bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Pulmonary and Sleep Disorders on COVID-19 Infection Severity in a Large Clinical Biobank
Authors: Cade Brian E. , Hassan Syed Moin , Mullington Janet M. , Karlson Elizabeth W. , Redline Susan
Published: February 2023

Rationale

Multiple pulmonary, sleep, and other disorders are associated with the severity of Covid-19 infections but may or may not directly affect the etiology of acute Covid-19 infection. Identifying the relative importance of concurrent risk factors may prioritize respiratory disease outbreaks research.

Objectives

To identify associations of common preexisting pulmonary and sleep disease on acute Covid-19 infection severity, investigate the relative contributions of each disease and selected risk factors, identify sex-specific effects, and examine whether additional electronic health record (EHR) information would affect these associations.

Methods

45 pulmonary and 6 sleep diseases were examined in 37,020 patients with Covid-19. We analyzed three outcomes: death; a composite measure of mechanical ventilation and/or ICU admission; and inpatient admission. The relative contribution of pre-infection covariates including other diseases, laboratory tests, clinical procedures, and clinical note terms was calculated using LASSO. Each pulmonary/sleep disease model was then further adjusted for covariates.

Measurements and main results

37 pulmonary/sleep diseases were associated with at least one outcome at Bonferroni significance, 6 of which had increased relative risk in LASSO analyses. Multiple prospectively collected non-pulmonary/sleep diseases, EHR terms and laboratory results attenuated the associations between preexisting disease and Covid-19 infection severity. Adjustment for counts of prior “blood urea nitrogen” phrases in clinical notes attenuated the odds ratio point estimates of 12 pulmonary disease associations with death in women by ≥1.

Conclusions

Pulmonary diseases are commonly associated with Covid-19 infection severity. Associations are partially attenuated by prospectively-collected EHR data, which may aid in risk stratification and physiological studies.
Longitudinal Humoral and Cell-Mediated Immune Responses in a Population-Based Cohort in Zurich, Switzerland between March and June 2022 - Evidence for Protection against Omicron SARS-CoV-2 Infection by Neutralizing Antibodies and Spike-specific T cell responses
Authors: Zens K.D. , Llanas-Cornejo D. , Menges D. , Fehr J.S. , Münz C. , Puhan M.A. , Frei A.
Published: February 2023

Background

The correlate(s) of protection against SARS-CoV-2 remain incompletely defined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection are needed.

Methods

We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed Spike (S)- and Nucleocapsid (N)-IgG and wildtype, delta, and omicron neutralizing antibodies. In a subset of 328 individuals, we evaluated S, Membrane (M) and N-specific T cells. 3 months later, we reassessed antibody (n=964) and T cell (n=141) responses and evaluated factors associated with protection from (re)infection.

Results

At study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Compared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. N-IgG titers in the top 33% of participants, omicron neutralizing antibodies in the top 25%, and S-specific T cell responses were all associated with reduced likelihood of (re)infection over time.

Conclusions

Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogenous. M/N T cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, omicron neutralizing antibodies and S-T cell responses may help estimate protection against SARS-CoV-2 (re)infection.
The effectiveness of digital delivery versus group-based face-to-face delivery of the English National Health Service Diabetes Prevention Programme: a non-inferiority retrospective cohort comparison study
Authors: Marsden Antonia M. , Hann Mark , Barron Emma , McGough Ben , Murray Elizabeth , Valabhji Jonathan , Cotterill Sarah
Published: February 2023

Introduction

Face-to-face group-based diabetes prevention programmes have been shown to be effective in many settings. Digital delivery may suit some patients, but research comparing the effectiveness of digital with face-to-face delivery is scarce. The aim was to assess if digital delivery of the English National Health Service Diabetes Prevention Programme (NHS DPP) is non-inferior to group-based face-to-face delivery in terms of weight change, and evaluate factors associated with differential change. The study included those recruited to the NHS DPP in 2017-2018.

Research design and methods

Individual-level data from a face-to-face cohort was compared to two cohorts on a digital pilot who (i) were offered no choice of delivery mode, or (ii) chose digital over face-to-face. Changes in weight at 6 and 12 months were analysed using mixed effects linear regression, having matched participants from the digital pilot to similar participants from face-to-face.

Results

Weight change on the digital pilot was non-inferior to face-to-face at both time points: it was similar in the comparison of those with no choice (difference in weight change: −0.284kg [95% CI: −0.712, 0.144] at 6 months) and greater in digital when participants were offered a choice (−1.165kg [95% CI: −1.841, −0.489]). Interactions between delivery mode and sex, ethnicity, age and deprivation were observed.

