Ferraresi for industrial production data. Particular thanks are due to the Centro Interuniversitario di Biologia Marina “G.Bacci” for its support in the coastal sampling. The satellite analysis was carried out as part of the SOON (Satellite Observations for inland and cOastal water quality during COVID lock-dowN) project, funded by the 10.13039/501100000844 European Space Agency via the contract Grant No. 4000128147/19/I-DT. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.scitotenv.2021.152412. ==== Refs References Aiken G.R. Hsu-Kim H. Ryan J.N. Influence of dissolved organic matter on the environmental fate of metals, nanoparticles, and colloids Environ. Sci. Technol. 45 2011 3196 3201 10.1021/es103992s 21405118 Andersson A. Jurgensone I. Rowe O.F. Simonelli P. Bignert A. Lundberg E. Karlsson J. Can humic water discharge counteract eutrophication in coastal Waters? PLoS One 8 2013 e61293 10.1371/journal.pone.0061293 Aufdenkampe A.K. Mayorga E. Raymond P.A. Melack J.M. Doney S.C. Alin S.R. Aalto R.E. Yoo K. Riverine coupling of biogeochemical cycles between land, oceans, and atmosphere Front. Ecol. 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10.1016/j.scitotenv.2021.152412

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==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Elsevier B.V. S0048-9697(21)00242-4 10.1016/j.scitotenv.2021.145176 145176 Short Communication Effect of the COVID-19 pandemic on heatstroke-related ambulance dispatch in the 47 prefectures of Japan Hatakeyama Koya a Ota Junko a Takahashi Yoshiko a Kawamitsu Saki a Seposo Xerxes b⁎ a International Health Development Course, Department of Global Health, Nagasaki University School of Tropical Medicine and Global Health, Nagasaki, Japan b Nagasaki University School of Tropical Medicine and Global Health, Nagasaki, Japan ⁎ Corresponding author at: School of Tropical Medicine and Global Health, Nagasaki University, Japan. 2 2 2021 10 5 2021 2 2 2021 768 145176145176 6 11 2020 6 1 2021 13 1 2021 © 2021 Elsevier B.V. All rights reserved. 2021 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. In 2020, Coronavirus disease 2019 (COVID-19) pandemic has brought a huge impact in daily life and has prompted people to take preventive measures. In the summertime, however, the Japanese government has cautioned that some COVID-19 pandemic conditions may affect the risk to heatstroke. This study investigated how the COVID-19 pandemic setting affected heatstroke-related ambulance dispatches (HSAD). Daily HSAD data and relevant weather parameters from June to September from 2016 to 2020 of 47 prefectures in Japan were obtained from the Fire and Disaster Management Agency (FDMA) database. A binary variable representing COVID-19 impact was created, whereby years 2016 to 2019 were coded as 0, while 2020 as 1. We employed a two-stage analysis in elucidating the impact of COVID-19 pandemic on HSAD. Firstly, we regressed HSAD with the COVID-19 binary variable after adjusting for relevant covariates to obtain prefecture-specific effect estimates. Prefecture-specific estimates were subsequently pooled via random effects meta-analysis in generating the pooled estimate. Pooled Relative Risk (RR) of HSAD during the COVID-19 pandemic was 0.78 (95% Confidential Interval [CI], 0.75–0.82). We found an overall statistically significant decrease in HSAD risk during the COVID-19 pandemic in Japan. Specifically, the decrease in the risk of HSAD may be linked to the COVID-19 precautionary measures such as stay-home request and availability of alternative consultation services, which may have decreased the direct exposure of the population to extreme heat. Graphical abstract Unlabelled Image Keywords COVID-19 Heatstroke Ambulance dispatch Protective effects Precautionary measure Editor: SCOTT SHERIDAN ==== Body pmc1 Introduction Globally, a devastating and prolonged pandemic of coronavirus disease 2019 (COVID-19) has brought a huge impact in daily life, leaving many cases of incidence and mortality (Lai et al., 2020). In Japan, the number of COVID-19 newly-confirmed cases peaked in the first week of August 2020 and has been a decreasing trend across the country (NIID, 2020). As of October 11, 2020, the total number of confirmed COVID-19 cases and deaths are at 88.2 thousand and 1.6 thousand, respectively (MHLW, 2020c). In response to COVID-19, the Japanese government has made several policy adaptation and requests, such as telework, temporary closure of schools, cancellation of large-scale events (Shaw et al., 2020). The Ministry of Health, Labour and Welfare (MHLW) enacted a recommendation on specific preventive measures for individuals, such as social distance, wearing masks and ventilating indoor space as part of the pandemic response (MHLW, 2020a). While facing COVID-19 pandemic, heat-related illnesses have been a serious public health concern under a changing climate (Sanderson et al., 2017). Annual temperature in the country has increased by 1.19 °C in the last 100 years (MOEJ, 2018). As temperatures increase, several heat-sensitive health outcomes are at risk of increasing, such is the case for heat-stroke ambulance dispatch (HSAD), which has been increasing since 2010 with record-breaking number of cases at 95,137 in 2018 (MIC, 2019; MOEJ, 2018). Additionally, the number of deaths due to heatstroke has also been increasing reaching 1581 deaths in 2018 (MHLW, 2019). Several previous studies have reported that older people are more vulnerable to heat exposure (Ito et al., 2018; Kuzuya, 2013; Yokota and Miyake, 2016). Based on recent nationally-representative data, people aged more than 65 years old account for 52% of HSAD cases in 2019 and 81.5% of death due to heatstroke in 2018 (MHLW, 2019; MIC, 2019). As a country which has entered the super-aged society, heatstroke is recognized as a serious public health concern and has led to an increase in heat awareness in recent years (Martinez et al., 2011). In response to the current situation, MHLW has made public warnings particularly for the possibility in the increase of heatstroke cases during summertime under the new lifestyle in the COVID-19 period. Prior to summer, an MHLW-led technical working group has cautioned that several preventive measures under the COVID-19 setting, such as open room ventilation, in the absence of air conditioning, as well as wearing snug-fit masks when outdoors, may possibly contribute to the predisposition of heat-related illnesses, such as heatstroke (MHLW, 2020). Previous studies have documented the association of HSAD and meteorological parameters, such as maximum and average temperature, during the summer season in Japan (Fuse et al., 2014; Murakami et al., 2012; Ng et al., 2014). However, to the best of our knowledge, no study has been done to examine whether the current COVID-19 period conditions have affected the risk of HSAD. 2 Methods 2.1 Data source Daily HSAD data in June to September from 2016 to 2020 of the 47 prefectures in Japan were obtained from the Fire and Disaster Management Agency (FDMA) database (FDMA, 2020b). All HSAD data were obtained as aggregated daily counts from the FMDA, which are reported by the prefectural governments. Heat stroke-related diagnoses are coded using the International Classification of Diseases (ICD) 10. Specifically, the following diagnoses are reported and aggregated as heat stroke: “heatstroke and sun stroke” (T67.0), “heat syncope” (T67.1), “heat cramp” (T67.2), “heat exhaustion, anhidrotic” (T67.3), “heat fatigue, unspecified” (T67.5), “heat fatigue, transient” (T67.6), “heat edema” (T67.7), and “other effects of heat and light” (T67.8) (FDMA, 2020c; JAAM, 2015). Whereas, relevant meteorological parameters such as (average/minimum/maximum) temperature (in degrees Celsius; °C) and relative humidity (in %) in the study period were obtained from the Atmospheric Environment Regional Observation System (AEROS) (AEROS, 2020). We utilized a binary variable to collectively represent the impact of COVID-19 period/conditions, whereby 2016 to 2019 were coded with 0 and 2020 was 1. 2.2 Data management and analysis Health outcome and exposure data were compiled and managed in Microsoft Excel. We employed a two-stage analysis to assess the impact of COVID-19 conditions on HSAD. In the first-stage analysis, we examined the prefecture-specific associations by utilizing a generalized linear model with a quasi-Poisson distribution accounting for overdispersion. Prefecture-specific HSAD was regressed with the COVID-19 indicator variable after adjusting for the relevant covariates. In this study, maximum temperature and relative humidity were treated as a priori confounders (Murakami et al., 2012; Ng et al., 2014), together with the day of the week (DOW), holiday, month and date (for the day of the year); as shown in Eq. (1).(1) Yt=Quasipoissont Yt=α+β1COVID19+β2MaxTempthr+β3Humidity+β4DOW+β5Holiday+β6Month+β7Date+ε Whereby, Y t is the daily HSAD; α is the intercept; COVID19 is a binary variable; MaxTemp thr is the maximum temperature with threshold; Humidity is relative humidity; DOW is a categorical variable of day of the week; Holiday is a binary variable of national holiday in Japan; Month is a categorical variable representing the months of June to September; Date is the temporal variable representing continuous time; ε is the error term; all beta coefficients of the relevant independent variables are represented as (β 1, β 2, β 3, β 4, β 5, β 6, and β 7). In the second-stage analysis, we performed a random effects meta-analysis to pool the prefecture-specific effects estimates. Temperature was assumed with a threshold due to the discernable increasing pattern after a possible change point, as shown in Fig. S1. We examined the possible change point temperature whereby we observe a sharp increase in the number of HSAD cases. Prefecture-specific absolute temperatures were transformed to relative temperatures using an empirical cumulative distribution function which is inherent to the “base” package of R statistical programming (R Core Team, 2020). Prefecture-specific relative temperatures were utilized for a change point detection via a segmented regression implemented through the “segmented” package (Muggeo, 2003). These change point temperatures were then treated as the prefecture-specific thresholds of the relative temperature (Table S1). We then plotted the distribution of the prefecture-specific thresholds (Fig. S2). After observing an apparent skewed distribution of the thresholds, we took the median value of this distribution, which was at the 80th temperature percentile. We implemented the prefecture-specific threshold specification for the absolute temperature using prefecture-specific 80th temperature percentile as an upper threshold point, which was parameterized through the onebasis function in the “dlnm” package (Gasparrini, 2011). In brief, the association of HSAD and absolute maximum temperature below 80th temperature percentile is assumed to be null, whereas beyond the threshold is assumed to follow linear functional shapes. We also considered the additional control for PM2.5 in the model, however, due to the unavailability of the 2019 data, we did not include it in the final model. The non-inclusion of the PM2.5 into the final model is also supported by the sensitivity analysis in Table S2. In brief, since current publicly available PM2.5 data is only available from 2016 to 2018 and 2020, we shortened the period to 2016–2018 for the non-pandemic setting, instead of the 2016–2019. There is no significant difference among the prefecture-specific estimates and the pooled estimate, even after adjusting for PM2.5 (in Table S2). We assumed that this non-significant difference after PM2.5 adjustment would also be the same in context of the 2016–2019 period. A more detailed description can be found in the accompanying text of Table S2. In this study, p-value of 0.05 was considered as statistically significant. All analyses were performed using R statistical programming (R Core Team, 2020). 3 Results Summary statistics for HSAD and meteorological parameters of the 47 prefectures are provided in Table 1 . While overall mean daily HSAD cases of the 47 prefectures in pre-pandemic and pandemic periods are nearly similar (mean = 11.2 and mean = 11.3, respectively), pre-pandemic (2016–2019) variations in daily HSAD were slightly higher than during the pandemic (standard deviation = 23.7 and standard deviation = 22.8, respectively). Highest maximum temperature was observed in 2018 with 29.8 °C, while the lowest one was in 2017 with 29.2 °C. On the other hand, relative humidity was lowest in 2017 with 73.8%, with the highest record of the study period in 2019 at 76.7%.Table 1 Annual summary statistics of daily HSAD and meteorological parameters during summer (June to September) in 47 prefectures.a Table 1 Pre-COVID-19 COVID-19 Year 2016 2017 2018 2019 Total (2016–2019) 2020 HSAD (cases/day) 8.31 8.65 16.2 11.7 11.2 11.3 (±12.9) (±14.1) (±34.4) (±25.5) (±23.7) (±22.8) Maximum temp (°C) 29.5 29.2 29.8 29.3 29.4 29.6 (±3.99) (±3.95) (±4.69) (±3.95) (±4.16) (±4.02) Humidity (%) 75.7 73.8 75.1 76.7 75.3 77.4 (±10.4) (±10.8) (±10.7) (±9.82) (±10.5) (±10.3) a Mean (±standard deviation); degrees Celsius (°C); percentage (%); HSAD ≣ heat stroke ambulance dispatch. A more detailed summary statistic for all study prefectures are listed in Table S3 of the Supplementary Materials. Majority of the prefecture-level estimates, in Fig. 1 , indicated potential protective effect for HSAD, with lowest relative risk (RR) recorded in Chiba (RR = 0.57, 95% CI: 0.44–0.74). Kumamoto, on the other hand, recorded a statistically significant highest RR of 1.01 (95% CI: 1.26–1.57). Pooled effects estimate from the random effects meta-analysis indicated an overall protective effect with an RR of 0.78 (95% CI: 0.75–0.82), with significant moderate heterogeneity (I2 = 48.74%).Fig. 1 Forest plot of prefecture-specific relative risk estimates. Prefecture-specific estimates are reflected by the horizontal error bars. The dotted black line crossing the prefecture-specific estimates are set at RR = 1. The lowermost diamond-shaped symbol represents the pooled effects estimate. Majority of the prefectures indicate a negative association of COVID-19 pandemic and the risk of HSAD, except for Kumamoto, whereby risks were found to be positively and statistically significant. Fig. 1 4 Discussion We found an overall statistically significant decrease in HSAD risk during the COVID-19 pandemic in Japan. Under the COVID-19 pandemic, non-binding self-restriction requests were issued by the Japanese government because the legislation in Japan does not allow its government to apply an enforcement of a forced lockdown (Shaw et al., 2020). However, some studies conducted in Japan actually have observed some behavioral changes, such as hand hygiene, social distancing, and even going-out self-restriction under certain contexts (Machida et al., 2020; Parady et al., 2020). Along with preventive strategies for heatstroke and COVID-19, it is possible that behavioral changes followed by a raised awareness of staying healthy may have been a protective influence on HSAD, either apparent reduction of HSAD or possible reduction of heatstroke itself, during the COVID-19 pandemic setting. The potential factors behind the overall reduction may be linked to the precautionary measures in response to COVID-19, namely: stay-home request and availability of alternative consultation services. 4.1 Stay-home request The frequency of HSAD in outdoor settings, which mostly occur in roads (15.6%) and general outdoor public areas (12.5%), may have simply decreased by staying indoors longer (MIC, 2019). Whereas for HSAD occurring in indoor settings, some studies reported inconsistent results on self-perceptions of risks for heat impacts and changes in their preventive practices (Bassil and Cole, 2010). A few studies found preventive measures, such as staying in an air-conditioned space, were practiced among vulnerable people who recognized their risk to heat (Kosatsky et al., 2009). It is plausible that the stay-home request with increased public warnings for heatstroke may have led to a reduced risk in HSAD both in outdoor and indoor settings. 4.2 Alternative consultation services Based on previous studies conducted in Japan and the United States, the number of patients transported by ambulance or visited emergency departments have decreased due to increasing concerns about the risk of contracting COVID-19 (Boserup et al., 2020; Katayama et al., 2020; Lange et al., 2020). In Japan, call centers and consultation centers for COVID-19 have been established as alternative consultation service to triage suspected cases properly (MHLW, 2020b). 4.3 Potential increase in HSAD risk: case of Kumamoto While several prefectures indicated a decrease in the risk of HSAD during the COVID-19 pandemic, it is interesting to note that Kumamoto prefecture exhibited a statistically significant increase (RR = 1.01; 95% CI: 1.26–1.57). The increase in the risk may possibly be related to the record-breaking rainfall which occurred in the Kyushu region due to seasonal rain front, causing thousands of houses damaged completely or partially and prolonged power outage notably in some areas of Kumamoto prefecture (FDMA, 2020a; JMA, 2020; Kyushu Electric Power Co., 2020). Hundreds to thousands of households in the areas could not use air-conditioners, and even to operate shelters in this year, preventive measures to prevent both COVID-19 and heatstroke were required (Kumamoto Prefectural Government, 2020; Kyushu Electric Power Co., 2020), which may have further increased the HSAD risk. While this is an isolated case, the potential for a natural hazard to amplify temperature-related health risks should be explored in future studies which present similar scenarios. This study has several limitations. First, the finer scale geographical data was not available, the addition of these data, whenever possible, is warranted due to the possible disproportionate effect of heat across a geographical domain. Second, given the ecological nature of the study, several personal-level characteristics were not considered. The apparent statistically significant low-to-moderate heterogeneity (I2 = 48.74%) (Higgins et al., 2003) may be related to several unaccounted factors varying between prefectures, which, however, is beyond the scope of this study. Future studies may potentially examine this through further analyses with suitable meta-regressors. Amidst these limitations, the study has several strengths. To the best of our knowledge, this is the first study to examine the impact of the COVID-19 pandemic setting on HSAD. Likewise, the multi-location setting allows for a more robust estimate with increased precision. We believe that the study results provide insightful observations on the impact of the COVID-19 pandemic setting on HSAD and its implication with the currently best available data. Also, results from this study would provide a platform to further understand the individual-level characteristics which could explain such protective effect. 5 Conclusion COVID-19 pandemic setting resulted to a decrease in HSAD in Japan. The decrease in HSAD may possibly be attributed to several precautionary measures targeting to COVID-19. CRediT authorship contribution statement Koya Hatakeyama: Study conceptualization, data curation, statistical analysis, writing-original draft; Junko Ota: Study conceptualization, data curation, writing-original draft; Yoshiko Takahashi: Study conceptualization, data curation, writing-original draft; Saki Kawamitsu: Study conceptualization, data curation; Xerxes Seposo: Study conceptualization, data curation, statistical analysis, writing-original draft, reviewing and editing. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data Supplementary material Image 1 Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.scitotenv.2021.145176. ==== Refs References AEROS Atmospheric Environmental Regional Observation System: AEROS. 2020, Japan 2020 Bassil K.L. Cole D.C. Effectiveness of public health interventions in reducing morbidity and mortality during heat episodes: a structured review Int. J. Environ. Res. Public Health 7 2010 991 1001 20617014 Boserup B. McKenney M. Elkbuli A. The impact of the COVID-19 pandemic on emergency department visits and patient safety in the United States Am. J. Emerg. Med. 38 2020 1732 1736 32738468 FDMA Damage Caused by Heavy Rainfall in July 2020 and Response Status of Fire Department (54th Report) 2020 FDMA Fire and Disaster Management Agency 2020 2020 FDMA Japan FDMA Office of Emergency Planning FaDMA消 Survey of the Number of People Transported to Emergency Rooms Due to Heat Stroke During the Summer (夏期における熱中症による救急搬送人員の調査) 2020 Fire and Disaster Management Agency Fuse A. Saka S. Fuse R. Araki T. Kin S. Miyauchi M. Weather data can predict the number of heat stroke patient Nihon Kyukyu Igakukai Zasshi 25 2014 757 765 Gasparrini A. Distributed Lag Linear and Non-linear Models in R: The Package dlnm. 2011 43 2011 20 Higgins J.P.T. Thompson S.G. Deeks J.J. Altman D.G. Measuring inconsistency in meta-analyses BMJ 327 2003 557 560 12958120 Ito Y. Akahane M. Imamura T. Impact of temperature in summer on emergency transportation for heat-related diseases in Japan Chin. Med. J. 131 2018 574 582 29483392 JAAM Medicine JAfA Medical Practice Guidelines for Heat Stroke (熱中症診療ガイドライン) 2015 Japanese Association for Acute Medicine JMA Prompt Report on Heavy Rain in July 2020 2020 Katayama Y. Kiyohara K. Kitamura T. Hayashida S. Shimazu T. Influence of the COVID-19 pandemic on an emergency medical service system: a population-based, descriptive study in Osaka, Japan Acute Medicine & Surgery 7 2020 e534 Kosatsky T. Dufresne J. Richard L. Renouf A. Giannetti N. Bourbeau J. Heat awareness and response among Montreal residents with chronic cardiac and pulmonary disease Canadian Journal of Public Health 100 2009 237 240 19507730 Kumamoto Prefectural Government Meeting of Kumamoto Prefecture Disaster Countermeasures Headquarters Regarding Heavy Rainfall in July 2020 (20th Meeting) 2020 Kuzuya M. Heatstroke in older adults Japan Medical Association Journal 56 2013 193 198 Kyushu Electric Power Co I. Disaster Response 2020 Lai C.C. Wang C.Y. Wang Y.H. Hsueh S.C. Ko W.C. Hsueh P.R. Global epidemiology of coronavirus disease 2019 (COVID-19): disease incidence, daily cumulative index, mortality, and their association with country healthcare resources and economic status Int. J. Antimicrob. Agents 55 2020 105946 32199877 Lange S.J. Ritchey M.D. Goodman A.B. Dias T. Twentyman E. Fuld J. Potential indirect effects of the COVID-19 pandemic on use of emergency departments for acute life-threatening conditions - United States, January–May 2020 MMWR Morb. Mortal. Wkly Rep. 69 2020 795 800 32584802 Machida M. Nakamura I. Saito R. Nakaya T. Hanibuchi T. Takamiya T. Changes in implementation of personal protective measures by ordinary Japanese citizens: a longitudinal study from the early phase to the community transmission phase of the COVID-19 outbreak Int. J. Infect. Dis. 96 2020 371 375 32425637 Martinez G.S. Imai C. Masumo K. Local heat stroke prevention plans in Japan: characteristics and elements for public health adaptation to climate change Int. J. Environ. Res. Public Health 8 2011 4563 4581 22408589 MHLW MHLW Yearly Trends of Death Due to Heatstroke by Age Group From Vital Statistics 2020 2019 MHLW Japan MHLW Preventive Actions against Heatstroke for 2020 2020 2020 MHLW MHLW Example of the New Lifestyle in the COVID19 Period 2020 2020 MHLW Japan MHLW MHLW For National Citizens (COVID-19 Infection) 2020 2020 MHLW Japan MHLW Outbreak Status Within the Country 2020 2020 MHLW Japan MIC Situations of Heatstroke-related Ambulance Dispatches During May to September in 2019 2020 2019 MIC Japan MOEJ Synthesis Report on Observations, Projections and Impact Assessments of Climate Change 2018 Muggeo V.M.R. Estimating regression models with unknown break-points Stat. Med. 22 2003 3055 3071 12973787 Murakami S. Miyatake N. Sakano N. Changes in air temperature and its relation to ambulance transports due to heat stroke in all 47 prefectures of Japan J. Prev. Med. Public Health 45 2012 309 315 23091656 Ng C.F. Ueda K. Ono M. Nitta H. Takami A. Characterizing the effect of summer temperature on heatstroke-related emergency ambulance dispatches in the Kanto area of Japan Int. J. Biometeorol. 58 2014 941 948 23700200 NIID Current Situation of Infection, September 9, 2020 2020 2020 NIDD Japan Parady G. Taniguchi A. Takami K. Travel behavior changes during the COVID-19 pandemic in Japan: analyzing the effects of risk perception and social influence on going-out self-restriction Transportation Research Interdisciplinary Perspectives 7 2020 100181 R Core Team R: A Language and Environment for Statistical Computing 2020 R Foundation for Statistical Computing Vienna, Austria Sanderson M. Arbuthnott K. Kovats S. Hajat S. Falloon P. The use of climate information to estimate future mortality from high ambient temperature: a systematic literature review PLoS One 12 2017 e0180369 28686743 Shaw R. Y-k Kim Hua J. Governance, technology and citizen behavior in pandemic: lessons from COVID-19 in East Asia Progress in Disaster Science 6 2020 100090 34171010 Yokota H. Miyake Y. The problems of heat stroke in the aging society from the Heat stroke Surveillance Committee of the Japanese Association for Acute Medicine (JAAM) Journal of the Japanese Council of Traffic Science 15 2016 3 8

