title: FiMAP: A Fast Identity-by-Descent Mapping Test for Biobank-scale Cohorts

abstract: Although genome-wide association studies (GWAS) have identified tens of thousands of genetic loci, the genetic architecture is still not fully understood for many complex traits. Most GWAS and sequencing association studies have focused on single nucleotide polymorphisms or copy number variations, including common and rare genetic variants. However, phased haplotype information is often ignored in GWAS or variant set tests for rare variants. Here we leverage the identity-by-descent (IBD) segments inferred from a random projection-based IBD detection algorithm in the mapping of genetic associations with complex traits, to develop a computationally efficient statistical test for IBD mapping in biobank-scale cohorts. We used sparse linear algebra and random matrix algorithms to speed up the computation, and a genome-wide IBD mapping scan of more than 400,000 samples finished within a few hours. Simulation studies showed that our new method had well-controlled type I error rates under the null hypothesis of no genetic association in large biobank-scale cohorts, and outperformed traditional GWAS approaches and variant set tests when the causal variants were untyped and rare, or in the presence of haplotype effects. We also applied our method to IBD mapping of six anthropometric traits using the UK Biobank data and identified a 4 cM region on chromosome 8 associated with multiple traits related to body fat distribution or weight.


title: Low dose mRNA-1273 COVID-19 vaccine generates durable T cell memory and antibodies enhanced by pre-existing crossreactive T cell memory

abstract:
Understanding human immune responses to SARS-CoV-2 RNA vaccines is of interest for a panoply of reasons. Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 g Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 g) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFN{gamma}-expressing cells. Spike CD8+ T cells were generated in 88% of subjects, with equivalent percentages of CD8+ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing crossreactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4+ T cells.

One-Sentence SummaryThe mRNA-1273 vaccine induces a durable and functional T cell and antibody response comparable to natural infection.

category: infectious diseases


title: Structural connectivity of subthalamic nucleus stimulation for improving freezing of gait

abstract: Gait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinsons disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinsons Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.

category: neurology


title: Model-informed target product profiles of long acting-injectables for use as seasonal malaria prevention

abstract: 1.Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine(SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimizing LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process.

category: epidemiology


title: Angiotensin II receptor I auto-antibodies following SARS-CoV-2 infection

abstract:
BACKGROUNDCoronavirus disease 2019 (COVID-19) is associated with endothelial activation and coagulopathy, which may be related to pre-existing or infection-induced pro-thrombotic autoantibodies such as those targeting angiotensin II type I receptor (AT1R-Ab).

METHODSWe compared prevalence and levels of AT1R-Ab in COVID-19 cases with mild or severe disease to age and sex matched negative controls.

RESULTSThere were no significant differences between cases and controls. However, there were trends toward a higher proportion with AT1R-Ab positivity among severe cases versus controls (32% vs. 11%, p=0.1) and higher levels in those with mild COVID-19 compared to controls (median 9.5U/mL vs. 5.9U/mL, p=0.06).

CONCLUSIONSThese findings suggest that AT1R-Ab are not consistently associated with COVID-19 but do not exclude a contribution to endothelial pathology in a subset of people.


title: SARS-CoV-2 environmental contamination from hospitalised COVID-19 patients receiving aerosol generating procedures

abstract:
BackgroundContinuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered  aerosol-generating procedures (AGPs) in the treatment of COVID-19. We aimed to measure air and surface environmental contamination of SARS-CoV-2 virus when CPAP and HFNO were used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients.

Methods30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen [≥]0.4 to maintain oxygen saturations [≥]94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. RT qPCR analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus.

ResultsOverall 21/30 (70%) of participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination. Only one nasopharyngeal sample was culture positive.

ConclusionsThe use of CPAP and HFNO to treat moderate/severe COVID-19 was not associated with significantly higher levels of air or surface viral contamination in the immediate care environment.

category: respiratory medicine


title: Social isolation, loneliness and all-cause dementia: a longitudinal and imaging-genetic study in the UK Biobank cohort

abstract:
INTRODUCTIONCurrent findings of the relative influence of social isolation and loneliness on dementia are contradictory, and the potential neurobiological mechanisms are unclear.

METHODSWe utilized the UK Biobank to investigate the relationships of social isolation and loneliness with dementia (n = 462,619). Neuroanatomical correlates were identified in a subset of participants (n = 32,263). The transcriptomic signatures of related brain changes were characterized by gene enrichment analysis.

RESULTSAfter full adjustment, social isolation but not loneliness was associated with dementia (hazard ratio: 1.28, 95% confidence interval: 1.17-1.39). Isolated individuals had reduced gray matter volumes in temporal, frontal, occipital and subcortical regions (e.g., hippocampus and amygdala). Relevant brain changes were spatially correlated with genes involved in mitochondrial dysfunction and oxidative phosphorylation, and down-regulated Alzheimers disease-related genes.

DISCUSSIONSocial isolation is an independent risk factor for dementia, which could be partly explained by related structural changes coupling with altered molecular functions.

category: psychiatry and clinical psychology


title: Impacts of school closure due to COVID-19 on the mobility trend of Japanese citizens

abstract: School closure was the only main control measure that Japan took into action from late February to late March in 2020. Accurate evaluation of how Japanese citizens responded to the impact of school closure remains a challenge. Data from the Google COVID-19 Community Mobility Report was used to analyze the mobility trend of Japanese citizens regarding six categories, including retail and recreation, grocery and pharmacy, parks, transit stations, workplace, and residential. The median percentage of mobility in all 47 prefectures of Japan was calculated during five periods of time, including one week before school closure, one week, two weeks, three weeks, and four weeks after school closure. There was a significant decline in the mobility trend of transit stations, grocery and pharmacy, parks, retail and recreation, and workplace at the moment after school closure compared to the prior period. Inversely, the mobility trend in staying at home remarkably increased following the implementation of school closure. Our study determined a significant change in the mobility trend of Japanese citizens before and after school closure. These data reflected the responsibility and the consciousness of Japanese citizens in mitigating COVID-19.

category: public and global health


title: Clinical usage of non-invasive ventilation by physical therapists in cystic fibrosis centres across Australia: A cross-sectional survey study

abstract:
BACKGROUNDThis study investigated clinical usage of non-invasive ventilation during physical therapy for people with cystic fibrosis. Specific research questions were: What are the clinical indications, contraindications and patient selection criteria for non-invasive ventilation use as an adjunct to physical therapy in people with cystic fibrosis? 2. Who implements non-invasive ventilation, what settings are used and how are they determined? 3. What outcome measures are used to determine the effectiveness of non-invasive ventilation as an adjunct to physical therapy and what are the main benefits and complications?

METHODSA purpose-designed survey was sent to 23 Australian cystic fibrosis centres.

RESULTSFifteen centres (65%) responded, with 13 reporting current utilization of non-invasive ventilation to assist physical therapy. Non-invasive ventilation was most commonly (85%) used in patients with lung function <40% predicted. Physical therapy clinical indications included shortness of breath at rest (100%) and during airway clearance (100%), and fatigue during airway clearance (100%). Physical therapists were responsible for initiating non-invasive ventilation (62%), setting up (85%) and determining settings (62%). Bi-level ventilation was the only chosen ventilation mode. Benefits reported included improved ease of airway clearance (100%), reduced fatigue (92%) and decreased dyspnoea (85%). Only one complication of haemoptysis was reported.

CONCLUSIONSNon-invasive ventilation was used during physical therapy in people with cystic fibrosis who had severe disease, mostly during airway clearance to improve tolerability of treatment. Australian physical therapists initiated non-invasive ventilation when people with cystic fibrosis experienced shortness of breath or fatigue during treatment, aligning with current clinical guidelines. Clinical usage was largely consistent across centres, with numerous benefits and few complications reported. Further research is required to explore benefits of non-invasive ventilation use during physical therapy.


title: Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study

abstract:
BackgroundPatients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear.

ObjectivesTo evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3rd dose (3D).

DesignProspective observational.

Setting, Patients, intervention and measurementsREIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients.

ResultsVaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23-21.54]; p=0.029).

LimitationsLimited number of patients injected with 3D.

ConclusionStandard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3rd dose of vaccine.

RegistrationNCT04881396

Funding SourceNone

category: nephrology


title: Object and Instance Detection Within Image Scenes

abstract: This paper compares state-of-the-art methods in object and instance detection, and examines why YOLO (You Only Look Once) outperforms top detection methods. Different Pascal VOC dataset is used as the benchmark to explore mean average precision(mAP). YOLO is twice as accurate to prior works on real-time detection. The outcome of of merging YOLO with Fast R-CNN is an increased mean average precision (mAP) which results in performance boost. Hence, YOLO is an enhanced model of top detection methods.

category: health informatics


title: SARS-CoV-2 B.1.1.7 lineage rapidly spreads and overwhelms R.1 lineage in Japan: serial and stationary observation in a community

abstract:
BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) circulates in the world and acquires mutations during evolution. To identify the new emergent variants, the surveillance of the variants of concern (VOC) and variants of interest (VOI) is ongoing. This study aimed to determine how the transition of viral lineage occurred by stationary genome analysis in Yamanashi, Japan.

