bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review of empiric studies on lockdowns, workplace closures, and other non-pharmaceutical interventions in non-healthcare workplaces during the initial year of the COVID-19 pandemic: benefits and selected unintended consequences
Authors: Ahmed Faruque , Shafer Livvy , Malla Pallavi , Hopkins Roderick , Moreland Sarah , Zviedrite Nicole , Uzicanin Amra
Published: March 2024

Background

We conducted a systematic review aimed to evaluate the effects of non-pharmaceutical interventions within non-healthcare workplaces and community-level workplace closures and lockdowns on COVID-19 morbidity and mortality, selected mental disorders, and employment outcomes in workers or the general population.

Methods

The inclusion criteria included randomized controlled trials and non-randomized studies of interventions. The exclusion criteria included modeling studies. Electronic searches were conducted using MEDLINE, Embase, and other databases from January 1, 2020, through May 11, 2021. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Meta-analysis and sign tests were performed.

Results

A total of 60 observational studies met the inclusion criteria. There were 40 studies on COVID-19 outcomes, 15 on anxiety and depression symptoms, and five on unemployment and labor force participation. There was a paucity of studies on physical distancing, physical barriers, and symptom and temperature screening within workplaces. The sign test indicated that lockdown reduced COVID-19 incidence or case growth rate (23 studies, p < 0.001), reproduction number (11 studies, p < 0.001), and COVID-19 mortality or death growth rate (seven studies, p < 0.05) in the general population. Lockdown did not have any effect on anxiety symptoms (pooled standardized mean difference = -0.02, 95% CI: -0.06, 0.02). Lockdown had a small effect on increasing depression symptoms (pooled standardized mean difference = 0.16, 95% CI: 0.10, 0.21), but publication bias could account for the observed effect. Lockdown increased unemployment (pooled mean difference = 4.48 percentage points, 95% CI: 1.79, 7.17) and decreased labor force participation (pooled mean difference = -2.46 percentage points, 95% CI: -3.16, -1.77). The risk of bias for most of the studies on COVID-19 or employment outcomes was moderate or serious. The risk of bias for the studies on anxiety or depression symptoms was serious or critical.

Conclusions

Empiric studies indicated that lockdown reduced the impact of COVID-19, but that it had notable unwanted effects. There is a pronounced paucity of studies on the effect of interventions within still-open workplaces. It is important for countries that implement lockdown in future pandemics to consider strategies to mitigate these unintended consequences.

Systematic review registration

PROSPERO registration # CRD42020182660.
Evaluation of Z-plasty versus Heineke-Mikulicz scrotoplasty in the management of penoscrotal web in pediatric age group
Authors: Elrouby Ahmed
Published: March 2024

Background

The penoscrotal web may be congenital or acquired following excessive ventral skin removal during circumcision. Several surgical techniques were described for the treatment of congenital webbed penis without a clear comparison between their outcomes. This prospective study aimed at comparing the surgical results of Z-scrotoplasty and Heineke-Mikulicz scrotoplasty in the treatment of congenital webbed penis in uncircumcised pediatric patients.

Methods

Our study included 40 uncircumcised patients who were divided randomly into two groups; Group A included 20 patients who were treated by Z-scrotoplasty and Group B included the other 20 patients who were treated by Heineke-Mikulicz scrotoplasty. All patients were circumcised at the end of the procedure.

Results

The surgical outcome was good without a significant difference between the two groups in 36 patients. Recurrent webbing developed in one patient of Group A and in three patients of Group B (FEp = 0.605) The only significant difference between the two groups was the operative duration which was shorter in Group B than in Group A (P < 0.001*).

Conclusions

Treatment of congenital penoscrotal web in the pediatric age group could be done with either Z-scrotoplasty or Heineke-Mikulicz scrotoplasty with satisfactory results, however, without significant difference in the surgical outcomes.

Trial registration

• Registration Number: ClinicalTrials.gov ID: NCT05817760.

• Registration release date: April 5, 2023.
Auxiliary occlusal devices for IO scanning in a complete digital workflow of implant-supported crowns: a randomized controlled trial
Authors: Ren Shuxin , Jiang Xi , Di Ping
Published: March 2024

Objectives

To compare the crown accuracy and time efficiency of a complete digital workflow, utilizing an auxiliary occlusal device and IO scanning, with a conventional workflow, for multiple implant-supported single crowns.