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==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Elsevier B.V. S0048-9697(21)01200-6 10.1016/j.scitotenv.2021.146133 146133 Short Communication Prevalence and stability of SARS-CoV-2 RNA on Bangladeshi banknotes Akter Selina a Roy Pravas Chandra a Ferdaus Amina a Ibnat Habiba a Alam A.S.M. Rubayet Ul a Nigar Shireen b Jahid Iqbal Kabir a Hossain M. Anwar cd⁎ a Department of Microbiology, Jashore University of Science and Technology, Jashore, Bangladesh b Department of Nutrition and Food Technology, Jashore University of Science and Technology, Jashore, Bangladesh c Jashore University of Science and Technology, Jashore, Bangladesh d Department of Microbiology, University of Dhaka, Dhaka, Bangladesh ⁎ Corresponding author at: Jashore University of Science and Technology, Jashore, Bangladesh. 4 3 2021 20 7 2021 4 3 2021 779 146133146133 15 11 2020 22 2 2021 22 2 2021 © 2021 Elsevier B.V. All rights reserved. 2021 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Originating in December 2019 in China, SARS-CoV-2 has emerged as the deadliest pandemic in humankind's history. Along with direct contact and droplet contaminations, the possibility of infections through contaminated surfaces and fomites is investigating. This study aims to assess SARS-CoV-2 viral RNA's prevalence by real-time one-step reverse transcriptase PCR on banknotes circulating in Bangladesh. We also evaluated the persistence of the virus on banknotes spiked with SARS-CoV-2 positive diluted human nasopharyngeal samples. Among the 425 banknote samples collected from different entities, 7.29% (n = 31) were tested positive for targeted genes. Twenty-four positive representative samples were assessed for n gene fragments by conventional PCR and sequenced. All the samples that carry viral RNA belonged to the GR clade, the predominantly circulating clade in Bangladesh. In the stability test, the n gene was detected for up to 72 h on banknotes spiked with nasopharyngeal samples, and CT values increase significantly with time (p < 0.05). orf1b gene was observed to be less stable, especially on old banknotes, and usually went beyond detectable limit within 8 to 10 h. The stability of virus RNA well fitted by the Weibull model and concave curve for new banknotes and convex curve for old banknotes revealed. Handling banknotes is unavoidable; hence, these findings imply that proper hygiene practice is needed to limit SARS-CoV-2 transmission through banknotes. Graphical abstract Unlabelled Image Keywords Coronavirus COVID-19 Currency Fomite Pandemic Transmission Editor: Ewa Korzeniewska ==== Body pmc1 Literature review Severe acute respiratory virus (SARS), a member of Betacoronavirus, was responsible for two previous epidemics in just two decades; in November 2002 as SARS in China and in June 2012 as MERS (Middle East respiratory syndrome coronavirus) in Saudi Arabia (Zaki et al., 2012; Zhong et al., 2003). At the end of December 2019, another SARS-like outbreak was confirmed in China that turned pandemic quickly. WHO named the disease COVID-19 (WHO, 2020), and the virus was announced as SARS-CoV-2 as suggested by the International Committee on Taxonomy of Viruses (Gorbalenya et al., 2020). As of January 09, 2021, the pandemic claimed over 1.9 million deaths, with 87.59 million confirmed cases; new areas or populations are infected daily (WHO, 2021). Several researchers reported that the virus quickly accumulated mutations and became predominant or co-exited together (Islam et al., 2020a; Islam et al., 2020b; Nextstrain, 2020; GISAID, 2020; Rambaut et al., 2020). GISAID proposed nomenclature represents the worldwide phylogenetic circulating diversity under seven major clades: GV, GH, GR, G, V, L, and S. Community transmission is playing a significant role in the SARS-CoV-2 pandemic. The direct transmission routes include coughing or sneezing mediated infectious droplets and mechanical ventilation, including talking or singing (Stadnytskyi et al., 2020; van Doremalen et al., 2020). Similarly, direct physical contact is also responsible for SARS-CoV-2 transmission. Another unreported and poorly understood indirect route of virus transmission is contaminated surfaces and fomites. Transmission through contaminated surfaces is rare but cannot be denied. Various respiratory viruses, e.g., SARS-CoV, Influenza, Rhinovirus, etc., can persist in multiple fomites without losing infectivity for a certain period (Thomas et al., 2008). After the SARS-CoV-2 pandemic, researchers are reporting the presence of SARS-CoV-2 RNA on various surfaces such as patients' masks (Li et al., 2020); door handles and sanitizer dispenser (Razzini et al., 2020); different surface areas of the hospital (Santarpia et al., 2020); sewage pools (Wang et al., 2020). Unlike previous pandemic-causing coronaviruses (e.g., SARS and MERS), SARS-CoV-2 has a higher basic reproduction number (Ro), thus is highly contagious with a low incubation period but a higher infection rate (Xie and Chen, 2020). It is pertinent to identify the potential infection source in the community, characterize the route, and break the transmission chain to control the outbreak. Like other fomites, the banknote is an ideal source of pathogenic microbes (Gabriel et al., 2013; Hiko et al., 2016; Jalali et al., 2015; Maritz et al., 2017; Pal and Bhadada, 2020; Thomas et al., 2008). Microbes remain infective in papers, and stability depends on the surrounding environment's initial loads, temperature, and moisture content (Pastorino et al., 2020). The banknote is the most ubiquitous and transferable object in present world. Developing countries, including Bangladesh, have limited users of virtual banking and are dependent on paper banknotes. However, few countries decontaminate their paper notes at regular intervals and assess the microbial contamination, which is seemingly not possible for many nations. The reasons behind microbial contamination in paper notes are material composition, specifically moisture absorbing and dust retaining capacity, and high frequency of exchange (Vriesekoop et al., 2010). Paper-based banknotes' rough surface also provides the necessary support for microbes to settle down and be accumulated. A recent report showed that SARS-CoV-2 survives on banknotes for 28 days at 20 °C (Riddell et al., 2020). However, to the best of our knowledge, there is no data regarding the prevalence of SARS CoV-2 on banknotes as it may survive longer (Riddell et al., 2020). Although microbial can survive on different surfaces as linear regression (Riddell et al., 2020), many researchers documented the microbial survival as nonlinear, concave, or convex with sigmoid shapes (Buzrul and Alpas, 2007; Coroller et al., 2006; Jahid et al., 2013; Mafart et al., 2002). In this research, we aimed to determine the prevalence of SARS-CoV-2 RNA on circulatory Bangladeshi banknotes and assess the stability of SARS-CoV-2 on spiked banknotes. 2 Material and methods 2.1 Ethics approval The work has been conducted in the Genome Centre of Jashore University of Science and Technology, providing SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction (RT-PCR) diagnostic service of the national COVID-19 response and surveillance program (https://dghs.gov.bd/images/docs/Notice/rt_pcr_lab.pdf). Jashore University of Science and Technology's institutional ethical review board has reviewed the research project with an exemption of consent from the patients (ref: ERC/FBS/JUST/2020-42). The nonissuable banknotes used in this study were collected from a public bank, withdrawn from circulation for destruction. 2.2 Sample collection and processing We have collected circulating banknotes of varying denominations as an exchange of payment from retail shops, ticket vendors and auto-rickshaw drivers, etc., at places in two Southern Districts, namely Khulna, Jashore Bangladesh. During the collection of banknotes, we avoid selection bias. Hence, the banknotes are not equally distributed but representing the natural circulation frequencies among denominations. Sample collectors were asked to put the paper banknotes directly into a biohazard sample collection bag and zipped that, and transported them to the laboratory, preferably within 2 h. Each banknote was removed from the bag in a biosafety Class IIa cabinet and kept on a sterile polystyrene petry dish. We swabbed both sides of the banknotes with nylon flocked round (oral) swab (biovencer Healthcare Pvt. Ltd., India) soaked with 0.9% saline containing Rnasin (Sunsure Biotech, China). The swab head is cut and put into 80.0 μL 0.9% saline containing Rnasin in a DNase/RNase-free microcentrifuge tube and mixed vigorously. We aliquoted 20.0 μL suspension into 20.0 μL of ice-cold RNA extraction buffer (QuickExtract™ RNA Extraction kit, Lucigen) and vortexed for 1 min. The extract was chilled immediately on ice and kept at −20 °C till real-time RT-PCR amplification of SARS-CoV-2 specific genes. To assess the SARS-CoV-2, we used the methodology as described later in section 2.4. 2.3 Preparation of banknote notes spiked with SARS-CoV-2 positive sample 2.3.1 Experimental setup To assess the stability of SARS-CoV-2 RNA on the paper banknote, we have selected three SARS-CoV-2 positive human samples from the Genome Centre of Jashore University of Science and Technology containing both nasal and oro-pharyngeal swab collected in 2.0 mL 0.9% saline water. The Center is routinely diagnosing the COVID-19 patients' samples by real-time RT-PCR method. Among SARS-CoV-2 positive (CT = 22) routine diagnosis samples, we selected three. We used six different banknotes, three were visibly old and dirty circulated for years, and the other three were new and clean but tore apart. We cut the banknotes (nonissuable) into circular pieces of 28 sq. mm (3 mm of radius) size, and three random parts from each banknote were tested for SARS-CoV-2 RNA by real-time RT-PCR method and found negative. All the pieces of banknotes were placed in a polystyrene Petri dish and spiked with ten microlitres of two-times diluted SARS-CoV-2 positive samples (we spiked 39 pieces of each banknote type with each of the three types of positive samples), allowed to dry in a biosafety IIa cabinet. When the banknotes were visibly dry, the Petri dishes were placed inside a clear biohazard bag and sealed. We set all experient inside the biosafety Class IIa cabinet at room temperature with negative pressure. After setting the whole experiment, three replica spiked banknote pieces were picked from each set and kept in micro-centrifuge tubes at different time intervals (i.e., zero hours, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 60 h, and 72 h). The temperature was monitored and recorded throughout the experiment by a thermometer (Model: SHX-RPT-6, Shanghai, China). Researchers took suitable biosafety precautions (e.g., overhead gown with N95 respirator) throughout the work and handled suspected samples and spiked banknotes only in BSC IIa facilities. 2.3.2 RNA extraction from the spiked banknote After each time interval, we collected pieces of spiked banknotes and put each of the pieces in twenty microlitres of 0.9% saline in microcentrifuge tubes. RNA extracted, as mentioned in section 2.2, and detection of SARS-CoV-2 as in section 2.4. 2.4 Detection of SARS-CoV-2 RNA We used the primer and probe sequences and protocol designed and utilized by Chu et al. (2020). The sequences of primers and probes used for this study are enlisted in Table A2. Due to the lack of suitable positive control, we used RNA extracted from a previously characterized in our laboratory (the whole genome sequenced, accession no. EPI_ISL_561377) positive sample as positive control and 0.9% saline prepared with RNase free water as a negative control in this assay. We used The GoTaq® Probe 1-Step RT-qPCR Reaction Mix (Promega, USA) for the duplex reaction. We prepared the reaction mixture following the kit's protocol, except for using 9 μL RNA extract as a template and preparing a final reaction volume of 25 μL (instead of 20 μL). We optimized the thermal Cycling parameters as followed: Reverse transcription at 45 °C for 30 min; Reverse transcriptase inactivation and GoTaq® DNA Polymerase activation at 95 °C for 2 min, and 45 cycles of the regime of denaturation at 95 °C for 15 s and annealing with extension at 60 °C for 1 min. We performed The PCR reaction in a QuantStudio™ 3 Real-Time PCR System (The Applied Biosystems, USA) in a 96-well plate (0.2 mL) and analyzed it in Quantstudio design and analysis software (v1.3.3). We interpreted the sigmoid curve for either orf1b or n gene or both with a CT value of ≤36 as positive. We repeated samples with CT values between 36 and 39 were and above those were considered negative in the prevalence study. For the assay of stability of SARS-CoV-2 RNA on banknotes, we created standard curves for n- and orf genes by a serial of 2-fold diluted inoculum following the identical RNA extraction and real-time RT-PCR protocol. 2.5 Preparation of cDNA for targeted PCR According to the manufacturer, we prepared cDNA for the representative 21 SARS-CoV-2 positive samples from the leftover RNA using the ProtoScript® II First Strand cDNA Synthesis Kit (NEB, UK) instruction with some modifications. In short, we omitted the ‘denaturation of RNA secondary structure’ step described in the manual, wherein we mixed 6 μL of extracted RNA with 2 μL of random primers and used other components as mentioned in the protocol. The mixture was then annealed and incubated at 42 °C and 48 °C for 5 and 20 min, respectively, followed by deactivating enzyme at 80 °C for 5 min and immediate chilling on ice. The final reaction mix was 20 μL for each cDNA synthesis reaction. 2.6 Determining the intactness of viral RNA genome on banknotes For checking the virus's intactness and possibly the infectivity, we targeted an 850 bp large segment of the viral genome, which spans the receptor-binding region (RBD) of the spike protein-coding sequence. The forward and reverse primers are S_F2 (GCTGTAGACTGTGCACTTGACCC) and S_R2 (GTAGTGTCAGCAATGTCTCTGCC), respectively. We carried out the PCR in 10 μL reaction volume comprising of 4 μL cDNA, 5 μL hot-start color master mixture (GoTaq® G2 Green Master; Promega, USA), 0.5 μM of each forward and reverse primer. The thermocycling conditions were as followed: the initial denaturation at 95 °C for 1 min, 35 cycles of denaturation at 95 °C for 30 s, annealing at 56 °C for 30 s, and extension at 72 °C for 50 s and a final extension at 72 °C for 5 min. Finally, we electrophoresed PCR products on a 1% (w/v) agarose gel stained with ethidium bromide (UltraPure™ Ethidium Bromide, 10 mg/mL; Thermo Fisher, USA) and visualized using a gel documentation system (Bio-Rad, USA). 2.7 Targeted Sanger sequencing of SARS-CoV-2 genes We used the randomly amplified cDNA as a template for the PCR targeting N protein-coding sequence for detecting the viral phylogenetic clade (M. T. Islam et al., 2020). After purifying the PCR products with the ExoSAP-IT™ PCR product cleanup reagent as per manufacturers instruction (Thermo Fisher Scientific, USA). The BigDye Terminator v3.1cycle sequencing ready reaction kit (Thermo Fisher Scientific) was used in a way to optimize the cost than as mentioned in the Islam et al. (2020). Instead of 0.5 μL, 0.25 μL (per 10 μL reaction) undiluted BigDye Terminator v3.1 Ready Reaction mix was used together with 1 μL 5× sequencing buffer, 0.3 μL primer, 3.0 μL template DNA, and 5.7 μL nuclease-free water. We set up the cycle sequencing PCR condition according to the kit protocol. Accession IDs to the submitted sequences as an archetype are available in the GISAID EpiFlu™ database (Table A5). We performed further bioinformatics analyses considering Wuhan-Hu-1 (NC_045512.2) as the reference sequence using Molecular Evolutionary Genetics Analysis (MEGA X) software (Kumar et al., 2018). 2.8 Scanning electron micrograph We air-dried representative disc of new and old banknotes, mounted on a scanning electron microscope (SEM) sample loading disc with carbon tape. We sputter-coated the loaded samples with gold using the timed gold sputter preset recipe in Q150RS plus machine (Quorum technologies ltd., UK) at the following conditions: sputter current of 20 mA, sputter time of 120 s with tooling factor 2.30. We examined and took the micrograph in a field-emission scanning electron microscope, FESEM (Gemini Sigma 300, Zeiss, Germany), and collected digitized images by Smart SEM software (Zeiss, Germany). 2.9 Nonlinear regression analysis Generally, the Weibull model is used to estimate different parameters, which is a nonlinear model. The equation is the following:(1) LogNtN0=−12.303tαn where α is scale parameters (unit is min or sec) and n is shape parameters (unitless) (van Boekel, 2002). Nt is the number of microorganisms (CFU/mL or cm2) after survival time t. N0 is the initial number of microorganisms, and t is the survival time of microorganisms (h). n values equal to 1 correspond to linear survival curves, n values >1 correspond to downward concave survival curves, n values <1 conforms to convex survival curves. However, Eq. (1) can be reparametrized by Coroller et al. (2006) as the following equation:LOG10N=log1010∗∗N0/1+10∗∗α∗10∗∗−t/ẟ1∗∗ρ+α+10∗∗−t/ẟ2∗∗p Here, α = log10(N 01/N 02) (the difference between two subpopulations). ẟ1 and δ2 are the scale parameters of the first and second subpopulation, respectively. ρ is the shape parameter. For the old banknotes, the Eq. (1) can be reparametrized by Mafart et al., (2002) as follows:(2) LogNtN0=−tδρ Here, ρ is the shape parameter, and δ is the scale parameter (Mafart et al., 2002). If the model fits appropriately, a linear shape if ρ is equal to 1, a concave shape if ρ is >1, and a convex shape if ρ is <1. Root Mean Square Error (RMSE) was calculated from the software to know the model's goodness of fit to the death rate. The RMSE values closer to 0 and adjusted R2 values close to 1.0 indicate the model's better fitness. The model has been used to fit for survival kinetics of both old and new banknotes. 2.10 Statistical analysis To determine the prevalence and stability of SARS-CoV-2 RNA on banknotes, we repeated all experiments three times. In the stability experiment on banknotes, we transformed CT values as 1/CT ∗ 100 and plotted with respective time (h) by using Microsoft Excel 2010 Add-in GInaFiT 1.6 (Geeraerd et al., 2005) (https://cit.kuleuven.be/biotec/software/GinaFit). We calculated root mean square error (RMSE) using the software, and values closer to 0 indicate a better fit to the model. The initial virus concentrations and analysis of Weibull parameters by carrying out ANOVA using SAS software (version 9.4 SAS Institute Inc., Cary, NC, USA) for a completely randomized design. The effect has been considered significant (p < 0.05); Duncan's multiple range test accomplished separation of the means. 3 Result and discussion 3.1 Prevalence of SARS-CoV2 on banknotes We collected a total of 425 (n) banknotes from 56 (N) entities over three months. The entity includes pharmacies, ticket vendors/collectors, and drivers of local and inter-city transports, various shops, and restaurants (Table A1). We have collected 7.58 banknotes on average (minimum two and maximum of 19 banknotes per entity, data not shown) among the entity. In total, we found 7.29% (31/425) banknote samples were positive for SARS-CoV-2 RNA assessed by real-time one-step RT-PCR method. The entity of local transport (N = 11, n = 84) includes banknotes from drivers of three-wheelers (e.g., auto-rickshaw and mechanically driven three-wheeler), which accounted for the highest prevalence (14.28%) among the entities. In a case, we found seven (out of 19) SARS-CoV-2 RNA positive banknotes from a particular auto-rickshaw driver. This event contributed to the overall higher prevalence rates among the banknotes collected from local transports. On the contrary, banknotes sampled from the ticket vendors and - collectors at inter-city transport (bus) were negative for the viral RNA. During the study, the intercity transport authority ensured that the passengers wearing masks maintained social distancing (carrying 50% of total capacity) with personal hygiene. We detected SARS-CoV-2 RNA on around 8 to 10% of banknote samples collected from restaurants & food shops (N = 5, n = 38) and grocery shops (N = 13, n = 106). Table A1 enlisted detailed results. The study was designed and started when the number of SARS-CoV-2 infected confirmed cases was at the peak (end of June 2020) in the country. The weekly cases of new SARS-CoV-2 infection were around 21 K in July and declined periodically to about 5 K at the end of September 2020 (Fig. A1). In this study, we collected banknote in a random basis which included higher denomination (1000 TK, 500 TK, 100 TK) (n = 22), medium denomination (50 TK and 20 TK) (n = 143), and lower denomination (10 TK, 5 TK, 2 TK) (n = 260) banknotes. Although the sample distribution was not uniform, we found a high prevalence in the higher denomination (13.63%, 3/22) compared to medium (4.89%; 7/143) and lower denomination banknotes (8.07%; 21/260). The higher denomination banknotes usually have fewer transaction frequencies and cleaner than middle or lower denominations. The higher prevalence in this group was not predicted but could be due to the larger surface area. However, we found that the new clean banknote supports more stability or recovery of SARS-CoV-2 RNA than the older one (discussed later). The samples were not similar in terms of monthly distribution, but the percentage of the positive cases among samples was homogenous (Table A5). However, the samples were collected only for three months; hence Levene's test could not be performed to calculate the homogeneity of variance. All the samples collected from the environment were not related to the hospital or isolation center for SARS-CoV-2 patients. The presence of SARS-CoV-2 RNA on the circulating banknotes indicates the frequent movement of infected patients, either asymptomatic or with mild symptoms. Milder symptomatic patients may have a higher viral load (low CT value) and can shed the virus (Jan et al., 2020). A recent survey on 2157 human subjects in Bangladesh found out that 16.3% do not wear masks, and 24.6% do not avoid crowds, even having milder SARS-CoV-2 like symptoms (Hossain et al., 2020). Detection of viral RNA does not ensure the presence of infective viral particles but, at the same time, does not exclude the possibility of having it. 3.2 SARS-CoV-2 gene sequencing Randomly selected banknote samples, tested positive for SARS-CoV-2 RNA in real-time RT-PCR method, were also amplified for different segments of other genes by conventional PCR method, and PCR products of 24 representative samples were sequenced. Sequence data evaluated that all the samples contained SARS-CoV-2 virus belongs to GR clade strains. The result signifies this clade's dominant presence in Bangladesh, as described in another study (Alam et al., 2020). In Bangladesh, 80% (401/501) of the viral strains are of GR clade as per GISAID sequence information, whereas 34% (106,454/309,040) of the viruses are of the clade worldwide. Notably, we did not find any long amplified products, i.e. 850 bp targeted amplicon spanning RBD region, for each of the samples, that states the lacking of intactness of the viral genome on the banknote, thus infectivity of the virus. 3.3 Stability kinetics of spiked samples The survival kinetics of spiked samples of the present study on new and old banknotes were determined using Microsoft Excel 2010 Add-in GInaFiT 1.6 (Geeraerd et al., 2005) (https://cit.kuleuven.be/biotec/software/GinaFit). The results revealed that the overall survival of SARS-CoV-2 on new banknotes was higher compared to older banknotes. The n gene stability was higher compared to the orf gene (Fig. 1 ).The graphs show the stability of SARS-CoV-2 n gene to time (h) for new banknotes (Fig. 2A), n-gene for old banknotes (Fig. 2B), orf gene for new banknotes (Fig. 2C), and orf gene for old banknotes (Fig. 2D). For n gene in new banknotes, all three virus samples survived up to 60 h but absent after 72 h (Fig. 2A). The results also revealed that the values stabilize to 10 h for the new banknotes and gradually decrease to 60 h. The n gene stability was less for the old banknotes, and the value was zero after 60 h (Fig. 2B). For old banknotes, except one sample, the other two did not show any stability for the initial 10 h and later hours. The graph shows a sharp decrease in the case of old banknotes (Fig. 2B). All the samples were stable up to 60 h for the orf gene (Fig. 2C), whereas only 10 h for old banknotes (Fig. 2D). The graph is a concave type in new banknotes, while in old banknotes, it is a convex type. Therefore, we hypothesize that SARS-CoV-2 in old banknotes are less stable. Our results of stability of SARS-CoV-2 on new banknotes show similarity with the findings of Kampf et al. (2020).Fig. 1 Stability of SARS-CoV-2 on banknotes spiked with crude samples. Line graphs representing the changes in CT values of ‘n’ and ‘orf1b’ genes on new and old banknotes (non-issuable) spiked with Sample 1 (panel A), 2 (panel B) and 3 (panel C) at different time intervals (starting from zero to 72 h). Values are the mean (with standard deviation as error bars) of three independent replica experiments. Within each variable, values with the same letter are not significantly different according to Duncan's multiple range test (P = 0.05); lower case letters are used for mean values of experiments on new currencies and upper case letters for experiments old banknotes. Fig. 1 Fig. 2 SARS-CoV-2 stability on spiked banknotes and fitness to modified Weibull model. SARS-CoV-2 RNA stability on banknotes spiked with RT-PCR tested positive diluted human nasopharyngeal swab samples on new and old banknotes. The spiked banknotes are incubated at room temperature, and stability of RNA detected at different times. The points represent the mean ± square error of mean (SEM) of 3 independent experiments, and vertical bars indicate the duration of time to keep the samples. Curves were fit to a modified Weibull model using GInaFiT 1.6 software: (A) curves for n gene of new banknotes of samples 1, 2, and 3; (B) curves for orf1b gene of new banknotes of samples 1, 2, and 3; (C) curves for n gene of old banknotes of samples 1, 2, and 3; (D) curves for orf1b gene of old banknotes of samples 1, 2, and 3. Fig. 2 The researchers found stability for SARS-CoV on paper surfaces. Riddell et al. (2020) found that the virus survived less than seven days on banknotes at 30 °C and one day at 40 °C. Our laboratory temperature was around 35 °C during the experimental conditions. Even though we used the samples from the patient's nasopharyngeal swab, whereas the authors used the virus grown in the Vero cell line, our study's results agreed with Riddell et al. (2020) and Kampf et al. (2020). Reports say that SARS-CoV-2 stays infective in various inanimate objects (e.g., metal, plastics, etc.) for 2 h to 9 days (Kampf et al., 2020). In another study, coronavirus exposed to various metals (copper or copper alloy) harms the virus, irreversibly damaged the intactness of the virus and RNA (Warnes et al., 2015). Temperature and relative humidity can negatively affect the stability of SARS-CoV-2 and reduce the transmissibility over time (Demongeot et al., 2020), which may be right for other respiratory enveloped virus, but this may be still inconclusive (Ma et al., 2020; To et al., 2021), more research needs to be performed for the SARS-CoV-2. 3.4 Mixed Weibull kinetics of SARS-CoV-2 RNA stability on spiked banknotes Table A6 shows the Weibull model parameters and goodness-of-fit values of news and old banknotes spiked with SARS-CoV-2. The Weibull model accurately predicted with both n gene and orf gene, with adjusted correlation coefficients (R2) of ≥0.8.0. Estimated RMSE was <0.3, meaning that the Weibull model was a good fit for all the new and old banknotes' survival curves. As in the Weibull model, α, δ1, p, and δ2 influence the data's curves and fitness. The analysis shows that α parameters were significantly different (p ≤ 0.05) according to ANOVA, which means that subpopulations 1 and 2 for new were significantly different. We found that for samples 1, 2, and 3 for n gene and orf gene of new banknotes, differences in α, δ1, δ1, p, and δ2 were not significant (p > 0.05). The same parameters were non-significant (p ≥ 0.05) for old banknotes. In most of the cases of old banknotes, the p values were ˂1.0 means the convex curve for the old banknotes (Table A6). As the virus was most unstable, for old banknotes, the curves were fitted by Mafart et al. (2002), not by double Weibull of Coroller et al. (2006). Suman et al. (2020) reviewed the stability of SARS-CoV-2 on different surfaces, and none of the surfaces shows more than 72 h survival time. Even the authors demonstrated that infection capability is linear; however, their graphs show initial stability and then gradual decrease of the virus. Kwon et al. (2020) analyzed the virus on different surfaces and found a linear reduction of the virus. Riddell et al. (2020) also examined the survival curve with linear regression, but at 20 °C the graphs seem nonlinear. 3.5 FESEM observation of banknotes The observation stipulates the possibility for the presence of exogenous RNases sourced from sweat or dirt on banknotes. We could not assess the contaminating viruses' infectivity; however, the dirtier and old banknotes are less likely to support the stability of SARS-CoV-2 RNA. The scanning electron micrograph (Fig. 3 ) revealed that a loose layer of dirt almost covered the old banknotes (before spike with SARS-CoV-2 positive human sample), which possibly provide rooms for the predator microbes and harbor the exogenous RNases. On the other hand, the new banknotes were observed to have a more fibrous and compact texture and seemed more absorbent.Fig. 3 Field Emission Scanning Electron Micrograph of New (A1 to A3) and Old (B1 to B3) Bangladeshi Banknotes (representative fields). Emission and scanning parameters are: ‘electron high tension’ (EHT) = 5.0 kV, Signal A = secondary electron detector (SE2) at different magnifications. The arrow-a has pointed to show the paper banknote's fibrous structure, and arrow-b points loosely attached dirt particles on the banknote. Fig. 3 3.6 Limitations of the study Due to the strict lockdown conditions, we could not collect samples at the early stages of the SARS-CoV-2 pandemic in Bangladesh, and sampling was limited to only two districts. We had no operational biosafety-level-3 laboratory (BSL 3) in our region and could not perform experiments in the cell line to isolate the virus or test its infectivity. 4 Conclusions The presence of SARS-CoV-2 RNA in various environmental samples and surfaces profoundly affects viral epidemiology and infection. In our research, we found a significant portion of Bangladeshi banknotes contaminated with either virus or RNA. Fomites like banknote mediated transmission could exaggerate the overall situation and posed a risk for susceptible individuals. Implementing personal hygiene, avoiding touching unnecessary surfaces, washing hands after handling banknotes, and an effective decontamination strategy might prevent the fomite-mediated SARS-CoV-2 community transmission. CRediT authorship contribution statement S. Akter conceived the idea, performed the experiment, analyzed the data, and helped write the draft manuscript. P.C. Roy performed the experiment, analyzed the data, and wrote the draft manuscript. A. Ferdaus collected the entire samples and, with the help of S. Nigar, extracted RNA for RT-PCR assay. H. Ibnat and A.S.M. Rubayet Ul Alam performed the experiment involved in the polymerase chain reaction, operation, analysis, and deposition of the gene sequences. Iqbal Kabir Jahid and M. Anwar Hossain contributed significantly to the research design, supervision, result interpretation, statistical analyses, and manuscript improvement to its finished version. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper. Appendix A Supplementary data Supplementary data containing additional tables (Table A1 through A6) and figures (Fig. A1 through A2) to this article can be found online at https://doi.org/10.1016/j.scitotenv.2021.146133 Image 1 Acknowledgements We researched under the fund allocated from Jashore University of Science and Technology through the University Grants Commission (UGC) of Bangladesh. Special thanks to the Directorate General of Health Services, Ministry of Health & Family Welfare, Bangladesh, for approving the Genome Centre of our institution to provide real-time RT-PCR diagnostic service in the national COVID-19 response strategies. Thanks to Sonali Bank Limited, Corporate Branch, Jashore, Bangladesh, for providing nonissuable banknotes to support the research. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.scitotenv.2021.146133. ==== Refs References Alam, A.S.M.R.U., Islam, M.R., Rahman, M.S., Islam, O.K., Hossain, M.A., 2020. 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Med. 382 2020 1564 1567 10.1056/NEJMc2004973 32182409 Vriesekoop F. Russell C. Alvarez-Mayorga B. Aidoo K. Yuan Q. Scannell A. Beumer R.R. Jiang X. Barro N. Otokunefor K. Smith-Arnold C. Heap A. Chen J. Iturriage M.H. Hazeleger W. DeSlandes J. Kinley B. Wilson K. Menz G. Dirty money: an investigation into the hygiene status of some of the world’s currencies as obtained from food outlets Foodborne Pathog. Dis. 7 2010 1497 1502 10.1089/fpd.2010.0606 20704502 Wang J. Feng H. Zhang S. Ni Z. Ni L. Chen Y. Zhuo L. Zhong Z. Qu T. SARS-CoV-2 RNA detection of hospital isolation wards hygiene monitoring during the coronavirus disease 2019 outbreak in a Chinese hospital Int. J. Infect. Dis. 94 2020 103 106 10.1016/j.ijid.2020.04.024 32311449 Warnes S.L. Little Z.R. Keevil C.W. Human coronavirus 229E remains infectious on common touch surface materials MBio 6 2015 10.1128/mBio.01697-15 e01697-15 WHO, 2021. Corona virus disease (COVID-19) situation report [WWW Document]. January 10. URL https://www.who.int/emergencies/diseases/novel-coronavirus-2019/. Xie M. Chen Q. Insight into 2019 novel coronavirus - an updated interim review and lessons from SARS-CoV and MERS-CoV Int. J. Infect. Dis. 94 2020 119 124 10.1016/j.ijid.2020.03.071 32247050 Zaki A.M. van Boheemen S. Bestebroer T.M. Osterhaus A.D.M.E. Fouchier R.A.M. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia N. Engl. J. Med. 367 2012 1814 1820 10.1056/NEJMoa1211721 23075143 Zhong N.S. Zheng B.J. Li Y.M. Poon Xie Z.H. Chan K.H. Li P.H. Tan S.Y. Chang Q. Xie J.P. Liu X.Q. Xu J. Li D.X. Yuen K.Y. Peiris Guan Y. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February 2003 Lancet (London, England) 362 2003 1353 1358 10.1016/s0140-6736(03)14630-2 14585636