MethodsWe performed the whole genome sequencing using SARS-CoV-2 positive samples (n=325) collected from February 2020 to the end of June 2021. The number of analyzed samples accounted for 15.4% of the total 2,109 samples identified in our community. Viral lineage was defined by the Phylogenetic Assignment of Named Global Outbreak (PANGO) lineages.

ResultsWe identified 13 types of viral lineages including R.1, P.1, B.1.1.7 (Alpha) and B.1.617.2 (Delta) These virus lineages had distinct periods of expansion and decline. After the emerging of the R.1 lineage harboring E484K variant (designated VOI in Japan), the prevalent B.1.1.214 lineage were no longer identified. The R.1 lineages were temporarily prevalent afterwards, but the influx of B.1.1.7 lineage (designated VOC) led to a decline in R.1. Currently, B.1.1.7 has become dominant after mid-April, 2021.

ConclusionWe clearly elucidated the transition and replacement of viral lineage by the community-based analysis. The virus completely replaced by more infectious lineages, therefore, it will be necessary to continue to monitor the VOC and VOI.


title: Sex- and Gender-specific Risk Factors of Post-COVID-19 Syndrome: A Population-based Cohort Study in Switzerland

abstract:
BackgroundEvidence to date indicates that mortality of acute coronavirus disease (COVID-19) is higher in men than in women. Conversely, women seem more likely to suffer from long-term consequences of the disease and pronounced negative social and economic impacts. Sex- and gender specific risk factors of COVID-19-related long-term effects are unknown.

MethodsWe conducted a multicentre prospective observational cohort study of 5838 (44.6% women) individuals in Switzerland who were tested positive for SARS-CoV-2 RNA between February and December 2020. Of all surviving individuals who met the inclusion criteria, 2799 (1285 [45.9%] women) completed a follow-up questionnaire.

FindingsAfter a mean follow-up time of 197{+/-}77 days, women more often reported at least one persistent symptom (43.0% vs 31.5%, p<0.001) with reduced exercise tolerance and reduced resilience being the most frequently reported symptom in both sexes. Critical illness (intermediate or intensive care unit admission) during acute SARS-CoV-2 infection (odds ratio[95%CI]: 4.00[2.66-6.02], p<0.0001 was a risk factor of post-COVID syndrome in both women and men. Women with pre-existing mental illness (1.81[1.00-3.26], p=0.049), cardiovascular risk factors (1.39[1.03-1.89], p=0.033), higher self-reported domestic stress levels (1.15[1.08-1.22], p<0.0001), and feminine gender identity (1.12[1.02-1.24], p=0.02) increased the odds of experiencing post-COVID syndrome. Conversely, obesity (1.44[1.03-2.02], p=0.034) increased the odds of post-COVID syndrome in men, but not in women. Being responsible for household work (men, OR 0.82[0.69-0.97], p=0.021), taking care of children/relatives (women, 0.90[0.84-0.96], p=0.002) or being pregnant at the time of acute COVID-19 illness (OR 0.48[0.23-1.01], p=0.054) was associated with lower odds of post-COVID syndrome.

InterpretationPredictors of post-COVID syndrome differ between men and women. Our data reinforce the importance to include sex and gender to identify patients at risk for post-COVID syndrome so that access to care and early intervention can be tailored to their different needs.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe performed a PubMed search for studies investigating short- and long-term health sequelae in COVID-19 survivors. We included all studies published prior to May 30th, 2021. The search comprised the following terms: (COVID-19 OR SARS-CoV-2 OR Coronavirus disease 2019 OR 2019-nCoV) AND (post COVID OR long COVID OR survivor OR recover OR persistent OR follow up OR discharge OR long-term OR sequelae). Previous studies have reported a variety of symptoms in COVID-19 survivors from different countries such as China (Wuhan), the UK, and the U.S. Overall, these studies showed that a substantial burden of health issues spanning multiple organ systems is experienced by patients who survive after the acute phase of COVID-19. The most frequent symptoms reported after acute infection were fatigue, muscle weakness, sleep disturbances, headache, dyspnoea, anxiety, depression, and anosmia. Two studies indicate that women are overrepresented amongst post-COVID-19 syndrome patients suffering from fatigue, headache, dyspnoea, or anosmia. However, the representativeness of the studies and the explicitness of provided information were insufficient due to lacking variables and/or small numbers of cases and the short duration of follow-up. Sex-and gender-specific predictors of post-COVID-19 syndrome are currently unknown.

Added value of this studyIn a large cohort study (n=2799) with long follow-up (mean follow-up 197{+/-}77 days), we investigated sex- and gender-specific predictors of post-COVID-19 health sequalae. Our data allow for identification of sex- and gender-specific predictors of post-COVID-19 syndrome. In a multivariable association model, post-COVID-19 syndrome was associated with severity of illness and number of symptoms during acute SARS-CoV-2 infection in both sexes, while pre-existing mental illness and cardiovascular risk factors were significant predictors only in women. Conversely, obesity was independently associated with post-COVID-19 syndrome in men, but not in women. Gender-related risk factors of post-COVID syndrome were feminine traits and higher amount of domestic stress, both increasing the odds of post-COVID-19 syndrome in women, while pregnancy during acute COVID-19 illness and responsibility for childcare protected women, and responsibility for household work protected men from experiencing post-COVID-19 syndrome.

Implications of all the available evidenceEvidence indicates that mortality from COVID-19 infection is higher in men than women. We provide evidence that female sex and gender is associated with long-term sequalae of COVID-19. Our data reinforce the importance of including gender to identify patients at risk for post-COVID-19 syndrome so that the functional return of both male and female COVID-19 survivors can be maximized.


title: Quantifying contribution of Lipoprotein (a) to atherogenic lipoprotein burden: a novel particle-based approach

abstract:
BackgroundElevated lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). As clinical LDL cholesterol [LDL-C] incorporates cholesterol from Lp(a) [Lp(a)-C], there is interest in quantifying the contribution of Lp(a)-C to LDL-C given implications for risk assessment, diagnosis, and treatment. Estimating Lp(a)-C is subject to inaccuracies; measuring Lp(a) particle number [Lp(a)-P] is more accurate.

ObjectiveTo capture how Lp(a) contributes to the atherogenic lipoprotein burden, we demonstrate a particle-based approach using readily available measures of Lp(a)-P and apolipoprotein B (apoB).

MethodsUsing the Very Large Database of Lipids (VLDbL), we compared Lp(a)-P (nmol/L) with all atherogenic particles ("non-HDL-P"). Non-HDL-P was calculated by converting apoB mass to molar concentration using the preserved molecular weight of apoB100 (512 kg/mol). We calculated the percentage of Lp(a)-P relative to non-HDL-P by Lp(a)-P deciles and stratified across sex, age, triglycerides, LDL-C, and non-HDL-C.

Results158,260 patients from the VLDbL were included. The fraction Lp(a)-P/non-HDL-P increased with rising Lp(a)-P. Lp(a)-P comprised on average 3% of atherogenic particles among the study population and 15% at the highest Lp(a)-P decile. Findings were similar when stratified by sex. When stratified by age, Lp(a)-P/non-HDL-P was highest among the youngest and oldest patients. Lp(a)-P/non-HDL-P decreased at higher levels of triglycerides and LDL-C owing to larger contributions from VLDL and LDL.

ConclusionsWe demonstrate a particle-based approach to quantify the contribution of Lp(a) to total atherogenic particle burden using validated and widely available laboratory assays. Future research applying this method could define clinically meaningful thresholds and inform use in risk assessment and management.

category: cardiovascular medicine


title: A cross-sectional cohort study of prevalence of antibodies to COVID-19 in Port-au-Prince, Haiti

abstract:
IntroAs of January 14, 2021, Haiti has had 10,781 confirmed (first case March 19th) and 45,927 suspected cases of COVID-19, with 240 official deaths.

MethodsFrom May until September, 2020, we tested visitors to 20 clinics, for COVID-19 in five neighborhoods of Port-au-Prince as part of a public health effort to determine prevalence of COVID-19 in the general community. In order to estimate changes in number of deaths, the team visited eighteen funeral homes to solicit data on the number of funerals conducted for each month in 2019 and through October 2020. We also sought to evaluate the attitudes of Port-au-Prince citizens towards a generic COVID-19 vaccine in April 2021.

ResultsIn May and July 2020, 11.4% and 9.1% of those tested were positive for antibodies to COVID-19, respectively. The number of funerals held in the Port-au-Prince area increased by 69.6.% (CI 95% 56.1-83.1) since the official arrival of COVID-19 on March 19th. We found high rates of vaccine hesitancy with 76% saying they would not take a free COVID-19 vaccine. Further research is needed to validate the findings here, but there are strong suggestions that COVID-19 has had more of an impact than previously reported.