Materials and methods

24 patients with two adjacent posterior implants were included. 12 patients were randomly assigned to digital workflow group, involving intra-oral scanning with an auxiliary occlusal device and manufacture of customized abutments and zirconia single crowns (test group). The other 12 were assigned to the conventional workflow (control group), involving conventional impression and CAD-CAM crowns based on stone casts. Crown scanning was done before and after clinical adjustment using an intraoral scanner. Two 3D digital models were overlapped to assess dimension changes. Chair-side and laboratory times for the entire workflow were recorded and a linear mixed model and Independent-sample t tests were used for the statistical analysis.

Results

The maximum occlusal deviation was 279.67 ± 112.17 μm and 479.59 ± 203.63 μm in the test and control group, respectively (p < 0.001). The sizes of the occlusion adjustment areas were 12.12 ± 10.51 mm2 and 25.12 ± 14.14 mm2 in the test and control groups, respectively (p = 0.013). The mean laboratory time was 46.08 ± 5.45 and 105.92 ± 6.10 min in the test and control groups, respectively (p < 0.001).The proximal contact adjustment and mean chair-side time showed no statistically significant difference between two groups.

Conclusions

A digital workflow for two implants-supported single crowns using an auxiliary device required fewer occlusal crown adjustments, and less laboratory time compared to conventional workflow.

Clinical Relevance

The use of auxiliary occlusal devices in IOS enhances the accuracy of virtual maxillomandibular relationship in extended edentulous spans. Consequently, employing a digital workflow for multiple implants-supported crowns using IO scanning and an auxiliary occlusal device proves to be a feasible, accurate and efficient approach.
Investigation of the relationship between the mandibular third molar teeth and the inferior alveolar nerve using posteroanterior radiographs: a pilot study
Authors: Apaydın Burak Kerem , Icoz Derya , Uzun Ezgi , Orhan Kaan
Published: March 2024

Background

The most severe complication that can occur after mandibular third molar (MM3) surgery is inferior alveolar nerve (IAN) damage. It is crucial to have a comprehensive radiographic evaluation to reduce the possibility of nerve damage. The objective of this study is to assess the diagnostic accuracy of panoramic radiographs (PR) and posteroanterior (PA) radiographs in identifying the association between impacted MM3 roots and IAN.

Methods

This study included individuals who had PR, PA radiographs, and cone beam computed tomography (CBCT) and who had at least one impacted MM3. A total of 141 impacted MM3s were evaluated on CBCT images, and the findings were considered gold standard. The relationship between impacted MM3 roots and IAN was also evaluated on PR and PA radiographies. The data was analyzed using the McNemar and Chi-squared tests. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of PR and PA radiographies were determined.

Results

Considering CBCT the gold standard, the relationship between MM3 roots and IAN was found to be statistically significant between PR and CBCT (p = 0.00). However, there was no statistically significant relationship between PA radiography and CBCT (0.227). The study revealed that the most prevalent limitation of the PR in assessing the relationship between MM3 roots and IAN was the identification of false-positive relationship.

Conclusions

PA radiography may be a good alternative in developing countries to find out if there is a contact between MM3 roots and IAN because it is easier to get to, cheaper, and uses less radiation.
Discussing systemic racism and racial privilege at a large, academic health center using a modified privilege walk
Authors: Brown Elizabeth A. , Jones Rosemarie
Published: March 2024

Background

There is a motivation for organizations to understand race and racism from the perspective of minoritized individuals. Academic health centers (AHC) are ideal organizations to have these conversations as they educate healthcare providers, support research in health disparities, and care for diverse patients.

Methods

We piloted and evaluated a virtual Modified Privilege Walk (MPW) with faculty, staff, and students at an AHC in July 2020 to promote difficult conversations about race/racism, social class, and privilege. Each MPW session was voluntary, held virtually over Zoom, and lasted one hour and thirty minutes. Before attending, participants answered questions based on their race/ethnicity and social class to calculate a “privilege score.” After each session, attendees were asked to complete an evaluation survey.

Results

There were five virtual MPWs with 132 attendees, and 74 participants completed an evaluation survey (56% response rate). Many respondents were students (n = 29, 39.2%). Most respondents either agreed (n = 36, 48.6%) or strongly agreed (n = 32, 43.2%) that the virtual MPW positively impacted how they will interact with those of a different race/ethnicity. Attendees requested having more virtual MPWs with leadership, incorporating virtual MPWs in various program curricula, and requiring new employees to participate.