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==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Elsevier B.V. S0048-9697(21)01597-7 10.1016/j.scitotenv.2021.146529 146529 Article The water-energy-food nexus and COVID-19: Towards a systematization of impacts and responses Al-Saidi Mohammad a⁎ Hussein Hussam b a Center for Sustainable Development, College of Arts and Sciences, Qatar University, P.O. Box: 2713, Doha, Qatar b Department of Politics and International Relations (DPIR), University of Oxford, Manor Road, OX1 3UQ Oxford, UK ⁎ Corresponding author at: Qatar University, Center for Sustainable Development, P.O. Box: 2713, Doha, Qatar. 18 3 2021 20 7 2021 18 3 2021 779 146529146529 21 11 2020 7 3 2021 11 3 2021 © 2021 Elsevier B.V. All rights reserved. 2021 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The COVID-19 pandemic offers an opportunity to examine the impacts of system-wide crises on key supply sectors such as water, energy and food. These sectors are becoming increasingly interlinked in environmental policy-making and with regard to achieving supply security. There is a pressing need for a systematization of impacts and responses beyond individual disruptions. This paper provides a holistic assessment of the implications of COVID-19 on the water–energy–food (WEF) nexus. First, it integrates the academic literature related to single cases and disruptions to provide a broader view of COVID-19 demand- and supply-side disruptions and immediate effects. Then, the major, long-term impact categories of medicalization/hygienization, (re)localization of production, and demand fluctuations are highlighted. These impacts result in priority cross-links such as irrigation, energy requirements for local food production, energy use for water and wastewater treatment, or water for energy use. Finally, sector-level insights on impacts and responses are provided, drawing from illustrative cases. The analysis of impacts of COVID-19 on the WEF nexus reflects heterogeneous experiences of short-term adaptations, and highlights the revaluation of the water–food–trade nexus. Revived debates on food sufficiency can benefit from green applications to minimize expected trade-offs. The current crisis also reveals some gaps in the WEF nexus debates with regard to the lack of risk-based perspectives and the need for a better consideration of spatial aspects in resource integration. Regarding resource-security issues in the WEF nexus, the COVID-19 stress test boosts debates concerning the adequacy of the production value chains (e.g., contingency and storage, diversification, and self-sufficiency) and the value of cross-border integration (e.g., trade, globalization, and aid). Graphical abstract Unlabelled Image Keywords Environmental security WEF nexus Sustainable development Basic supply infrastructure Food security Middle East Editor: Martin Drews ==== Body pmc1 Introduction COVID-19 has had wide health and economic repercussions affecting the basic supply sectors and the environmental sector in general (Barbier and Burgess, 2020; Cohen, 2020; Naidoo and Fisher, 2020; O'Callaghan-Gordo and Antó, 2020). It has caused many tangible impacts such as the increase in medical waste and some improvements in air quality and carbon emissions (Ilyas et al., 2020; Saadat et al., 2020). In fact, COVID-19's environmental impacts have been conflictive. Major recent reviews cover a wide range of impacts that vary depending on the location, time, and the setting of COVID-19 responses (Cheval et al., 2020; Eufemia and Hussein, 2020; Hussein and Greco, 2020; Sarkar et al., 2021; Shakil et al., 2020). These reviews tend to contrast the human, health, and economic cost of the pandemic with positive aspects such as reduction in emissions, pollution, or noise. However, such positive observations are not specific to the pandemic; they can be caused in any case of downscaling of societal throughput, and besides, positive impacts do not always equate with positive news. COVID-19's environmental benefits are neither stable in the long term (once we “live with” or “defeat” the virus), nor possible nor desirable to induce again in the same manner (by arranging another pandemic). Not unexpectedly, having fewer cars, planes and tourists translates into less environmental damage and smaller ecological footprints, but the repercussions of the COVID-19 crisis are both far-reaching and complex. We need to document immediate impacts, understand long-term implications, and unfold the interrelated aspects of the COVID-19 crisis. At the same time, investigating the significance of this crisis as a “stress test” for our sustainability targets, policies and management approaches can be quite a fruitful exercise. COVD-19 is shaping the environmental research agenda into the foreseeable future. It represents a unique experiment with long-term implications for environmental policies, climate regulations, and economics, as well as for our perception of globalization, equity and environmental responsibility (Deslatte et al., 2020; Helm, 2020). Several scholars have expressed how the current pandemic can reset, onset or delay key items of the global sustainability agenda such as the Sustainable Development Goals or the Paris Agreement (Barbier and Burgess, 2020; Cohen, 2020; Naidoo and Fisher, 2020; Rifai, 2020). In fact, our responses in terms of restarting economies, providing relief, and managing the adaptation of key environmental sectors can determine the final outcomes in terms of either causing more damage and inequalities or creating opportunities for a greener and more just transition. Water, energy and food represent the main sectors for achieving basic supply and key environmental outcomes (Hoff, 2011; Simpson and Jewitt, 2019; World Economic Forum, 2011). Together, they form a water–energy–food (WEF) nexus of interlinked resource-use issues wherein decisions or pressures in one sector have multiple consequences for the other ones (Al-Saidi and Elagib, 2017; Hoff, 2011). The WEF nexus is a much-debated sustainability paradigm focusing on the increased integration between the water, energy and food sectors and the possible implications for resource security (Al-Saidi and Elagib, 2017; Hoff, 2011; World Economic Forum, 2011). COVID-19 represents a systematic and highly relevant stress on the WEF nexus, as this paper explains. Most research in the field has focused on analyzing how COVID-19 affects individual sectors (e.g., water, food and energy), but there have so far been few holistic analyses on the cascading or cross-sectoral impacts of pandemics on these vital sectors. So far, some nexus-related studies exist measuring COVID-19's impacts on access to water, food or energy in Africa (Durodola et al., 2020), and showcasing the relevance of COVID-19 for related nexus framings, e.g., the water–human health–environment–nutrition nexus (Nhamo and Ndlela, 2021). There is a pressing need for greater systematization of the impacts of COVID-19, including practical insights into the reactions of basic supply sectors to the disease considering the increased integration among these sectors. The aim of this paper is to analyze the impacts, responses and practical adaptation strategies of the WEF sector to the COVID-19 crisis. The unique nature of the COVID-19 stress test is highlighted using a conceptual systematization, recent literature on pandemics, practical insights, and country-level examples from the Middle East as a focal region. This pandemic can inform us about the merits and limits of integrative approaches such as the WEF nexus. In view of this, the final section of this paper discusses the tangible impacts, critical factors and long-term perspectives related to the COVID-19 crisis and the WEF sectors. The main hypothesis of this paper is that COVID-19 has redefined the notion of resource security by increasing the importance of debates on risk-based assessments and cross-border integration and revaluing food-related aspects within the WEF nexus. Using the Middle East as a case study, the practical relevance of the COVID-19 crisis to the core WEF nexus objectives of resource security and improved well-being of communities is highlighted. Furthermore, by linking pandemics to the planning and management requirements of environmental sectors, this paper provides an initial examination of COVID-19 with the goal of informing environmental policymaking in situations characterized by crisis and sudden change. 2 Methods 2.1 The systematization approach using a three-layer nexus This paper investigates COVID-19 and its impacts on the WEF nexus by providing a systematized or structured analysis of these impacts and illustrating their practical relevance. To this end, the paper has a two-part structure. Firstly, it maps global interactions using conceptualizations and recent literature (3.1, 3.2). Secondly, it undertakes an analysis based on a case study (the Middle East) using country-level insights (Section 3.3). As a general approach for the systematization, we relied on the three understandings of the WEF nexus provided by Al-Saidi and Elagib (2017), namely incorporation, crosslinking, and assimilation. These three understanding together provide a coherent framework for examining the interactions in the WEF nexus from three different views: incorporation as a whole-system view (Section 3.1), cross-linking as a partial view of certain priority trade-offs and leverage points (Section 3.2), and assimilation as a practical view of sectoral management (the case-study portion of Section 3.3). Fig. 1 explains the overall layout with the aim of providing a systematization of the analysis using the framework of the three-layer nexus put forward by Al-Saidi and Elagib (2017). The three views of the nexus under this framework can be explained as follows: Under incorporation, the analysis is carried out using a “bird's eye view” of the whole system and interlinkages; i.e., in our case, the totality of how COVID-19 affects the WEF sector. This perspective aims at providing an overview or a holistic picture of possible interactions without providing detailed sector-level or country-level details. In the cross-linking analysis, an “inside-out view” is used to highlight the priority linkages; i.e., which cross-sectoral issues are most affected by the consequences of COVID-19. The cross-linking perspective is a practical view that concentrates on the intersections (i.e., links or cross-cutting impacts) of at least two resources. In our analysis, we use both the incorporation and cross-linking analyses to provide a global view of the COVID-19 interactions. This is carried out through conceptualizing these interactions using recent evidence of the disruption caused by COVID-19. Finally, using country-level examples and issues raised in the discussion section, we deploy the assimilation perspective. This perspective represents the sectoral view of sectoral managers and decision-makers seeking to accommodate the concerns of other sectors into their strategies. Here, we highlight some preeminent management issues and provide recommendations for sectoral-level decision-making in order to better accommodate disruptions from COVID-19 while considering pressures from other sectors.Fig. 1 Linking COVID-19 and the WEF nexus: overall outline and steps. Fig. 1 The three perspectives on integration in the nexus together provide a clear and holistic picture of COVID-19 and the WEF nexus. Incorporation, cross-linking, and assimilation are also useful for different levels of management, namely for planning, coordination or regulation, and operational management, respectively (Al-Saidi and Elagib, 2017; Hogeboom et al., 2021). With this multi-layered investigation (see Fig. 1), this paper can capture the impacts of COVID-19 as an additional external layer added to the complex interactions within the WEF nexus. Traditionally, these impacts (e.g., on energy supply changes, food and water demand changes, or waste management) have been treated as stand-alone disruptions. In practice, however, they are often cross-sectoral, with ramifications felt immediately by operational managers in other sectors. For example, an increase in food demand means more requirement for water, and thus more energy required for water pumping, delivery, and treatment. COVID-19 provides a stress scenario with simultaneous impacts across the WEF subsectors. It is also a test case for the resilience of basic supply systems as a highly important topic in WEF nexus research (Al-Saidi and Saliba, 2019), as well as for the viability of current (crisis) management responses and the level of integration in decisions affecting the WEF nexus. 2.2 Literature selection and case-study data To carry out the analysis using the three nexus layers, we mainly relied on secondary academic literature on the impacts of COVID-19 in the WEF sectors. There have been a considerable number of publications on COVID-19 and the water, energy, and food sectors. A quick search of the scientific database Scopus resulted in more than 3000 publications having COVID-19 and at least one of these sectors in the title, keywords or abstracts. In our literature selection, we developed two databases (Appendix A), for the global analysis and the case-study focus. For the first part of the paper on the global interactions between COVID-19 and the WEF nexus (the incorporation and cross-linking views), we searched in Scopus for peer-reviewed papers for the period from December 2019 to February 2021 that include in the title, keywords, or abstract the keywords of COVID-19 and either water security, food security, or energy security. These resource securities comprise the major theme within debates on the WEF nexus (Al-Saidi and Elagib, 2017; Hoff, 2011; World Economic Forum, 2011). Since we aimed to provide a global overview of interactions, no particular geographies or cases were selected for this dataset. The resulting dataset of 274 publications was further processed to exclude irrelevant ones, namely publications that use the key terms (COVID-19 and water security, energy security, or food security) merely as buzzwords, mainly relate to larger impacts (e.g., economic or health impacts), or have a narrow focus (i.e., they do not seek to provide a holistic or sector-wide analysis of COVID-19 impacts). The resulting set had a predominant focus on food security. On the one hand, this apparent bias towards the food sector can reflect the relatively heavy impacts of COVID-19 on food security. On the other hand, it should be balanced out in our analysis in order to cover the impacts on and interlinkages with the other sectors. In order to overcome this bias, key papers linking energy and water securities with COVID-19 were searched for and added by the authors – who have a background in the WEF nexus and water and/or energy sectors – to the final dataset (43 papers). Furthermore, to provide more cross-sectoral insights, we also studied papers with a wider focus on the whole WEF nexus (Durodola et al., 2020; Nhamo and Ndlela, 2021), or on COVID-19's cross-sectoral environmental impacts (Cheval et al., 2020; Helm, 2020; Saadat et al., 2020; Shakil et al., 2020; Zambrano-Monserrate et al., 2020). Alongside the main dataset for the first part of the paper, other papers were used for the background and discussion of the larger context of COVID-19 and the WEF nexus. Alongside the analysis of the global interaction between COVID-19 and the WEF nexus, there is an urgent need to break down COVID-19's impacts on critical supply sectors in order to provide practical insights and recommendations. Such a sectoral view is presented in the case study section of this paper. The insights from regions characterized by scarcity of natural resources and significant anthropogenic pressures, are valuable for better assimilation of the integrated management mindset, and particularly when facing crises such as major health-related ones. Therefore, the case study section focuses on the Middle East, and particularly Jordan, Lebanon and the Gulf Cooperation Council (GCC) region. Lebanon is a particularly interesting case due to the compounded impacts of the ongoing economic crisis and COVID-19-related food security issues. Jordan is an exemplary case for severe water scarcity, which is exacerbated by COVID-19's impact on both the water and food sectors. The GCC region is usually listed among the highest-ranked countries for food security due to the wide availability of financial resources, but the region exhibits some of the world's largest energy and carbon footprints (due to energy requirements for cooling or desalination) (Al-Saidi and Elagib, 2018; Al-Saidi and Saliba, 2019). It is for this reason that the impacts on the energy sector were highlighted for this region. For the case-study section, a Scopus search was carried out for publications from December 2019 to February 2021 with the keywords COVID-19 and Middle East, Jordan, Lebanon, or GCC, that also include either water, energy or food. In the resulting dataset of 117 papers, the overall majority of entries were not specific to the regional focus, or were focused on other impacts of COVID-19 (mainly related to health). After sorting the data, the resulting reduced dataset (only nine papers) was supplemented with media reports and publications from international organizations (an additional seven publications) providing country-level insights into the earlier-mentioned countries. 3 Results 3.1 Initial mapping using a bird's eye view of COVID-19 and the WEF sectors COVID-19 affects the basic supply sectors through a range of disruptions, which we seek to systematize in this section as well as outlining the broad picture of interactions (the incorporation perspective). Fig. 2 summarizes this systematization. We have identified ten major disruptions relevant to the WEF sectors (Fig. 2). We also differentiate between whether a disruption is mainly transmitted through a change in demand patterns, or a supply problem/shortage. There are relationships among the disruptions but they can also occur independently. For example, increased hygiene habits usually lead to dangerous biomedical waste, although this is not necessarily the case; e.g., in the case of sound waste management or the use of biodegradable materials (Das et al., 2020). In fact, within demand-induced disruptions, the increased use of hygiene products and the increase in medical waste have often been highlighted in the COVID-19 literature. The two issues mainly affect the water sector, namely deteriorating water quality or higher demand for water, and in consequence, energy demand for water (Kalina and Tilley, 2020; Norouzi et al., 2020; Rhee, 2020; Vanapalli et al., 2021). Water is a key instrument in the global fight against COVID-19, even in low-income countries lacking chemical-based disinfectants (Amegah, 2020; Anim and Ofori-Asenso, 2020). Hand washing, disposal of materials used for COVID-19 control and treatment, handling of casualties of the virus, and disinfection of affected areas are expected to increase the demand for water and wastewater treatment, thus affecting water quality as well as quantity (Sivakumar, 2020). In the short term, the increase in water demand might be offset by the economic downturn, and, in the long term, tackled through improved efficiency, innovation or (digital) monitoring (Poch et al., 2020). Biomedical waste such as masks, gloves and other protective materials can greatly affect water-related ecosystems and thus threaten water supply sources, environmental health, and ultimately, human well-being (Kalina and Tilley, 2020; You et al., 2020). For example, disposable face masks have been reported to have reached oceans in Hong Kong, while microplastic pollution can threaten freshwater ecosystems (Fadare and Okoffo, 2020). Some authors point to similar problems from post-disaster responses; e.g., discarded water bottles in post-hurricane Haiti (Kalina and Tilley, 2020).Fig. 2 A global overview (incorporation) of initial disruptions from COVID-19 in the WEF sectors. Fig. 2 Demand effects such as the reduction in everyday mobility (e.g., for work or social events) can result in lower energy requirements, and hence some decreased demand for certain water types such as produced water. Other systematic (cross-sectoral and simultaneous) disruptions can lead to demand reductions across the WEF sectors. Decreased leisure activities (e.g., tourism, holidays, or irregular outdoor activities) will lead to lower demand for energy and food, and hence water. Significant energy-demand disruptions are expected as a result of lockdowns and restrictions (e.g., less primary energy consumption) (Sovacool et al., 2020), with significant reductions in electricity demand reported in some European countries during the first wave of COVID-19 (Bahmanyar et al., 2020). Dietary changes can have significant impacts, particularly on the water sector. Healthier diets that include less red meat are important for combatting COVID-19 (Abdulah and Hassan, 2020; Muscogiuri et al., 2020), and as a result, people might demand less meat (which exhibits a high water footprint in its production) in the long run. However, initial evidence from Italy, Spain and some Latin American countries has indicated no or only a slight increase in self-reported intake or purchase of processed and red meat in the short term (Batlle-Bayer et al., 2020; Ruiz-Roso et al., 2020). Other studies have reported an increased intake of processed meat with a decreased intake of low-fat meat (Górnicka et al., 2020). These changes might vary depending on culture, infection rate, and income level. In developing countries, for example, people might choose to spend less on meat due to economic hardship. At the same time, disruptions in eating habits (e.g., more food consumption at home) require more attention to the food losses in households and the relocations in consumption (Aldaco et al., 2020). Finally, increased requirements for digitalization can have an effect on energy demands in the long term, although the final impact is yet to be studied. Finally, some of the supply-induced impacts represent systemic disruptions. Mortality and morbidity affect the labor supply across industries (del Rio-Chanona et al., 2020), and particularly in critical ones such as the food industry (Mardones et al., 2020; Parks et al., 2020; Savary et al., 2020). The economic downturn caused by decreased or delayed consumption, trade disturbances and reduced mobility can cause supply disruptions affecting, for example, the food trade or the production of other basic supplies (Laborde et al., 2020). Restrictions on mobility have resulted in the lack of farm labor, livelihood losses for farmers, and other constraints on the food supply chains (Adamchick and Perez, 2020; Bochtis et al., 2020; Inegbedion, 2020; Mor et al., 2020; Niles et al., 2020). Furthermore, several disruptions have been reported to the global food trade, e.g., affecting agricultural exports from China (Cao et al., 2020) and those developing countries highly integrated in the global food markets (Erokhin and Gao, 2020). At the same time, the postponements of major events, e.g., major sporting events or megaprojects, can decrease the pressure on basic supply but also affect related infrastructure development. In some parts of the world, e.g., the Arab states of the Gulf, or some parts of Africa, megaprojects are driving much of the newer infrastructure development and rehabilitation (Al-Saidi and Elagib, 2018). Similarly, quarantine regulations can lead to a combined disruption of both supply and demand. Confinement and travel restrictions can result in labor shortages in basic supply, especially in the agricultural sector and among seasonal workers. Developing countries exhibit the highest vulnerability to food insecurity as a result of the COVID-19 crisis (Udmale et al., 2020). In Africa, for example, food security is greatly threatened by the COVID-19 pandemic due to the lack of social protection and health insurance (Lawson-Lartego and Cohen, 2020). As a result, food insecurities induced by the COVID-19 pandemic can jeopardize not only human health and well-being but also key developmental goals (e.g., the Sustainable Development Goals (SDGs)) on the African continent (Ezirigwe et al., 2021; Nhamo and Ndlela, 2021). At the same time, household consumption of energy (e.g., for cooling purposes) increased in homes (e.g., around 6% to 8% in the US) (Saadat et al., 2020), thus affecting other sectors such as water (e.g., requirements for produced water or cooling water). 3.2 An inside-out look at key pandemic crosslinks The inside-out view (cross-linking perspective) on COVID-19 and the WEF nexus seeks to highlight priority crosslinks and provide an informed focus. Such a focus is required to reduce the high complexity in terms of possible disruptions and impact directions. In order to do this, we summarized the COVID-19 disruption categories and linked them to WEF sub-nexuses (Fig. 3 ). From the disruptions highlighted earlier, we synthesized three main impacts (i.e., categories of disruptions oriented towards the longer term) of the COVID-19 crisis on the three basic supply sectors (Fig. 3).Fig. 3 Crosslinks between COVID-19 and WEF subsectors. Fig. 3 Firstly, the increased medicalization and hygienization of society is mainly affecting two sub-nexuses. This category affects the food/land–water nexus through the pollution of (arable) land, and therefore water sources, as well as the energy–water nexus through increased requirements for water and energy for wastewater treatment or water production. There have been several studies highlighting the environmental interactions between COVID-19 and water use, wastewater, soil and water pollution, and energy use for wastewater treatment (Klemeš et al., 2020; Poch et al., 2020; Sivakumar, 2020; The Lancet Global Health, 2020; Zambrano-Monserrate et al., 2020). We have already pointed out some of the issues within this category of COVID-19 impacts; for example, water pollution through biomedical waste (Kalina and Tilley, 2020; Rhee, 2020; Vanapalli et al., 2021; You et al., 2020), energy requirements for wastewater treatment and monitoring (Adelodun et al., 2020; Street et al., 2020), and increased need for water for disinfection and hygiene (Chiluba et al., 2020; The Lancet Global Health, 2020). However, the long-term impacts of this impact category of medicalization and hygienization are yet to unfold, and will arguably linger for a long while. In considering these impacts, both the environmental health and human livelihoods of communities living in the impacted ecosystems should be analyzed (Nhamo and Ndlela, 2021). Secondly, several disruptions related to mobility, sickness, quarantine and changing diets translate into (re)localizations of the production of basic supplies (Benton, 2020; Espitia et al., 2020; Pu and Zhong, 2020). In some countries, COVID-19 will result in rising demands for local food production, and national governments may choose to reinstate food-security and self-sufficiency policies (Fontan Sers and Mughal, 2020; Keulertz et al., 2020; Woertz, 2020). This impact is forcing revaluation of the crosslinks between COVID-19 and the food–water and energy–food sub-nexuses, mainly through energy and water requirements for enhanced food self-sufficiency or local food policies. In practical terms, if labor and energy should decrease for major food exporters, this may negatively impact the availability of food products on the international market (Adamchick and Perez, 2020; Cao et al., 2020; Erokhin and Gao, 2020). At the same time, a decrease in labor in the agricultural sector in importing countries – due, for instance, to travel restrictions, quarantine, and sickness – would result in increased food demand from the international market to cover the decrease in their national production (Hussein and Greco, 2020; Woertz, 2020). In the long term, responses to the COVID-19 crisis might strengthen agri-food and green innovations using local or regional partnerships (e.g., the European Green Deal initiative with the new EU Farm to Fork Strategy) (Rowan and Galanakis, 2020). They also revalue the role of food science in improving local food systems and enhancing food-related entitlements and transfers (Devereux et al., 2020), particularly in the context of humanitarian food aid policies in vulnerable regions such as the African Sahel (Bounie et al., 2020). For this, resilient food-supply chains are important and they should be dealt with comprehensively by including equity considerations at the levels of individuals, households, and communities (Gillespie, 2020). Furthermore, for Small Island Developing States, enhancing local food security has become an even bigger priority in view of the triple burden of climate change, COVID-19, and malnutrition (Hickey and Unwin, 2020). Thirdly and finally, some COVID-19-related disruptions will result in short-term fluctuations in demand or capacity to produce water or energy resources. However, these might be relatively uncertain and site-specific. For example, stay-at-home COVID-19 strategies increase the demand for cooling in some regions (and heating in others), resulting in higher electricity and water demands (Hospers et al., 2020). While the energy demands (and electricity bills) might increase, the consumption load profile can fluctuate, and the willingness to conserve energy or invest in energy management systems can increase (Chen et al., 2020). These COVID-19-related changes might compensate each other, e.g., increased electricity use at home and decreased energy use elsewhere. In fact, the type of COVID-19 containment measures influences the overall consumption profile (Bahmanyar et al., 2020). Due to this instability of insights, there is so far little knowledge on COVID-19-related changes in water use for electricity supply. Similarly, disruptions due to COVID-19 can lead to short-term fluctuations in industrial and household demand for water, thus affecting the required energy input. Generally, these fluctuations are expected to be less stable than those related to the other two impact categories of local food policies and COVID-19 prevention and treatment. 