 What is already known on this subject?Very little is known about the true epidemiology of COVID-19 in Haiti due to lack of testing, stigma, and lack of resources. The Ministry of Health reports Haiti has had 10,781 confirmed (first case March 19th) and 45,927 suspected cases of COVID-19, with 240 official deaths. Most officials accept these numbers as vast underestimates.

 What does this study add?This study estimates a prevalence of 10% for COVID-19 antibodies in the population of Port-au-Prince in May to August 2020. Only 19-38% of those surveyed with confirmed antibodies reported experiencing symptoms in the last few months prior to the survey. We found a 69% increase in funerals per month in Port-au-Prince for the first six months post-COVID (March 2020) compared to the 14 months prior.

Finally, we found significant vaccine hesitancy with only 24% reporting "Yes" or "Maybe" when asked if theyd take a free of charge vaccine.


title: Persistent HBV replication and serological response during up to fifteen years of tenofovir-based antiretroviral therapy in HIV-hepatitis B coinfected patients: a multicenter prospective cohort study

abstract:
ObjectivesTo determine the extent of hepatitis B virus (HBV) suppression and its association with hepatitis "e" antigen (HBeAg) and hepatitis B surface antigen (HBsAg)-seroclearance in HIV-HBV-coinfected patients undergoing long-term tenofovir (TDF)-based antiretroviral therapy (ART).

MethodsWe prospectively followed 165 HIV-HBV-coinfected patients undergoing TDF-based ART. Serum HBV-DNA viral loads, HBeAg and HBsAg were obtained at TDF-initiation and every 6-12 months. We calculated the proportion achieving virological response (VR, <60 IU/mL) during follow-up. We also calculated rates of HBeAg- and HBsAg-seroclearance, which were compared between those who achieved versus never achieved VR during follow-up using an exact binomial test.

ResultsDuring a median 8.1 years (IQR=4.0-13.2) of TDF-treatment, 152 (92.1%) patients were able to achieve VR and 13 (7.9%) never achieved VR (median HBV-DNA at the end of follow-up=608 IU/mL, range=67-52,400,000). The prevalence of individuals with detectable HBV-DNA ([≥]60 IU/mL) decreased during TDF-treatment: 15.1% (n=14/93) at 5-years, 3.2% (n=2/62) at 10-years and, 3.2% (n=1/31) at 15-years. 44/96 HBeAg-positive patients (6.15/100 person-years) had HBeAg-seroclearance and 13/165 patients overall (0.87/100 person-years) had HBsAg-seroclearance. No difference in HBeAg-seroclearance was observed between those who achieved versus never achieved VR (7.4 versus 3.7/100 person-years, p=0.33), while HBsAg-seroclearance was only observed in those with VR (1.0 versus 0/100 person-years, p=0.49; respectively). Individuals with VR also had a higher frequency of undetectable HIV-RNA during treatment (p<0.001).

ConclusionsDuring long-term TDF-based ART for HIV-HBV coinfection, persistent HBV viremia is apparent, but becomes less frequent over time. HBsAg-seroclearance only occurred in those with full HBV and relatively high HIV suppression.

category: hiv aids


title: Humoral and cellular responses to mRNA vaccines against SARS-CoV2 in patients with a history of CD20-B-cell depleting therapy

abstract:
BackgroundB-cell depleting therapies increase COVID19 morbidity and mortality. For this specific population, evidence-based vaccination strategies are lacking. Here, we investigated humoral and cell mediated immune responses to SARS-CoV2 mRNA-based vaccines in patients receiving CD20-B-cell depleting agents for autoimmune disease, malignancy, or transplantation.

MethodsPatients at the Bern University Hospital with a treatment history of anti-CD20 depleting agents (rituximab or ocrelizumab) were enrolled for analysis of humoral and cell-mediated immune responses (by interferon-{gamma} release assay) after completing vaccination against SARS-CoV2. Primary outcome was the the anti-spike antibody response in anti-CD20-treated patients (n=96) in comparison to immunocompetent controls (n=29).

ResultsAnti-spike IgG antibodies were detected in 49% of patients 1.79 months after the second vaccine dose (interquartile range, IQR: 1.16-2.48) compared to 100% of controls (p<0.001). SARS-CoV2 specific interferon-{gamma} release was detected in 20% of patients and 75% of healthy controls (p<0.001). Only 11% of patients, but 75%of healthy controls showed positive reactions in both assays, respectively (p<0.001). Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/{micro}l), and CD4+ lymphocyte count (>653/{micro}l) predicted humoral vaccine response (area under the curve [AUC]: 67% [CI 56-78], 67% [CI 55-80] and 66% [CI 54-79], (positive predictive value [PPV]: 0.78, 0.7 and 0.71).

ConclusionThis study provides evidence for blunted humoral and cell-mediated immune responses elicited by SARS-CoV2 mRNA vaccines in patients with CD20-depleting treatment history. Lymphocyte subpopulation counts are associated with vaccine response in this highly vulnerable population. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)


title: Individual-Level Heterogeneity in Mask-wearing During the COVID-19 Pandemic in Malaysia

abstract: Wearing a face mask has been a key approach to contain or slow down the spread of COVID-19 in the ongoing pandemic. However, there is huge heterogeneity among individuals in their willingness to wear face masks during an epidemic. This research aims to investigate the individual heterogeneity to wear face masks and its associated predictors during the COVID-19 pandemic when mask-wearing was not mandatory but individuals choices. Based on a survey of 708 Malaysian adults and a multivariate least-squares fitting analysis, the results reveal a significant variance among individuals in wearing masks, as 34% of the individual adults did not always wear masks in public places. Female, individuals who wash their hands more frequently, and those who reported more availability of personal protective equipment were more likely to practice mask-wearing. The identification of less compliant groups of mask-wearing has critical implications by enabling more specific health communication campaigns.


title: High Seroprevalence of anti-SARS-CoV-2 antibodies among Ethiopian healthcare workers

abstract:
BackgroundCOVID-19 pandemic has a devastating impact on the economies and health care system of sub-Saharan Africa. Healthcare workers (HWs), the main actors of the health system, are at higher-risk because of their occupation. Serology-based estimates of SARS-CoV-2 infection among HWs represent a measure of HWs exposure to the virus and a guide to the prevalence of SARS-CoV-2 in the community. This information is currently lacking in Ethiopia and other African countries. This study aimed to develop an in-house antibody testing assay, assess the prevalence of SARS-CoV-2 antibodies among Ethiopian high-risk frontline HWs.

Methods and findingsA cross-sectional seroprevalence study was conducted among HWs in five public hospitals located in different geographic regions of Ethiopia. Socio-demographic and clinical data were collected using questionnaire-based interviews. From consenting HWs, blood samples were collected between December 2020 and February 2021, the period between the two peaks of COVID-19 in Ethiopia. The collected sera were tested using an in-house immunoglobin G (IgG) enzyme-linked immunosorbent assay (ELISA) for SARS-CoV-2 specific antibodies on sera collected from HWs. Of 1,997 HWs who provided a blood sample, demographic and clinical data, 50.5% were female, 74.0% had no symptoms compatible with COVID-19, and 29.0% had history of contact with suspected or confirmed patient with SARS-CoV-2 infection. The overall seroprevalence was 39.6%. The lowest (24.5%) and the highest (48.0%) seroprevalence rates were found in Hiwot Fana Specialized Hospital in Harar and ALERT Hospital in Addis Ababa, respectively. Of the 821 seropositive HWs, 224(27.3%) had history of symptoms consistent with COVID-19. A history of close contact with suspected/confirmed COVID-19 cases was strongly associated with seropositivity (Adjusted odds Ratio (AOR) =1.4, 95% CI 1.1-1.8; p=0.015).

ConclusionHigh SARS-CoV-2 seroprevalence levels were observed in the five Ethiopian hospitals. These findings highlight the significant burden of asymptomatic infection in Ethiopia, and may reflect the scale of transmission in the general population.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LISevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health threat, including Africa
C_LIO_LIThe actual morbidity and mortality associated with SARS-CoV-2 infection in Ethiopia underestimated due to the limited molecular testing capacity.
C_LIO_LIWe have limited knowledge about the seroprevalence of COVID-19 among health workers in Ethiopia.
C_LIO_LIThis study aimed to develop an in-house immunoglobin G (IgG) enzyme-linked immunosorbent assay (ELISA) for SARS-CoV-2 specific antibodies on sera collected from HWs and to find out the proportion of healthcare workers who have developed antibodies specific to SARS-CoV-2 from five public hospitals located in the different regions of Ethiopia.
C_LI

What did the researchers do and find?O_LIA cross-sectional seroprevalence study was conducted among HWs in five public hospitals located in different geographic regions of Ethiopia.
C_LIO_LISocio-demographic and clinical data were collected from recruited and consented participants using questionnaire-based interviews.
C_LIO_LIBlood samples were collected from participants between December 2020 and February 2021, the period between the two peaks of COVID-19 in Ethiopia.
C_LIO_LIThe collected sera were tested using an in-house ELISA for SARS-CoV-2 specific antibodies on sera collected from HWs.
C_LIO_LIApproximately 40% of the 1,997 healthcare workers who participated in this study had antibodies against SARS-CoV-2 infection.
C_LIO_LINo association between seropositivity and study participants age, gender, occupation, and comorbid medical conditions.
C_LI

