title: Constitutional thinness and anorexia nervosa differ on a genomic level

abstract:
Constitutional thinness and anorexia nervosa are both characterised by persistent, extremely low weight with body mass indices (BMI) below 18.5 kg/m2. Individuals with anorexia nervosa concurrently show distorted perceptions of their own body and engage in weight-loss behaviours, whereas individuals with constitutional thinness typically wish to gain weight. Both are heritable, share genomics with BMI, but have not been shown to be genetically correlated with each other. We aim to differentiate between constitutional thinness and anorexia nervosa on a genomic level.

First, we estimated genetic correlations between constitutional thinness and eleven psychiatric disorders and compared them with anorexia nervosa using publicly available data. Second, we identified individuals with constitutional thinness in the Avon Longitudinal Study of Parents and Children (ALSPAC) by latent class growth analysis of measured BMI from 10 to 24 years (n = 8,505) and assigned polygenic scores for eleven psychiatric disorders and a range of anthropometric traits to evaluate associations.

In contrast to anorexia nervosa, attention deficit hyperactivity disorder (rgAN = 0.02 vs. rgCT = -0.24) and alcohol dependence (rgAN = 0.07 vs. rgCT = -0.44) showed a statistically significant negative genetic correlation with constitutional thinness. A higher polygenic score for posttraumatic stress disorder was associated with an increased risk of constitutional thinness in the ALSPAC cohort (OR = 1.27; Q = 0.03) whereas posttraumatic stress disorder shows no genetic correlation with anorexia nervosa (rg = -0.02). Overall, results suggest that constitutional thinness is different from anorexia nervosa on the genomic level.


title: Process evaluation of the development and remote recruitment for Essential Coaching for Every Mother during COVID-19

abstract:
BackgroundWith a decrease in in-person support and increase in perinatal mental health concerns during the coronavirus pandemic, innovative strategies, such as mHealth, are more important than ever. However, due to physical distancing recommendations, recruitments for perinatal research needs to shift. The objective of this study is to desire the process evaluation of recruitment and retention of women for an mHealth pre-post intervention study for Essential Coaching for Every Mother.

MethodsThree methods were used for recruitment: social media, posters in hospital, and media outreach. First time mothers were eligible for enrollment antenatally (37+ weeks) and postnatally (<3 weeks). Eligibility screening occurred remotely via text message. Outcomes were days to recruit 75 participants, eligibility vs. ineligibility rates, dropout and exclusion reasons, survey completion rates, perinatal timing of enrollment, and recruitment sources.

ResultsRecruitment ran July 15th-September 19th (67 days) with 200 screened and 88 enrolled, 70% antenatally. It took 50 days to enroll 75 participants. Mothers recruited antenatally (n=53) were more likely to receive all intervention message (68% vs. 19%). Mothers recruited postnatally (n=35) missed more messages on average (13.8 vs. 6.4). Participants heard about the study through family/friends (31%), news (20%), Facebook groups (16%), Facebook ads (14%), posters (12%), or other ways (7%).

ConclusionAntenatal recruitment resulted in participants enrolling earlier and receiving more of the study messages. Word of mouth and media outreach were successful, followed by advertisement on Facebook. Remote recruitment was a feasible way to recruit for Essential Coaching for Every Mother.

category: public and global health


title: Remote recruitment for Essential Coaching for Every Mother during COVID-19


title: Evaluating the impacts of tiered restrictions introduced in England, during October and December 2020 on COVID-19 cases: A synthetic control study.

abstract:
BackgroundIn 2020, a second wave of COVID-19 cases unevenly affected places in England leading to the introduction of a tiered system of controls with different geographical areas subject to different levels of restrictions. Whilst previous research has examined the impact of national lockdowns on transmission, there has been limited research examining the marginal effect of differences in localised restrictions or how these effects vary between socioeconomic contexts. We therefore examined how Tier 3 restrictions in England implemented between October-December 2020, which included additional restrictions on the hospitality sector and people meeting outdoors affected COVID-19 case rates, compared to Tier 2 restrictions, and how these effects varied by level of deprivation.