3.3 Assimilating initial impacts on resource securities: the Middle East as a case study In this section, we highlight some sectoral or management-level perspectives on COVID-19 impacts focusing on resource-supply security and day-to-day challenges as well as actions in the water, energy and food sectors. These sectoral practices and impacts (Fig. 4 ) provide further details and country-level examples of the earlier-explained disruptions, impact categories and priority crosslinks.Fig. 4 Overview of some sector-level interactions and impacts of COVID-19. Fig. 4 In the water sector, the main direct impacts of the pandemic are the increased use of water and the resultant contamination, and some of the effects are translated through source-water contamination (land for water) and increased energy use for wastewater treatment and water supply. A recent study by Gerard (2020) analyzed the impacts of the pandemic on water uses in Jordan and found that COVID-19 is indeed impacting current domestic water-use patterns by increasing demand by 40% and forcing residents to embrace a water conservation mindset. This was generally seen as being due to hygiene requirements related to the pandemic, increased water use due to being at home rather than at school or work, and some newly adopted household activities, such as gardening. Nevertheless, interviewees also emphasized that while in lockdown, they were more inclined to conserve water as a result of the pandemic. This shows that in Jordan, the second most water-scarce country worldwide, the issue was the increased demand for water at the domestic level, which resulted in increased energy use for wastewater treatment. Jordan has been receiving international support throughout this pandemic to ensure water security for its population. For instance, the German cooperation effort has been working closely with the water utilities to identify additional water sources and aquifers in order to meet the increased water demand (MENAFN, 2020). As regards the food sector, in Jordan the government took measures in March and April of 2020 to ensure food security, maintaining the food supply chain and facilitating it through digitalization of payment transfers and movement licenses (Fathallah, 2020). However, the initial challenges due to the curfew were barriers to the farmers in accessing their land, and ensuring continuity of labor on the land. A recent study on Jordan (Gerard, 2020) that focused on the first months of the pandemic found that in the short term, the lockdown meant that countries such as Jordan that are heavily reliant on food imports, saw the border closures in neighboring countries and in the rest of the world as a challenge for the import and export of food products. In fact, Jordan has taken measures to restrict food exports, a measure to enhance local food security in the face of the COVID-19 pandemic (Nsour, 2020). Exporting the locally produced crops was difficult and led to a crisis in which farmers were attempting to sell their excess crops for extremely low prices. The pandemic pushed farmers and practitioners in Jordan to reflect on the possibility of switching to less water-intensive crops: “Hopefully, if COVID impacts longer into the next growing season, they will think about it” (ibid.). According to Gerard (2020), the pandemic is impacting the agricultural sector primarily through the disruption of exports. Because COVID-19 is disrupting the food supply chain, it has the potential to change future agricultural water use by decreasing the amount of crops grown by farmers. However, it is unclear whether COVID-19 is changing agricultural water use at the present time. Because most farmers had already grown most of their yearly crops by the time of the pandemic, COVID-19 has likely had little effect on agricultural water use up until this point. Assuming the effects of the pandemic last at least until the upcoming planting season, however, it seems likely that COVID-19 will influence agricultural water use, either through decreases in planting or through crop switching. According to Nsour (2020), though, “Nevertheless, overall, the Jordanian case shows how managers and policies contributed to maintaining internal trade and food trade, and access to it” (ibid.). Moreover, the pandemic also impacted the Jordanian food sector by pushing farmers to increase self-production, which, in turn, increased the demand for manpower and water resources. In the case of Lebanon, the pandemic has worsened food security, building on an ongoing economic and financial crisis. In fact, since autumn 2019, Lebanon has been facing the largest economic and financial fallout in history, worsened by the COVID-19 outbreak. COVID-19 forced lockdowns in April, May, and August of 2020, which severely exacerbated the economic and financial crisis, and consequently, the food security status reached an alarming level. International media, including the Telegraph, and the Guardian (Cheeseman, 2020; Chulov and Zavallis, 2020), highlighted in June 2020 that Lebanon was experiencing a food crisis, that “People will die within months,” and that “The Lebanese are at risk of famine.” These alarms regarding a heightened state of food insecurity have been expressed for other developing countries (Erokhin and Gao, 2020; Lawson-Lartego and Cohen, 2020), but Lebanon has proven particularly vulnerable due to the underlying economic problems. In Lebanon, people living in poverty are no longer able to buy all their needs, as prices of commodities and foodstuffs, even fruits and vegetables, increased by 58.43% since September 2019 when the tumbling of the Lebanese pound, pegged to the US dollar, initiated chaos. A recent report carried out by the World Food Program (2020) in June 2020, assessing the impact of the economic and COVID-19 crises in Lebanon, showed that the price of the Survival Minimum Expenditure Basket (SMEB) has been steadily increasing over time with cumulative inflation of 109% compared to the prices in September 2019. Amid this economic crisis, further exacerbated by the pandemic, in August 2020 – following the massive explosion at Beirut port – some of the grain reserves of the country were destroyed, and the naval food trade interrupted, pushing Lebanon further towards a food crisis. In this context, Lebanon is experiencing a food crisis in terms of affordability of food, as extensive segments of society who are living in poverty are not able to access food. Rural communities are therefore increasing the self-production of agricultural goods, and in turn increasing the demand for water resources. Moreover, recent research also confirms that the situation is particularly challenging in the Syrian refugee camps in Lebanon, where the quality of water was already an issue (Kassem and Jaafar, 2020). In this context,It is evident that sufficient access to clean water and sustainable treatment of wastewater are critical for the health of the refugees and the hosting communities, especially during the unfolding COVID-19 pandemic. Failure to address these issues promptly might lead to severe disease and outbreaks in these populations. (Kassem and Jaafar, 2020) A recent study on Jordan by Elsahoryi et al. (2020) suggests that the pandemic and the quarantine and other measures taken in response had an impact on food security. They recommend identifying appropriate strategies in order to support individuals at higher risk, including factors such as “the number of persons in the family, younger adults (18–30 years old), and those who do not own their houses” (Elsahoryi et al., 2020). Woertz (2020) highlights that especially in the GCC, it is necessary to ensure accessibility to food for the most vulnerable and marginalized members of the society (such as migrant labor) and considers also introducing policy measures for their support, such as a potentially “politically controversial” safety net. As noted by Ma et al. (2021), food security is also strongly affected in fragile states and those facing conflicts and political instability. They confirm that Yemen, Sudan and Syria are among the most vulnerable states when it comes to food security. The pandemic is, in fact, further exacerbating an already vulnerable situation:Prior to the pandemic, over 80% of Yemen's population are dependent on food aid and facing acute food insecurity. In Syria, 9.3 million people are food insecure due to record-high food price inflation. Sudan currently facing strict curfew while the food price inflated to 82% in April compared to the previous month. (Plecher cited in Ma et al., 2021) Sen (2020) notes that the impacts of the pandemic are also very visible in countries already facing political or economic embargos, blockades, and restrictions, such as in the case of Gaza. Smith and Wesselbaum (2020) point out that COVID-19-related food insecurity can act as a multiplier of the pandemic's impacts on health and human well-being, and as a result, it can also lead to increased rural–urban and international migrations. In the energy sector, the immediate impacts of the COVID-19 pandemic are reflected in fluctuating energy demands. Overall, the lockdowns and commercial restrictions seem to have lowered the overall demand for primary energy and electricity (Bahmanyar et al., 2020; Sovacool et al., 2020), although such reductions seem not to apply to the residential sectors. In New York during the lockdowns, for example, most households surveyed reported increased electricity usage and no morning or evening peaks during weekdays, with the lockdowns seeming to make weekday consumption curves similar to pre-COVID-19 weekend curves (Chen et al., 2020). Such a change in the electricity consumption profile indicates the revaluation of the water–energy link for management of the energy sector. This is more evident with regard to water requirements for cooling, particularly in hot and arid regions such as the GCC region. In Kuwait, for example, during the COVID-19-related lockdowns in 2020, there were noticeable reductions in energy consumption in governmental, industrial and commercial sectors, but an increase in power consumption and peak load in the residential sector (although less than the decreased load in other sectors), which accounted for over 80% of power consumption during the lockdown (Alhajeri et al., 2020). In the context of the hot and dry (and thus water-scarce) region of the Gulf Cooperation Council (GCC), most electricity consumption is used for space-cooling (up to 50% of total and 70% of peak electricity consumption in the GCC) (Eveloy and Ayou, 2019). This comes with a water footprint depending on the type of cooling system used (e.g., water usage in water-cooled chillers for large buildings or in district cooling for whole neighborhoods). The energy issue is especially important for GCC countries in terms of meeting the high domestic energy demands, but it should also be contextualized within the global fluctuations in oil prices that also impacted the GCC oil-producing countries (Jaffe, 2020). In response to this, GCC governments have in the past adopted measures to mitigate production fluctuations and ensure energy security in general. They have invested in the use of energy-efficient (and thus more climate-friendly) cooling technologies such as district cooling, which has 18–55% lower energy consumption, and 20–30% lower life-cycle cost than current cooling alternatives (Alajmi and Zedan, 2020). District cooling in the GCC region is mostly used for residential areas, the water source for which can theoretically stem from freshwater, desalinated water or treated wastewater (Alajmi and Zedan, 2020; Eveloy and Ayou, 2019). However, the supply of water is the main concern for district cooling companies in the region (10% of the plants' operational costs), and has been largely covered through desalinated water due to past concerns of these companies regarding corrosion and fouling associated with the use of seawater or treated wastewater (Rajan, 2009). In this context, managing any fluctuations in energy and cooling demands in the context of the COVID-19 crisis is linked to several water-related concerns. 4 Discussion and the way forward The current COVID-19 crisis is argued to be representative of the notion of modern risks associated with global change (e.g., in the climate or the earth's biodiversity) and increased integration between economies (i.e., globalization and increased mobility) in an era shaped by human alterations (the Anthropocene) (Manzanedo and Manning, 2020; McNamara and Newman, 2020; Norouzi et al., 2020; O'Callaghan-Gordo and Antó, 2020). It is also revealing of the limits and interdependence of today's environmental policy-making related to natural resource management and supply security. In this context, in this section, we discuss the short- and long-term implications of COVID-19 for management responses in the WEF sectors, and draw lessons for the nexus paradigm. Firstly, with regard to short-term implications, the COVID-19 crisis has translated itself broadly into immediate disruptions and persistent fluctuations in demands. We highlighted the nature and interrelations of these impacts, while the management responses are still underway. These responses can be characterized as coping mechanisms that vary from one case to another and that can result in trade-offs with long-term policy objectives; e.g., ad hoc or unplanned responses can affect the long-term, planned development or the resilience of a certain sector. More developed countries (particularly those prone to disasters or disruptions) might be economically more resilient and have better anticipation and adaptation strategies in place, while the picture is more heterogeneous in developing ones. In Australia, for example, disruptions in the water systems are not new due to recurrent extreme events (e.g., drought or fires), and thus knowledge, monitoring systems, danger signals, and regulations already exist to some extent (Daniell, 2020). In the energy sector, short-term fluctuations seem to be well handled, arguably due to the overall energy-decreasing effect of COVID-19, for example, in India where no noticeable power interruptions were observed (Madurai Elavarasan et al., 2020). As noted earlier, the food-related disruptions have been significant in some developing countries, while the efficacy of responses often depends on the quality of ad hoc decisions and international aid (Bounie et al., 2020; Lewin, 2020). Importantly, the ability to deal with sectoral supply disruptions is a function of the overall management of the COVID-19 health crisis, as well as the level of success in managing the associated panic, installing trust, and improving the quality of communication and information (Mocatta and Hawley, 2020). In the long term, the COVID-19 crisis is expected to lead to revaluation of some issues and links in the WEF nexus. From our previous analysis, the water–food–trade sub-nexus seems to stand out. National food-security priorities might be revisited in light of the debates reignited by the current crisis regarding self-sufficiency, trade risks, resilient value chains and production relocations. Here, negative long-term impacts on national water and energy footprints are not necessarily pre-programmed. Several options have been put forward for enhancing local and sustainable (i.e., low-carbon and water-efficient) food production in a post-COVID-19 world; e.g., using smart agriculture, traditional irrigation, or integrated greenhouses (Awjah Almehmadi et al., 2020; Chazarra-Zapata et al., 2020). It is important also to incorporate food-security approaches linking human health and well-being to environment health (Nhamo and Ndlela, 2021), and to reflect the important issues of equity, food access for vulnerable groups, and fair food prices (Clapp and Moseley, 2020; Gillespie, 2020; O'Hara and Toussaint, 2021). These suggestions on the way forward go hand in hand with long-term recommendations for the energy sectors to accelerate the energy transition in a holistic way (including commercial availability, planning institutions, and public participation) (Vanegas Cantarero, 2020), and to advance renewables on different regional scales (i.e., also for rural areas or residential uses) (D'Adamo et al., 2020; Madurai Elavarasan et al., 2020). Such recommendations are in line with the current debate about the “green recovery” from COVID-19; e.g., pro-environment fiscal stimulus, comprehensive sustainability spending (Green New Deal), and support for green investments (Mukanjari and Sterner, 2020; Rosenbloom and Markard, 2020; Sovacool et al., 2020). Finally, there are some implications of the COVID-19 crisis related to the merits and current limits of the integrative approach of the WEF nexus. In this paper, the analysis of impacts, responses and new debates reiterates the importance of integrated perspectives and the notion of change in analyzing the three resources. Such a change, which drives integration within the nexus, has been attributed to endogenous (e.g., socio-economic change in infrastructure, policies or lifestyles) or exogenous (e.g., climate, technological and market-related changes) factors (Abulibdeh et al., 2019). This core focus of the WEF nexus on change, integration and securities has been enriched by debates on the importance of sustainable livelihoods and environmental considerations (Biggs et al., 2015; Hellegers et al., 2008). The COVID-19 pandemic particularly highlights two gaps in the current debates. Firstly, the impact of pandemics on resource integration has not featured highly in previous WEF nexus debates, but the expected impacts (e.g., disruptions, or revaluation of food-security links to water and trade) might not necessarily result in new interlinkages. Moreover, COVID-19's impacts are reminders of the broader point with regard to redefining the security debate within the WEF nexus. So far, the bulk of resource-security debates have focused on aspects related to stability (regulating the integrated resource-supply systems through policies, rights or incentives) and reliability (improving performance, efficiency, or coverage) (Al-Saidi and Saliba, 2019). COVID-19 highlights the need for security assessments and risk perspectives focusing on the highly integrated resource-supply systems, such as issues related to risk management, resilience assessments, or storage and contingencies. The resilience perspective is a highly demanded but rather underrepresented theme within the WEF nexus debates (Al-Saidi and Saliba, 2019; Hogeboom et al., 2021). Secondly, spatial aspects need to be reexamined and better analyzed in the WEF nexus. This includes a deeper consideration of cross-regional interdependences or trade issues, globalization, relocations of production, or international collaboration (e.g., for aid or short-term supply compensation). In summary, we highlight the following points regarding the way forward for integrating insights from the COVID-19 crisis into the current research and debates within the WEF nexus:• Security-based assessments within the WEF nexus should better incorporate risk- and shock-related aspects, while the focus should not only be on the nature of short-term disruptions. The post-pandemic research can capitalize on long-term lessons learnt in order to re-examine the issues of resource security and integration within the WEF nexus. Related to this, resilience-enhancing strategies that consider integration among the WEF sectors are essential, and they should be prepared in advance in order to avoid ad hoc or suboptimal reactions to sudden shocks. • During the COVID-19 pandemic, food security has emerged as the primer for understanding resilience and vulnerability within the WEF nexus. Particularly in developing countries, it is important that food-related aspects are addressed within the nexus. They can be approached through a re-thinking and re-optimizing of the use of resources (land, water, and energy) towards more sustainable (i.e., a green agri-food industry) local food production. • COVID-19 has highlighted the temporal aspects of resource-supply security within the WEF nexus since negative impacts on the food, water and energy sectors are transmitted at different speeds. While it can be possible to provide short-term and local alternatives to water and energy supplies, food-supply shortages are immediately felt and difficult to compensate for. Water- and energy-related disruptions can also be unstable or temporary, or, if sustained in the long term, lead to exacerbated food crises. Here, it is important to address the temporality of the WEF nexus interlinkages in a way that can enhance resource supply security; e.g., through a better understanding of contingency planning or the nature of adaptations within the nexus. • Cross-boundary spatial aspects have been pushed to the forefront by the COVID-19 pandemic, although they have not featured highly within the traditional WEF nexus debates on integration and security. Future WEF nexus analyses should relate more to international aspects highlighted by global shocks; e.g., food–water and trade (aspects of optimal integration, dependence, and responsibility) as well as food–energy–health and international cooperation (e.g. state-based cooperation/geopolitics, international aid, access, or justice). • Beyond the immediate environmental impacts of health-related crises, the COVID-19 crisis has spawned new, cross-sectoral issues. For example, the medicalization and digitalization of societies as well as the relocation of production might be sustained for some time to come, thus leading to profound impacts on the use and integration of water, energy and land resources. These emerging or accelerating issues need to be monitored and probably integrated within future WEF nexus debates. 5 Conclusions So far, research related to COVID-19's environmental impacts has focused on describing individual disruptions, analyzing short-term drawbacks and benefits, and stating long-term perspectives for the sustainability agenda. However, this pandemic represents a unique and systematic stress test that goes beyond single natural-resources sectors and requires analysis beyond immediate or temporary symptoms. It is, therefore, important to provide a systematization of impact, current responses and long-term perspectives of COVID-19 with regard to the three increasingly interlinked sectors of water, energy and food. The cross-cutting ramifications of the pandemic provide an additional layer of complexity and urgency in studying integration within the WEF nexus, and the potential consequences on our understanding of environmental or resource-supply security. This paper carries out this systematic analysis in three steps: i) a global or “bird's eye” view of disruptions, ii) an “inside-out view” of preeminent linkages and priorities, and iii) a “managerial view” of country-level responses in assimilating COVID-19 cross-sectoral impacts. In the broad or global picture, we highlighted how supply and demand disruptions associated with COVID-19 can result in multidirectional effects that can last for years to come. Some of these disruptions (e.g., decreased leisure activities, restrictions on mobility, economic downturn, and postponement of activities) cut across the WEF sectors, while many of the predicted production and demand fluctuations might be unstable and dependent on the localized nature of disruptions. On the priority crosslinks, we synthesized three main impact categories of COVID-19 and discussed the priorities and cross-sectoral issues. Firstly, the increased medicalization and hygienization are associated with increased requirements for wastewater treatment (hence more energy use) and the protection of water sources and arable land from pollution and contamination. Secondly, the (re)localization of production seems to increase tendencies for local food production, thus increasing pressure on water for irrigation and energy use in local agriculture. Thirdly, fluctuations in demand can bring uncertain pressures on the water–energy interlinks; e.g., water for cooling requirements, or energy for water production. Regarding the managerial responses, we highlighted several sectoral experiences from case studies, particularly from the Middle East, showing largely overwhelmed institutions and ad hoc reactions, particularly with regard to food-security impacts. These sectoral responses also confirm the identified trends such as the localization of food production, increased pressures on water resources, and fluctuations in energy demands. Finally, the COVID-19 crisis offers an opportunity for reflection on management responses across the WEF nexus sectors. In the short term, these responses seem to be variable and largely dependent on the overall quality of pandemic management, but also on the existing local capacities in the WEF nexus to withstand the COVID-19 storm. With regard to resource-supply security, the developed and disaster-prone countries might be well prepared, whereas developing countries' experiences are heterogeneous, with factors such as trade dependences, aid flow, and adequate communication proving important. In the long term, the COVID-19 crisis forces revaluation of the water–food–trade nexus as it revives debates about self-sufficiency, supply security, and local food production. These debates should also be linked to broader issues of livelihoods, environmental protection and sustainable development as overarching objectives. Here, incorporating green or sustainable resource-production systems can help in minimizing trade-offs of production relocations; e.g., sustainable agriculture, use of renewables, recycling, and smart and efficient systems. At the same time, this crisis reveals some gaps in previous integration and security debates within the WEF nexus. These gaps relate to the need for a more risk-based perspective on integration and resource security as well as better incorporation of spatial aspects (beyond the local) in analyzing interdependences and linkages among the vital resources of water, energy and food. The following is the supplementary data related to this article.Appendix A Literature datasets. Appendix A CRediT authorship contribution statement Mohammad Al-Saidi: Conceptualization, Investigation, Formal analysis, Validation, Writing – original draft, Writing – review & editing. Hussam Hussein: Investigation, Formal analysis, Validation, Writing – original draft, Writing – review & editing. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ==== Refs References Abdulah D.M. Hassan A.B. Relation of dietary factors with infection and mortality rates of COVID-19 across the world J. Nutr. Health Aging 2020 10.1007/s12603-020-1434-0 Abulibdeh A. Zaidan E. Al-Saidi M. Development drivers of the water-energy-food nexus in the Gulf Cooperation Council region Dev. Pract. 29 5 2019 582 593 Adamchick J. Perez A.M. 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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01284-8 10.1016/S0140-6736(21)01284-8 World Report ACT Accelerator strains donors' aid budgets Usher Ann Danaiya 3 6 2021 5-11 June 2021 3 6 2021 397 10290 21372137 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe continued shortfall in funding for the international COVID-19 response raises the question of whether alternative forms of financing should be explored. Ann Danaiya Usher reports. The Access to COVID-19 Tools Accelerator (ACT-A) is facing a daunting funding crisis. Set up in April, 2020, by the European Commission, France, and the Bill & Melinda Gates Foundation, and coordinated by WHO, it aims to accelerate the development, production, and equitable access to COVID-19 tests, treatments, and vaccines. However, as of May 28, 2021, ACT-A is US$18 billion short of its $33 billion budget for 2021. Moreover, most of the money provided so far has paid for vaccines; tests, medical oxygen, and protective equipment for health workers are badly underfunded. The inability to raise the required funds from donors is raising the question of whether alternative forms of financing can fill the gap. For months, UN Secretary-General António Guterres has argued against using scarce official development assistance (ODA) to finance the pandemic response. Donor countries have not heeded these warnings, relying on their aid budgets to finance ACT-A. “We will never find this money in traditional ODA budgets”, Guterres warned last September. “Without an exceptional mobilisation of resources, the amounts [needed] will never be reached.” Global ODA increased slightly to $161 billion in 2020. But humanitarian requirements reported by the UN skyrocketed to an unprecedented $40 billion last year, with donors financing only 50%, the lowest proportion in a decade. How to generate billions of dollars for ACT-A fast without crippling ODA has become a pressing question. One alternative to help raise the missing billions is an expansion in the International Finance Facility for Immunisation (IFFIm). IFFIm raises funds on international capital markets by issuing vaccine bonds against long-term, legally binding grant agreements from sovereign donors. This mobilises cash in real time, which donors then pay back out of future aid budgets, a “give now, pay later” scheme, as Desmond McNeill at the University of Oslo, Oslo, Norway, describes it. Australia, Norway, Sweden, and the UK, have already used IFFIm to finance their contributions to ACT-A. The UK has drawn most heavily on the facility, covering 60% of its $1·13 billion contribution through IFFIm bonds. Former UK Prime Minister Gordon Brown advocates extending IFFIm as a way of “making our aid money go further”. He says $2 billion in guarantees plus a small amount of grant financing would generate $8 billion that could be used on the pandemic response. However, because IFFIm borrows from future aid budgets, it may crowd out other needs many years ahead. Another option, originally proposed by the G20, is an extraordinary allocation of $650 billion in special drawing rights (SDRs) by the International Monetary Fund (IMF). This would provide approximately $21 billion worth of SDRs in direct liquidity support to low-income countries, according to the US Treasury. A new IMF report states that the fund is “exploring options to channel SDRs from [high-income] countries...to support global public policy goals” such as vaccines and other COVID-19-related tools. This could take the form of guidelines for channelling excess SDRs to low-income countries. The allocation proposal is likely to be put before the IMF board of governors in August, 2021. The Financial Working Group of the ACT-A Facilitation Council, chaired by Norway and South Africa, has considered both IFFIm and the SDR allocation in scenarios for generating resources to fully finance the pandemic response. The working group has devised a formula for fair burden sharing of the ACT-A budget, where the USA would contribute approximately a quarter of the bill, EU 23%, the UK and Japan 5–6%, and so on. Norway and South Africa have carried out an unprecedented diplomatic effort to move the funding discussion out of the development ministries and into the finance ministries, “where it belongs”, as one diplomat put it. Norwegian Prime Minister Erna Solberg and South African President Cyril Ramaphosa have sent letters to 89 countries, including the G20, urging them to give their fair share. Although great hopes were pinned on the G20 Global Health Summit on May 21, 2020, the G20 as a whole did not deliver funding on anywhere near the scale that is needed. WHO figures show that $1·3 billion were pledged by three countries—France, Italy, and Switzerland—some of this was earmarked for 2022. Addressing the gathering, Kristalina Georgieva, managing director of the IMF, argued for much more ambition from donors to end the pandemic faster, reduce loss of life, and accelerate the global economic recovery. She said $13 billion in grant financing from donors (in addition to a fully funded ACT-A) and $15 billion in concessional funding would help low-income and middle-income countries reach 60% vaccine coverage by July, 2022. This “requires not just commitments but upfront financing, upfront vaccine donations, and upfront at-risk precautionary investments. It is essential that all necessary financing is available as soon as possible”, she said. Hopes for big pledges are now turning to the G7 summit on June 11, 2021.