Conclusions

Digital delivery of the NHS DPP achieved weight loss at least as good as face-to-face. Patients who were offered a choice and opted for digital experienced better weight loss, compared to patients offered face-to-face only.
INTEGRATED NCDs TREATMENT AND CARE AMONG PEOPLE LIVING WITH HIV/AIDS ATTENDING CARE AND TREATMENT AT A HEALTH FACILITY
Authors: Musyani Atuganile , Mosi Grace , Kinyenje Erik , Damasceno Albertino , Mizinduko Mucho , Kishimba Rogath , Shimwela Meshack , Subi Leonard
Published: February 2023

Introduction

Persons living with HIV (PLHIV) in Tanzania now live longer due to the advancement of HIV care programs. For this reason, they are at an increased risk of developing Non-Communicable Diseases (NCDs). Despite many resources committed to HIV care programs, NCDs care is not effectively integrated into these programs. The study aimed at describing missed opportunities to diagnose and manage hypertension and diabetes and implementing and evaluating the effect of three months of preventive efforts among among PLHIV attending care and treatment centers (CTC)

Materials and methods

We evaluated 333 PLHIV attending CTC for blood pressure and blood sugar levels. Patients who were diagnosed with high blood pressure equal to or above 140/90 mm Hg, or on treatment for hypertension and a fasting blood sugar above 7.0 mmol/L (126 mg/dl) were subjected to a small intervention aimed at increasing health literacy on the adherence to and control of their pathologies. Re-evaluation of their blood pressure and blood sugar levels was done at the end of a 3 months intervention.

Results

Of the evaluated 333 PLHIV, 71 (21.32%) had hypertension and 9 (2.70%) had high blood sugar. Among 177 PLHIV who never had their BP measured before, 37/177 ((20.90%) were diagnosed with hypertension. The cohort group involved analysis of 76 patients with either uncontrolled hypertension or diabetes followed for three months. By the end of the 3rdmonth of intervention, 26/71 (36.6%) were able to control their blood pressure (BP < 140 SBP and < 90 DBP). The mean blood pressure decreased from 164/99.5 mmHg to 159 /96mmHg. Of the 9 PLHIV with high blood glucose levels, 5/9 (55.5%) had their blood sugar normalized at the end of the intervention. In a focused group discussion, most patients reported difficulties in controlling their BP due to the high cost of medication and consequently poor adherence to medication.

Conclusion

The burden of undiagnosed NCDs among PLHIV attending care and treatment clinic is remarkably high. Interventions to address such diseases in CTC seem to work. HIV care and treatment programs should provide integrated care that includes NCDs care.
Active methods, and their educational strategies during residencies of health professions: a scope review
Authors: Garcia Vera Lúcia , Soeiro Everton , de Oliveira José Maurício , Schiesari Laura , Gomes Romeu , Riera Rachel
Published: February 2023

The objective of this study is to map and evaluate the scientific production, on the different strategies / active methods in the context of residences of health professions. The study will be developed at Hospital Sírio-Libanês, São Paulo, Brazil. The scope review will be developed based on the methodological framework of the Joanna Brigss Institute (Peters et al., 2017). The review report will follow recommendations of the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for scoping reviews (PRISMA ScR) (Tricco, 2018). The protocol for this review was planned and made available on the MEdRxiv preprint database prior to the start of conducting the review. The following research question will guide for searching in databases: What and how are the different active methods used in the context of residencies of health professions? A broad and sensitive search will be carried out in the literature through structured search strategies, with relevant descriptors and synonyms, for the following databases or data repositories in the areas of education and/or health listed below: Biblioteca Virtual de Saúde (BVS), British Education Index (BEI), Campbell Collaboration, Cochrane Library (via Wiley), Education Research Complete (via EBSCO), Educational Resources Information Center – ERIC, Excerpta Medica Database (EMBASE, via Elsevier), Medical Literature Analysis and Retrieval System Online (MEDLINE, via PubMed), Online Education Database.
A Compendium of manually annotated genetic variants for Alkaptonuria-AKUHub
Authors: Akila S , Arun Kumar T.C , Shofia S , Srividya S , Suriyamoorthy N , Vijhayalakshmi R , scaria Vinod , Mehta Ratnesh Bhai
Published: February 2023

1.