What do these findings mean?O_LIThe observed high seroprevalence among healthcare workers regardless of their occupation suggests the cryptic but massive SARS-CoV-2 transmission in urban hospital settings.
C_LIO_LIMost of the seropositive healthcare workers in the present study were asymptomatic, and might pose a threat to the most vulnerable populations such as individuals with comorbid medical conditions.
C_LIO_LIGiven the low level of vaccine roll-out (1%), this study highlights the need to strengthen health workers adherence to personal protection practices such as wearing face masks to protect individuals at high risk of developing severe COVID-19 illness after SARS-CoV-2 infection.
C_LI


title: Whole-genome sequencing of SARS-COV-2 reveals a substantially lower frequency of the UK variant than previously announced in Libya

abstract: Alpha (B.1.1.7) SARS-COV-2 variant was detected in September 2020 in minks and humans in Denmark and UK. This variant has several mutations in the spike region (S) which could increase the transmissibility of the virus 43-90% over previously circulating variants. The National Center for Disease Control (NCDC) announced on 24th February 2021 a 25% frequency of B.1.1.7 strain in Libya using a reverse-transcriptase quantitative PCR assay. This assay relies on the specific identification of the H69-V70 deletion in S gene which causes its failure of amplification (SGTF). This deletion is not specific for B.1.1.7; but is also characteristic of two other SARS-COV-2 variants. This study aimed to estimate the frequency of B.1.1.7 and identify other variants circulating in Libya in February 2021. We performed whole genome sequencing of 67 positive SARS-COV-2 samples collected on 25th February 2021 in Libya which were also tested by RT-qPCR for SGTF. Our results showed that 55% of samples had mutations specific to B.1.525 strain and only [~]3% of samples belonged to B.1.1.7. These findings suggested that B.1.525 was spreading widely in Libya. The use of such RT-qPCR assay although useful to track some variants, it cannot discriminate between variants with H69-V70 deletion. RT-qPCR assays could be multiplexed to identify multiple variants and screen samples prior to sequencing. We emphasize on the need for providing whole-genome sequencing to the main COVID-19 diagnostic laboratories in Libya as well as establishing international collaboration for building capacity and advancing research in this time of the pandemic.


title: Whole-genome sequencing of SARS-COV-2 showed wide spread of B.1.525 in February 2021 in Libya


title: Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City

abstract: The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. Their median age was 48 years; seven required hospitalization and one died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in chi-squared and McNemar tests (p>0.1) highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.


title: Ultrasound Guided Brachial Plexus Block in Upper Extremity Surgeries: Experiences from a Tertiary Care Hospital of Bangladesh

abstract: Brachial plexus block has been gained popularity after its introduction because of provision of quality anesthesia and optimal postoperative analgesia in upper arm surgeries, and introduction of ultrasound guidance in recent years further enhances the practice because of efficacy and safety of procedure. This retrospective observational study evaluated the outcome and safety of ultrasound-guided brachial plexus block (supraclavicular and interscalene approach) in a tertiary care hospital of Bangladesh over 3-years period (January 2017 to December 2019) through analyzing preoperative anesthesia evaluation form, anesthesia documents and postoperative records. 113 patients were covered during the study period, of which 59 (52.2%) were males and 54 (47.8%) were females. Mean age of the patients were 38.94 {+/-} 20.37 years. Majority of the patients (63.7%) were in ASA grading I. Operative time for surgeries were 115.30 {+/-} 35.19 minutes. duration of sensory and motor block were 618 {+/-} 55 minutes and 450 {+/-} 74 minutes respectively. And first dose of postoperative analgesic was given after 705 {+/-} 94 minutes of surgery. Tachycardia and hypertension were observed in 4.4% patients, where failure of motor blockade and puncture of subclavian vein were recoreded 1.8% and 0.9% respectively. Current study found that with ultrasound guidance in skilled hands, brachial plexus blockade through combination of supraclavicular and interscalene approaches can provide quality anesthesia and analgesia with minimal complications.

category: anesthesia


title: Fragmented QRS is independently predictive of long-term adverse clinical outcomes in Asian patients hospitalized for heart failure: a retrospective cohort study

abstract:
BackgroundFragmented QRS (fQRS) results from myocardial scarring and predicts cardiovascular mortality and ventricular arrhythmia (VA). We evaluated the prevalence and prognostic value of fQRS in Asian patients hospitalized for heart failure.

Methods and resultsThis was a retrospective cohort study of adult patients hospitalized for heart failure between 1st January 2010 and 31st December 2016 at a tertiary center in Hong Kong. The baseline ECG was analysed. QRS complexes (<120 ms) with fragmented morphology in [≥]2 contiguous leads were defined as fQRS. The primary outcome was a composite of cardiovascular mortality, VA, and sudden cardiac death (SCD). The secondary outcomes were the components of the primary outcome, myocardial infarction, and new-onset atrial fibrillation. In total, 2192 patients were included, of whom 179 (8.20%) exhibited fQRS. The follow-up duration was 5.63{+/-}4.09 years. fQRS in any leads was associated with a higher risk of the primary outcome (adjusted hazard ratio (HR) 1.541 [1.185, 2.004], p=0.001), but not myocardial infarction or new-onset atrial fibrillation. fQRS in >2 contiguous leads was an independent predictor of SCD (HR 2.679 [1.252, 5.729], p=0.011). In patients without ischaemic heart disease (N=1396), fQRS in any leads remained predictive of VA and SCD (adjusted HR 3.336 [1.343, 8.282], p=0.009, and 1.928 [1.135, 3.278], p=0.015, respectively), but not cardiovascular mortality (adjusted HR 1.049 [0.662, 1.662], p=0.839).

ConclusionfQRS is an independent predictor of cardiovascular mortality, VA, and SCD. Higher fQRS burden increased SCD risk. The implications of fQRS in heart failure patients without ischaemic heart disease require further studies.


title: Late surges in COVID-19 cases and varying transmission potential partially due to public health policy changes in 5 Western states, March 10, 2020-January 10, 2021

abstract:
ObjectiveThis study investigates how the SARS-CoV-2 transmission potential varied in North Dakota, South Dakota, Montana, Wyoming, and Idaho from March 2020 through January 2021.

MethodsTime-varying reproduction numbers, Rt, of a 7-day-sliding-window and of non-overlapping-windows between policy changes were estimated utilizing the instantaneous reproduction number method. Linear regression was performed to evaluate if per-capita cumulative case-count varied across counties with different population size.

ResultsThe median 7-day-sliding-window Rt estimates across the studied region varied between 1 and 1.25 during September through November 2020. Between November 13 and 18, Rt was reduced by 14.71% (95% credible interval, CrI, [14.41%, 14.99%]) in North Dakota following a mask mandate; Idaho saw a 1.93% (95% CrI [1.87%, 1.99%]) reduction and Montana saw a 9.63% (95% CrI [9.26%, 9.98%]) reduction following the tightening of restrictions. High-population counties had higher per-capita cumulative case-count in North Dakota at four time points (June 30, August 31, October 31, and December 31, 2020). In Idaho, North Dakota, and South Dakota, there was a positive correlation between population size and per-capita weekly incident case-count, adjusted for calendar time and social vulnerability index variables.

ConclusionsRt decreased after mask mandate during the regions case-count spike suggested reduction in SARS-CoV-2 transmission.


title: The impact of demographic factors on the accumulated number of COVID-19 cases per capita in Europe and the regions of Ukraine in the summer of 2021

abstract: The accumulated number of COVID-19 cases per capita is an important characteristic of the pandemic dynamics that may also indicate the effectiveness of quarantine, testing and vaccination. As this value increases monotonically over time, the end of June 2021 was chosen, when the growth rate in Ukraine and the vast majority of European countries was small. This allowed us to draw some intermediate conclusions about the influence of the volume of population, its density, and the level of urbanization on the accumulated number of laboratory-confirmed cases per capita in European countries and regions of Ukraine. A simple analysis showed that the number of cases per capita does not depend on these demographic factors, although it may differ by about 4 times for different regions of Ukraine and more than 9 times for different European countries. The number of COVID-19 per capita registered in Ukraine is comparable with the same characteristic in other European countries but much higher than in China, South Korea and Japan.


title: Predictors of hospitalisation and death due to SARS-CoV-2 infection in Finland: a population-based register study with implications to vaccinations

abstract:
IntroductionThe aim of this study was to investigate how age and underlying medical conditions affect the risk of severe outcomes following SARS-CoV-2 infection and how they should be weighed while prioritising vaccinations against COVID-19.

