bluuebunny/crossref_metadata_2025 huggingface dataset:
Parental overproduction allows siblicidal bird to adjust brood size to climate-driven prey variation
Authors: Bizberg-Barraza Iván , Rodríguez Cristina , Drummond Hugh
Published: February 2024

Parental overproduction is hypothesized to hedge against uncertainty over food availability and stochastic death of offspring and to improve brood fitness. Understanding the evolution of overproduction requires quantifying its benefits to parents across a wide range of ecological conditions, which has rarely been done. Using a multiple hypotheses approach and 30 years of data, we evaluated the benefits of overproduction in the Blue-footed booby, a seabird that lays up to three eggs asynchronously, resulting in an aggressive brood hierarchy that facilitates the death of last-hatched chicks under low food abundance. Results support the resource-tracking hypothesis, as low prey abundance (estimated from sea surface temperature and chlorophyll-a concentration) led to rapid brood reduction. The insurance hypothesis was supported in broods of three, where last-hatched chicks’ survival increased after a sibling’s death. Conversely, in broods of two, results suggested that parents abandoned last-hatched chicks following first-hatched chicks’ deaths. No direct evidence supported the facilitation hypothesis: the presence of a last-hatched chick during development did not enhance its sibling’s fitness in the short or long term. The value of last-hatched offspring to parents, as “extra” or “insurance” varied with indices of food abundance, brood size, and parental age. Ninety percent of overproduction benefits came from enabling parents to capitalize on favorable conditions by fledging additional offspring. Our study provides insight into the forces driving overproduction, explaining the adaptiveness of this apparently wasteful behavior and allowing us to better predict how overproduction’s benefits might be modified by ocean warming.
State-of-the-Art Review: Use of Antimicrobials at the End of Life
Authors: Karlin Daniel , Pham Christine , Furukawa Daisuke , Kaur Ishminder , Martin Emily , Kates Olivia , Vijayan Tara
Published: February 2024

Navigating antibiotics at the end of life is a challenge for infectious disease (ID) physicians who remain deeply committed to providing patient-centered care and engaging in shared decision making. ID physicians, who often see patients in both inpatient and outpatient settings and maintain continuity of care for patients with refractory or recurrent infections, are ideally situated to provide guidance that aligns with patients’ goals and values. Complex communication skills, including navigating difficult emotions around end-of-life care, can be used to better direct shared decision making and assist with antibiotic stewardship.
Cefoxitin for Intra-amniotic Infections and Endometritis: A Retrospective Comparison to Traditional Antimicrobial Therapy Regimens Within a Healthcare System
Authors: Bailey Pamela , Schacht Lance , Pazienza Grace , Kohn Joseph , Yunusa Ismaeel , Seal Patricia , Crockett Amy , Justo Julie Ann
Published: February 2024

Background

Local institutional guidelines and order sets were updated in June 2023 to recommend first-line cefoxitin monotherapy for the treatment of intra-amniotic infections (IAIs) and endometritis. This study evaluated the clinical impact of this change.

Methods

This was a retrospective, observational cohort study in an 11-campus health system comparing clinical outcomes of patients with chorioamnionitis, endometritis, or septic abortion receiving intravenous antimicrobial therapy before and after implementation of first-line cefoxitin monotherapy recommendations for the treatment of these infections. Primary outcome was a composite of serious clinical events postdelivery (ie, intensive care unit admission, death, hospital readmission related to IAI or endometritis within 30 days, additional surgery or procedures, or deep surgical site infection). Baseline characteristics between the pre- and post-cefoxitin groups were compared via Student's t tests for continuous variables and chi-square tests for categorical variables. Outcomes were evaluated via generalized linear modeling.

Results

A total of 472 patients were enrolled, 350 (74%) in the pre-cefoxitin group and 122 (26%) in the post-cefoxitin group. Groups were significantly different by race, healthcare payor, and hospital campus. Cefoxitin was rarely used in the pre-cefoxitin group (n = 2, <0.1%) and commonly used in the post-cefoxitin group (n = 112, 91.8%). After controlling for group differences, odds of experiencing serious clinical event postdelivery in the post-cefoxitin group were noninferior to those in the pre-cefoxitin group (adjusted odds ratio, .37; 95% CI, .17–.76; P = .010).

Conclusions

Local institutional guidelines with predominant use of cefoxitin therapy were noninferior to traditional antimicrobial therapy regimens for the treatment of IAI.
Development of Patient Safety Measures to Identify Inappropriate Diagnosis of Common Infections
Authors: White Andrea T , Vaughn Valerie M , Petty Lindsay A , Gandhi Tejal N , Horowitz Jennifer K , Flanders Scott A , Bernstein Steven J , Hofer Timothy P , Ratz David , McLaughlin Elizabeth S , Nielsen Daniel , Czilok Tawny , Minock Jennifer , Gupta Ashwin
Published: February 2024

Background

Inappropriate diagnosis of infections results in antibiotic overuse and may delay diagnosis of underlying conditions. Here we describe the development and characteristics of 2 safety measures of inappropriate diagnosis of urinary tract infection (UTI) and community-acquired pneumonia (CAP), the most common inpatient infections on general medicine services.

Methods

Measures were developed from guidelines and literature and adapted based on data from patients hospitalized with UTI and CAP in 49 Michigan hospitals and feedback from end-users, a technical expert panel (TEP), and a patient focus group. Each measure was assessed for reliability, validity, feasibility, and usability.