Alkaptonuria or ‘black urine disease’ is a rare autosomal recessive disorder caused by dysfunctional homogentisate 1,2-dioxygenase (HGD) gene (3q13.33) leading to accumulation of homogentisic acid in the body. This inborn error in metabolism of phenylalanine and tyrosine causes accumulation of homogentisic acid leading to ochronosis, pigmentation in the sclera, ear cartilage, mitral valve calcification and osteoarthropathy. Advances in sequencing technologies have helped us to map genetic variants associated with alkaptonuria in diverse populations and regions. Currently, no centralized resource of all the reported actionable variants with uniformity in annotation exists for the HGD gene. We have compiled HGD exonic variants from various data sources and systematically annotated their pathogenicity according to American College of Medical Genetics and the Association of Molecular Pathologists (ACMG/AMP) variant classification framework. A total of 1686 exonic variants were catalogued and manually curated, creating one of the most comprehensive Alkaptonuria variant databases (AKUHub) which is publicly available.
Multicenter analysis of atrioesophageal fistula rates before and after adoption of active esophageal cooling during atrial fibrillation ablation
Authors: Sanchez Javier , Woods Christopher , Zagrodzky Jason , Nazari Jose , Singleton Matthew , Schricker Amir , Ruppert Annie , Brumback Babette , Jenny Benjamin , Athill Charles , Joseph Christopher , Shah Dipak , Upadhyay Gaurav , Kulstad Erik , Cogan John , Leyton-Mange Jordan , Cooper Julie , Tamirisa Kamala , Omotoye Samuel , Timilsina Saroj , Perez-Verdia Alejandro , Kaplan Andrew , Patel Apoor , Ro Alex , Corsello Andrew , Kolli Arun , Greet Brian , Willms Danya , Burkland David , Castillo Demetrio , Zahwe Firas , Nayak Hemal , Daniels James , MacGregor John , Sackett Matthew , Kutayli Michael , Barakat Michel , Percell Robert , Akrivakis Spyridon , Hao Steven C. , Liu Taylor , Panico Ambrose , Ramireddy Archana , Lanes Daniel Benhayon , Sze Edward , Francisco Greg , Silva Jose , McHugh Julia , Sung Kai , Feldman Leon , Serafini Nicholas , Kawasaki Raymond , Hongo Richard , Kuk Richard , Hayward Robert , Park Shirley , Vu Andrew , Henry Christopher , Bailey Shane , Mickelsen Steven , Taneja Taresh , Fisher Westby , Metzl Mark
Published: February 2023

Background

Active esophageal cooling reduces the incidence of endoscopically identified severe esophageal lesions during radiofrequency (RF) catheter ablation of the left atrium for the treatment of atrial fibrillation. No atrioesophageal fistula (AEF) has been reported to date with active esophageal cooling, and only one pericardio-esophageal fistula has been reported; however, a formal analysis of the AEF rate with active esophageal cooling has not previously been performed.

Methods

Atrial fibrillation ablation procedure volumes before and after adoption of active cooling using a dedicated esophageal cooling device (ensoETM, Attune Medical) were determined across 25 hospital systems with the highest total use of esophageal cooling during RF ablation. The number of AEFs occurring in equivalent time frames before and after adoption of cooling were then determined, and AEF rates were compared using generalized estimating equations robust to cluster correlation.

Results

Throughout the 25 hospital systems, which included a total of 30 separate hospitals, 14,224 patients received active esophageal cooling during RF ablation, with the earliest adoption beginning in March 2019 and the most recent beginning in March 2022. In the time frames prior to adoption of active cooling, a total of 10,962 patients received primarily luminal esophageal temperature (LET) monitoring during their RF ablations. In this pre-adoption cohort a total of 16 AEFs occurred, for an AEF rate of 0.146%, in line with other published estimates of <0.1% to 0.25%. No AEFs were found in the cohort treated after adoption of active esophageal cooling, yielding an AEF rate of 0% (P<0.0001).

Conclusion

Adoption of active esophageal cooling during RF ablation of the left atrium for the treatment of atrial fibrillation was associated with a significant reduction in AEF rate.
Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides
Authors: Stankov Sylvia , Vitali Cecilia , Park Joseph , Nguyen David , Mayne Leland , Englander S. Walter ,   Regeneron Genetics Center, Levin Michael G. , Vujkovic Marijana , Hand Nicholas J. , Phillips Michael C. , Rader Daniel J.
Published: February 2023

Background

Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, geneAPOA5) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring humanAPOA5variants can provide novel insights.

Methods

We used hydrogen-deuterium exchange mass spectrometry to determine the secondary structure of human apoA-V in lipid-free and lipid-associated conditions and identified a C-terminal hydrophobic face. Then, we used genomic data in the Penn Medicine Biobank to identify a rare variant, Q252X, predicted to specifically eliminate this region. We interrogated the function of apoA-V Q252X using recombinant proteinin vitroandin vivoinapoa5knockout mice.

Results

Human apoA-V Q252X carriers exhibited elevated plasma TG levels consistent with loss of function.Apoa5knockout mice injected with AAV vectors expressing wildtype and variantAPOA5-AAV recapitulated this phenotype. Part of the loss of function is due to reduced mRNA expression. Functionally, recombinant apoA-V Q252X was more readily soluble in aqueous solutions and more exchangeable with lipoproteins than WT apoA-V. Despite lacking the C- terminal hydrophobic region (a putative lipid binding domain) this protein also decreased plasma TGin vivo.