MethodsThis population-based register study includes all SARS-CoV-2 PCR-test-positive cases until 24 Feb 2021, based on the Finnish National Infectious Diseases Register. The cases were linked to other registers to identify presence of comorbidities and severe outcomes (hospitalisation, intensive care treatment, death). The odds of severe outcomes were compared in those with and without the pre-specified comorbidities using logistic regression. Furthermore, population-based rates were compared between those with a given comorbidity and those without any of the specified comorbidities using negative binomial regression.

ResultsAge and various comorbidities were found to be predictors of severe COVID-19. Compared to 60-69-year-olds, the odds ratio (OR) of death was 7.1 for 70-79-year-olds, 26.7 for 80-89-year-olds, and 55.8 for [≥]90-year-olds. Among the 20-69-year-olds, chronic renal disease (OR 9.4), malignant neoplasms (5.8), hematologic malignancy (5.6), chronic pulmonary disease (5.4), and cerebral palsy or other paralytic syndromes (4.6) were strongly associated with COVID-19 mortality; severe disorders of the immune system (8.0), organ or stem cell transplant (7.2), chronic renal disease (6.7), and diseases of myoneural junction and muscle (5.5) were strongly associated with COVID-19 hospitalisation. Type 2 diabetes and asthma, two very common comorbidities, were associated with all three outcomes, with ORs from 2.1 to 4.3. The population-based rate of SARS-CoV-2 infection decreased with age. Taking the 60-69-year-olds as reference, the rate ratio was highest (3.0) for 20-29-year-olds but <1 for 70-79-year-olds and 80-89-year-olds.

ConclusionComorbidities predispose for severe COVID-19 among younger ages. In vaccine prioritisation both the risk of infection and the risk of severe outcomes, if infected, should be combined.


title: Transmission dynamics of COVID-19 in Ghana and the impact of public health interventions

abstract: The study characterized COVID-19 transmission in Ghana in 2020-21 by estimating the time-varying reproduction number (Rt) and exploring its association with various public health interventions at the national and regional levels. Ghana experienced four pandemic waves with epidemic peaks in July 2020, and January, August and December, 2021. The epidemic peak was the highest nationwide in December 2021 with Rt [≥]2. Throughout 2020-21, per-capita cumulative case count by region increased with population size. Mobility data suggested negative correlation between Rt and staying home in the first 90 days of the pandemic. The relaxation of movement restrictions and religious gatherings were not associated with increased Rt in the regions with lower case burdens. Rt decreased from above 1 when schools reopened in January 2021 to below 1 after vaccination rollout in March 2021. Findings indicated most public health interventions were associated with Rt reduction at the national and regional levels.


title: Safety and Pharmacokinetics of Intranasally Administered Heparin

abstract:
PurposeIntranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity.

MethodsDouble-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 g) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects.

ResultsUFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements.

No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 hours, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 hours.

ConclusionsUFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 hours after dosing.

category: pharmacology and therapeutics


title: Depressive disorders are associated with increased peripheral blood cell deformability: A cross-sectional case-control study (Mood-Morph)

abstract:
BackgroundPathophysiological landmarks of depressive disorders are chronic low-grade inflammation and elevated glucocorticoid output. Both can potentially interfere with cell membrane bending and cell function, suggesting altered cell morpho-rheological properties like cell deformability and other cell mechanical features in depressive disorders.

MethodWe performed a cross-sectional case-control study using image-based morpho-rheological characterization of unmanipulated blood samples facilitating real-time deformability cytometry (RT-DC). Sixty-nine pre-screened individuals at high-risk for depressive disorders and 70 matched healthy controls were included and clinically evaluated by Composite International Diagnostic Interview. Facilitating deep learning on blood cell images, major blood cell types were classified and morpho-rheological parameters such as cell size and cell deformability of every individual cell was quantified.

ResultsWe found peripheral blood cells to be more deformable in patients with depressive disorders compared to controls, while cell size was not affected. Lifetime persistent depressive disorder was associated with an increased cell deformability in monocytes and neutrophils, while in current persistent depressive disorder erythrocytes deformed more. Lymphocytes were more deformable in current major depressive disorder, while for lifetime major depressive disorder no differences could be identified.

ConclusionsThis is the first study analyzing morpho-rheological properties of entire blood cells and highlighting depressive disorders and in particular persistent depressive disorders to be associated with increased blood cell deformability. While all major blood cells tend to be more deformable, lymphocytes, monocytes, and neutrophils are mostly affected. This indicates that immune cell mechanical changes occur in depressive disorders, which might be predictive for persistent immune response.


title: Genomic Surveillance of SARS-CoV-2 in Erie County, New York

abstract: Early in the SAR-CoV-2 pandemic, we established a whole genome sequencing pipeline to assess lineages circulating in Western New York. Initial sequences revealed entry into the region via Europe, similar to observations in New York City. However, as the pandemic progressed and variants of concern emerged, we observed distinct patterns in lineages relative to NYC. Notably, B.1.427 became dominant in Western New York, before it was displaced by B.1.1.7. Our hierarchical cluster analysis of B.1.1.7 lineages, which by May 2021 made up [~] 80% of all cases, indicated both multiple introductions and community spread. Our work highlights the importance of widespread, regional surveillance of SARS-CoV-2 across the United States.


title: Attitudes towards a mandatory COVID-19 vaccination in France for the general population or healthcare workers in May 2021

abstract:
ObjectivesReaching the last pockets of unvaccinated people is challenging, and has led to consider COVID-19 mandatory vaccination. Our aim was to assess attitudes toward COVID-19 mandatory vaccination in France before the announcement and factors associated with opposition to this type of policy.

MethodsBetween the 10th and the 23rd of May 2021, we conducted a cross-sectional online survey among a representative sample of the French population aged 18 and over and a specific sample of the French Senior Population over 65.

ResultsAmong 3,056 respondents, 1,314 (43.0 %) were in favor of mandatory COVID-19 vaccination, 1,281 (41.9 %) were opposed to such a policy, and 461 (15.1 %) were undecided. Among opponents to COVID-19 mandatory vaccination for the general population, 385 (30.05 %) were in favor of a mandatory COVID-19 vaccination for healthcare workers (HCWs). In multivariate analysis, age groups 18-24 years, and 25-34 years were significantly more opposed than the reference group (>75 years old) with respective adjusted odds ratio (aOR) and 95 % confidence interval (95 % CI) 4.67 (1.73-12.61) and 3.74 (1.57-8.93). No intention of getting COVID-19 vaccine was strongly associated with opposition to mandatory vaccination with aOR 10.67 (95 % CI 6.41-17.76). In comparison with partisans of the center, partisans of the far left and green parties were more likely to be opposed to COVID-19 mandatory vaccine with respective aOR (95 % CI) 1;89 (1.06-3.38) and 2.08 (1.14-3.81).

ConclusionAttitudes toward mandatory COVID-19 vaccination are split in the French general population, and the debate might become politicized.


title: Public opinion on a mandatory COVID-19 vaccination policy in France: a cross sectional survey


title: COVID-19 Vaccination acceptance in the canton of Geneva: A Cross-Sectional Population-Based Study

abstract:
ObjectiveThis study aimed to assess acceptance of COVID-19 vaccination as well as its sociodemographic and clinical determinants in a general population sample three months after the launch of the vaccination program in Switzerland.

MethodsIn March 2021, an online questionnaire on vaccination acceptance was proposed to adults included in a longitudinal cohort study of previous population-based serosurveys carried out in the canton of Geneva. Questions were asked about COVID-19 vaccination acceptance, reasons of acceptance or refusal, and attitudes about vaccination in general. Data on demographic (age, sex, education, income, professional status, living conditions) and health-related characteristics (having a chronic disease, COVID-19 diagnosis, smoking status) were assessed at inclusion in the cohort (December 2020).

ResultsOverall, 4067 participants (completion rate of 77.4%) responded to the survey between March 17 and April 1, 2021. The mean age of respondents was 53.3 years and 56.0% were women. Most had completed tertiary education (64.7%) and over 60% were currently professionally active. At the time of the survey, 17.2% of respondents had already been vaccinated with at least one dose or had made an appointment to get vaccinated, and an additional 58.5% intended or rather intended to get vaccinated. The overall acceptance of COVID-19 vaccination was 75.7%, with a higher acceptance among men compared to women, older adults compared to younger adults, high-income individuals compared to those with a low income, participants living in urban and semi-urban areas compared to rural, and retirees and students compared to employed individuals. Acceptance was lower among individuals having completed apprenticeships and secondary education compared to those with tertiary education. The most common reasons reported by participants intending to get vaccinated were the desire to  get back to normal, to protect themselves, their community and/or society, and their relatives or friends against the risk of infection by SARS-CoV-2, as well as the desire to travel. Less than half (45.6%) of participants having children were willing or rather willing to have their children vaccinated against COVID-19 if it were recommended by public health authorities.