Results

Two measures, now endorsed by the National Quality Forum (NQF), were developed. Measure reliability (derived from 24 483 patients) was excellent (0.90 for UTI; 0.91 for CAP). Both measures had strong validity demonstrated through (a) face validity by hospital users, the TEPs, and patient focus group, (b) implicit case review (ĸ 0.72 for UTI; ĸ 0.72 for CAP), and (c) rare case misclassification (4% for UTI; 0% for CAP) due to data errors (<2% for UTI; 6.3% for CAP). Measure implementation through hospital peer comparison in Michigan hospitals (2017 to 2020) demonstrated significant decreases in inappropriate diagnosis of UTI and CAP (37% and 32%, respectively, P < .001), supporting usability.

Conclusions

We developed highly reliable, valid, and usable measures of inappropriate diagnosis of UTI and CAP for hospitalized patients. Hospitals seeking to improve diagnostic safety, antibiotic use, and patient care should consider using these measures to reduce inappropriate diagnosis of CAP and UTI.
Use of ACEi/ARBs, SGLT2 inhibitors and MRAs can help us reach the therapeutic ceiling in CKD
Authors: Sarafidis Pantelis
Published: February 2024

Chronic kidney disease (CKD) is increasing in prevalence worldwide, posing major implications for public health such as kidney failure requiring dialysis, and increased risk of cardiovascular and all-cause mortality. Diabetic and hypertensive kidney disease represent the two most common causes of CKD. Until a few years ago, lifestyle modifications, blood pressure, glycaemic and lipid control, along with angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker monotherapy were the only measures for retarding these two diseases and were the cornerstone of treatment for CKD of any aetiology. Effective application of all these measures could reduce the estimated glomerular filtration rate (eGFR) decline in proteinuric CKD roughly from 10–12 to 5–6 mL/min/1.73 m2/year, hence leaving a large unmet need in CKD treatment. In recent years, major kidney outcome trials showed that the addition of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD with or without type 2 diabetes (T2D) and of the non-steroidal mineralocorticoid receptor antagonist finerenone in patients with CKD with T2D can largely improve kidney and cardiovascular outcomes. Elegant analyses of these trials shed further light on these effects, showing that SGLT2i or finerenone use on top of standard-of-care treatment in patients with albuminuric CKD can further reduce chronic eGFR annual loss to 2–2.5 mL/min/1.73 m2, while SGLT2is in normoalbuminuric CKD can reduce this loss <0.5 mL/min/1.73 m2, i.e. well below the aging-related GFR loss. Therefore, current evidence suggests that available treatments, if properly implemented, can help us reach the therapeutic ceiling in the majority of CKD patients.
‘Back from the silence with something to say’: Ursula Le Guin’sLaviniaand silence as classical reception
Authors: Hauser Emily
Published: February 2024

This article explores the power of silence in the feminist recovery of classical texts to open up engaged spaces for women’s creative reworkings, taking as a case study Lavinia and her reception in Ursula Le Guin’s (2008) novel of the same name. By re-evaluating silence in dialogue with feminist and classical reception scholarship, I argue that Le Guin is able to bring a different angle to the reception of classical literary women, focusing on the gaps and spaces in Lavinia’s character that provide a medium for engagement with the incomplete text of the Aeneid. Silence thus becomes a locus in which Le Guin can transform Vergil’s silencing of Lavinia into a generative vision of the open space of interpretation available in classical literature and its reception.
Why, how, when, and for whom does digital disconnection work? A process-based framework of digital disconnection
Authors: Vanden Abeele Mariek M P , Vandebosch Heidi , Koster Ernst H W , De Leyn Tom , Van Gaeveren Kyle , de Segovia Vicente David , Van Bruyssel Sara , van Timmeren Tim , De Marez Lieven , Poels Karolien , DeSmet Ann , De Wever Bram , Verbruggen Marijke , Baillien Elfi
Published: February 2024

Digital disconnection has emerged as a concept describing the actions people take to limit their digital connectivity to enhance their well-being. To date, evidence on its effectiveness is mixed, leading to calls for greater consideration of why, how, when, and for whom digital disconnection works. This article responds to these calls, presenting a framework that differentiates four key harms that contribute to experiences of digital ill-being (time displacement, interference, role blurring, and exposure effects). Using these four harms as a starting point, the framework explains: (1) why people are motivated to digitally disconnect; (2) how specific disconnection strategies (i.e., placing limits on time, access, channels, and contents, interactions and features) may help them; and for whom (3) and under which conditions (when) these strategies can be effective.
ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection
Authors: Bredow Clara , Thery Fabien , Wirth Eva Katrin , Ochs Sarah , Kespohl Meike , Kleinau Gunnar , Kelm Nicolas , Gimber Niclas , Schmoranzer Jan , Voss Martin , Klingel Karin , Spranger Joachim , Renko Kostja , Ralser Markus , Mülleder Michael , Heuser Arnd , Knobeloch Klaus-Peter , Scheerer Patrick , Kirwan Jennifer , Brüning Ulrike , Berndt Nikolaus , Impens Francis , Beling Antje
Published: February 2024

Aims

Virus infection triggers inflammation and, may impose nutrient shortage to the heart. Supported by type I interferon (IFN) signalling, cardiomyocytes counteract infection by various effector processes, with the IFN-stimulated gene of 15 kDa (ISG15) system being intensively regulated and protein modification with ISG15 protecting mice Coxsackievirus B3 (CVB3) infection. The underlying molecular aspects how the ISG15 system affects the functional properties of respective protein substrates in the heart are unknown.