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)01107-7 10.1016/S0140-6736(21)01107-7 Correspondence HERA: a new era for health emergency preparedness in Europe? Villa Simone a van Leeuwen Remko b Gray Claire Craig c van der Sande Marianne de Konradsen Flemming f Fröschl Günter g Nord David Gisselsson h da Costa Clarissa Prazeres i Ramirez-Rubio Oriana j Abubakar Ibrahim k Bärnighausen Till l Casamitjana Núria j Berner-Rodoreda Astrid l Cobelens Frank b Plasència Antoni j Raviglione Mario a a Centre for Multidisciplinary Research in Health Science, University of Milan, 20122 Milan, Italy b Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands c League of European Research Universities, Leuven, Belgium d Julius Global Health, University Medical Center Utrecht, Utrecht, Netherlands e Institute of Tropical Medicine Antwerp, Antwerp, Belgium f School of Global Health, University of Copenhagen, Copenhagen, Denmark g Division of Infectious Diseases and Tropical Medicine, University Hospital, Ludwig Maximilian University, Munich, Germany h Centre for Social Medicine and Global Health, Lund University, Lund, Sweden i Institute for Medical Microbiology, Immunology and Hygiene, Center for Global Health, Technical University Munich, Munich, Germany j Barcelona Institute for Global Health, ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain k Institute for Global Health, University College London, London, UK l Heidelberg Institute of Global Health, Heidelberg University, Heidelberg, Germany. All institutions (apart from the League of European Research Universities) are members of the European Global Health Research Institutes Network 18 5 2021 5-11 June 2021 18 5 2021 397 10290 21452147 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAfter the first wave of COVID-19 in Europe, the European Commission (EC) committed to take bold actions in preventing and managing similar threats in the future.1 The EC recognised that there was a lack of capability in the EU regarding the demand-to-supply dimension of devices, commodities, and products essential for preparedness and response. Consequently, the EC proposed to create a new agency devoted to well organised stockpiling of preparedness and response tools as countermeasures: the European Health Emergency Preparedness and Response Authority (HERA). Public consultation was open until May 12, 2021, and the exact remit of HERA will be set out in a legislative proposal later in 2021. We believe HERA should embrace the global dimension of health threats and the three main components of preparedness (ie, risk assessment, risk management, and risk communication), in close collaboration with other existing EU agencies (eg, the European Centre for Disease Prevention and Control [ECDC] and the European Medicines Agency [EMA]) and relevant non-EU agencies (eg, WHO), in a five-prong bundled model (panel ). HERA, through effective stockpiling, could incentivise a more coherent response to emergencies and simultaneously strengthen all key elements of a comprehensive and timely response to health emergencies in the EU and elsewhere.Panel A five-prong bundled model for health emergency preparedness • Technological innovation and rapid response to market and regulatory challenges • Harmonisation of policy development and adaptable policy implementation at national and sub-national levels • Monitoring, preparedness and response mechanisms • Horizon scanning to adequately detect cross-border threats and hazards in Europe or elsewhere and to monitor and evaluate new countermeasure products, devices, and technologies • Education and training with the contribution of academic and public health institutions offering cross-disciplinary didactic plans First, HERA must support technological innovations and rapid response to market and regulatory challenges, starting with stockpiling and distribution mechanisms of key response countermeasures (eg, protective equipment, medical devices, reagents, medicines, vaccines) and protocols. This response will require a stimulation of technologies and identification of solutions to overcome market and regulatory challenges for existing or new products. Essential to this response is facilitating equitable global access by removing or addressing existing barriers and promoting transparency in the procurement and costs of these products. A strong market intelligence focus is needed to monitor available stocks of countermeasures and to ensure that market blockages for needed supplies are detected and addressed where necessary. As stockpiling and emergency preparedness data are sensitive, interlinkages with civil defence bodies will be necessary. Second, HERA could bring member states together to pursue common and homogeneous ways for flexible policy formulation and adaptable implementation at national and sub-national level in close collaboration with other EU (eg, ECDC and EMA) and non-EU entities (WHO, Africa Centres for Disease Control and Prevention [CDC] and US CDC) that are crucial in the international pandemic response. This harmonisation of policy development should include coordinated stockpiling rules, development of joint operational procedures, and essential item lists for an effective EU and global response. Harmonisation of policies across decentralised or federal systems where difficulties exist in ensuring a coherent response can thus be addressed. Emphasis is also needed in developing and implementing consistent tools for timely adaptive risk communication to the general public on risks and mitigation strategies to prevent undermining of shared policy frameworks. Establishing an accountability framework with a clear description of responsibilities will help identify focal points—eg, for distributions of commodities and furthering targeted education and training of personnel. Third, monitoring, preparedness, and response mechanisms should be regularly tested to allow an early and bold response. Weaknesses should be identified with preparedness assessment tools. Adherence to established WHO recommendations for 2005 International Health Regulations self-assessment and regular external evaluation and the United Nations Office for Disaster Risk Reduction's Sendai Framework for Disaster Risk Reduction 2015–2030, coordinated jointly by agencies such as HERA and ECDC, should become a condition to benefit from stockpiling. Fourth, horizon scanning activities will require strengthening and establishment of a robust and accessible joint EU and WHO surveillance system, managed by ECDC, with the capacity to identify cross-border threats early, and a monitoring framework in collaboration with EMA to gain knowledge and assess countermeasure products, devices, and technologies under development worldwide in a timely fashion. Both surveillance and monitoring require backing by strong political commitment and engagement with other EU agencies like ECDC and EMA, as well as global initiatives for pandemic preparedness and WHO.2, 3 Use of data science and digital technology (eg, artificial intelligence) is important to predict future scenarios for risk mitigation. Technologically advanced horizon scanning tools would promote a more precise global health response.4 Fifth, building fresh and specific competence for health and non-health personnel across the EU through education and training is fundamental. Training activities should focus on augmented surveillance and preparedness monitoring, pursuing cost-effective policies, improving biopharmaceutical development and production, developing and using advanced tools for horizon scanning, and studying emerging health threats. Through the Erasmus+ programme, for example, knowledge, skills, and experiences can be exchanged, thereby harmonising and enriching the way preparedness strategies are developed and applied. European universities and research institutions have much to offer through programmes of strategically important research, platforms for specialised technical knowledge, and additional know-how on risk and mitigation strategies, as well as education and training opportunities for future experts (eg, in biomanufacturing capacities). Multidisciplinarity, interdisciplinarity, and transdisciplinarity will be vital to solve complex public health emergencies of the future. Finally, the bundled approach cannot be accomplished without two additional cross-cutting elements: promoting research and innovation for a preparedness agenda; and fostering international partnerships with non-EU countries, including low-income and middle-income countries, and stakeholders who are critical for timely communication and containment of global threats. These partnerships require a new vision for a well structured bilateral and multilateral cooperation with all regions worldwide, starting with a closer engagement with WHO as a global supranational moderator. This approach will be equally attractive to partners outside the EU, as health threats might originate inside the EU and spread beyond its borders. By bundling together these five components and the two cross-cutting elements, HERA can become a lighthouse in the EU and worldwide, equipping each member state for timely and effective response to emerging threats. This goal, however, cannot be achieved without a modern and sustainable global health approach that promotes a more just and equitable preparedness system. If, through HERA, the EU successfully implements an exemplary preparedness framework, the global community would enjoy efficient tools and a balanced architecture to boldly respond to future pandemics and emergencies. For League of European Research Universities see www.leru.org For Global Health Research Institutes Network see www.eghrin.eu The authors received no specific funding for this Correspondence. RvL is a member of the Biotech companies in Europe combating AntiMicrobial Resistance Alliance. TB reports grants from Horizon 2020, EIT Health, German Research Foundation, US National Institutes of Health, German Ministry of Education and Research, Alexander von Humboldt Foundation, Else-Kröner-Fresenius-Foundation, Wellcome Trust, Bill & Melinda Gates Foundation, KfW, UNAIDS, and WHO. All other authors declare no competing interests. FC, AP, and MR contributed equally. ==== Refs References 1 European Commission Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions. Building a European Health Union: reinforcing the EU's resilience for cross-border health threats https://ec.europa.eu/commission/presscorner/detail/en/ip_20_2041 Nov 11, 2020 2 WHO Global leaders unite in urgent call for international pandemic treaty https://www.who.int/news/item/30-03-2021-global-leaders-unite-in-urgent-call-for-international-pandemic-treaty March 30, 2021 3 Villa S Lombardi A Mangioni D The COVID-19 pandemic preparedness… or lack thereof: from China to Italy Global Health Med 2 2020 73 77 4 Sheath DJ de Castañeda RR Bempong N-E Precision global health: a roadmap for augmented action J Public Health Emerg 4 2020 1 12