Conclusions

Deletion of apoA-V’s C-terminus leads to reduced apoA-V bioavailabilityin vivoand higher TG levels. However, the C-terminus is not required for lipoprotein binding or enhancement of intravascular lipolytic activity. WT apoA-V is highly prone to aggregation, and this property is markedly reduced in recombinant apoA-V lacking the C-terminus.
Differential age-specific effects of LDL cholesterol and body mass index on the risk of coronary heart disease
Authors: Xiao Jun , Chen Liangwan , Ye Weimin , Huang Wuqing
Published: February 2023

Background

Low-density lipoprotein cholesterol (LDLc) and body mass index (BMI) are not always correlated and their relationship is probably dependent on age, indicating differential age-specific effects of these two factors on health outcomes. We thus aimed to discriminate the effects of LDLc and BMI on the risk of coronary heart disease (CHD) across different age groups.

Methods

This is a prospective cohort study of 368,274 participants aged 38-73 years and free of CHD at baseline. LDLc and BMI were measured at baseline, and incident CHD was the main outcome. Cox proportional hazards model and restricted cubic spline (RCS) regression were used to estimate hazard ratio (HR) and 95% confidence interval (CI) of exposure on CHD.

Results

Similar relationships of LDLc and BMI with CHD risk were observed in overall population but in differential age-specific patterns. Across the age groups of <50, 50-54, 55-59, 60-64 and >=65 years, the LDLc-CHD association diminished with the adjusted HRs decreasing from 1.35, 1.26, 1.19, 1.11 to 1.08; while no declining trend was found in BMI-CHD relationship with the adjusted HRs of 1.15, 1.11, 1.12, 1.13 and 1.15, respectively. The interaction and mediation between LDLc and BMI on CHD risk were only present at young-age groups. And the LDLc-CHD but not BMI-CHD association was dependent on sex, metabolic syndrome and lipid-lowering drugs use.

Conclusion

There were differential age-specific effects of LDLc and BMI on the risk of developing CHD, calling for future efforts to discriminate the age-different benefits from lipids management or weight control on the primary prevention for CHD.

Clinical Perspective

What Is New?

This study shows, for the first time, that there were differential age-specific effects of LDLc and BMI on the risk of developing coronary heart disease (CHD), in which the LDLc-CHD association diminished with increasing age while no declining trend was found in BMI-CHD relationship.

The interaction and mediation between LDLc and BMI on the risk of coronary heart disease were only present in young adults.

What Are the Clinical Implications?

Future efforts are called to discriminate the age-different benefits from lipids management or weight control on the primary prevention for CHD.

Findings from this study highlighted that lipids management at young age was expected to have a much more favorable benefit in CHD prevention; and weight control shouldn’t be overlooked, especially for elderly adults, as lipid-lowering therapy might not contribute to the reduction of obesity-related CHD.
Educational attainment in hemorrhagic stroke severity and functional outcome
Authors: Yechoor Nirupama , Rist Pamela , Ganbold Alena , Kourkoulis Christina , Mora Samantha , Mayerhofer Ernst , Parodi Livia , Anderson Christopher D. , Rosand Jonathan
Published: February 2023

Introduction

While stroke education is a hallmark of clinical care in primary stroke centers, the educational attainment of patients is rarely considered. The objective of this study is to determine whether educational attainment, in addition to traditional risk factors, is associated with intracerebral hemorrhage (ICH) severity and functional outcomes.

Methods

Subjects were enrolled in a prospectively ascertained cohort of patients with primary ICH from 1994 until 2020 at the Massachusetts General Hospital Neurosciences Intensive Care Unit. Data on social determinants of health (SDOH), past medical history for ICH risk factors, and ICH severity were obtained on admission. The primary outcome was stroke severity, calculated using the ICH score. The secondary outcome was 12-month modified Rankin Score (mRS).

Results

Of 2,539 patients eligible for analyses, 1,744 (69%) presented with mild ICH (ICH Score < 3) and 795 (31%) presented with severe ICH (ICH score ≥3). In a multivariable logistic regression analysis controlling for age, income, and a pre-stroke diagnosis of coronary artery disease, only educational attainment was associated with stroke severity, with patients with high school-only education more likely to present with a severe ICH compared to college diplomates (odds ratio 2.37, 95% CI 1.77, 3.19).

Additionally, those with high school-only education were less likely to recover to a good functional outcome (mRS<4) after ICH when compared to college diplomates (odds ratio 0.43, 95% CI 0.19, 0.93) when controlling for stroke severity, and pre-stroke diagnoses of hypertension and dementia.