Methods and results

Based on the protective properties due to protein ISGylation, we set out a study investigating CVB3-infected mice in depth and found cardiac atrophy with lower cardiac output in ISG15−/− mice. By mass spectrometry, we identified the protein targets of the ISG15 conjugation machinery in heart tissue and explored how ISGylation affects their function. The cardiac ISGylome showed a strong enrichment of ISGylation substrates within glycolytic metabolic processes. Two control enzymes of the glycolytic pathway, hexokinase 2 (HK2) and phosphofructokinase muscle form (PFK1), were identified as bona fide ISGylation targets during infection. In an integrative approach complemented with enzymatic functional testing and structural modelling, we demonstrate that protein ISGylation obstructs the activity of HK2 and PFK1. Seahorse-based investigation of glycolysis in cardiomyocytes revealed that, by conjugating proteins, the ISG15 system prevents the infection-/IFN-induced up-regulation of glycolysis. We complemented our analysis with proteomics-based advanced computational modelling of cardiac energy metabolism. Our calculations revealed an ISG15-dependent preservation of the metabolic capacity in cardiac tissue during CVB3 infection. Functional profiling of mitochondrial respiration in cardiomyocytes and mouse heart tissue by Seahorse technology showed an enhanced oxidative activity in cells with a competent ISG15 system.

Conclusion

Our study demonstrates that ISG15 controls critical nodes in cardiac metabolism. ISG15 reduces the glucose demand, supports higher ATP production capacity in the heart, despite nutrient shortage in infection, and counteracts cardiac atrophy and dysfunction.
Anterior mitral leaflet laceration using the MitraCut technique for transapical transcatheter Tendyne implantation after unsuccessful Carillon indirect annuloplasty: a case report
Authors: de Manna Nunzio Davide , Martens Andreas , Jüttner Marieke , Berliner Dominik , Bauersachs Johann , Ruhparwar Arjang , Kempf Tibor , Ius Fabio
Published: February 2024

Background

The introduction of a transapical transcatheter beating heart replacement system has significantly expanded therapeutic options for patients with severely diseased mitral valves, particularly those ineligibles for traditional surgery or transcatheter repair. However, challenges, such as left ventricular outflow tract obstruction (LVOT-O) and the risk of dynamic systolic anterior motion (SAM) in cases with elongated anterior mitral leaflet (AML) post-prosthesis implantation, impede the widespread adoption of transcatheter mitral valve replacement (TMVR).

Case summary

In 2022, a 75-year-old male with severe mixed-genesis mitral regurgitation (MR) underwent Carillon Mitral Contour System annuloplasty. Recurrent heart failure admissions (New York Heart Association IV) and prohibitive risk for open-heart surgery (European System for Cardiac Operative Risk Evaluation II 8.27%) prompted evaluation for Tendyne TMVR with the MitraCut technique. This beating heart transapical approach involved scissor-mediated splitting of the elongated 27 mm AML, essential for mitigating LVOT-O risk and dynamic SAM. The screening echocardiogram revealed the poorly tethered AML near the thickened septum at the simulated neo-LVOT site.

Discussion

This case underscores the intricate management challenges associated with severe MR, highlighting the successful application of the MitraCut technique as a viable alternative in high-risk scenarios. The imperative for further research and clinical studies is emphasized to comprehensively elucidate outcomes and safety parameters, providing valuable insights for refining TMVR applications within this context.
A case report of right bundle branch block and junctional beats during ablation at the right ventricle outflow tract: metallic occluder’s unanticipated effect
Authors: Pu Sijia , Liu Huiyi , Deng Hai , Xue Yumei , Lin Weidong
Published: February 2024

Background

Previously, ablation at the outflow tract was considered to be safe and rarely affected the His–Purkinje system due to their spatial distance. However, we have reported a case of right bundle branch block (RBBB) and junctional beats that were recorded during radiofrequency catheter ablation in a patient who had a history of peri-membranous ventricular septal defect (pmVSD) closure and the implantation of a metallic occluder.

Case summary

A 16-year-old girl with a metallic occluder for peri-membranous ventricular septum defect underwent an ablation procedure for premature ventricular complexes. During the ablation at the right ventricular outflow tract (RVOT), RBBB and junctional beats were recorded. His bundle potentials and the high-frequency potential generated by electrical interference were observed when mapping the margin of the occluder. To ensure safety, we attempted ablation at the right coronary cusp in the left ventricular outflow tract, which eventually proved to be successful, presenting an alternative ablation strategy.