34015340

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2022-12-16 23:25:24

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Lancet. 2021 May 18 5-11 June; 397(10290):2145-2147

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Lancet

10.1016/S0140-6736(21)01107-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(20)32383-7 10.1016/S0140-6736(20)32383-7 Correspondence Universal health coverage for the poorest billion: justice and equity considerations Amri Michelle M ab a Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 1P8, Canada b Takemi Program in International Health, Harvard University, Boston, MA, USA 4 2 2021 6-12 February 2021 4 2 2021 397 10273 472473 © 2020 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcGene Bukhman and colleagues' work in The Lancet NCDI Poverty Commission is certainly important, particularly for the “world's poorest people”.1 However, how the non-communicable disease and injury (NCDI) Poverty Network seeks to apply the Commission's work on NCDI poverty2 has room for additional consideration around justice and equity. My own and others' research show that many existing approaches to health equity are ambiguous and contradictory. For example, in striving for health equity through adopting the Commission's recommendations, will the NCDI Poverty Network seek to measure inequalities across individuals or groups? The Commission called for data on socioeconomic status to be collected. Although these data allow for comparisons across individuals within countries, cross-group inequities might be missed without comparisons across groups. Similarly, will interventions strive to attain a baseline level of health (largely among the poorest billion), or will this be in addition to reducing societal inequalities? These types of considerations should be at the forefront of the work of the NCDI Poverty Network and countries where national-level NCDI Poverty Commissions have been established. Furthermore, consideration should be afforded to the various capabilities of individuals,3 and to individual choice and agency. Simply stated, not all individuals provided with the same resources will have the same outcomes, because it depends on individuals' own capabilities. Evidently, this approach is highly applicable to work around justice and equity, and yields considerations for the NCDI Poverty Network. In addressing the burden of NCDIs, specific considerations for Amartya Sen's question “equality of what?”4 will lead to more deliberate action. I declare no competing interests. ==== Refs References 1 Bukhman G Mocumbi AO Atun R The Lancet NCDI Poverty Commission: bridging a gap in universal health coverage for the poorest billion Lancet 396 2020 991 1044 32941823 2 Zuccala E Horton R Reframing the NCD agenda: a matter of justice and equity Lancet 396 2020 939 940 32941826 3 Sen A Development as freedom 2000 Anchor Books New York, NY 4 Sen A Inequality reexamined 1995 Harvard University Press Cambridge, MA

33549188

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2022-12-16 23:25:24

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Lancet. 2021 Feb 4 6-12 February; 397(10273):472-473

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Lancet

10.1016/S0140-6736(20)32383-7

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(20)32382-5 10.1016/S0140-6736(20)32382-5 Correspondence Universal health coverage for the poorest billion: justice and equity considerations Jarvis Jordan D a Townsend Belinda b a Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK b Menzies Centre for Health Governance, School of Regulation and Global Governance, Australian National University, Canberra, ACT, Australia 4 2 2021 6-12 February 2021 4 2 2021 397 10273 473474 © 2020 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe Lancet NCDI Poverty Commission report by Gene Bukhman and colleagues makes a compelling case that the needs of people affected by non-communicable disease and injury (NCDI), and poverty have been largely neglected.1 The Commission report lays out crucial evidence and health sector interventions, and calls for increased solidarity and development assistance to redress these health inequities. However, what will it take to convince global actors and national governments to act on this issue? We believe that the call for solidarity offers an opportunity to also tackle the underlying structural determinants that cause and perpetuate poverty. These structural determinants facilitate the neoliberal world order, including international corporate tax avoidance, the accumulation of extreme wealth, and macroeconomic policy making that reduces government revenue and shrinks policy space. In 2013, international tax avoidance in low-income countries resulted in government revenue losses that exceeded domestic public health expenditures.2 Oxfam reported that numerous multinational pharmaceutical companies appeared to dodge US$112 million per tax year across seven low-income and middle-income countries—an amount that would have paid for the human papillomavirus vaccine for 10 million adolescents.3 Approaches to curtail corporate tax avoidance could generate income to spend on universal health coverage.2 Global inequality has worsened during the COVID-19 pandemic, while billionaires have increased their wealth.4 One of these billionaires is Bill Gates, whose foundation has used its outsized power to dictate global health and development priorities.5 Although the role of power is not explicitly mentioned in the Commission report, implicitly, it offers insight on how institutions, epistemic communities, and high-income countries have exercised their power to shape global health policy. All the while, countries and individuals most affected have had little influence on setting priorities. NCDI advocates can show solidarity with social movements like the People's Health Movement, which works towards a more equitable distribution of wealth, power, resources, and fair and inclusive decision making processes. Although we agree with Elizabeth Zuccala and Richard Horton6 that non-communicable diseases should be reframed as a matter of justice and equity, these frames and the people most affected are currently silenced in the dominant context of neoliberal ideology. For example, outside of the health system, governments are guided by neoliberal thinking in signing trade agreements that have constrained regulatory space and reduced government revenue from tariffs, especially impactful for low-income countries. What is needed is not just reframing but a collective reimagining of a new global political economy that prioritises justice and equity first and foremost. © 2021 Brazil Photos/Getty Images 2021 We declare no competing interests. ==== Refs References 1 Bukhman G Mocumbi AO Atun R The Lancet NCDI Poverty Commission: bridging a gap in universal health coverage for the poorest billion Lancet 396 2020 991 1044 32941823 2 O'Hare BA International corporate tax avoidance and domestic government health expenditure Bull World Health Organ 97 2019 746 753 31673190 3 Fried M Prescription for poverty. Drug companies as tax dodgers, price gougers, and influence peddlers https://www.oxfam.org/en/research/prescription-poverty Sept 17, 2018 4 Ahmed N COVID-19 has let the virus of inequality run rampant https://www.weforum.org/agenda/2020/07/covid19-inequality-billionaires-oxfam/ July 14, 2020 5 Birn AE Philanthrocapitalism, past and present: The Rockefeller Foundation, the Gates Foundation, and the setting(s) of the international/global health agenda Hypothesis 12 2014 e8 6 Zuccala E Horton R Reframing the NCD agenda: a matter of justice and equity Lancet 396 2020 939 940 32941826