MethodsWe used data on weekly reported COVID-19 cases for 7201 neighbourhoods in England and adjusted these for changing case-detection rates to provide an estimate of weekly SARS-CoV-2 infections in each neighbourhood. We identified those areas that entered Tier 3 restrictions at two time points in October and December, and constructed a synthetic control group of similar places that had entered Tier 2 restrictions, using calibration weights to match them on a wide range of covariates that may influence transmission. We then compared the change in weekly infections between those entering Tier 3 to the synthetic control group to estimate the proportional reduction of cases resulting from Tier 3 restrictions compared to Tier 2 restrictions, over a 4-week period. We further used interaction analysis to estimate whether this effect differed based on the level of socioeconomic deprivation in each neighbourhood and whether effects were modified by the prevalence of a new more infectious variant of SARS-CoV-2 (B.1.1.7) in each area.

ResultsThe introduction of Tier 3 restrictions in October and December was associated with a 14% (95% CI 10% to 19%) and 20% (95% CI 13% to 29%) reduction in infections respectively, compared to the rates expected if only Tier 2 restrictions had been in place in those areas. We found that effects were similar across levels of deprivation and limited evidence that Tier 3 restrictions had a greater effect in areas where the new more infectious variant was more prevalent.

InterpretationAdditional restrictions on hospitality and meeting outdoors introduced in Tier 3 areas in England had a moderate effect on transmission and these restrictions did not appear to increase inequalities, having a similar impact across areas with differing levels of socioeconomic deprivation. Where transmission risks vary between geographical areas a tiered approach of local restrictions on outdoor mixing and hospitality can contribute to control of SARS-CoV-2 and is unlikely to increases inequalities in transmission.


title: Changes in eating habits and lifestyles in Peruvian population during social isolation by the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic caused that some governments have implemented house confinement measures with probable consequences on lifestyle, particularly affecting eating habits, physical activity, sleep quality, and mental health.

ObjectivesThe aim of this study was to assess the frequency of lifestyles, physical activity and sleep characteristics, as well as changes in eating habits in the Peruvian population during COVID-19 pandemic.

MethodsA Cross-sectional descriptive study was performed. We analyzed adults from Peru between July to August 2020 based on an online self-administered questionnaire divided into sociodemographic, anthropometrics and COVID-19 diagnostic reported, lifestyle habits and frequency of consumption of foods.

FindingsDuring confinement by COVID-19, 1176 participants were studied, 39% were student, 37.5% were workers and 46% were assert not to work. The population asserted gain weight (1 to 3 Kg) and 35.7% were overweight. The lifestyles habits showed that 54.8% affirmed to doing physical activity and a large proportion (37.2%) asserted sleep less. The Peruvian population presented a main feeding patter of breakfast (95.7%), lunch (97.5%), dinner (89.1%) and brunch (44.9%). Likewise, feeding habits before and during COVID-19 pandemic showed that vegetables (OR:1.56, CI95% 1.21 - 200), fruit (OR: 1.42, CI95% 1.10 - 1.81), legumes (OR:1.67, CI95% 1.23 - 2.28) and eggs (OR: 2.00, CI95% 1.52 - 2.65) presented significantly consumption increase during social isolation, while bakery products (OR: 0.74, CI95% 0.56 - 0.97), meat, snack, refreshment and fast-food decrease consumption. Other food no significant differences were presented.

ConclusionThis study in a Peruvian population showed an important frequency of overweight and sleep disorders. There was a slight increase in physical activity despite the social isolation measures and an increase in health eating habits, nevertheless a majority reported gaining weight.


title: Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study

abstract:
BackgroundRelatively few COVID-19 cases and deaths have been reported through much of sub-Saharan Africa, including South Sudan, although the extent of SARS-CoV-2 spread remains unclear due to weak surveillance systems and few population-representative serosurveys.

MethodsWe conducted a representative household-based cross-sectional serosurvey in Juba, South Sudan. We quantified IgG antibody responses to SARS-CoV-2 spike protein receptor-binding domain and estimated seroprevalence using a Bayesian regression model accounting for test performance.