Conclusion

This is a rare report of RBBB and junctional beats observed during ablation at RVOT in a patient with pmVSD and a metallic occluder. The observed damage to the His–Purkinje system may be attributed to uncontrolled radiofrequency energy heating up caused by the metallic device. This case emphasizes the importance of thorough electroanatomic and activation mapping prior to starting the ablation procedure, especially in complicated cases. Furthermore, it suggests that ablation at a relatively remote position is both feasible and relatively safe for patients with occluder devices.
Effects of Cognitive Inhibition Preceding Voluntary Step Responses to Visual Stimuli in Young and Older Adults
Authors: Kwag Eunyoung , Bachmann Dominic , Kim Kyungwan , Komnik Igor , Zijlstra Wiebren
Published: February 2024

Objectives

Age-related changes in executive functions, especially inhibitory control, correlate to decreased balance control and increased fall risk. However, only a few studies focused on the performance of tasks integrating balance and inhibitory control. This study aims to determine the effects of cognitive inhibition preceding the initiation of voluntary steps in young and older adults.

Methods

Performance of 3 stepping tasks (a Simon, Flanker, and a combined Simon–Flanker task [SFT]) were analyzed in 23 young adults and 43 older adults. Each task included congruent and incongruent trials in different step directions. Analyses focused on temporal aspects of step responses as identified by changes in Center of Pressure (CoP) and foot position. A 3-way repeated-measures ANOVA was used to evaluate “inhibition,” “age,” and “task” effects.

Results

With large effect sizes, “inhibition” as well as “age” resulted in longer durations of an initial preparatory phase as well as the step response phase. The SFT showed the largest “task” effects. Duration of CoP movement had the largest impact on total step execution in older adults. A significant interaction effect of “age*inhibition” was found on the duration of CoP movement, but not on CoP onset.

Discussion

Overall, our results demonstrate that cognitive inhibition has more impact in older adults, the longer duration of CoP movements in older adults may reflect an ineffective step preparation. Our examination of the duration of subsequent phases which comprise perceptual processing and conflict resolution, response initiation, and step execution sheds light on how cognitive inhibition affects voluntary stepping behavior in young and older adults.
Associations Between Self-Reported Visual and Hearing Functioning and Cognitive Function Among Hispanics/Latino: Hispanic Community Health Study
Authors: Zheng D Diane , Lam Byron L , Joslin Charlotte E , Gonzalez Hector M , Baiduc Rachael R , Tarraf Wassim , Stickel Ariana , Daviglus Martha , Garcia-Bedoya Olga , Schneiderman Neil , Gonzalez Franklyn , Lee David J
Published: February 2024

Background and Objectives

To investigate the associations between self-reported visual functioning (VF) and hearing functioning with cognition in the Hispanic/Latino population.

Research Design and Methods

We utilized data from the Miami Ocular Study of Latinos ancillary study to Hispanic Community Health Study/Study of Latinos with 1,056 participants aged 45 and older. The outcomes were cognitive performances assessed by the Digit Symbol Substitution Test (DSST), Word Fluency, Brief-Spanish English Verbal Learning Test-recall (B-SEVLT recall), words recalled over 3 trials, and the Six-Item Screener. VF was measured by National Eye Institute Visual Function Questionnaire (NEI-VFQ), and hearing function was measured by Hearing Handicap Inventory Screening Questionnaire for Adults and Elderly (HHIA/E-S). Multiple regressions were performed for each cognitive outcome while controlling for covariates and complex sampling design.

Results

NEI-VFQ was associated with 3 of the 5 cognitive outcomes. A 4-point NEI-VFQ score difference was associated with a 0.56-point difference in DSST (standard error [SE] = 0.27, p < .001), 0.17 in Word fluency (SE = 0.16, p < .01), and 0.08 in B-SEVLT-recall (SE = 0.07, p < .01). HHIA/E-S was not associated with any of the cognitive measures examined.

Discussion and Implications

These data suggest that impaired VF is associated with worse cognition in the Hispanic/Latino population. Although previous work in this cohort indicated hearing loss assessed by pure tone audiometry was associated with worse cognition, we found self-perceived hearing function was not associated with cognition, suggesting the potential limitation of self-reported hearing function as a proxy for hearing loss in epidemiological research in Hispanic/Latino populations. Results also imply impaired VF and hearing function may be linked to cognition differently in the Hispanic population, and more research is needed to better understand the underlying linking mechanisms. Visual and hearing impairments are common and treatable and represent important modifiable risk factors that can be treated to preserve cognitive function in Hispanics/Latinos.
Participatory approaches to programme design, planning and early implementation: experiences from a safe surgery project in Nigeria
Authors: Atta Kabiru , Abdulazeez Jumare , Khan Farhad , Efem Iyeme , Abdullahi Halimatu Sadiyya , Dada Mansur , Uro-Chukwu Henry C , Levin Karen , Stafford Renae
Published: February 2024