33549189

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2022-12-16 23:25:24

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Lancet. 2021 Feb 4 6-12 February; 397(10273):473-474

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Lancet

10.1016/S0140-6736(20)32382-5

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==== Front Lancet Lancet Lancet (London, England) 0140-6736 1474-547X Elsevier Ltd. S0140-6736(21)00945-4 10.1016/S0140-6736(21)00945-4 Correspondence Inclusion and diversity in the PRINCIPLE trial Patel Mahendra G ab Dorward Jienchi ac Yu Ly-Mee a Hobbs FD Richard a Butler Christopher C a on behalf of the PRINCIPLE Trial Collaborative Group a Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK b School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK c Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu–Natal, Durban, South Africa 10 6 2021 12-18 June 2021 10 6 2021 397 10291 22512252 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcWe welcome the call from Paramjit Gill and colleagues1 for diverse participation in clinical trials like PRINCIPLE.2We initiated many inclusive recruitment strategies, including the appointment of a leading and national pharmacist expert working with minority ethnic communities who was tasked with targeting socioeconomically deprived areas, minority ethnic communities, and people with learning difficulties; developing UK-wide relationships with community and religious organisations (including places of worship); collaborating with universities and national and regional health-care institutions; and gathering nationwide support from minority ethnic leaders, health professionals, and their organisations (appendix). We consistently promoted the trial in many languages, via local and UK national media channels, the internet, and social media platforms. Our pharmacy networks and general practice networks helped establish PRINCIPLE footprints in approximately 7500 community pharmacies UK-wide, with more than 1000 general practice co-investigators helping with participant recruitment from a range of settings. This strategy contributed to the inclusion of 55 (4·0%) South Asian and seven (0·5%) Black participants in our analysis of azithromycin for treatment of suspected COVID-19,2 which was comparable to 3·7% Asian ethnicity and 1·6% Black ethnicity among people older than 50 years (PRINCIPLE's target age group) in England and Wales.3 The proportions of participants' in Index of Multiple Deprivation (IMD) quintiles were (from most to least socioeconomically deprived): 352 (26%) of 1375 in IMD1; 267 (19%) of 1375 in IMD2; 270 (20%) of 1375 in IMD3; 241 (18%) of 1375 in IMD4, and 245 (17%) of 1375 in IMD5. Overall, this shows good recruitment from socioeconomically deprived and minority ethnic communities. PRINCIPLE's innovative approach now supports the recruitment of minority ethnic participants to other UK national trials. We recognise that our initial outreach strategy requires further and targeted investment, initiatives, collaboration, and institutional support to enable sustainable engagement of people from minority ethnic communities in primary care research, ultimately for inclusive, equitable health for all. © 2021 Adaniel Leal-Olivas/Getty Images 2021 We declare no competing interests. FDRH and CCB are joint corresponding authors. Supplementary Material Supplementary appendix ==== Refs References 1 Gill PS Poduval S Thakur JS Iqbal R COVID-19, community trials, and inclusion Lancet 397 2021 1036 1037 33743853 2 PRINCIPLE Trial Collaborative Group Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial Lancet 397 2021 1063 1074 33676597 3 Office of National Statistics UK population by ethnicity: England and Wales 2011 Census https://www.ethnicity-facts-figures.service.gov.uk/uk-population-by-ethnicity/demographics/age-groups/latest#average-age-by-ethnicity 2018