ResultsWe recruited 2,214 participants from August 10 to September 11, 2020 and 22.3% had anti-SARS-CoV-2 IgG titers above levels in pre-pandemic samples. After accounting for waning antibody levels, age, and sex, we estimated that 38.5% (32.1 - 46.8) of the population had been infected with SARS-CoV-2. For each RT-PCR confirmed COVID-19 case, 104 (87-126) infections were unreported. Background antibody reactivity was higher in pre-pandemic samples from Juba compared to Boston, where the serological test was validated. The estimated proportion of the population infected ranged from 30.1% to 60.6% depending on assumptions about test performance and prevalence of clinically severe infections.

ConclusionsSARS-CoV-2 has spread extensively within Juba. Validation of serological tests in sub-Saharan African populations is critical to improve our ability to use serosurveillance to understand and mitigate transmission.


title: Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients

abstract: Data concerning the anti-SARS-CoV-2 antibody response after mRNA COVID-19 vaccine in kidney transplant recipients (KTRs) are currently lacking. Here, we sought to examine this issue by analyzing the serological response observed in 241 KTRs after a first vaccine injection. Our results indicate that KTRs have a weak anti-SARS-CoV-2 antibody response, ultimately resulting in a low seroconversion rate (26/241, 10.8%). This phenomenon likely stems from a high immunosuppression burden in this clinical population.

category: transplantation


title: How do Hemodialysis Center Prevent the Secondary COVID-19 Transmission in Poverty-Stricken Rural Region of China: Eperiences and Strategies

abstract: The COVID-19 pandemic has caused an evolving public health crisis and challenged the medical system globally, especially in the rural-stricken regions. There is concern about the spread of coronavirus in regions with lower education level, weaker health systems and underdeveloped economy. The risk of viral transmission in HD center is elevated because of the densely-populated and high mobility in an enclosed environment.This paper demonstrated the main experiences and strategies of preventing secondary COVID-19 transmission in a HD center from a poverty-stricken rural region in China. Data of subjects including 17 medical workers and 249 patients were collected from the HD center in Huangchuan County Peoples Hospital from February to April 2020. It is the first paper to provide the experiences and strategies about preventing COVID-19 secondary transmission in HD center for poverty-stricken rural region.

category: nephrology


title: ROC plot and AUC with binary classifiers: pragmatic analysis of cognitive screening instruments

abstract: Receiver operating characteristic (ROC) plots are a performance graphing method showing the relative trade-off between test benefits (true positive rate) and costs (false positive rate) with the area under the curve (AUC) giving a scalar value of test performance. It has been suggested that ROC and AUC may be potentially misleading when examining binary predictors rather than continuous scales. The purpose of this study was to examine ROC plots and AUC values for two binary classifiers of cognitive status (applause sign, attended with sign), a cognitive screening instrument producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrookes Cognitive Examination), the latter two also analysed with single fixed threshold tests. For each of these plots, AUC was calculated using different methods. The findings indicate that if categorical or continuous measures are dichotomised then the calculated AUC may be an underestimate, thus affecting screening or diagnostic test accuracy which in the context of clinical practice may prove to be misleading.

category: neurology


title: Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimers disease

abstract: Posterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimers disease-associated neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) {varepsilon}4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two independent cohorts (University of California, San Francisco, UCSF, and Alzheimers Disease Neuroimaging Initiative, ADNI) underwent MRI and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir tau-PET within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Brain regions were defined in native space using FreeSurfer. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and had less severe cognitive impairment than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR ({Delta}R2 = .09 to .21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in ADNI ({Delta}R2 = .04, p = .008) but not UCSF ({Delta}R2 < .01, p = .52), and did not improve the inferior parietal models ({Delta}R2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Models including molecular pathology in functionally connected regions, defined based on task-free functional MRI data from the Neurosynth database, or APOE {varepsilon}4 did not outperform local models. Overall, hypometabolism in cognitively impaired patients primarily reflected local atrophy and tau pathology, with an added contribution of medial temporal lobe degeneration at earlier disease stages. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or the presence of the APOE {varepsilon}4 allele in impaired participants. FDG-PET reflects structural neurodegeneration and tau, but not amyloid, pathology at symptomatic stages of Alzheimers disease.


title: What role for asbestos in idiopathic pulmonary fibrosis? Findings from the IPF job exposures study

abstract:
RationaleAsbestos is posited to cause otherwise  idiopathic pulmonary fibrosis (IPF); establishing this has important diagnostic and therapeutic implications.