MOMENTUM Safe Surgery in Family Planning and Obstetrics is a global project that strengthens surgical ecosystems through partnership with country institutions. In Nigeria, the project implements in Bauchi, Ebonyi, Kebbi and Sokoto states and the Federal Capital Territory, focusing on surgical obstetrics, holistic fistula care and female genital mutilation/cutting prevention and care. The project utilized participatory approaches during its design, planning and early implementation phases. During the design phase, the project employed a co-creation process featuring a desk review, key informant interviews and stakeholder workshops at community, facility, and government levels to actively listen to, identify and incorporate local perspectives on surgical ecosystem gaps and priorities. Initial findings, shared at state- and national-level workshops, helped collectively identify and prioritize context-specific interventions. The resulting co-created workplan features interventions to strengthen surgical services based on the National Surgical, Obstetrics, Anaesthesia and Nursing Plan (NSOANP). Upon workplan approval, the planning phase involved meeting with each State Ministry of Health (MOH) to prioritize workplan interventions for implementation and to define the finer details needed to drive early implementation processes. Preliminary achievements during early implementation include state commitments to include a costed facility NSOANP in 2023 annual operational plans, mitigation of health facility staffing shortages and review of national fistula and surgical Health Management Information System indicator data flow and advocacy to the Federal MOH resulting in improved fistula data quality and availability. Well-established state and national systems, structures, policies and guidelines enable this programming approach. Since communication between institutional actors is often limited, these approaches necessitate building and maintaining relationships and knowledge-sharing, which requires a significant up-front time investment that must be balanced with donor/partner desires for rapid deliverables. Linking different actors within the health system together through co-creation/co-implementation represents a crucial step in building sustainable country ownership and oversight for surgical ecosystems strengthening interventions.
Assessing the relationship between coverage of essential health services and poverty levels in low- and middle-income countries
Authors: Guerra Stefanny , Roope Laurence Sj , Tsiachristas Apostolos
Published: February 2024

Universal health coverage (UHC) aims to provide essential health services and financial protection to all. This study aimed to assess the relationship between the service coverage aspect of universal health coverage and poverty in low- and middle-income countries (LMICs). Using country-level data from 96 LMICs from 1990 to 2017, we employed fixed-effects and random-effects regressions to investigate the association of eight service coverage indicators (inpatient admissions; antenatal care; skilled birth attendance; full immunization; cervical and breast cancer screening rates; diarrhoea and acute respiratory infection treatment rates) with poverty headcount ratios and gaps at the $1.90, $3.20 and $5.50 poverty lines. Missing data were imputed using within-country linear interpolation or extrapolation. One-unit increases in seven service indicators (breast cancer screening being the only one with no significant associations) were associated with reduced poverty headcounts by 2.54, 2.46 and 1.81 percentage points at the $1.90, $3.20 and $5.50 lines, respectively. The corresponding reductions in poverty gaps were 0.99 ($1.90), 1.83 ($3.20) and 1.89 ($5.50) percentage points. Apart from cervical cancer screening, which was only significant in one poverty headcount model ($5.50 line), all other service indicators were significant in either the poverty headcount or gap models at both $1.90 and $3.20 poverty lines. In LMICs, higher service coverage rates are associated with lower incidence and intensity of poverty. Further research is warranted to identify the causal pathways and specific circumstances in which improved health services in LMICs might help to reduce poverty.
Effect of supplementary private health insurance on out-of-pocket inpatient medical expenditure: evidence from Malaysia
Authors: Ng Rui Jie , Choo Wan Yuen , Ng Chiu-Wan , Hairi Noran Naqiah
Published: February 2024

The vital role of healthcare financing in achieving universal health coverage is indisputable. However, most countries, including Malaysia, face challenges in establishing an equitable and sustainable healthcare financing system due to escalating healthcare costs, an ageing population and a growing disease burden. With desirable pre-payment and risk pooling features, private health insurance (PHI) is considered an alternative financing option to reduce out-of-pocket (OOP) medical expenditure. However, ongoing theoretical and empirical debates persist regarding the adequacy of financial risk protection provided by PHI largely because it depends on its role, the benefit design and the regulations in place. Our study aimed to investigate the effect of supplementary PHI on OOP inpatient medical expenditure in Malaysia. Secondary data analysis was conducted using the Malaysian National Health and Morbidity Survey 2019 dataset. A total of 983 respondents with a history of inpatient hospitalization in the past 12 months were included in the study. Instrumental variable analysis using a two-stage residual inclusion was performed to address endogeneity bias, with wealth status and education level as the instrumental variables. Tobit regression model was used in the second stage considering the censored distribution of the outcome variable. Missing data were handled using multiple imputation. About one-fifth of the respondents had PHI. In this study, we found that having PHI significantly increased OOP inpatient medical expenditure in all three marginal effects. Additionally, age, residential location, ethnicity (citizenship), being covered by government guarantee letter, government funding and employer-sponsored health insurance were other significant factors associated with OOP inpatient medical expenditure. Our findings undermine a key justification to advocate PHI uptake among the population, with a need for the Malaysian government to reassess the role of PHI in healthcare financing and reconsider PHI subsidization policy. Regulations should also be strengthened to enhance the financial risk protection provided by PHI.
Lessons from the coronavirus pandemic: a review of how the disease spreads in indoor spaces
Authors: Abdin Taqui Ahmed Reda , Mahmoud Ayman Hassaan Ahmed
Published: February 2024