Conclusions

American organizations, particularly AHCs, should provide safe spaces and support these discussions surrounding race and racism as many were founded, built, or operated during a time of free labor and segregation that exerted power and control over minoritized individuals. Authors provide recommendations to dismantle organizational racism and support minoritized employees, patients, and students.
Translation and measurement properties of pregnancy and childbirth questionnaire in Iranian postpartum women
Authors: Abdolalipour Somayeh , Abbasalizadeh Shamsi , Mohammad-Alizadeh-Charandabi Sakineh , Abbasalizadeh Fatemeh , Jahanfar Shayesteh , Asghari Jafarabadi Mohammad , Abdollahi Kosar , Mirghafourvadsnd Mojgan
Published: March 2024

Background

Perceived care quality and patient satisfaction have been important care quality indicators in recent decades, and healthcare professionals have been influential on women’s childbirth experience. This study investigated the measurement properties of the Persian version of the Pregnancy and Childbirth Questionnaire (PCQ), designed to measure mothers’ satisfaction with the quality of healthcare services provided during pregnancy and childbirth.

Methods

This is a cross-sectional methodological study. Instrument translation, face validity, content validity, structural validity, and reliability evaluation were performed to determine the measurement properties of the PCQ’s Persian version. A backward-forward approach was employed for the translation process. Impact scores were selected based on the items’ importance to measure face validity. Content validity index (CVI) and content validity ratio (CVR) were calculated to measure content validity, and exploratory and confirmatory factor analyses were used to measure structural validity. The cluster random sampling method was used, resulting in a sample of 250 eligible women referred to the health centers of Tabriz, Iran, who were 4 to 6 weeks after giving birth. Cronbach’s alpha coefficient and Intraclass Correlation Coefficient (ICC) using a test-retest approach were used to determine the questionnaire’s reliability.

Results

The impact scores of all items were above 1.5, which indicates a suitable face validity. The content validity was also favorable (CVR = 0.95, CVI = 0.90). Exploratory factor analysis on 25 items led to the removal of item 2 due to a factor loading of less than 0.3 and the extraction of three factors explaining 65.07% of the variances. The results of the sample adequacy size were significant (< 0.001, and Kaiser-Meyer-Olkin = 0.886). The model’s validity was confirmed based on the confirmatory factor analysis fit indicators (i.e., RMSEA = 0.08, SRMR = 0.09, TLI = 0.91, CFI = 0.93, x2/df = 4.65). The tool’s reliability was also confirmed (Cronbach’s alpha = 0.88, and ICC (95% CI) = 0.93 (0.88 to 0.95)).

Conclusion

The validity and reliability of the PCQ’s Persian version were suitable to measure the extent to which Iranian women are satisfied with the quality of prenatal and intrapartum care.
Sleep alterations as a function of 88 health indicators
Authors: Ujma Péter Przemyslaw , Bódizs Róbert
Published: March 2024

Background

Alterations in sleep have been described in multiple health conditions and as a function of several medication effects. However, evidence generally stems from small univariate studies. Here, we apply a large-sample, data-driven approach to investigate patterns between in sleep macrostructure, quantitative sleep EEG, and health.

Methods

We use data from the MrOS Sleep Study, containing polysomnography and health data from a large sample (N = 3086) of elderly American men to establish associations between sleep macrostructure, the spectral composition of the electroencephalogram, 38 medical disorders, 2 health behaviors, and the use of 48 medications.

Results

Of sleep macrostructure variables, increased REM latency and reduced REM duration were the most common findings across health indicators, along with increased sleep latency and reduced sleep efficiency. We found that the majority of health indicators were not associated with objective EEG power spectral density (PSD) alterations. Associations with the rest were highly stereotypical, with two principal components accounting for 85–95% of the PSD-health association. PC1 consists of a decrease of slow and an increase of fast PSD components, mainly in NREM. This pattern was most strongly associated with depression/SSRI medication use and age-related disorders. PC2 consists of changes in mid-frequency activity. Increased mid-frequency activity was associated with benzodiazepine use, while decreases were associated with cardiovascular problems and associated medications, in line with a recently proposed hypothesis of immune-mediated circadian demodulation in these disorders. Specific increases in sleep spindle frequency activity were associated with taking benzodiazepines and zolpidem. Sensitivity analyses supported the presence of both disorder and medication effects.