ObjectivesTo determine the association between occupational asbestos exposure and IPF; to investigate interaction with MUC5B rs35705950 genotype.

MethodsMulti-centre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 United Kingdom hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was measured using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs3570950 was investigated using a genetic dominant model.

Measurements and Main Results327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls, had cumulative exposure estimates [≥] 25 fibre.ml-1.years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1(95%CI 0.8-1.4; p=0.6) and there was no gene-environment interaction (p=0.2). Ever smoking was associated with IPF, OR 1.4 (95%CI 1-1.9; p=0.04). When stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs3570950.

ConclusionsOccupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. However, exposure to asbestos and smoking interact to increase IPF risk in carriers of the minor allele of MUC5B rs3570950.

Clinical trial registered with www.clinicaltrials.gov (NCT03211507).

category: occupational and environmental health


title: The importance of a consistent workflow to estimate muscle-tendon lengths based on joint angles from the conventional gait model

abstract:
BackgroundMusculoskeletal models enable us to estimate muscle-tendon length, which has been shown to improve clinical decision-making and outcomes in children with cerebral palsy. Most clinical gait analysis services, however, do not include muscle-tendon length estimation in their clinical routine. This is due, in part, to a lack of knowledge and trust in the musculoskeletal models, and to the complexity involved in the workflow to obtain the muscle-tendon length.

Research questionCan the joint angles obtained with the conventional gait model (CGM) be used to generate accurate muscle-tendon length estimates?

MethodsThree-dimensional motion capture data of 15 children with cerebral palsy and 15 typically developing children were retrospectively analyzed and used to estimate muscle-tendon length with the following four modelling frameworks: (1) 2392-OSM-IK-angles: standard OpenSim workflow including scaling, inverse kinematics and muscle analysis; (2) 2392-OSM-CGM-angle: generic 2392-OpenSim model driven with joint angles from the CGM; (3) modif-OSM-IK-angles: standard OpenSim workflow including inverse kinematics and a modified model with segment coordinate systems and joint degrees-of-freedom similar to the CGM; (4) modif-OSM-CGM-angles: modified model driven with joint angles from the CGM. Joint kinematics and muscle-tendon length were compared between the different modelling frameworks.

ResultsLarge differences in hip joint kinematics were observed between the CGM and the 2392-OpenSim model. The modif-OSM showed similar kinematics as the CGM. Muscle-tendon length obtained with modif-OSM-IK-angles and modif-OSM-CGM-angles were similar, whereas large differences in some muscle-tendon length were observed between 2392-OSM-IK-angles and 2392-OSM-CGM-angles.

SignificanceThe modif-OSM-CGM-angles framework enabled us to estimate muscle-tendon lengths without the need for scaling a musculoskeletal model and running inverse kinematics. Hence, muscle-tendon length estimates can be obtained simply, without the need for the complexity, knowledge and time required for musculoskeletal modeling and associated software. An instruction showing how the framework can be used in a clinical setting is provided on https://github.com/HansUniVie/MuscleLength.

category: orthopedics


title: Multicenter, Randomized, Open-Label, Comparative Study of Therapeutic Efficacy, Safety, and Tolerability of BNO 1030 application in the technology of delayed prescription of antibiotics in patients with severe acute tonsillitis.

abstract:
Acute bacterial tonsillitis occurs in 20 -30 % of immunocompetent children; however, the frequency of antibacterial drug prescriptions reaches up to 90 %. Delayed antibiotic prescription is recommended by current guidelines. The study objective was to determine the efficacy of phytoneering extract BNO 1030 in the technology of delayed antibiotic prescription in patients with severe acute tonsillitis.