ConclusionAlthough our study found a 75.7% acceptance of COVID-19 vaccination, there were noticeable socio-demographic disparities in vaccination acceptance. These data will be useful for public health measures targeting hesitant populations when developing health communication strategies. These results will be updated over time with a new release of the survey in autumn 2021.


title: Modeling the COVID-19 Vaccination Dynamics in the United States: An Estimation of Coverage Velocity and Carrying Capacity Based on Socio-demographic Vulnerability Indices in California

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) disparities among vulnerable populations are of paramount concern that extend to vaccine administration. With recent uptick in infection rates, dominance of the delta variant, and proposal of a third booster shot, understanding the population-level vaccine coverage dynamics and underlying sociodemographic factors is critical for achieving equity in public health outcomes. This study aimed to characterize the scope of vaccine inequity in California counties through modeling the trends of vaccination using the Social Vulnerability Index (SVI).

MethodsOverall SVI, its four themes, and 9228 data points of daily vaccination numbers from December 15, 2020, to May 23, 2021, across all 58 California counties were used to model the growth velocity and anticipated maximum proportion of population vaccinated, defined as having received at least one dose of vaccine.

ResultsBased on the overall SVI, the vaccination coverage velocity was lower in counties in the high vulnerability category (v=0.0346, 95% CI: 0.0334, 0.0358) compared to moderate (v=0.0396, 95% CI: 0.0385, 0.0408) and low (v=0.0414, 95% CI: 0.0403, 0.0425) vulnerability categories. SVI Theme 3 (minority status and language) yielded the largest disparity in coverage velocity between low and high-vulnerable counties (v=0.0423 versus v=0.035, P<0.001). Based on the current trajectory, while counties in low-vulnerability category of overall SVI are estimated to achieve a higher proportion of vaccinated individuals, our models yielded a higher asymptotic maximum for highly vulnerable counties of Theme 3 (K=0.544, 95% CI: 0.527, 0.561) compared to low-vulnerability counterparts (K=0.441, 95% CI: 0.432, 0.450). The largest disparity in asymptotic proportion vaccinated between the low and high-vulnerability categories was observed in Theme 2 describing the household composition and disability (K=0.602, 95% CI: 0.592, 0.612; versus K=0.425, 95% CI: 0.413, 0.436). Overall, the large initial disparities in vaccination rates by SVI status attenuated over time, particularly based on Theme 3 status which yielded a large decrease in cumulative vaccination rate ratio of low to high-vulnerability categories from 1.42 to 0.95 (P=0.002).

ConclusionsThis study provides insight into the problem of COVID-19 vaccine disparity across California which can help promote equity during the current pandemic and guide the allocation of future vaccines such as COVID-19 booster shots.

Key MessagesO_LIThe Social Vulnerability Index (SVI) and its four themes along with the daily proportion of vaccinated individuals across the 58 California counties were used to model, overall and by theme, the growth velocity and anticipated maximum proportion of population vaccinated.
C_LIO_LIOverall, high vulnerability counties in California had a lower vaccine coverage velocity compared to low and moderate vulnerability counties.
C_LIO_LIThe largest disparity in coverage velocity between low and high vulnerability counties was observed based on the SVI Theme 3 status (minority status & language).
C_LIO_LIBased on the current trajectory, highly vulnerable counties based on SVI Theme 3 are expected to eventually achieve a higher proportion of vaccinated individuals compared to low vulnerable counterparts.
C_LIO_LIUnderstanding the vaccine coverage dynamics and underlying sociodemographic factors is critical for achieving equity in public health outcomes during disease outbreaks and catastrophes.
C_LI


title: Informing University COVID-19 Decisions Using Simple Compartmental Models

abstract: Tracking the COVID-19 pandemic has been a major challenge for policy makers. Although, several efforts are ongoing for accurate forecasting of cases, deaths, and hospitalization at various resolutions, few have been attempted for college campuses despite their potential to become COVID-19 hot-spots. In this paper, we present a real-time effort towards weekly forecasting of campus-level cases during the fall semester for four universities in Virginia, United States. We discuss the challenges related to data curation. A causal model is employed for forecasting with one free time-varying parameter, calibrated against case data. The model is then run forward in time to obtain multiple forecasts. We retrospectively evaluate the performance and, while forecast quality suffers during the campus reopening phase, the model makes reasonable forecasts as the fall semester progresses. We provide sensitivity analysis for the several model parameters. In addition, the forecasts are provided weekly to various state and local agencies.


title: The accuracy of Japanese administrative data in identifying acute exacerbation of idiopathic pulmonary fibrosis

abstract:
BackgroundThis study aimed to develop criteria for identifying patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) from Japanese administrative data and validate the pre-existing criteria.

MethodsThis retrospective, multi-center validation study was conducted at eight institutes in Japan to verify the diagnostic accuracy of the disease name for AE-IPF. We used the Japanese Diagnosis Procedure Combination data to identify patients with a disease name that could meet the diagnostic criteria for AE-IPF, who were admitted to the eight institutes from January 2016 to February 2019. As a reference standard, two respiratory physicians performed a chart review to determine whether the patients had a disease that met the diagnostic criteria for AE-IPF. Furthermore, two radiologists interpreted the chest computed tomography findings of cases considered AE-IPF and confirmed the diagnosis. We calculated the positive predictive value (PPV) for each disease name and its combination.

ResultsWe included 830 patients; among them, 216 were diagnosed with AE-IPF through the chart review. We combined the groups of disease names and yielded two criteria: the criteria with the highest PPV (0.72 [95% confidence interval 0.62 to 0.81]) and that with a slightly less PPV (0.61 [0.53 to 0.68]) but more true positives. Pre-existing criteria showed a PPV of 0.40 (0.31 to 0.49).

ConclusionThe criteria derived in this study for identifying AE-IPF from Japanese administrative data show a fair PPV. Although these criteria should be carefully interpreted according to the target population, our findings could be utilized in future database studies on AE-IPF.


title: Knowledge, attitude, and practice related to the COVID-19 pandemic among undergraduate medical students in Indonesia: a nationwide cross-sectional study

abstract:
IntroductionThe potential role of medical students in raising awareness during public health emergencies has been acknowledged. To further explore their potentials as public educators and role models for the communities during the coronavirus disease 2019 (COVID-19) pandemic, a study is conducted to assess the knowledge, attitude, and practice of these students toward COVID-19.

MethodsAn online cross-sectional survey was conducted among undergraduate medical students in Indonesia. Socio-demographical characteristics, social interaction history, information-seeking behavior, as well as knowledge, attitude, and practice toward COVID-19 were collected through a self-reported questionnaire. A p-value of <0.05 indicated statistical significance.

ResultsOut of 4870 respondents, 64.9% and 51.5% had positive attitude and practice toward COVID-19 while only 29.8% had adequate knowledge. Knowledge was slightly positively correlated with attitude and practice ({rho}=0.074 and {rho}=0.054, respectively; both p<0.001), while attitude was weakly correlated with practice ({rho}=0.234, p<0.001). Several factors including age, sex, place of residence, institution type, academic level, family income, history of chronic illness, prior volunteering experience, and perceptual awareness on COVID-19 were significantly associated with either knowledge, attitude, and/or practice toward COVID-19. Furthermore, health institutions and the governments press releases, as well as health expert opinions were deemed as the most reliable sources of COVID-19-related information - yet trivially none of these sources were associated with knowledge, attitude, and practice in the study population.

ConclusionMany undergraduate medical students in Indonesia had positive attitude and practice against COVID-19, yet only a few had adequate knowledge. This warrants further interventions to keep them updated with COVID-19 evidence to maximize their potentials in raising public awareness on COVID-19.

category: medical education


title: Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington's disease

abstract: The gating of movement depends on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways - the direct and indirect basal ganglia pathway. Both are complex and polysynaptic but the overall effect of activity within these pathways is thought to encourage and inhibit movement respectively. In Huntingtons disease (HD), the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition giving rise to the characteristic motor features of the condition. But early HD is also associated with apathy, a loss of motivation and failure to engage in goal-directed movement. We hypothesised that in HD, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction respectively. We used spectral dynamic casual modelling of resting state fMRI data to model effective connectivity in a model of these cortico-striatal pathways. We tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal HD. Using an advanced approach at the group level by combining Parametric Empirical Bayes and Bayesian Model Reduction procedure to generate large number of competing models and compare them by using Bayesian model comparison. With this automated Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. Firstly, more severe motor signs in HD were associated with altered connectivity in the indirect pathway components of our model and, by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component. The empirical evidence we provide here is demonstrates that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of HD and may have important implications for therapeutics.


title: Lipid peroxidation and pathological disruption of the ApoE/Reelin-ApoER2-DAB1 axis in sporadic Alzheimer's disease

abstract:
Structured AbstractO_ST_ABSBackgroundC_ST_ABSSporadic Alzheimers disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the central core of neuritic plaques, the hallmark plaques and tangles, and the selective vulnerability of entorhinal-hippocampal structures.

ObjectiveWe hypothesized that (1) high expression of ApoER2 (receptor for ApoE and Reelin) could help explain the selective anatomical vulnerability; and (2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting ApoE delivery and Reelin-ApoER2 signaling cascades.