Conclusions

Sleep alterations are present in various health conditions.
Carbon quantum dots of ginsenoside Rb1 for application in a mouse model of intracerebral Hemorrhage
Authors: Tang Xiaolong , Yang Xinyu , Yu Yamei , Wu Miaojing , Li Yuanyuan , Zhang Zhe , Jia Guangyu , Wang Qi , Tu Wei , Wang Ye , Zhu Xingen , Li Shiyong
Published: March 2024

After intracerebral hemorrhage (ICH) occurs, the overproduction of reactive oxygen species (ROS) and iron ion overload are the leading causes of secondary damage. Removing excess iron ions and ROS in the meningeal system can effectively alleviate the secondary damage after ICH. This study synthesized ginsenoside Rb1 carbon quantum dots (RBCQDs) using ginsenoside Rb1 and ethylenediamine via a hydrothermal method. RBCQDs exhibit potent capabilities in scavenging ABTS + free radicals and iron ions in solution. After intrathecal injection, the distribution of RBCQDs is predominantly localized in the subarachnoid space. RBCQDs can eliminate ROS and chelate iron ions within the meningeal system. Treatment with RBCQDs significantly improves blood flow in the meningeal system, effectively protecting dying neurons, improving neurological function, and providing a new therapeutic approach for the clinical treatment of ICH.
Multimorbidity healthcare expenditure in Belgium: a 4-year analysis (COMORB study)
Authors: Tran Phuong Bich , Nikolaidis Georgios F. , Abatih Emmanuel , Bos Philippe , Berete Finaba , Gorasso Vanessa , Van der Heyden Johan , Kazibwe Joseph , Tomeny Ewan Morgan , Van Hal Guido , Beutels Philippe , van Olmen Josefien
Published: March 2024

Background

The complex management of health needs in multimorbid patients, alongside limited cost data, presents challenges in developing cost-effective patient-care pathways. We estimated the costs of managing 171 dyads and 969 triads in Belgium, taking into account the influence of morbidity interactions on costs.

Methods

We followed a retrospective longitudinal study design, using the linked Belgian Health Interview Survey 2018 and the administrative claim database 2017–2020 hosted by the Intermutualistic Agency. We included people aged 15 and older, who had complete profiles (N = 9753). Applying a system costing perspective, the average annual direct cost per person per dyad/triad was presented in 2022 Euro and comprised mainly direct medical costs. We developed mixed models to analyse the impact of single chronic conditions, dyads and triads on healthcare costs, considering two-/three-way interactions within dyads/triads, key cost determinants and clustering at the household level.

Results

People with multimorbidity constituted nearly half of the study population and their total healthcare cost constituted around three quarters of the healthcare cost of the study population. The most common dyad, arthropathies + dorsopathies, with a 14% prevalence rate, accounted for 11% of the total national health expenditure. The most frequent triad, arthropathies + dorsopathies + hypertension, with a 5% prevalence rate, contributed 5%. The average annual direct costs per person with dyad and triad were €3515 (95% CI 3093–3937) and €4592 (95% CI 3920–5264), respectively. Dyads and triads associated with cancer, diabetes, chronic fatigue, and genitourinary problems incurred the highest costs. In most cases, the cost associated with multimorbidity was lower or not substantially different from the combined cost of the same conditions observed in separate patients.

Conclusion

Prevalent morbidity combinations, rather than high-cost ones, made a greater contribution to total national health expenditure. Our study contributes to the sparse evidence on this topic globally and in Europe, with the aim of improving cost-effective care for patients with diverse needs.
Intriguing insight into unanswered questions about Mpox: exploring health policy implications and considerations
Authors: Manirambona Emery , Khan Sheharyar Hassan , Siddiq Abdelmonem , Albakri Khaled , Salamah Hazem Mohamed , Hassan Noheir Ashraf Ibrahem Fathy , Musa Shuaibu Saidu , Dhama Kuldeep
Published: March 2024