Discussion

Pre-stroke educational attainment is an independent predictor of ICH severity and subsequent functional outcomes at 12-month post-stroke. Given the association with recovery, tailoring inpatient stroke education to level of educational attainment may serve to reduce the disparity in outcomes after hemorrhagic stroke. Educational attainment may act as both a social and a biological determinant, and could represent a modifiable risk factor for ICH survivors.
Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis
Authors: Kayvanjoo Amir Hossein , Splichalova Iva , Bejarano David Alejandro , Huang Hao , Mauel Katharina , Makdissi Nikola , Heider David , Balzer Nora Reka , Osei-Sarpong Collins , Baßler Kevin , Schultze Joachim L. , Uderhardt Stefan , Kiermaier Eva , Beyer Marc , Schlitzer Andreas , Mass Elvira
Published: February 2023

During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
SARS-CoV2 mRNA-vaccination-induced Immunological Memory in Human Non-Lymphoid and Lymphoid Tissues
Authors: Proß Vanessa , Sattler Arne , Lukassen Sören , Tóth Laura , Laura Thole Linda Marie , Siegle Janine , Stahl Carolin , He An , Damm Georg , Seehofer Daniel , Götz Christina , Bayerl Christian , Jäger Pia , Macke Alexander , Eggeling Stephan , Kirzinger Bernadette , Mayr Thomas , Herbst Hermann , Beyer Katharina , Laue Dominik , Krönke Jan , Braune Jan , Rosseck Friederike , Friedersdorff Frank , Hubatsch Mandy , Weinberger Sarah , Lachmann Nils , Hofmann Veit Maria , Schrezenmeier Eva , Ludwig Carolin , Schrezenmeier Hubert , Jechow Katharina , Conrad Christian , Kotsch Katja
Published: February 2023

Tissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination has not been comprehensively analyzed in humans. We therefore studied SARS-CoV2 mRNA-vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow and spleen in comparison to paired blood samples from largely virus-naïve individuals. As opposed to lymphoid tissues, non-lymphoid organs harbored significantly elevated frequencies of Spike-specific CD4+T cells compared to paired peripheral blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived, vaccine-specific T helper (Th) cells were characterized by increased portions of multifunctional cells over those detected in blood. Single-cell RNA sequencing revealed functional rather than organ-specific clusters of Spike-reactive Th cells, indicating similar diversification programs across tissues. T cell receptor (TCR) repertoire analysis indicated that the TCR sequence is a major determinant of transcriptomic state in tissue-resident, vaccine-specific CD4+T cells. In summary, our data demonstrate that SARS-CoV2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.

One sentence summary

SARS-CoV2 mRNA vaccination-induced CD4+Th cells reside in both human lymphoid and non-lymphoid organs showing distinct adaptations in tissues with respect to memory differentiation, retention and function.
Assessing the feasibility of Phase 3 vaccine trials against Marburg Virus Disease: a modelling study
Authors: Qian George Y , Jombart Thibaut , Edmunds W John
Published: February 2023

Background

Outbreaks of Marburg virus disease (MVD) are rare and small in size, with only 16 recorded outbreaks since 1967, only two of which involved more than 100 cases. It has been proposed, therefore, that Phase 3 trials for MVD vaccines should be held open over multiple outbreaks until sufficient end points accrue to enable vaccine efficacy (VE) to be calculated. Here we estimate how many outbreaks might be needed for VE to be estimated.

Methods

We adapt a mathematical model of MVD transmission to simulate a Phase 3 individually randomised placebo controlled vaccine trial. We assume in the base case that vaccine efficacy is 70% and that 50% of individuals in affected areas are enrolled into the trial (1:1 randomisation). We further assume that the vaccine trial starts two weeks after public health interventions are put in place and that cases occurring within 10 days of vaccination are not included in VE calculations.

Results

The median size of simulated outbreaks was 2 cases. Only 0.3% of simulated outbreaks were predicted to have more than 100 MVD cases. 95% of simulated outbreaks terminated before cases accrued in the placebo and vaccine arms. Therefore the number of outbreaks required to estimate VE was large: after 100 outbreaks, the estimated VE was 69% but with considerable uncertainty (95% CIs: 0% - 100%) while the estimated VE after 200 outbreaks was 67% (95% CIs: 42% - 85%). Altering base-case assumptions made little difference to the findings.

Conclusions

It is unlikely that the efficacy of any candidate vaccine can be calculated before more MVD outbreaks have occurred than have been recorded to date. This is because MVD outbreaks tend to be small, public health interventions have been historically effective at reducing transmission, and vaccine trials are only likely to start after these interventions are already in place. Hence, it is expected that outbreaks will terminate before, or shortly after, cases start to accrue in the vaccine and placebo arms. Manufacturers may want to consider alternative routes to licensure than Phase 3 trials for MVD vaccines.
Examining the governance arrangements for healthcare worker COVID-19 protection in Kenya: A Scoping Review
Authors: Kazungu Jacob , Kagwanja Nancy N , Wang Huihui , Chuma Jane , Munge Kenneth
Published: February 2023

Healthcare workers (HCWs) face a high risk of infection during pandemics or public health emergencies as demonstrated in the ongoing COVID-19 pandemic. Understanding how governments respond can inform public health control measures and support health system functioning. An economic impact analysis examining HCW COVID-19 infections in Kenya and three other countries estimated that the total economic costs related to HCW COVID-19 infections costs and deaths in Kenya were US$113.2 million (range US$35.8-US$246.1). We examined the governance arrangements for HCW protection during the COVID-19 pandemic in Kenya between March 2020 and March 2021.