MethodsWe conducted in vitro biochemical experiments, single-marker immunohistochemistry (IHC), and multiplex fluorescence-IHC (MP-IHC) in postmortem specimens from 26 individuals who died cognitively normal, with Mild Cognitive Impairment or with sAD.

ResultsIn biochemical experiments, Lys- and His-enriched peptides within the binding domains of ApoE and ApoER2 and their corresponding recombinant proteins, were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC and MP-IHC, we observed that: (1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal  perforant path projections that underlie memory; (2) ApoE and lipid aldehyde-modified ApoE, Reelin, ApoER2 and several downstream components of Reelin-ApoER2 signaling cascades accumulated in the immediate vicinity of neuritic plaques in perforant path terminal zones in sAD cases; and (3) several ApoE/Reelin-ApoER2 pathway markers--including the ApoER2 ligand binding domain, Disabled homolog-1 (Dab1), and Thr19-phosphorylated PSD95 (marker of synaptic disassembly)--were higher in sAD cases than controls and positively correlated with histological progression and cognitive deficits.

ConclusionResults provide proof-of-concept that ApoE and ApoER2 are vulnerable to lipid aldehyde induced adduction and crosslinking and demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in AD. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE particles and ApoE receptors in sAD in humans.


title: Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer's disease in humans


title: Covid-19 Vaccination in Pregnancy: A Systematic Review

abstract:
ObjectivePregnancy is a risk factor for severe Covid-19. Looking for safe vaccines that evoke protective maternal and fetal antibody response is important.

MethodsWe searched from registries (ClinicalTrials.gov, the WHO Clinical Trial Registry, and the EU Clinical Trial Registry) and databases (MEDLINE, ScienceDirect, Cochrane Library, Proquest, and Springer) up until June 20, 2021. Articles were selected based on inclusion and exclusion criteria after duplicates were removed. Infection rate, maternal antibody response, placental antibody transfer, and adverse events were described. This systematic review was performed with quality assessment and semi-quantitative synthesis according to PRISMA guidelines.

ResultsTwelve observational studies with a total of 40.509 pregnant women included. The mRNA based vaccines (Pfizer-BioNTech and Moderna) can prevent future SARS-CoV-2 infections (p=0.0004). Both vaccines did not affect pregnancy, delivery, and neonatal outcomes. The most commonly encountered adverse reactions are injection-site pain, fatigue, and headache but only transient. Antibody responses were rapid after the prime dose of vaccines. After booster, antibody responses were higher and associated with better placental antibody transfer. Longer intervals between first vaccination dose and delivery were also associated with higher antibody fetal IgG and better antibody transfer ratio.

ConclusionsThe Pfizer-BioNTech and Moderna vaccines are efficacious for preventing future SARS-CoV-2 infections. These vaccines can be considered as a safe option for pregnancy and their fetus. Two doses of vaccines were recommended for more robust maternal and fetal antibody responses. Longer latency was associated with higher fetal antibody responses.

Systematic Review RegistrationPROSPERO (CRD42021261684)

category: obstetrics and gynecology


title: Giving birth in a Pandemic: Women's Birth Experiences in England during COVID-19

abstract:
BackgroundExpectant parents worldwide have experienced changes in the way they give birth as a result of COVID-19, including restrictions relating to access to birthing units and the presence of birthing partners during the birth, and changes to birth plans. This paper reports the experiences of women in England.

MethodsData were obtained from both closed- and open-ended responses collected as part of the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 477 families) between 15th July 2020 - 29th March 2021. Frequency data are presented alongside the results of a sentiment analysis; the open-ended data was analysed thematically.

ResultsTwo-thirds of expectant women reported giving birth via spontaneous vaginal delivery (SVD) (66.1%) and a third via caesarean section (CS) (32.6%) or  other (1.3%). Just under half (49.7%) of the CS were reported to have been elective/planned, with 47.7% being emergencies. A third (37.4%) of participants reported having no changes to their delivery, with a further 25% reporting COVID-related changes, and 37.4% reporting non-COVID related changes (e.g., medical intervention). Experiences of COVID-related changes included limited birthing options and reduced feelings of control; difficulties accessing pain-relief and assistance, and feelings of distress and anxiety. Under half of the respondents reported not knowing whether there could be someone present at the birth (44.8%), with 2.3% of respondents reporting no birthing partner being present due to COVID-related restrictions. Parental experiences of communication and advice provided by the hospital prior to delivery were mixed, with significant stress and anxiety being reported in relation to both the fluctuating guidance and lack of certainty regarding the presence of birthing partners at the birth. The sentiment analysis revealed that participant experiences of giving birth during the pandemic were predominately negative (46.9%) particularly in relation to the first national lockdown, with a smaller proportion of positive (33.2%) and neutral responses (19.9%).

ConclusionParents reported an overall increase in birthing interventions (e.g., emergency CS), increased uncertainties related to the birth, and poor communication, leading to increased feelings of anxiety and high levels of negative emotions. The implications of these findings are discussed.


title: Maternal plasma lipids are involved in the pathogenesis of preterm birth

abstract:
BackgroundPreterm birth is defined by the onset of labor at a gestational age shorter than 37 weeks and it can lead to premature birth and impose a threat to newborns health. The Puerto Rico PROTECT cohort is a well-characterized prospective birth cohort that was designed to investigate environmental and social contributors to preterm birth in Puerto Rico, where preterm birth rates have been elevated in recent decades. To elucidate possible relationships between metabolites and preterm birth in this cohort, we conducted a nested case-control study to conduct untargeted metabolomic characterization of maternal plasma of 31 preterm birth women and 69 full-term labor controls at 24-28 gestational weeks.

ResultsA total of 333 metabolites were identified and annotated with liquid chromatography/mass spectrometry. Subsequent weighted gene correlation network analysis shows the fatty acid and carene enriched module has a significant positive association (p-value=8e-04) with preterm birth. After controlling for potential clinical confounders, a total of 38 metabolites demonstrated significant changes uniquely associated with preterm birth, where 17 of them were preterm biomarkers. Among seven machine-learning classifiers, application of random forest achieved the highly accurate and specific prediction (AUC = 0.92) for preterm birth in testing data, demonstrating their strong potential as biomarkers for preterm births. The 17 preterm biomarkers are involved in cell signaling, lipid metabolism, and lipid peroxidation functions. Further causality analysis infers that suberic acid upregulates several fatty acids to promote preterm birth.

ConclusionsAltogether, this study demonstrates the involvement of lipids, particularly fatty acids, in the pathogenesis of preterm birth.

category: genetic and genomic medicine


title: Real time scalable data acquisition of COVID-19 in six continents through PySpark - a big data tool

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared as a global emergency in January 2020 due to its pandemic outbreak. To examine this Coronavirus disease 2019 (COVID-19) effects various data are being generated through different platforms. This study was focused on the clinical data of COVID-19 which relied on python programming. Here, we proposed a machine learning approach to provide a insights into the COVID-19 information. PySpark is a machine learning approach which also known as Apache spark an accurate tool for the searching of results with minimum time intervals as compare to Hadoop and other tools. World Health Organization (WHO) started gathering corona patients data from last week of the February 2020. On March 11, 2020, the WHO declared COVID-19 a global pandemic. The cases became more evident and common after mid-March. This paper used the live owid (our world in data) dataset and will analyse and find out the following details on the live COVID-19 dataset. (1) The daily Corona virus scenario on various continents using PySpark in microseconds of Processor time. (2) After the various antibodies have been implemented, how they impact new cases on a regular basis utilizing various graphs. (3) Tabular representation of COVID-19 new cases in all the continents.


title: Crowd Annotations Can Approximate Clinical Autism Impressions from Short Home Videos with Privacy Protections

abstract: Artificial Intelligence (A.I.) solutions are increasingly considered for telemedicine. For these methods to adapt to the field of behavioral pediatrics, serving children and their families in home settings, it will be crucial to ensure the privacy of the child and parent subjects in the videos. To address this challenge in A.I. for healthcare, we explore the potential for global image transformations to provide privacy while preserving behavioral annotation quality. Crowd workers have previously been shown to reliably annotate behavioral features in unstructured home videos, allowing machine learning classifiers to detect autism using the annotations as input. We evaluate this method with videos altered via pixelation, dense optical flow, and Gaussian blurring. On a balanced test set of 30 videos of children with autism and 30 neurotypical controls, we find that the visual privacy alterations do not drastically alter any individual behavioral annotation at the item level. The AUROC on the evaluation set was 90.0% +/- 7.5% for the unaltered condition, 85.0% +/- 9.0% for pixelation, 85.0% +/- 9.0% for optical flow, and 83.3% +/- 9.3% for blurring, demonstrating that an aggregation of small changes across multiple behavioral questions can collectively result in increased misdiagnosis rates. We also compare crowd answers against clinicians who provided the same annotations on the same videos and find that clinicians are more sensitive to autism-related symptoms. We also find that there is a linear correlation (r=0.75, p<0.0001) between the mean Clinical Global Impression (CGI) score provided by professional clinicians and the corresponding classifier score emitted by the logistic regression classifier with crowd inputs, indicating that the classifiers output probability is a reliable estimate of clinical impression of autism from home videos. A significant correlation is maintained with privacy alterations, indicating that crowd annotations can approximate clinician-provided autism impression from home videos in a privacy-preserved manner.


title: Mild SARS-CoV-2 infection modifies DNA methylation of peripheral blood mononuclear cells from COVID-19 convalescents

abstract:
BackgroundEpigenetic alterations upon microbial challenge have been described as both a defence strategy and a result of pathogenic manipulation. While most COVID-19 studies focus on inflammatory and immune-mediated responses, little is known about epigenetic modifications in response to SARS-CoV-2 infection.

MethodsEpigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated in vitro with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation and module identification analyses.

ResultsDifferential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified in vivo, comprising 66 genes of which six (TP53, INS, HSPA4, SP1, ESR1 and FAS) were present in corresponding in vitro analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome.

ConclusionsAltered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. As in vitro SARS-CoV-2 infection corroborated in vivo exposure results, this indicates DNA methylation is involved in immune cell responses to challenge with this virus. Future studies should determine whether this reflects host-induced protective antiviral defence or targeted viral hijacking to evade host defence.


title: Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells


title: High frequency transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes among schoolchildren exposed to scarlet fever: a longitudinal multi-cohort moleculo-epidemiological contact tracing study.

abstract:
BackgroundDespite recommendations regarding prompt treatment of cases and enhanced hygiene measures, scarlet fever outbreaks increased in England between 2014-2018. We aimed to assess the impact of standard interventions on transmission of Streptococcus pyogenes to classroom contacts, households, and classroom environments.

MethodsWe undertook a prospective, contact tracing study in schools with 2 consecutive scarlet fever cases that were reported to local Health Protection teams in London between March 1st and May 31st in 2018 and 2019. We cultured throat swabs from cases, household contacts, and classroom contacts at four time points. We also cultured hand swabs and cough plates from all cases, and from classroom contacts in 2019. Surface swabs from toys and other fomites in classrooms were cultured in 2018, and settle plates from classrooms were collected in 2019. Any sample with S. pyogenes detected was recorded as positive and underwent emm genotyping and genome sequencing to compare with the outbreak strain.

FindingsSix classes, comprising 12 scarlet fever cases, 17 household contacts, and 278 classroom contacts were recruited from March 1st to May 31st in 2018 and the same period in 2019. Prevalence of the outbreak S. pyogenes strain in throat swabs from asymptomatic classroom contacts was high, increasing from 9.6% (11/115) in week 1, to 26.9% (34/126) in week 2, to 24.1% (26/108) in week 3, then 14.3% (5/35) in week 4. Colonisation with non-outbreak and non-genotyped S. pyogenes strains was 1.7% (2/115); 3.9% (5/126); 5.6% (6/108); and 0/35 in the same weeks. Genome sequencing showed clonality of isolates within each of six classes, confirming recent transmission accounted for high carriage. When transmissibility was tested, children who were asymptomatic carriers of emm4 and emm3.93 had positive cough plates on 1/14 (7.1%) and 7/21 (33.3%) occasions respectively. Only 1/60 surface swabs taken in 3 classrooms yielded the outbreak S. pyogenes strain. In contrast, 2/12 and 6/12 settle plates placed in elevated locations yielded the outbreak S. pyogenes strain in the two classrooms tested.

InterpretationS. pyogenes transmission in schools is intense and may occur prior to, or inspite of reported treatment of cases, underlining a need for rapid case management. Despite guideline adherence, heavy shedding of S. pyogenes by small numbers of classroom contacts may perpetuate outbreaks, and airborne transmission has a plausible role in spread. The findings highlight the need for research to improve understanding and assess effectiveness of interventions to reduce S. pyogenes airborne transmission.


title: Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes among schoolchildren exposed to scarlet fever: a longitudinal multi-cohort molecular epidemiology contact tracing study.


title: Death profiling of hospitalized patients with COVID-19: Experience from a specialized hospital in Bangladesh

abstract:
BackgroundThe information on characteristics and causes of mortality in deceased patients with coronavirus disease 2019 (COVID-19) is scarce in the literature. This study aimed to document the clinical profile with causes of death in deceased patients admitted in a COVID-19 dedicated hospital in Dhaka, Bangladesh.

MethodsThis cross-sectional retrospective study included 108 COVID-19 associated deceased patients admitted in Kurmitola general hospital, Dhaka, Bangladesh between 25 March 2020 and 24 June 2020) Data were collected from hospital record. Causes of death were categorized into early and late with cut-off of 48 hours of hospitalization.

ResultsAmong 809 hospitalized cases of COVID-19, 108 patient died (13.35%) over three months of study period. The mean age of the deceased patients was 60.22{+/-}13.94 years; 86.1% were male. About 85% had at least one comorbidity with diabetes mellitus (65.7%) was the most common one. The most common symptoms were breathlessness (88.0%), fever (65.7%) and cough (43.5%). Nearly 75% presented with severe disease. Patients had altered biochemical profiles and treated with different drugs including antibiotics and steroids. Young age and malnutrition were two characteristic features. Only one third got intensive care support. The most common cause of death was acute respiratory syndrome (95.37%). Septic shock & acute myocardial infarction were predominantly early and uremia, hepatic failure & hyperglycemic crisis were the predominant causes of late hospital death.

ConclusionsThe findings of this study will help clinicians as well as policy makers to take necessary steps to prevent death from COVID-19 in Bangladeshi population.


title: Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

abstract:
BackgroundPrimaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not.

MethodsGlucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured either daily or on days 1, 3, 6 and 13, and additionally on day 10 in the primaquine 14-day groups.

ResultsDay 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.53 (95% CI: 0.39-0.73) fold lower, trough carboxyprimaquine concentrations 0.45 (95% CI: 0.35-0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence.

ConclusionYoung children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.


title: Assessment of COVID-19 risk and prevention effectiveness among spectators of mass gathering events

abstract: There is a need to evaluate and minimise the risk of novel coronavirus infections at mass gathering events, such as sports. In particular, to consider how to hold mass gathering events, it is important to clarify how the local infection prevalence, the number of spectators, the capacity proportion, and the implementation of preventions affect the infection risk. In this study, we used an environmental exposure model to analyse the relationship between infection risk and infection prevalence, the number of spectators, and the capacity proportion at mass gathering events in football and baseball games. In addition to assessing risk reduction through the implementation of various preventive measures, we assessed how face-mask-wearing proportion affects infection risk. Furthermore, the model was applied to estimate the number of infectors who entered the stadium and the number of newly infected individuals, and to compare them with actual reported cases. The model analysis revealed an 86%-95% reduction in the infection risk due to the implementation of face-mask wearing and hand washing. Among the individual measures, face-mask wearing was particularly effective, and the infection risk increased as the face-mask-wearing proportion decreased. A linear relationship was observed between infection risk at mass gathering events and the infection prevalence. Furthermore, the number of newly infected individuals was also dependent on the number of spectators and the capacity proportion independent of the infection prevalence, confirming the importance of considering spectator capacity in infection risk management. These results highlight that it is beneficial for organisers to ensure prevention compliance and to mitigate or limit the number of spectators according to the prevalence of local infection. Both the estimated and reported numbers of newly infected individuals after the events were small, below 10 per 3-4 million spectators, despite a small gap between these numbers.


title: Pneumococcal exposure routes for infants: a nested cross-sectional survey in Nha Trang, Vietnam

abstract:
BackgroundInfants are at highest risk of pneumococcal disease. Their added protection through herd effects is a key part in the considerations on optimal pneumococcal vaccination strategies. Yet, little is currently known about the main transmission pathways to this vulnerable age group.

Methods and findingsWe conducted a nested cross-sectional contact and nasopharyngeal swabbing survey in randomly selected infants across all 27 communes of Nha Trang, Vietnam. Bayesian logistic regression models were used to estimate age specific carriage prevalence in the population, a proxy for the probability that a contact of a given age could lead to pneumococcal exposure for the infant. We used another Bayesian logistic regression model to estimate the correlation between infant carriage and the probability that at least one of their reported contacts carried pneumococci, controlling for age and locality. In total 1583 infants between 4 and 13 months old participated, with 7428 contacts reported. Few infants (5%) attended day care and carriage prevalence was 22%. Most infants (61%) had less than a 25% probability to have had close contact with a pneumococcal carrier on the surveyed day. Pneumococcal infection risk and contact behavior were highly correlated: if adjusted for age and locality the odds of an infants carriage increased by 22% (95%CI:15-29) per 10 percentage points increase in the probability to have had close contact with at least one pneumococcal carrier. Two to six year old children contributed 51% (95%CI: 39-63) to the total pneumococcal exposure risks to infants in this setting.

ConclusionsCross-sectional contact and infection studies can help identify pneumococcal transmission routes. In Nha Trang, preschool age children are the largest reservoir for pneumococcal transmission to infants.