The 2022 multi-country Monkeypox (Mpox) outbreak has added concerns to scientific research. However, unanswered questions about the disease remain. These unanswered questions lie in different aspects, such as transmission, the affected community, clinical presentations, infection and prevention control and treatment and vaccination. It is imperative to address these issues to stop the spread and transmission of disease. We documented unanswered questions with Mpox and offered suggestions that could help put health policy into practice. One of those questions is why gay, bisexual or other men who have sex with men (gbMSM) are the most affected community, underscoring the importance of prioritizing this community regarding treatment, vaccination and post-exposure prophylaxis. In addition, destigmatizing gbMSM and implementing community-based gbMSM consultation and action alongside ethical surveillance can facilitate other preventive measures such as ring vaccination to curb disease transmission and track vaccine efficacy. Relevant to that, vaccine and drug side effects have implied the questionability of their use and stimulated the importance of health policy development regarding expanded access and off-label use, expressing the need for safe drug and vaccine development manufacturing. The possibility of reverse zoonotic has also been raised, thus indicating the requirement to screen not only humans, but also their related animals to understand the real magnitude of reverse zoonosis and its potential risks. Implementing infection prevention and control measures to stop the virus circulation at the human–animal interface that includes One Health approach is essential.
Inhibition of the MALT1-LPCAT3 axis protects cartilage degeneration and osteoarthritis
Authors: Kondreddy Vijay , Banerjee Rajkumar , Devi B. L. A. Prabhavathi , Muralidharan Kathirvel , Piramanayagam Selvakumar
Published: March 2024

The proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1β-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1β-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1β-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.

Graphical Abstract
A system dynamics approach to understand Dutch adolescents’ sleep health using a causal loop diagram
Authors: Heemskerk Danique M. , Busch Vincent , Piotrowski Jessica T. , Waterlander Wilma E. , Renders Carry M. , van Stralen Maartje M.
Published: March 2024

Background

Healthy sleep is crucial for the physical and mental wellbeing of adolescents. However, many adolescents suffer from poor sleep health. Little is known about how to effectively improve adolescent sleep health as it is shaped by a complex adaptive system of many interacting factors. This study aims to provide insights into the system dynamics underlying adolescent sleep health and to identify impactful leverage points for sleep health promotion interventions.

Methods

Three rounds of single-actor workshops, applying Group Model Building techniques, were held with adolescents (n = 23, 12–15 years), parents (n = 14) and relevant professionals (n = 26). The workshops resulted in a multi-actor Causal Loop Diagram (CLD) visualizing the system dynamics underlying adolescent sleep health. This CLD was supplemented with evidence from the literature. Subsystems, feedback loops and underlying causal mechanisms were identified to understand overarching system dynamics. Potential leverage points for action were identified applying the Action Scales Model (ASM).

Results

The resulting CLD comprised six subsystems around the following themes: (1) School environment; (2) Mental wellbeing; (3) Digital environment; (4) Family & Home environment; (5) Health behaviors & Leisure activities; (6) Personal system. Within and between these subsystems, 16 reinforcing and 7 balancing feedback loops were identified. Approximately 60 potential leverage points on different levels of the system were identified as well.

Conclusions

The multi-actor CLD and identified system dynamics illustrate the complexity of adolescent sleep health and supports the need for developing a coherent package of activities targeting different leverage points at all system levels to induce system change.
HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy
Authors: Shi Hongjie , Yuan Ming , Cai Jie , Lan Lan , Wang Yumou , Wang Wei , Zhou Jianliang , Wang Bin , Yu Wenjun , Dong Zhe , Deng Dawei , Qian Qiaofeng , Li Yang , Zhou Xianwu , Liu Jinping
Published: March 2024

Background

The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear.

Methods and results

RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson’s analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM.

Conclusions

The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.
Targeting inflammation as cancer therapy
Authors: Wang Manni , Chen Siyuan , He Xuemei , Yuan Yong , Wei Xiawei
Published: March 2024

Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.
Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition
Authors: Deben Christophe , Boullosa Laurie Freire , Fortes Felicia Rodrigues , De La Hoz Edgar Cardenas , Le Compte Maxim , Seghers Sofie , Peeters Marc , Vanlanduit Steve , Lin Abraham , Dijkstra Krijn K. , Van Schil Paul , Hendriks Jeroen M. H. , Prenen Hans , Roeyen Geert , Lardon Filip , Smits Evelien
Published: March 2024

Background

This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF.

Methods

Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy.

Results

The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids.