Governance arrangements were examined following a scoping review of 44 policy and legislative documents and reports of HCW protection and 22 media articles. We adopted the transparency, accountability, participation, integrity and capacity (TAPIC) governance framework to analyse and summarize our findings into policy gaps and implementation challenges.

Policy design gaps included inadequate provisions for emerging threats, inconsistencies with the devolved context and inadequate structures to monitor, inform and respond to HCW COVID-19 infections. Implementation challenges were attributed to inadequate quantity and quality of PPE, difficulty in accessing medical care for HCWs, delays in HCW remuneration, insufficient infection prevention and control measures, the top-down application of plans, difficulties in working in a decentralized context, and pre-existing public finance management (PFM) bottlenecks.

Implementation of HCW protection during the COVID-19 pandemic and beyond could leverage the revamping of current legislation on labour relations to reflect devolved governance and develop a broader and long-term approach to occupational health and safety implementation that considers all HCWs. Improvements in PFM arrangements coupled with increased investment in the health sector and attention to efficient use of resources will also impact positively on HCW protection.
Association of newly diagnosed atrial fibrillation with remote intracerebral hemorrhage after intravenous thrombolysis: Results from a multicenter study in China
Authors: Pan Xiaoling , Pei Yingjian , Zhang Meixia , Zhong Wansi , Hu Jin , Wang Zhimin , Xu Dongjuan , Lou Min , Chen HongFang , Chen Zhicai
Published: February 2023

Objective

To investigate the association of atrial fibrillation (AF), especially newly diagnosed AF, with remote intracerebral hemorrhage (rICH) in patients with ischemic stroke treated by intravenous thrombolysis.

Methods

This is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator whose data were taken from a multicenter prospective registry of a Chinese population. RICH was defined as any extraischemic hemorrhage detected by imaging examination ≤ 24 hours after intravenous thrombolysis. We collected the demographic data and clinical characteristics of all the patients. We compared patients with rICH and those without any type of hemorrhagic transformation. The association of AF and rICH was analyzed by univariate analysis and binary logistic regression.

Results

We evaluated 20697 patients, 1566 (7.6%) of whom developed intracerebral hemorrhage (ICH), 586 (2.8%) of whom experienced rICH, and 19131 (92.4%) of whom did not experience any type of hemorrhagic transformation. Univariate analysis showed that there were significant differences in age, prethrombolysis systolic blood pressure, baseline NIHSS score, known AF, newly diagnosed AF, coronary heart disease, congestive heart failure, hyperhomocysteinemia and history of thrombolysis between the rICH and control groups (P < 0.05). Further multivariate logistic regression analysis showed that total AF [OR 1.821, (95%CI, 1.082-3.065), P < 0.05], known AF [OR 1.470, (95%CI, 1.170-1.847)] and newly diagnosed AF [OR 1.920, (95%CI, 1.304-2.825)] were all independently associated with rICH.

Conclusions

This study suggests that AF (regardless of the newly diagnosed or known AF) may be associated with the occurrence of rICH after intravenous thrombolysis. Interestingly, newly diagnosed AF may have a greater impact on rICH than known AF, but that finding needs to be confirmed by a larger prospective sample.
Hydraulic adjustments of Scots pine colonizing a harsh environment on volcano slopes
Authors: Barigah Têtè Sévérien , Santos Farnese Fernanda Dos , De Menezes Silva Paulo , Humbert Paul , Ennajeh Mustapha , Ngao Jérôme , Badel Eric , Cochard Hervé , Herbette Stephane
Published: February 2023

The ability of trees to survive and naturally regenerate in increasing drought conditions will depend on their capacity to vary key hydraulic and morphological traits that increase drought tolerance. Despite many studies investigating variability in these drought-tolerant traits, there has been limited investigation into this variability under recurrent severe drought conditions since the establishment phase.

We investigated the long-term hydraulic and leaf trait adjustments of Scots pine trees settled in an abandoned slag quarry by comparing them across three different topographic positions inducing contrasted effects on growth and development. We measured xylem and foliar traits to compare the water status of trees according to tree location and to evaluate the respective risk for xylem hydraulic failure using the soil-plant hydraulic modelSurEau.