In the post-coronavirus era, it is important to understand how infections spread in the indoor environment. The modes of transmission that are of interest to this research are droplet-borne and airborne transmission. In these transmission cases, there is a dependency on air to transport pathogens. The buoyancy of pathogens depends on the mass of the particles or droplets, volume of the indoor space and air velocity. Understanding this is key to reaching a sound methodology for control. The case studies consist of two main groups: the first group is research based published prior to the onset of the pandemic, and the second group is based on studies of actual infection cases subsequent to the onset of the pandemic. When examining the cases, it is apparent that the three main factors that are constantly recurrent are population density, airflow rate and air recirculation. In a lot of cases, air stagnation and lack of air change are conclusive causative factors of infection transmission, while in a couple of cases, it was shown that infective agents can travel more than 3 m, another factor to be taken into consideration. When there is a total lack of airflow and air change, population density becomes the main causative factor. This research presents a set of guidelines for the ventilation of spaces in different types of indoor environment through exploring the role of the built environment in the transmission of infection and how building design can effect change on public health.
Safety, Tolerability, and Immunogenicity of an mRNA-Based Respiratory Syncytial Virus Vaccine in Healthy Young Adults in a Phase 1 Clinical Trial
Authors: Shaw Christine A , Mithani Runa , Kapoor Archana , Dhar Rakesh , Wilson Lauren , El Asmar Laila , Schnyder-Ghamloush Sabine , Schaefers Kristi , August Allison , Stoszek Sonia K , Chen Grace L
Published: February 2024

Background

Respiratory syncytial virus (RSV) presents a global health concern. A lipid nanoparticle–encapsulated mRNA-based RSV vaccine (mRNA-1345) that encodes the membrane-anchored RSV prefusion–stabilized F glycoprotein is under clinical investigation.

Methods

This phase 1 dose escalation study was based on a randomized, observer-blind, placebo-controlled design, and it assessed the safety and immunogenicity of mRNA-1345 in healthy adults aged 18 to 49 years. Participants were randomized to receive 1 dose of mRNA-1345 (50, 100, or 200 µg) or placebo or 3 doses of mRNA-1345 (100 µg) or placebo 56 days apart.

Results

mRNA-1345 was well tolerated at all dose levels. The most common solicited adverse reactions were pain, headache, fatigue, myalgia, or chills, which were all generally mild to moderate. At 1 month postinjection, a single injection of mRNA-1345 boosted RSV neutralizing antibody titers (geometric mean fold rise: RSV-A, 20.0–23.5; RSV-B, 11.7–16.0) and RSV prefusion binding antibody concentrations (geometric mean fold rise, 16.1–21.8), with no apparent dose response. Antibody levels remained above baseline through 6 months. Sequential doses of 100 µg were well tolerated but did not further boost antibody levels.

Conclusions

A single mRNA-1345 injection demonstrated an acceptable safety profile in younger adults and induced a durable neutralizing antibody response, supporting its continued development.

Clinical Trials Registration

ClinicalTrials.gov NCT04528719.
Minimal Impact on the Resistome of Children in Botswana After Azithromycin Treatment for Acute Severe Diarrheal Disease
Authors: Guitor Allison K , Katyukhina Anna , Mokomane Margaret , Lechiile Kwana , Goldfarb David M , Wright Gerard D , McArthur Andrew G , Pernica Jeffrey M
Published: February 2024

Background

Macrolide antibiotics, including azithromycin, can reduce under 5 years of age mortality rates and treat various infections in children in sub-Saharan Africa. These exposures, however, can select for antibiotic-resistant bacteria in the gut microbiota.

Methods

Our previous randomized controlled trial (RCT) of a rapid-test-and-treat strategy for severe acute diarrheal disease in children in Botswana included an intervention (3-day azithromycin dose) group and a control group that received supportive treatment. In this prospective matched cohort study using stools collected at baseline and 60 days after treatment from RCT participants, the collection of antibiotic resistance genes or resistome was compared between groups.

Results

Certain macrolide resistance genes increased in prevalence by 13%–55% at 60 days, without differences in gene presence between the intervention and control groups. These genes were linked to tetracycline resistance genes and mobile genetic elements.

Conclusions

Azithromycin treatment for bacterial diarrhea for young children in Botswana resulted in similar effects on the gut resistome as the supportive treatment and did not provide additional selective pressure for macrolide resistance gene maintenance. The gut microbiota of these children contains diverse macrolide resistance genes that may be transferred within the gut upon repeated exposures to azithromycin or coselected by other antibiotics.

Clinical Trials Registration

NCT02803827.
Does soil history decline in influencing the structure of bacterial communities of Brassica napus host plants across different growth stages?
Authors: Blakney Andrew J C , St-Arnaud Marc , Hijri Mohamed
Published: February 2024

Soil history has been shown to condition future rhizosphere microbial communities. However, previous experiments have also illustrated that mature, adult plants can “re-write,” or mask, different soil histories through host plant–soil community feedbacks. This leaves a knowledge gap concerning how soil history influences bacterial community structure across different growth stages. Thus, here we tested the hypothesis that previously established soil histories will decrease in influencing the structure of Brassica napus bacterial communities over the growing season. We used an on-going agricultural field experiment to establish three different soil histories, plots of monocrop canola (B. napus), or rotations of wheat-canola, or pea-barley-canola. During the following season, we repeatedly sampled the surrounding bulk soil, rhizosphere, and roots of the B. napus hosts at different growth stages—the initial seeding conditions, seedling, rosette, bolting, and flower—from all three soil history plots. We compared composition and diversity of the B. napus soil bacterial communities, as estimated using 16S rRNA gene metabarcoding, to identify any changes associated with soil history and growth stages. We found that soil history remained significant across each growth stage in structuring the bacterial bulk soil and rhizosphere communities, but not the bacterial root communities. This suggests that the host plant’s capacity to “re-write” different soil histories may be quite limited as key components that constitute the soil history’s identity remain present, such that the previously established soil history continues to impact the bacterial rhizosphere communities, but not the root communities. For agriculture, this highlights how previously established soil histories persist and may have important long-term consequences on future plant–microbe communities, including bacteria.
The Methodological Machinery of Wargaming: A Path toward Discovering Wargaming’s Epistemological Foundations
Authors: Banks David E
Published: February 2024