Conclusion

Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.
txci-ATAC-seq: a massive-scale single-cell technique to profile chromatin accessibility
Authors: Zhang Hao , Mulqueen Ryan M. , Iannuzo Natalie , Farrera Dominique O. , Polverino Francesca , Galligan James J. , Ledford Julie G. , Adey Andrew C. , Cusanovich Darren A.
Published: March 2024

We develop a large-scale single-cell ATAC-seq method by combining Tn5-based pre-indexing with 10× Genomics barcoding, enabling the indexing of up to 200,000 nuclei across multiple samples in a single reaction. We profile 449,953 nuclei across diverse tissues, including the human cortex, mouse brain, human lung, mouse lung, mouse liver, and lung tissue from a club cell secretory protein knockout (CC16−/−) model. Our study of CC16−/−nuclei uncovers previously underappreciated technical artifacts derived from remnant 129 mouse strain genetic material, which cause profound cell-type-specific changes in regulatory elements near many genes, thereby confounding the interpretation of this commonly referenced mouse model.
Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study)
Authors: Streichart Lillian , Felldin Marie , Ekberg Jana , Mjörnstedt Lars , Lindnér Per , Lennerling Annette , Bröcker Verena , Mölne Johan , Holgersson Jan , Daenen Kristien , Wennberg Lars , Lorant Tomas , Baid-Agrawal Seema
Published: March 2024

Background

Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.

Methods

The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.

The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.

Discussion

No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.

Trial registration

ClinicalTrials.gov NCT04561986. Registered on September 24, 2020
Infantile atopic dermatitis – increasing severity predicts negative impacts on maternal and infant sleep: a mixed methods study
Authors: Harbottle Zoe , Nötzel Amanda , Golding Michael A. , Bhamra Manvir , Kopsch Isac , Wilking Erik , Jonsson Marina , Abrams Elissa M. , Halbrich Michelle A. , Simons Elinor , Roos Leslie E. , Keddy-Grant Jill A. , Gerstner Thomas V. , St-Vincent Jo-Anne , Ekström Sandra , Protudjer Jennifer L. P.
Published: March 2024

Background

While the impacts of atopic dermatitis (AD) on maternal and child sleep outcomes have been previously explored, less is known about the associations between infantile AD and sleep quality and quantity.

Objective

To describe the perceived causes of AD-associated maternal sleep disturbances and the association between AD severity and infant sleep outcomes.

Methods

Mothers with infants aged < 19 months old with a diagnosis of AD were recruited from social media and medical clinics in Winnipeg, Canada between October 2021 and May 2022. Infant AD severity was classified using maternal-reported data on the Patient-Oriented Scoring Atopic Dermatitis tool (PO-SCORAD). Quantitative data were collected via a series of questionnaires with a subset of mothers subsequently completing semi-structured interviews. Quantitative and qualitative data were integrated in the discussion.

Results

Mothers of infants with moderate/severe AD (6/12) were more likely to report their infant suffering from a higher degree of sleeplessness (i.e., ≥ 5 on a scale of 0–10) over the past 48 h compared to mothers of infants with mild AD (0/18). This was supported by qualitative findings where mothers described how their infant’s sleep quality and quantity worsened with AD severity. Additionally, 7/32 mothers reported that their child’s AD, regardless of severity, disturbed their sleep. Maternal sleep loss was most commonly attributed to infant itching (6/7), followed by worry (4/7).

Conclusion

Infantile AD severity was associated with worse sleep outcomes for both mothers and infants. We propose that maternal and infantile sleep quality and quantity can be improved by reducing AD severity through adherence to topical treatments.
Deep learning-based 3D cerebrovascular segmentation workflow on bright and black blood sequences magnetic resonance angiography
Authors: Zhou Langtao , Wu Huiting , Luo Guanghua , Zhou Hong
Published: March 2024

Background

Cerebrovascular diseases have emerged as significant threats to human life and health. Effectively segmenting brain blood vessels has become a crucial scientific challenge. We aimed to develop a fully automated deep learning workflow that achieves accurate 3D segmentation of cerebral blood vessels by incorporating classic convolutional neural networks (CNNs) and transformer models.

Methods

We used a public cerebrovascular segmentation dataset (CSD) containing 45 volumes of 1.5 T time-of-flight magnetic resonance angiography images. We collected data from another private middle cerebral artery (MCA) with lenticulostriate artery (LSA) segmentation dataset (MLD), which encompassed 3.0 T three-dimensional T1-weighted sequences of volumetric isotropic turbo spin echo acquisition MRI images of 107 patients aged 62 ± 11 years (42 females). The workflow includes data analysis, preprocessing, augmentation, model training with validation, and postprocessing techniques. Brain vessels were segmented using the U-Net, V-Net, UNETR, and SwinUNETR models. The model performances were evaluated using the dice similarity coefficient (DSC), average surface distance (ASD), precision (PRE), sensitivity (SEN), and specificity (SPE).