Compared to upslope and downslope trees, slope trees exhibited lower growth, vulnerability to embolism, specific hydraulic conductivity and photosynthetic pigment contents, as well as higher water potential at turgor loss point and midday water potentials. The hydraulic adjustments of trees settled on slag slopes reduced the risk for hydraulic failure and thus prevented an increase in embolism compared to downslope and upslope trees. These results suggest a prioritization of hydraulic safety over growth in Scots pine developed in a harsh environment, resulting in a dwarf phenotype.
A human cortical adaptive mutual inhibition circuit underlying competition for perceptual decision and repetition suppression reversal
Authors: Sousa Teresa , Sayal Alexandre , Duarte João V. , Costa Gabriel N. , Castelo-Branco Miguel
Published: February 2023

A model based on inhibitory coupling has been proposed to explain perceptual oscillations. This ‘adapting reciprocal inhibition’ model postulates that it is the strength of inhibitory coupling that determines the fate of competition between percepts. Here, we used an fMRI-based adaptation technique to reveal the influence of neighboring neuronal populations, such as reciprocal inhibition, in motion-selective hMT+/V5. If reciprocal inhibition exists in this region, the following predictions should hold: 1. stimulus-driven response would not simply decrease, as predicted by simple repetition-suppression of neuronal populations, but instead increase due to the activity from adjacent populations; 2. perceptual decision involving competing representations, should reflect decreased reciprocal inhibition by adaptation; 3. neural activity for the competing percept should also later on increase upon adaptation. Our results confirm these three predictions, showing that a model of perceptual decision based on adapting reciprocal inhibition holds true. Finally, they also show that the well-known repetition suppression phenomenon can be reversed by this mechanism.

Significance Statement

fMRI-based adaptation has been developed as a tool to identify functional selectivity in the human brain. This is based on the notion that stimulus-selective adaptation leads to direct response suppression. In this study, we go a step further by showing that adaptation can also reveal the influence of neighboring neuronal populations. Our data reveals neural evidence for a disinhibition effect as a result of the adaptation of adjacent populations, which is in line with the adapting reciprocal inhibition model. Reciprocal inhibition can, thus, be tracked in the human brain using fMRI, adding to the understanding of human multistable perception and the neural coding of visual information. Moreover, our results also provide a mechanism for reversal of repetition suppression.
Ventral premotor cortex influences spinal cord activation during force generation
Authors: Braaß Hanna , Feldheim Jan , Chu Ying , Tinnermann Alexandra , Finsterbusch Jürgen , Büchel Christian , Schulz Robert , Gerloff Christian
Published: February 2023

Force generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is influenced by cerebral primary motor and premotor areas is poorly understood. Here we conducted combined cortico-spinal functional MRI during a simple visually guided isometric force generation task in a group of 20 healthy young subjects. Activation was localized in the ipsilateral cervical spinal cord and contralateral primary motor and premotor areas. The main finding is that spinal activation was influenced by ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding which extends our understanding about human motor function beyond the animal literature.
Machine Learning-based Modeling of Olfactory Receptors in their Inactive State: Human OR51E2 as a Case Study
Authors: Alfonso-Prieto Mercedes , Capelli Riccardo
Published: February 2023

Atomistic-level investigation of olfactory receptors (ORs) is a challenging task due to the experimental/computational difficulties in the structural determination/prediction for members of this family of G-protein coupled receptors. Here we have developed a protocol that performs a series of molecular dynamics simulations from a set of structures predictedde novoby recent machine learning algorithms and apply it to a well-studied receptor, the human OR51E2. Our study demonstrates the need for simulations to refine and validate such models. Furthermore, we demonstrate the need for the sodium ion at a binding site near D2.50and E3.39to stabilize the inactive state of the receptor. Considering the conservation of these two acidic residues across human ORs, we surmise this requirement also applies to the other ∼400 members of this family.
Dispersal of PRC1 condensates disrupts polycomb chromatin domains and loops
Authors: Williamson Iain , Boyle Shelagh , Grimes Graeme , Friman Elias , Bickmore Wendy A.
Published: February 2023

Polycomb-repressive complex 1 (PRC1) has a strong influence on 3D genome organization, mediating local chromatin compaction as well as localized and chromosome-wide clustering of target loci. Several subunits of PRC1 have been shown to have the capacity to form biomolecular condensates through liquid-liquid phase separationin vitroand when tagged and over-expressed in cells. Here, we use 1,6-hexandiol, which disrupts liquid-like condensates, to examine the role of endogenous PRC1 biomolecular condensates on local and chromosome-wide clustering of PRC1-bound loci. Using imaging and chromatin immunoprecipitation combined with deep sequencing analyses, we show that PRC1-mediated chromatin compaction and clustering of targeted genomic loci – at megabase and tens of megabase length scales – can be reversibly disrupted by the addition and subsequent removal of 1,6-hexandiol to mouse embryonic stem cells. Decompaction and dispersal of polycomb domains and clusters cannot be solely attributable to the reduction of PRC1 binding following 1,6-hexandiol treatment as the addition of 2,5-hexandiol has similar effects on binding despite this alcohol not perturbing PRC1-mediated 3D clustering, at least at the sub-megabase and megabase scales. These results suggest that weak hydrophobic interactions between PRC1 molecules, characteristic of liquid-liquid phase separation, have a role in polycomb-mediated genome organization.
Label-free histological analysis of retrieved thrombi in acute ischemic stroke using optical diffraction tomography and deep learning
Authors: Chung Yoonjae , Kim Geon , Moon Ah-Rim , Ryu Donghun , Hugonnet Herve , Lee Mahn Jae , Shin Dongseong , Lee Seung-Jae , Lee Eek-Sung , Park Yongkeun
Published: February 2023