34119064

PMC9752781

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2022-12-16 23:25:24

no

Lancet. 2021 Jun 10 12-18 June; 397(10291):2251-2252

utf-8

Lancet

10.1016/S0140-6736(21)00945-4

oa_other

==== Front Sci Total Environ Sci Total Environ The Science of the Total Environment 0048-9697 1879-1026 Elsevier B.V. S0048-9697(21)05694-1 10.1016/j.scitotenv.2021.150616 150616 Article Recovery of microbiological quality of long-term stagnant tap water in university buildings during the COVID-19 pandemic Ye Chengsong a Xian Xuanxuan a Bao Ruihan a Zhang Yiting ab Feng Mingbao a Lin Wenfang b Yu Xin a⁎ a College of the Environment & Ecology, Xiamen University, Xiamen 361102, PR China b Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China ⁎ Corresponding author. 27 9 2021 1 2 2022 27 9 2021 806 150616150616 1 9 2021 19 9 2021 22 9 2021 © 2021 Elsevier B.V. All rights reserved. 2021 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Stagnant water can cause water quality deterioration and, in particular, microbiological contaminations, posing potential health risks to occupants. University buildings were unoccupied with little water usage during the COVID-19 pandemic. It's an opportunity to study microbiological quality of long-term stagnant water (LTSW) in university buildings. The tap water samples were collected for three months from four types of campus buildings to monitor water quality and microbial risks after long-term stagnation. Specifically, the residual chlorine, turbidity, and iron/zinc were disqualified, and the heterotrophic plate counts (HPC) exceeded the Chinese national standard above 100 times. It took 4-54 days for these parameters to recover to the routine levels. Six species of pathogens were detected with high frequency and levels (101-105 copies/100 mL). Remarkably, L. pneumophilia occurred in 91% of samples with turbidity > 1 NTU. The absence of the culturable cells for these bacteria possibly implied their occurrence in a viable but non-culturable (VBNC) status. The bacterial community of the stagnant tap water differed significantly and reached a steady state in more than 50 days. Furthermore, a high concentration of endotoxin (>10 EU/mL) was found in LTSW, which was in accordance with the high proportion of dead bacteria. The results suggested that the increased microbiological risks require more attention and the countermeasures before the building reopens should be taken. Graphical abstract Unlabelled Image Keywords University buildings Long-term stagnation water Pathogens Viable but non-culturable state Endotoxin Editor: Ouyang Wei ==== Body pmc1 Introduction The stagnation of tap water is usually a problem of individual and occasional cases in residential community buildings. However, it may be recurrent incidents in public buildings like university buildings because of the periodical reduction of water consumption during winter and summer vacations, which can last for one to three months. All of these phenomena cannot compare to the situation during the COVID-19 pandemic. Hundreds of millions of university students and faculty members all over the world were absent from campus for several months. For instance, all of the campus in China was unoccupied from December 2019, and the universities did not reopen until May or September 2020. Stagnation has been associated with the deterioration of water quality at the distribution system level with the ubiquitous presence of harmful chemicals (Arnold and Edwards, 2012; Dias et al., 2017) or pathogens (Rhoads et al., 2016; Salehi et al., 2020). It is quite worthy to find out what impact the tap water stagnation with such a long time and large scale has brought to tap water quality, especially to microbiological quality, which is essential for water safety. A significant decline in the physicochemical and aesthetic quality of drinking water would occur if the tap water stagnates in the distribution pipelines (Caitlin et al., 2020; Salehi et al., 2020). In the absence of fresh tap water supplements, the chlorine residue in water decayed rapidly from 2.0 mg/L to 0.5 mg/L in 2 days, to 0 mg/L in 5 days (Ling et al., 2018). Moreover, the disinfectant residue was found to decay >140 times faster than in corresponding municipal water at highly stagnant taps (Rhoads et al., 2016). The dissolved oxygen (DO) in the water will also go down (Caitlin et al., 2020). Both of them cause water to shift from the oxidizing to reducing environment, which would lead to the breakage and detachment of pipe wall scaling and dissolving of heavy metals from the pipe materials as well as the long-term immersion works. Zhang et al. (2020) found that the turbidity of tap water could increase from 0.3 to 1.7 NTU in 48 h stagnation. The same stagnation duration could result in a Cu increase from below detected to 1370 and 1680 μg/L in kitchen and bathroom tap water, respectively (Zlatanovic et al., 2017). The increases of heavy metals including Fe, Mn, Cu, Ni, Cd were also observed in unlined cast pipe scales in a longer period of stagnation (132 h) in Zhengzhou, China (Li et al., 2020). Microbial growth during water stagnation is well documented (Lautenschlager et al., 2010; Ling et al., 2018). For example, Chen et al. (2020) showed that the colony of total bacteria increased to >500 CFU/mL after short stagnation in water purifiers. Moreover, the stagnation was highly related to the occurrence of waterborne pathogenic microorganisms (Schwake et al., 2016; Kinsey et al., 2017). Several studies have identified the growth of Legionella, Mycobacterium avium, Pseudomonas aeruginosa during stagnation, although the curve may plateau (Bédard et al., 2016; Cooper et al., 2008; Haig et al., 2018). For example, in a hospital water pipe network with a retention time of 3-6 days, a high level of Legionella co-occurred with the high pipe scale debris detachment and low residual chlorine (Schwake et al., 2016), which matched well with the occurrence of Legionnaires disease. However, all of the above-mentioned studies mainly focused on the analysis of water quality variation during short-term stagnation with a duration from several hours to several days (Zhang et al., 2020; Zlatanovic et al., 2017), which was not comparable with the stagnation during the current COVID-19 outbreak. Unfortunately, very limited information is available regarding this long-term stagnation on the tap water quality, especially on the microbiological parameters. In this study, a field study was performed in University buildings located in a southeast city in China to elucidate the potential microbial risks and recovery periods of LTSW-induced contamination. Stagnation water samples were collected for three months (May to August 2020) from four types of college buildings, i.e., laboratory, canteen, teaching building, and dormitory buildings, after nearly four months of stagnation (middle January to May 2020). The samples were analyzed based on the physicochemical parameters, HPC, Taqman-based qPCR, flow cytometry (FCM), endotoxin analysis, and high-throughput sequencing. This study aims to address the knowledge gap of LTSW-induced microbial risks and provide useful advice on the safety control of drinking water. 2 Materials and methods 2.1 Sampling sites and water consumption The studied facilities were three universities and one residential community in a city in Fujian province, Southeastern China. The campus water supply usages include everyday life (except cooking), cooking in the canteen, teaching, and lab work, etc. The detailed information of sampling site locations including frequency and water usage is shown in Table 1 . All water samples were taken from the end of the water supply (tap water from the sink). University A was the main sampling site, of which the information is shown in Fig. 1 . For university A, the winter vacation began in January 2020. Then, the sampling areas had seldom used tap water until graduate students returned to school in May because of the unexpected COVID-19 pandemic. In May 2020, the first month of sampling, the research and teaching activities were far from the normal levels since only a small part of students (about 1/12) returned to the campus (Fig. S1). The water consumption in the laboratory and teaching building of University A was almost zero. With the increased numbers of students returning to campus, the water supply was gradually restored to normal in August 2020. As additional sampling sites for both endotoxin and Legionella pneumophila indicators, the sinks of Universities B and C did not open during the sampling period. Their campus was closed for students and only opens for faculty and staff. By contrast, the residential community is located near University B, and the water supply in the community had not been interrupted and normal water consumption was maintained.Table 1 Description of sampling site locations including frequency and water usage. Water usage was based on system operator's observations and knowledge of building operations. Table 1Sampling site Description Size Sampling frequency Usage 1 University A, laboratory, sink, 13,000 students 2600 faculty members Two times per week then reduced to weekly Low-frequency usage building 2 University A, canteen, sink, 2nd floor Two times per week then reduced to weekly Low-frequency usage building 3 University A, teaching building, washroom sink, 2nd floor Two times per week then reduced to weekly Low-frequency usage building 4 University A, dormitory, sink, Two times per week then reduced to weekly Low-frequency usage building 5 University A, dormitory, sink, Once Low-frequency usage building 6 Community near university B, sink 1027 families Monthly, two times Continuously water consumption building 7 University B, teaching building, washroom sink, 1nd floor 15,000 students 2590 faculty members Monthly, two times Long stagnation building 8 University B, dormitory, sink, 1nd floor Monthly, two times Long stagnation building 9 University C, laboratory, washroom sink, 1nd floor 20,000 students 1100 faculty members Monthly, three times Long stagnation building 10 University C, teaching building, washroom sink, 1nd floor Monthly, three times Long stagnation building 11 University C, dormitory, sink, 1nd floor Monthly, three times Long stagnation building Fig. 1 Photographs of (a) sampling site information of the university A, (b) laboratory sampling site taps, (c) canteen sampling site taps, (d) teach building sampling site taps, and (e) dormitory sampling site taps. Fig. 1 2.2 Water sampling The study was mainly carried out in University A, and stagnation water sampling was performed over three months between May 2020 and August 2020. The water samples were taken in four types of public buildings in the university (Fig. 1). Besides, water samples were taken from University B, C and a residential community near University B, along with University A to determine endotoxin and L. pneumophila for the hazard assessment of long-term water retention. The residential community could be regarded as a negative control since its water supply was uninterrupted (Table 1). All stagnant water samples were collected from the tap at the sink. The water containers and tools were sterilized before sampling to eliminate the possible interference of bacterial contamination. Before sampling, the tap water will be flushed for 3 min. 10 L of tap water was collected at each sampling point, and the samples were transferred to the laboratory within 6 h (Guo et al., 2020). 2.3 Measurements of the physicochemical parameters of water samples The chlorine residue, DO, oxidation-reduction potential (ORP), turbidity, temperature, and pH were determined in the field. The residual chlorine was measured using the N,N-diethyl-p-phenylenediamine (DPD) chlorine analyzer (HACH, USA). All other parameters were determined in situ by a multi-parameter water quality analyzer (HACH, USA). The water samples were firstly filtered using a 0.45 μm polyethersulfone (PES) membrane (Millipore, USA) to remove the particles. Heavy metals were analyzed with inductively coupled plasma mass spectrometry (ICP-MS) (Agilent Technologies Inc. USA) after acidizing the water samples with nitric acid (5 mL/L) to pH < 2 (Sigma, USA). The total organic carbon (TOC) was detected by the TOC analyzer (Shimadzu, Japan). The nutrients, including the total dissolved nitrogen (TDN), total dissolved phosphorus (TDP), NO2 -, NO3 -, and NH4 +, were determined by automatic nutrients analyzer AA3 (San++ analyzer, Germany). Specifically, TDN and TDP were oxidized by 4% alkaline potassium persulfate before analysis. The concentrations of the above parameters were calculated according to the pre-conFig.d standard curves. 2.4 Microbial counting 1 mL of water samples was applied on nutrient agar (NA) (Hopebio, China) at 37 °C for 48 h to enumerate the total bacteria. The selective media for screening frequently-occurred pathogens was used to count P. aeruginosa (CN agar), E. coli (mTEC agar), Enterococcus faecalis (mEI agar), Shigella sp. (SS agar) (Hopebio, China), Salmonella sp. (BSA agar) (BD, USA) (USEPA, Method 1103.1: 2002, USEPA, Method 1600: 2006; Guo et al., 2020). In detail, the 100 mL water samples were concentrated by 0.45 μm PES membrane (Millipore, USA). Filtration membranes containing enriched bacteria were cultured on selected media. Two parallel groups were set for each sample. The specific preparation method and corresponding pathogen culture conditions are shown in Text S1. Concerning endotoxin, its concentration was determined using an Endotoxin test Limulus Kit (Bioendo Technology Co., Ltd., China) following the manufacturer's instructions. The ratio of dead and alive bacterial cells was determined using FCM (Millipore Guava EasyCyte, USA) and LIVE/DEAD BacLight bacterial viability kit (Invitrogen, Inc. USA) according to Lin et al. (2017). SYTO 9 and propidium iodide (PI) were added into water samples with a final concentration of 2 μM and 20 μM, respectively. 5000 cells for each sample were counted after being stained for 20 min in the dark under 488 nm of light irradiation at room temperature. 2.5 Taqman probe-based qPCR The water samples for qPCR and Illumina sequencing were concentrated by 0.22 μm PES membrane (Millipore, USA) and stored at -20 °C prior to DNA extraction. The genomic DNA was extracted using the FastDNA SPIN Kit (MP Biomedicals, USA) following the manufacturer's instructions. The Taqman-based probe was selected and designed (Table S1). Six representative waterborne pathogens (i.e., E. faecalis, P. aeruginosa, E. coli, Salmonella sp., L. pneumophila, Shigella sp.) were determined. The qPCR system with a final volume of 20 μL contained 10 μL of 2 × Taqman™ Gene Expression Master Mix (Thermo Fisher Scientific, USA), 0.05 μL of the probe (10 μM) (Sangon Biotech, China), 0.8 μL of each primer (10 μM), 2 μL of template DNA, and 6.35 μL of DNA-free water. The qPCR program consisted of a pro-denaturation step for 60 s at 95 °C, followed by 40 cycles of a denaturation step for 15 s at 95 °C, and an annealing step for 60 s at 60 °C using the ABI Q6 system (Life Technology, Singapore). Each target gene was run in triplicates. The standard curves were constructed from 10-fold serial dilutions of the plasmid standards that carry the target genes (Table S1). By comparison, the negative control used DNA-free water as the DNA template. 2.6 High-throughput sequencing (HTS) The sequencing analysis of water samples was performed on the Illumina NovaSeq platform (Illumina, USA). Briefly, quality controlled genomic DNA (1 ng/μL) was amplified with the bacteria-specific primers (338 F/806 R) containing a barcode. The PCR products were detected by electrophoresis with 2% agarose gel and recovered using the gel recovery Kit (Qiagen, Germany). TruSeq® DNA PCR-Free Sample Preparation Kit (Illumina, USA) was used to construct the library. After the library was qualified, NovaSeq6000 was used for sequencing (Novogene Science and Technology Co., Ltd., China). 2.7 Data analysis The data were plotted in Prism 8.0 and processed with R studio, SPSS 16.0, and Prism 8.0. Uparse v7.0.1001 (http://www.drive5.com/uparse/) was adopted for OTU clustering. Mothur was used for species annotation according to the SSUrRNA database (http://www.arb-silva.de/), and BugBase was used for functional annotation. Continuous sampling was selected to characterize the repetition and stability of the data and reduce the experimental error. 3 Results and discussion 3.1 Increased Zn and Fe of stagnant water samples In this study, eighteen physicochemical water quality parameters of the samples in University A were regularly measured, all of which could meet the tap water quality standard except the ones in Fig. 2 . As seen, the long-time water retention resulted in the deterioration of two metals (Zn and Fe), residual chlorine, and turbidity. The other measured physicochemical parameters of stagnant water samples were summarized and are illustrated in Table S2. Long-term water retention did not have a significant impact on these indicators.Fig. 2 The unqualified physicochemical parameters of different types of water samples collected during the stagnation. (a) Zinc, (b) iron, (c) residual chlorine, and (d) turbidity. Point “0” on the abscissa represents the starting point of the four-month water retention. The ordinate value of the dotted line is the national standard limit value. Fig. 2 After long-time stagnation, the leaching of both zinc (Zn2+) and iron (Fe2+/Fe3+) occurred in the plumbing system (Fig. 2). On the first day of the restarted water consumption, all of the samples suffered from the highest zinc and iron levels. The concentrations of zinc reached 7716.0, 6378.0, and 3082.0 μg/L in the samples from the laboratory, teaching building, and dormitory, respectively, which dramatically exceeded the Chinese national standard (i.e., 1000 μg/L). Similarly, the corresponding levels of iron were 1620.8, 700.4, and 716.9 μg/L, respectively, which were higher than the national standards of 300 μg/L. As the water usage got back to routine, the concentrations of zinc dropped rapidly and below the national standard within a week. Comparatively, the iron was restored even more quickly in three days. Compared with the other buildings, the concentrations of zinc and iron from canteen samples were lower than the national standard all the time, which may be attributed to the higher frequency and amount of water usage. Cast iron and galvanized steel are widely used in the stem pipes in water distribution systems. It should be the main reason that the concentrations of zinc and iron in the stagnant water were elevated. Besides the debris detachment due to the long-term immersion, previous studies have confirmed that the metal ions could leak from the corrosion layer through the electrochemical reactions (Clark et al., 2015; Lasheen et al., 2008; Li et al., 2020). However, the iron and zinc concentrations in our study were much higher than those reported in Li et al. (2020) for metal release in 132 h of stagnation pipes (Fe: 190-260 μg/L, Zn: 1-10 μg/L), which might be attributed to that long retention time during the pandemic enhanced the corrosion and aquatic chemistry process. In addition, even the zinc and iron concentrations in the tap water could go down to the routine levels shortly in several days, special attention should be paid that the long water stagnation would probably have created corrosion “hot spots” in the pipe walls, which could pose long-term adverse impacts (Masters et al., 2015). 3.2 Decayed chlorine residue and increased turbidity of stagnant water samples The qualified drinking water should contain residual chlorine to suppress bacterial regrowth. Because of the chlorine decay, the stagnant water contained much lower chlorine levels than the fresh one. In the first week of the water re-consumption, the residual chlorine in all samples was below 0.05 mg/L, except for the canteen water samples (i.e., 0.05-0.11 mg/L) (Fig. 2(c)). While the retained water was subsequently consumed, more and more freshwater was supplemented into the water supply system. The residual chlorine concentrations gradually increased to the standard requirement (0.05 mg/L) in a period from 10 days to 48 days (the laboratory samples). According to the data issued by the local administration in December 2019 (before the COVID-19 pandemic) (Water Quality Bulletin, 2019), the level of residual chlorine in pipes of this area was 0.48 mg/L that was much higher. Residual chlorine has been well recognized as the most important factor for microbial inhibition (Caitlin et al., 2020; Zhang et al., 2020). The low level of residual chlorine in the pipe network is certainly a concerning safety hazard. In this study, the recovery duration of residual chlorine (especially laboratory water samples) was dramatically longer than the short period of water retention (Zhang et al., 2019, Zhang et al., 2020), which suggested the occurrence of a much longer microbiological risk. Except for the laboratory samples, the long-term water retention appears to exert much fewer effects on turbidity (Fig. 2(d)). The average turbidity of the dormitory, teaching building, and canteen was 0.30 NTU, 0.20 NTU, and 0.23 NTU, respectively, similar to those (<0.5 NTU) before the pandemic in this area. However, the maximum turbidity of the laboratory samples was 4.94 NTU, which exceeded the standard concentration (1 NTU) by nearly four times. It took 24 days to get back to the normal level. The water quality with high turbidity could probably provide suitable conditions for microbial attachment and biofilm formation (Schwake et al., 2016). In fact, this study also found that the high turbidity was accompanied by the detection of L. pneumophilia, which was discussed in detail in Section 3.5. 3.3 Significant increase in culturable bacteria The influence of tap water supply recovery on the total culturable bacteria is reported in Fig. 3 . It was observed that water retention would result in increased HPC values, which was consistent with the findings of previous studies (Pepper et al., 2004). However, compared with short-term stagnation (Chen et al., 2020), much more culturable bacteria were detected in this work due to the much longer retention. According to the issued data by the local administration, the HPCs were usually zero CFU/mL. But the measured bacteria in all four types of samples exceeded the Chinese national standard (100 CFU/mL). Because the scientific research activities were at a standstill during the epidemic, the laboratory samples had the most serious bacterial contamination with significantly higher HPC concentrations of up to 1.5 × 104 CFU/mL, two more magnitude orders than the standard. The recovery period for laboratory tap water was the longest. The HPC took about eight weeks to fall to the routine levels (no detection). Concerning three other sampling sites, the water usage was a little higher due to the daily life of the small number of persons on the campus. All of them fluctuated sharply during the first sampling month with several samples exceeding the standards, respectively. They merely differed from the laboratory samples in the much shorter recovery durations of 4-5 weeks.Fig. 3 HPC and residual chlorine levels during stagnation. The black arrow indicates that the number of culturable bacteria would not drop to 0 CFU/mL immediately after the increase of residual chlorine (>0.5 mg/L). The dotted line is the time point when the number of culturable bacteria drops to 0 CFU/mL. There was a lag relationship between culturable bacteria and residual chlorine. Fig. 3 Microbial growth depends on different environmental factors, such as temperature, disinfectant residue, nutrients, and pipe network material, etc. The correlations between the HPC concentration and residual chlorine was thus analyzed by using Spearman, in which a significant correlation (P < 0.05) was found between HPC and residual chlorine in the laboratory samples (Fig. 3). This phenomenon was also documented in a recent study on the HPC growth in the drinking water system (Lin et al., 2020). It was interesting that the HPC value always dropped to zero CFU/mL after one week when the residual chlorine level reached up to the national standard (0.05 mg/L) (see the black arrows in Fig. 3). Since the residue chlorine is easier and real-time to be detected, this time lag might be used as an indicator ahead of time for the microbiological safety of the tap water with a long stagnation. 3.4 Safety risks of pathogenic microorganisms After long-time retention, the structures of the bacterial community in four different sampling sites were significantly different. The Principal Co-ordinates Analysis (PCoA) analysis showed that at the beginning of this study, four kinds of tap water samples were distributed in four different quadrants (Fig. S2), that is, their distribution was very dispersed. However, when the water supply resumed for about two months, microbial communities of the laboratory, canteen, and dormitory became uniformed. Among them, the community structure of canteen samples did not change significantly, which may be related to the constant tap water usage during the pandemic period. On the contrary, the teaching work always adopted the online mode, and only a small amount of flushing water was consumed, which might lead to the unstable results of microbial communities. This phenomenon suggested that the biological stability was gradually recovered in the tap water along with the water supply resumption. Besides the total bacteria, the absolute abundance of six typical waterborne pathogens in the retained water samples was determined in this study since they were directly related to human health (Fig. 4 ). To obtain the occurrence of pathogenic bacteria more accurately, the Taqman-based qPCR method with higher sensitivity and specificity was adopted. Based on the standard curves (Table S1), the minimum detection limits (MDLs) of all pathogens were about 10 copies/mL, except for Shigella sp. and L. pneumophila whose MDLs were 10-100 copies/mL. As presented in Fig. 4, all pathogens were detected. The pathogen with the highest detection level (1.95 × 105 copies/100 mL) was from L. pneumophila in the laboratory samples. Comparatively, the highest levels for Salmonella spp., Shigella sp., E. coli, and P. aeruginosa were 1.70, 7.08, 7.24, 1.62 × 103 copies/100 mL, respectively. The recovery for these pathogenic microorganisms, i.e., below their MDL values, was about 2-5 weeks except for L. pneumophila. The absolute abundance of pathogens in different water samples was also higher when water quality parameters deteriorate. Guo et al. (2020) found that the levels of these pathogenic bacteria in the effluent of full-scale drinking water treatment plants (DWTP) remained at 0-102 copies/100 mL. The relatively high detection levels and long recovery period suggested that the health risks from the pathogenic bacteria in the retained water were much higher and should receive more attention.Fig. 4 The absolute abundance of typical pathogens by using Taqman-qPCR. (a) L. pneumophilia, (b) Salmonella spp., (c) Shigella sp., (d) E. coli, (e) P. aeruginosa, and (f) E. faecalis. Unit: log10 copies/100 mL. Fig. 4 3.5 Detection of L. pneumophila and its relationship with residual chlorine and turbidity It is noteworthy to mention that L. pneumophila was continuously detected at high levels within three months during the recovery period of tap water supply in the laboratory samples (Fig. 4). Garrison et al. (2016) concluded that L. pneumophila was one of the most established causes of potable water-related disease outbreaks in the building plumbing systems. The outbreak of L. pneumophila was mainly connected with residual chlorine decay, iron release, and water stagnation. In fact, the decay of chlorine, which is the specific agent to inhibit microbial growth, was somewhat the result of the latter and could be accelerated by the latter (Lautenschlager et al., 2010; Ling et al., 2018). Likewise, Beer et al. (2015) and Shah et al. (2018) identified that depletion of residual disinfectant was the reason for Legionnaires disease outbreaks in public buildings. The above results suggested that chlorine maintenance should play a key role in the control of L. pneumophila in the stagnant water and its recovery. For example, shock disinfection within three weeks of planned occupancy was recommended for controlling remediation of Legionella colonization in the USA (ASHRAE Standards Committee, 2018). In addition, it is of great significance to make early warning of Legionella in the LTSW environment. A co-occurring phenomenon was found for the detection of L. pneumophila and the initial turbidity of LTSW samples in this study. In particular, L. pneumophila was detected in 91% of the water samples with high turbidity (>1 NTU) (Fig. 5 ). L. pneumophila preferred to live in biofilm or other microbial aggregates in pipe walls or other media surfaces (Garrison et al., 2016; Proctor et al., 2018). In stagnant water, the mild hydraulic conditions and quick chlorine decay would accelerate biofilm formation. High turbidity implied higher numbers of particular matters such as the scaling debris, which was advantageous for biofilm formation. So the high turbidity might be used as an indicator of early warning of L. pneumophila.Fig. 5 The abundance of L. pneumophila at different levels of turbidity. Data were collected from the samples taken in the first month of University A, and samples from University B and C. Percentage indicated the detection rate of L. pneumophila under specific water quality conditions. For example, 91% means that under the condition of turbidity greater than 1 NTU, the detection rate of L. pneumophila is 91% in water samples. Fig. 5 3.6 VBNC bacteria in the stagnant water In this study, the bacterial colonies with different morphology and colors were selected on the mediums, and a total of 86 strains were identified (Fig. 6(a)). It could be seen that Sphingomona was the dominant genera, accounting for 54.7% of all bacteria detected, followed by Methylorubrum at 13.3%. In addition, Acinetobacter, Aeromonas, and Pseudomonas were screened. Sphingomona is persistent and widely distributed in poor nutrition environments (e.g., mineral water or tap water) (Koskinen et al., 2000; Lee et al., 2001) and seldom present virulence or pathogenicity to human beings. However, a large amount of the bacterial cells might accumulate endotoxins when they were dead and decomposed, which would be discussed later. Methylorubrum, Pseudomonas, Acinetobacter, and Aeromonas were all reported as chlorine-resistant bacteria (Koskinen et al., 2000; Zhang et al., 2019; Zeng et al., 2020). Zhang et al. (2019) found that, with the increased secretion of extracellular polymers, Methylorubrum can form biofilms and thus resist the disinfectants. Overall, these pathogens were persistent in the LTSW environment, which require more attention. UV-based disinfection methods (e.g., UV/hydrogen peroxide and UV/peroxymonosulfate) were recommended for efficient inactivation of chlorine-resistant bacteria (CRB), therefore inhibiting the formation of biofilms (Zeng et al., 2020).Fig. 6 Bacterial community composition of (a) culturable bacteria, (b) pathogens-HTS, and (c) top 35 genera-HTS of the samples from university A. Values indicate the log10-transformed relative abundance of bacteria in each genus. Fig. 6 In this study, the top 35 genera in bacteria communities analyzed via HTS are listed in Fig. 6(c). Phreatobacter was the dominant genera, and its abundance was ranged from 17% to 81%, followed by Sphingomona with an abundance of 2%-17%. HTS results further confirmed that the proportion of pathogens in the total bacterial community was relatively low. The possible pathogens-HTS results were selected for the composition analysis of the pathogenic microorganisms (Fig. 6(b)). We found that results were much different from that culturable bacteria identification. In addition to the identified pathogenic bacteria in Fig. 6(a), 16S rRNA gene fragments of the E. coli, Helicobacter, Legionella, Mycobacterium, Staphylococcus, Streptomyces, and other suspected pathogens were sequenced by the HTS analysis, while the culturable ones were not detected in the selective medium (Fig. S3). Although the HTS results do not mean the existence of the active microbes, the risks of pathogenic bacteria should not be ignored, especially considering their entrance into the VBNC state. Legionella and Mycobacterium had the highest abundance, reaching 7.2 × 10-4 and 5.2 × 10-3, respectively. These results were consistent with the Taqman-based qPCR method (Fig. 4). Based on the above analysis, VBNC pathogens occurred very likely in the LTSW environment and could evade the HPC detection standards. Similarly, Kinsey et al. (2017) reported that P. aeruginosa outbreak in a neonatal intensive care unit (ICU) was related to water retention in hospitals, which deserves more attention in terms of their potential health risks. Felföldi et al. (2010) observed a higher detection of positive samples for Legionellae using the qPCR technique compared to the cultivation method. Since the culturing methods as HPC are not applicable in detecting VBNC bacteria, the real infectious risks of the LTSW environment might be inaccurately estimated in many cases. 3.7 High-level endotoxin in LTSW Endotoxin, composed of lipopolysaccharides, is a component of the cell wall of gram-negative (G-) bacteria. It is also called “pyrogen”, which could cause fever, microcirculation disorder, endotoxin shock, and disseminated intravascular coagulation, etc. (Anderson et al., 2002; Liao et al., 2010). The endotoxin was mainly released by the G- bacteria after death (Ren et al., 2019; Xue et al., 2019). It could be concluded that the bacterial biomass kept relatively high levels in the stagnant tap water. During the beginning days of this study, the 16s rRNA genes were at log 7-9 copies/L, and most of the cultural bacteria were at log 1-4 CFU/mL. Since the stagnant period was over 4 months, which obviously exceeded the bacterial growth cycles in most natural and artificial circumstances, it could be inferred that the bacterial biomass would be in a pseudo-steady state (Chen et al., 2020), i.e., the dead bacterial cell numbers should be equivalent to the newly-divided cells, during most time of the stagnant. Therefore, another problem for LTSW was the accumulation of endotoxin produced by the in-situ lysis of the bacteria. In this study, the levels of endotoxin in LTSW samples (the initial stage of water supply restoration) were analyzed (Fig. 7 (a)). The results showed that the endotoxin levels were all increased in LTSW compared with the control group (i.e., tap water of always used). t-Test showed that the results were significantly different (P < 0.05), except for the D2 sample. FCM results showed that the proportion of dead bacteria in the LTSW (69.0%-96.7%) was significantly higher than that in the tap water always used (53.4%) (Fig. 7(b)). A greater proportion of bacteria in the retained water samples were in a state of membrane damage or even breakage. This further confirmed that high contents of endotoxin were related to the percentage of dead bacteria. Traditional biological indicators cannot reflect the contamination level of endotoxin. The presence of endotoxin in the LTSW is worthy of attention owing to its environmental persistence and pathogenicity.Fig. 7 (a) Content of endotoxin and (b) the proportion of dead and alive bacteria in different types of stagnant water. Data were collected from samples 6-11 in Table 1. B: blank control, water sample free of endotoxin; C: control (sample 6), the tap water came from the residential area nearly university; L: laboratory (sample 9); T: teaching building (sample 7, 10); D: dormitory (sample 5, 8, 9). “*” indicates a significant difference between the sample and the control group (P < 0.05). Fig. 7 3.8 Prevention of water quality issues during the COVID-19 pandemic The University buildings impacted by COVID-19 had reduced or no water use for months. Our study confirmed that long-term water retention poses serious microbiological risks and thus prevention of water quality issues is essential. First of all, routine flushing is the most direct solution to pathogen control. Freshwater is regularly introduced to the pipeline network, and the stagnant environment cannot be formed, which helps prevent the problems. For the secondary water supply system of university buildings, attention should be paid especially to the cleaning of water tanks. It should be noted that recommissioning flushing could only reduce the levels of coliforms and heavy metals (Caitlin et al., 2020) but opportunistic pathogens can continue to grow (Hozalski et al., 2020), so it must be carried out with routine flushing during the COVID-19 pandemic. However, the frequency of routine flushing is difficult to determine. Factors such as plumbing design, the complexity of components, and the stored volume of water relative to water use need to be considered comprehensively. In the case of Legionella, Totaro et al. (2018) showed that effective control was achieved by maintaining a flushing frequency of 2 h. In addition, it is necessary to clean the water tank again for the university buildings with secondary water supply. It is important to maintain a disinfectant residual. By introducing a high level of disinfection for a short time, shock disinfection could effectively control pathogenic bacteria but must be weighed against the formation of disinfection by-products. Also, the water quality of University buildings should be monitored more frequently. Tap water with unqualified residual chlorine could be used for landscape irrigation, floor washing and other non-drinking purposes. If conditional, an automatic disinfectant device could be added to increase the delivery of disinfectant residual. 4 Conclusions The global outbreak of the COVID-19 has led to the ultra long-term stagnation of tap water in public buildings such as those in university campuses all over the world. It was of common sense that stagnation would result in the overall deterioration of water quality including both the chemical and microbiological aspects. However, the impacts from such an ultra long-term stagnation, i.e. several months, were still unclear. Especially what microbiological risks the stagnation would bring was of great interest due to the increasing concerns from the public under the context of the epidemic. It was expected the conclusions below could answer at least part of the questions.1) Long-term tap water retention resulted in the deterioration of water quality, while heavy metals (e.g., iron and zinc), turbidity, and chlorine were four key physicochemical parameters significantly exceeding the water quality guidelines, among which the latter two were closely connected to the microbial contamination. 2) Significant microbial growth occurred in the stagnant water, and the highest HPC of the samples reached two magnitude orders higher than the standards. It took 1-2 months to recover the bacterial levels to routine levels, which were much longer than the physicochemical parameters. 3) The microbiological risks in the LTSW were further confirmed by ubiquitous occurrence of six pathogenic species, among which L. pneumophilia had the highest detection frequency. However, these pathogens should probably be in the VBNC state due to the absence of the culturable ones. High turbidity (>1 NTU) might be an indicator for L. pneumophilia, suggested by their co-occurrence. 4) Endotoxin was a risk that has been overlooked in previous studies. A higher concentration of endotoxin (>10 EU/mL) in LTSW samples was detected, which resulted from the death of the high contents of the G- bacteria. 5) Routine flushing and shock disinfection were recommended as the possible microbiological risks control methods during the COVID-19 pandemic. CRediT authorship contribution statement Chengsong Ye: Conceptualization, Methodology, Investigation, Software, Writing-original draft. Xuanxuan Xian: Sampling, Methodology, Visualization. Ruihan Bao: Sampling, Methodology. Yiting Zhang: Methodology, Visualization, Software. Mingbao Feng: Conceptualization, Writing-review & editing. Wenfang Lin: Writing-review & editing. Xin Yu: Conceptualization, Writing-review & editing, supervision. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data Supplementary material Image 1 Acknowledgments This research was supported by the 10.13039/501100001809 Natural Science Foundation of China (NSFC) (41861144023, and U2005206), 10.13039/100010166 Xiamen Municipal Bureau of Science and Technology (YDZX20203502000003), the 10.13039/501100003392 Natural Science Foundation of Fujian Province (2020J05090). Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.scitotenv.2021.150616. ==== Refs References Anderson W.B. Slawson R.M. Mayfied C.I. A review of drinking water-associated endotoxin, including potential routes of human exposure Can. J. Microbiol. 48 7 2002 567 587 12224557 Arnold R.B. Edwards M. Potential reversal and the effects of flow pattern on galvanic corrosion of lead Environ. Sci. Technol. 46 2012 10941 10947 22900550 ASHRAE Standards Committee ANSI/ASHRAE standard 188-2018. Legionellosis: risk management for building water systems. 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PMC9752782

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2022-12-16 23:25:24

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Sci Total Environ. 2022 Feb 1; 806:150616

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Sci Total Environ

10.1016/j.scitotenv.2021.150616

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