Results

During 4-fold cross-validation, SwinUNETR obtained the highest DSC in each fold. On the CSD test set, SwinUNETR achieved the best DSC (0.853), PRE (0.848), SEN (0.860), and SPE (0.9996), while V-Net achieved the best ASD (0.99). On the MLD test set, SwinUNETR demonstrated good MCA segmentation performance and had the best DSC, ASD, PRE, and SPE for segmenting the LSA.

Conclusions

The workflow demonstrated excellent performance on different sequences of MRI images for vessels of varying sizes. This method allows doctors to visualize cerebrovascular structures.

Critical relevance statement

A deep learning-based 3D cerebrovascular segmentation workflow is feasible and promising for visualizing cerebrovascular structures and monitoring cerebral small vessels, such as lenticulostriate arteries.

Key points

• The proposed deep learning-based workflow performs well in cerebrovascular segmentation tasks.

• Among comparison models, SwinUNETR achieved the best DSC, ASD, PRE, and SPE values in lenticulostriate artery segmentation.

• The proposed workflow can be used for different MR sequences, such as bright and black blood imaging.

Graphical Abstract
Genomic characterization of equine influenza A subtype H3N8 viruses by long read sequencing and functional analyses of the PB1-F2 virulence factor of A/equine/Paris/1/2018
Authors: Kleij Lena , Bruder Elise , Raoux-Barbot Dorothée , Lejal Nathalie , Nevers Quentin , Deloizy Charlotte , Da Costa Bruno , Legrand Loïc , Barrey Eric , Chenal Alexandre , Pronost Stéphane , Delmas Bernard , Dhorne-Pollet Sophie
Published: March 2024

Equine influenza virus (EIV) remains a threat to horses, despite the availability of vaccines. Strategies to monitor the virus and prevent potential vaccine failure revolve around serological assays, RT-qPCR amplification, and sequencing the viral hemagglutinin (HA) and neuraminidase (NA) genes. These approaches overlook the contribution of other viral proteins in driving virulence. This study assesses the potential of long-read nanopore sequencing for fast and precise sequencing of circulating equine influenza viruses. Therefore, two French Florida Clade 1 strains, including the one circulating in winter 2018–2019 exhibiting more pronounced pathogenicity than usual, as well as the two currently OIE-recommended vaccine strains, were sequenced. Our results demonstrated the reliability of this sequencing method in generating accurate sequences. Sequence analysis of HA revealed a subtle antigenic drift in the French EIV strains, with specific substitutions, such as T163I in A/equine/Paris/1/2018 and the N188T mutation in post-2015 strains; both substitutions were in antigenic site B. Antigenic site E exhibited modifications in post-2018 strains, with the N63D substitution. Segment 2 sequencing also revealed that the A/equine/Paris/1/2018 strain encodes a longer variant of the PB1-F2 protein when compared to other Florida clade 1 strains (90 amino acids long versus 81 amino acids long). Further biological and biochemistry assays demonstrated that this PB1-F2 variant has enhanced abilities to abolish the mitochondrial membrane potential ΔΨm and permeabilize synthetic membranes. Altogether, our results highlight the interest in rapidly characterizing the complete genome of circulating strains with next-generation sequencing technologies to adapt vaccines and identify specific virulence markers of EIV.
Energetic particle flux measurements from the Korean space weather monitor particle detector: a comparative study with the MPS-HI onboard GOES-16
Authors: Oh Daehyeon , Kim Jiyoung , Loto’aniu Paul T. M. , Lim Han-Cheol , Lee Dae-Young , Kim Dohyeong
Published: March 2024

The Korean space weather monitor (KSEM) aboard the GEO-KOMPSAT-2A (GK2A) has been continuously measuring energetic particle flux in geostationary orbit at 128.2°E longitude since July 2019. The particle detector (PD) component of KSEM comprises six particle telescopes viewing different directions that provide near-real-time electron flux observations within the energy range of 100 keV to 3.8 MeV. The KSEM PD on the GK2A satellite, together with the MPS-HI on the GOES-16 satellite 156.6° away, can provide valuable simultaneous observations of the asymmetric space environment and contributes to our understanding of this dynamic region. In this study, we present recent energetic electron flux measurements obtained from the KSEM PD and conduct preliminary cross-comparisons with data from the Magnetosphere Particle Sensor–High (MPS-HI) PD, which is part of the SEISS instrument suite onboard GOES-16. The inter-comparisons show that the electron fluxes of the two detectors are in reasonable similarity except for some energy bands under quiet conditions. Additionally, we provide a brief overview of the electron flux responses of both KSEM PD and MPS-HI under enhanced space environment conditions, which shows differences based on sensor characteristics and satellite location.