For patients with acute ischemic stroke, histological quantification of thrombus composition provides evidence for determining appropriate treatment. However, the traditional manual segmentation of stained thrombi is laborious and inconsistent. In this study, we propose a label-free method that combines optical diffraction tomography (ODT) and deep learning (DL) to automate the histological quantification process. The DL model classifies ODT image patches with 95% accuracy, and the collective prediction generates a whole-slide map of red blood cells and fibrin. The resulting whole-slide composition displays an average error of 1.1% and does not experience staining variability, facilitating faster analysis with reduced labor. The present approach will enable rapid and quantitative evaluation of blood clot composition, expediting the preclinical research and diagnosis of cardiovascular diseases.
A new look at the architecture and dynamics of theHydranerve net
Authors: Keramidioti Athina , Schneid Sandra , Busse Christina , von Laue Christoph Cramer , Bertulat Bianca , Salvenmoser Willi , Heß Martin , Alexandrova Olga , Glauber Kristine M. , Steele Robert E. , Hobmayer Bert , Holstein Thomas , David Charles N.
Published: February 2023

TheHydranervous system is the paradigm of a “simple nerve net”. Nerve cells inHydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of theHydranerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells inHydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM and serial block face SEM show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.
Bayesian inference of toothed whale lifespans
Authors: Ellis Samuel , Croft Darren P , Nielsen Mia Lybkær Kronborg , Franks Daniel W , Weiss Michael N
Published: February 2023

Accurate measures of lifespan and age-specific mortality are important both for understanding life history evolution and informing conservation and population management strategies. The most accurate data to estimate lifespan are from longitudinal studies, but for many species – especially those such as toothed whales that are wide-ranging and inhabit difficult-to-access environments - these longitudinal data are not available. However, other forms of age-structured data – such as from mass-strandings - are available for many toothed species, and using these data to infer patterns of age-specific mortality and lifespan remains an important outstanding challenge. Here we develop and test a Bayesian mortality model to derive parameters of a mortality function from age-structured data while accounting for potential error introduced by mistakes in age estimation, sampling biases and population growth. We then searched the literature to assemble a database of 269 published age-structured toothed whale datasets. We applied our mortality model to derive lifespan estimates for 32 species of female and 33 species of male toothed whale. We also use our model to characterise sex differences in lifespan in toothed whales. Our mortality model allows us to curate the most complete and accurate collection of toothed whale lifespans to date.
Seasonal and genetic effects on lipid profiles of juvenile Atlantic salmon
Authors: House Andrew H. , Debes Paul V. , Holopainen Minna , Käkelä Reijo , Donner Iikki , Frapin Morgane , Pashay Ehsan , Kurko Johanna , Ruhanen Hanna , Primmer Craig R.
Published: February 2023

Seasonality can influence many physiological traits requiring optimal energetic capacity for life-history stage transitions. In Atlantic salmon, high-energy status is essential for the initiation of maturation. Atlantic salmon lipid reserves are predominantly found in the viscera and myosepta in the muscle while the liver is essential for maintaining lipid metabolism. A genomic study found a region including a transcription co-factor-coding gene,vgll3, linked to Atlantic salmon maturation timing, which acts as an inhibitor of adipogenesis in mice, and mediates maturation via condition factor in Atlantic salmon. Here we investigate the influence of season andvgll3genotypes associating with early (EE) and late (LL) maturation on lipid profiles in the muscle and liver in juvenile Atlantic salmon. We reared Atlantic salmon for two years until the occurrence of sexually mature males and sampled muscle and liver at two time points: spring and autumn of the second year. We found no seasonal or genotype effect in lipid profiles in muscle of immature males and females. However, in the liver we did detect a triacylglycerol (TG) enrichment and a genotype specific direction of change in membrane lipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), from spring to autumn. Specifically, from spring to autumn membrane lipid concentrations increased in vgll3*EE individuals and decreased in vgll3*LL individuals. This could be explained with two possible scenarios 1) a seasonally more stable capacity of endoplasmic reticulum (ER) functions invgll3*EE individuals compared tovgll3*LL individuals or 2)vgll3*LL individuals storing larger lipid droplets from spring to autumn in the liver compared tovgll3*EE individuals at the expense of ER capacity. This genotype specific seasonal direction of change in membrane lipid concentrations provides more indirect evidence that a mechanism linkingvgll3with lipid metabolism and storage exists.

Highlights

Seasonal lipid species profile separation in muscle and liver in juvenile Atlantic salmon

Genotype specific direction of change of membrane lipids from spring to autumn

Indirect evidence that a mechanism linkingvgll3with lipid metabolism and storage exists