This paper proposes a comprehensive research program for determining the epistemological foundations of analytic wargaming. Wargaming has been used in military, government, and private sectors for decades, with tens of millions of dollars spent annually on it. In light of the changing strategic circumstances of the twenty-first century, it has only become more popular. However, the epistemological foundations of the method are poorly understood. Many professional wargamers contend that wargaming is an “art” and thus unable to be systemically evaluated. Recent work by a small coterie of international relations scholars has contended that wargaming can be reconciled with social science, typically by evaluating wargaming according to experimental standards. However, this solution strips wargames of most of their unique features and cannot explain why some of the most prominent wargames in history produced meaningful results. In this paper, I argue that in the attempt to better understand wargaming’s epistemology, scholars should begin by recognizing the prominent features of wargames and research each of these to determine if and how wargames produce rigorous knowledge. In making this argument, I identify five distinct “methodological machineries” of wargaming—the recurring processes through which wargames may produce knowledge—that distinguish wargaming from other social science methods: (i) they are representative, (ii) they feature consequential decisions made by human players, (iii) they are adjudicated, (iv) they are immersive, and (v) they are bespoke designs. I show how each of these machineries offers potential opportunities and dangers in the production of knowledge through the method of wargaming. In outlining these distinct features, I offer a clear and viable research program for epistemologists of wargaming.
Accreditation of antimicrobial stewardship programmes: addressing a global need to tackle antimicrobial resistance
Authors: Sneddon Jacqueline , Drummond Felicity , Guise Tracey , Gilchrist Mark , Jenkins David R
Published: February 2024

Accreditation of healthcare services provides quality assurance of hospital practice to support safe and effective care for patients. Accreditation programmes focused on antimicrobial stewardship (AMS) have been developed in high-income countries (HIC) and recently the WHO has developed a toolkit to support AMS practice in low and middle-income (LMIC) countries. BSAC has developed their Global Antimicrobial Stewardship Accreditation Scheme (GAMSAS) for hospitals based on globally applicable standards. GAMSAS aims to support healthcare organizations to build measurable AMS programmes and to support spread of best practice. GAMSAS involves a desktop assessment by BSAC experts followed by a hospital visit to gather further insight into how a hospital’s AMS programme operates. A final report of compliance with the GAMSAS standards and a recommendation about accreditation at one of three levels is formally approved at a GAMSAS panel meeting involving well-established global experts in AMS. The BSAC GAMSAS team reflect on progress during the first year and ambitions for future spread.
The effect of ciprofloxacin prophylaxis during haematopoietic cell transplantation on infection episodes, exposure to treatment antimicrobials and antimicrobial resistance: a single-centre retrospective cohort study
Authors: Baltas Ioannis , Kavallieros Konstantinos , Konstantinou Giannis , Koutoumanou Eirini , Gibani Malick M , Gilchrist Mark , Davies Frances , Pavlu Jiri
Published: February 2024

Objectives

Fluroquinolone prophylaxis during haematopoietic cell transplantation (HCT) remains contentious. We aimed to determine its effectiveness and association with exposure to treatment antimicrobials and antimicrobial resistance.

Methods

All admission episodes for HCT (N = 400 , 372 unique patients) in a tertiary centre between January 2020 and December 2022 were studied. Allogeneic HCT (allo-HCT) recipients received prophylaxis with ciprofloxacin during chemotherapy-induced neutropenia, while autologous HCT (auto-HCT) recipients did not.

Results

Allo-HCT was performed for 43.3% (173/400) of patients, auto-HCT for 56.7% (227/400). Allo-HCT was associated with an average of 1.01 fewer infection episodes per 100 admission days (95% CI 0.62–1.40, P < 0.001) compared with auto-HCT. In allo-HCT, the total exposure to all antimicrobials was higher [+24.8 days of therapy (DOT)/100 admission days, P < 0.001], as was exposure to ciprofloxacin (+40.5 DOT/100 admission days, P < 0.001). By contrast, exposure to meropenem (−4.5 DOT/100 admission days, P = 0.02), piperacillin/tazobactam (−5.2 DOT/100 admission days, P < 0.001), aminoglycosides (−4.5 DOT/100 admission days, P < 0.001) and glycopeptides (−6.4 DOT/100 admission days, P < 0.001) was reduced. Enterobacteriaceae isolated during allo-HCT were more resistant to ciprofloxacin (65.5%, 19/29 versus 6.1%, 2/33, P < 0001), ceftriaxone (65.5%, 19/29 versus 9.1%, 3/33, P < 0.001), other antimicrobial classes. Vancomycin-resistant enterococci were more common in allo-HCT recipients (11%, 19/173 versus 0.9%, 2/227, P < 0.001). Inpatient mortality during allo- and auto-HCT was 9.8% (17/173) and 0.4% (1/227). respectively (P < 0.001).