Graphical Abstract
Development of Epigallocatechin 3-gallate-Loaded Hydrogel Nanocomposites for Oral Submucous Fibrosis
Authors: Mehta Chetan Hasmukh , Velagacherla Varalakshmi , Manandhar Suman , Nayak Yogendra , Pai Sreedhara Ranganath K , Acharya Shruthi , Nayak Usha Yogendra
Published: March 2024

Oral submucous fibrosis (OSF) is a chronic progressive disease associated with increased collagen deposition and TGF-β1 release. The current therapy and management have been a limited success due to low efficacy and adverse drug reactions. This study aimed to evaluate epigallocatechin 3-gallate (EGCG) encapsulated nanoparticles loaded mucoadhesive hydrogel nanocomposite (HNC) for OSF. Developed HNC formulations were evaluated for their permeation behaviour using in vitro as well as ex vivo studies, followed by evaluation of efficacy and safety by in vivo studies using areca nut extract-induced OSF in rats. The disease condition in OSF-induced rats was assessed by mouth-opening and biochemical markers. The optimized polymeric nanoparticles exhibited the required particle size (162.93 ± 13.81 nm), positive zeta potential (22.50 ± 2.94 mV) with better mucoadhesive strength (0.40 ± 0.002 N), and faster permeation due to interactions of the positively charged surface with the negatively charged buccal mucosal membrane. HNC significantly improved disease conditions by reducing TGF-β1 and collagen concentration without showing toxicity and reverting the fibroid buccal mucosa to normal. Hence, the optimized formulation can be further tested to develop a clinically alternate therapeutic strategy for OSF.

Graphical Abstract
Effects of microRNA-305 knockdown on brain gene expression associated with division of labor in honey bee colonies (Apis mellifera)
Authors: Stuart Sarai H. , Ahmed Amy C. Cash , Kilikevicius Laura , Robinson Gene E.
Published: March 2024

Division of labor in honey bee colonies is based on the behavioral maturation of adult workers that involves a transition from working in the hive to foraging. This behavioral maturation is associated with distinct task-related transcriptomic profiles in the brain and abdominal fat body that are related to multiple regulatory factors including juvenile hormone (JH) and queen mandibular pheromone (QMP). A prominent physiological feature associated with behavioral maturation is a loss of abdominal lipid mass as bees transition to foraging. We used transcriptomic and physiological analyses to study whether microRNAs (miRNAs) are involved in the regulation of division of labor. We first identified two miRNAs that showed patterns of expression associated with behavioral maturation, ame-miR-305-5p and ame-miR-375-3p. We then downregulated the expression of these two miRNAs with sequence-specific antagomirs. Neither ame-miR-305-5p nor ame-miR-375-3p knockdown in the abdomen affected abdominal lipid mass on their own. Similarly, knockdown of ame-miR-305-5p in combination with JH or QMP also did not affect lipid mass. By contrast, ame-miR-305-5p knockdown in the abdomen caused substantial changes in gene expression in the brain. Brain gene expression changes included genes encoding transcription factors previously implicated in behavioral maturation. The results of these functional genomic experiments extend previous correlative associations of microRNAs with honey bee division of labor and point to specific roles for ame-miR-305-5p.
Acute kidney injury and hypercalcemia associated with veterinary supplements applications in adult man
Authors: Frutuoso Bezerra Rádames , De Souza Andrade Tacilla Hanny , Bezerra de Araújo Flávio , Siqueira Athayde Lima Rafael
Published: March 2024

The compound “ADE” is an injectable oil for veterinary use which contains large amounts of vitamins A, D and E. The parenteral application in humans leads to a granuloma reaction which triggers hypercalcemia. A 42-year-old man was admitted with lower limb pain, nephrolithiasis and nephrocalcinosis. Laboratory tests revealed creatinine 4.59 mg/dl, calcium 13.3 mg/dl and parathormone 13.8 pg/ml. He underwent an ureterolithotripsy, stent placement, intravenous crystalloid fluids, and corticosteroid. He improved symptoms, kidney function and normalized serum calcium. The “ADE”-induced hypercalcemia diagnosis can be challenging. The early diagnosis may avoid negative outcomes.