Conclusions

Ciprofloxacin prophylaxis in allo-HCT was associated with fewer infection episodes and reduced exposure to treatment antimicrobials. Mortality in auto-HCT remained low. A significant burden of antimicrobial resistance was detected in allo-HCT recipients.
Fentanyl as a marker of illicit drug use in morphine-positive urine specimens from workplace drug testing
Authors: Vikingsson Svante , Winecker Ruth E , Kuntz David J , Clark Michael , Jacques Martin , Hart E Dale , Hayes Eugene D , Flegel Ronald R , Davis Lisa S
Published: February 2024

Total morphine is an important urinary marker of heroin use but can also be present from prescriptions or poppy seed ingestion. In specimens with morphine concentrations consistent with poppy seed ingestion (<4,000 ng/mL), 6-acetylmorphine has served as an important marker of illicit drug use. However, as illicit fentanyl has become increasingly prevalent as a contaminant in the drug supply, fentanyl might be an alternative marker of illicit opioid use instead of or in combination with 6-acetylmorphine. The aim of this study was to quantify opiates, 6-acetylmorphine, fentanyl and fentanyl analogs in 504 morphine-positive (immunoassay 2,000 ng/mL cutoff) urine specimens from workplace drug testing. Almost half (43%) of morphine-positive specimens had morphine concentrations below 4,000 ng/mL, illustrating the need for markers to differentiate illicit drug use. In these specimens, fentanyl (22% co-positivity) was more prevalent than 6-acetylmorphine (12%). Co-positivity of 6-acetylmorphine and semi-synthetic opioids increased with morphine concentration, while fentanyl prevalence did not. In 110 fentanyl-positive specimens, the median norfentanyl concentration (1,520 ng/mL) was 9.6× higher than the median fentanyl concentration (159 ng/mL), illustrating the possibility of using norfentanyl as a urinary marker of fentanyl use. The only fentanyl analog identified was para-fluorofentanyl (n = 50), with results from most specimens consistent with para-fluorofentanyl contamination in illicit fentanyl. The results confirm the use of fentanyl by employees subject to workplace drug testing and highlight the potential of fentanyl and/or norfentanyl as important markers of illicit drug use.
Formation of the NLRP3 inflammasome inhibits stress granule assembly by multiple mechanisms
Authors: Yoshioka Daisuke , Nakamura Takanori , Kubota Yuji , Takekawa Mutsuhiro
Published: February 2024

Proper regulation of cellular response to environmental stress is crucial for maintaining biological homeostasis and is achieved by the balance between cell death processes, such as the formation of the pyroptosis-inducing NLRP3 inflammasome, and pro-survival processes, such as stress granule (SG) assembly. However, the functional interplay between these two stress-responsive organelles remains elusive. Here, we identified DHX33, a viral RNA sensor for the NLRP3 inflammasome, as a SG component, and the SG-nucleating protein G3BP as an NLRP3 inflammasome component. We also found that a decrease in intracellular potassium (K+) concentration, a key ‘common’ step in NLRP3 inflammasome activation, markedly inhibited SG assembly. Therefore, when macrophages are exposed to stress stimuli with the potential to induce both SGs and the NLRP3 inflammasome, such as cytoplasmic poly(I:C) stimulation, they preferentially form the NLRP3 inflammasome but avoid SG assembly by sequestering G3BP into the inflammasome and by inducing a reduction in intracellular K+ levels. Thus, under such conditions, DHX33 is primarily utilized as a viral RNA sensor for the inflammasome. Our data reveal the functional crosstalk between NLRP3 inflammasome-mediated pyroptosis and SG-mediated cell survival pathways and delineate a molecular mechanism that regulates cell-fate decisions and anti-viral innate immunity under stress.
Epigenetic regulation of innate immune dynamics during inflammation
Authors: Caldwell Blake A , Li Liwu
Published: February 2024

Innate immune cells play essential roles in modulating both immune defense and inflammation by expressing a diverse array of cytokines and inflammatory mediators, phagocytizing pathogens to promote immune clearance, and assisting with the adaptive immune processes through antigen presentation. Rudimentary innate immune “memory” states such as training, tolerance, and exhaustion develop based on the nature, strength, and duration of immune challenge, thereby enabling dynamic transcriptional reprogramming to alter present and future cell behavior. Underlying transcriptional reprogramming are broad changes to the epigenome, or chromatin alterations above the level of DNA sequence. These changes include direct modification of DNA through cytosine methylation as well as indirect modifications through alterations to histones that comprise the protein core of nucleosomes. In this review, we will discuss recent advances in our understanding of how these epigenetic changes influence the dynamic behavior of the innate immune system during both acute and chronic inflammation, as well as how stable changes to the epigenome result in long-term alterations of innate cell behavior related to pathophysiology.
The story of the R number: How an obscure epidemiological figure took over our lives. Part 1: History
Authors: Freeguard Gavin
Published: February 2024

The R number was the “breakout star” of the early weeks of the Covid-19 lockdowns, swiftly taking up residence in the general public’s consciousness and conversations. In this new six-part series, Gavin Freeguard will delve into the evolution of the R number and how it was modelled, used by the UK government and the media and regarded by the average person during the pandemic. He will also consider its limitations, lessons learned and how such statistical tools should be managed for disease planning and response in the future. In this first instalment, he introduces the history of this statistical concept.
Great graphics and the great minds behind them
Authors: Tarran Brian
Published: February 2024

Information designer Alberto Cairo talks to Brian Tarran about his new book and why bravery, reason and anarchy are intrinsic to all the best data visualisation