MethodsIn the multicenter, randomized, open-label, comparative study, 182 out of 200 randomized children with acute tonsillitis aged 6 -12 years completed the study. Evaluation criteria: a reduced severity of sore throat when swallowing and at rest, throat irritation at rest, hyperemia of the tonsils assessed by a physician according to a 4-point scale at each visit compared to Visit 1, dynamics of self-assessment of general well-being, intensity of sore throat and difficulty swallowing according to a 10-point visual analogue scale, frequency of antibiotic prescriptions, therapeutic benefit from BNO 1030 in days.

ResultsThe use of phytotherapeutic medicinal product BNO 1030 in addition to the standard symptomatic treatment of severe acute tonsillitis provides a clinically significant, adequate reduction in the symptom severity assessed by a physician at V2 (p < 0.005). There are significant differences in the patients self-assessment of the symptoms from treatment Day 2 (p < 0.005). This allows to significantly reduce the duration of systemic antipyretic administration (p < 0.005). In the first days of treatment, when a decision on delay of antibiotic prescription is made, a therapeutic benefit in two days in patients of the treatment group was observed compared to the control group. The use of BNO 1030 in patients with severe acute tonsillitis significantly reduces, by 43.7 % or 2.3 times, the need for prescribing antibiotic therapy as part of the technology of delayed antibiotic prescription (p < 0.005). During treatment, no side effects and complications of the disease were recorded.

ConclusionBNO 1030 is a safe and effective medicinal product for the treatment of severe acute tonsillitis in children aged 6 -12 years. It provides a significant therapeutic benefit when administered in addition to standard symptomatic therapy and reduces the irrational antibiotic prescription.

Trial registrationClinicalTrials.gov Identifier: NCT04537819 https://clinicaltrials.gov/ct2/show/NCT04537819?term=ATi-2&draw=2&rank=1

category: otolaryngology


title: HEARING MORE TO HEAR LESS: A SCOPING REVIEW OF HEARING AIDS FOR TINNITUS RELIEF

abstract:
BackgroundTinnitus, the perception of a sound in absence of an external auditory source, can significantly impact ones quality of life. As tinnitus is often associated with hearing loss, hearing aids have been proposed for tinnitus relief in literature for more than 70 years. While there is a long history of clinical work and research on this topic, there is a need for recent literature to be reviewed and guide decision making in tinnitus management.

ObjectiveThe aim of this scoping review is to provide an update of the available evidence on hearing aids for tinnitus, focusing on the effect of sound amplification, to draw conclusions for clinical practice and identify gaps in the field. A consultation exercise was included to discuss current issues that practitioners and carers themselves face but remain under-researched.

DesignThis scoping review was conducted based on the six-stage framework of Arksey et al. (2005). Studies were included if they investigated hearing aids for tinnitus and were published after 2011. Databases of PubMed and Scopus were explored on the 16th of November 2020. The search was limited to English manuscripts. A total of 28 primary research studies were selected.

ResultsPositive results of hearing aids for tinnitus relief were shown by 68 % of the studies, whereas 14 % demonstrated no change in tinnitus perception. As the quality of the evidence across studies was variable, no consensus can be reached regarding the use of hearing aids as a treatment for tinnitus. Nevertheless, recent studies were more likely to focus on optimizing the effect of hearing aids and better predicting which tinnitus patients benefit from hearing aids. The experts stated that the findings were in agreement with their view on the scientific evidence and they emphasized the importance of reaching consensus.

ConclusionsThe majority of the studies supported the use of hearing aids for tinnitus relief. Hence, there was some scientific support for it, but the quality of evidence was questioned. Stronger methodology in future studies is needed to reach consensus and support clinical guidelines development.


title: Methylome-wide association study of early life stressors and adult mental health reveals a relationship between birth date and cell type composition in blood

abstract: The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes in adulthood are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713,522 CpG sites from 9,537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive data on genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2 and ABI1) were annotated to CpG sites associated with preterm birth (P < 1.27 x 10 -9). A further two genes important to the development of sensory pathways (SOBP and RPGRIP1) were annotated to sites associated with low birth weight (P < 4.35 x 10-8). Genes and gene-sets annotated from associated CpGs sites and methylation profile scores were then used to quantify any overlap between the early life environment and mental health traits. However, there was no evidence of any overlap after applying a correction for multiple testing. Time of year of birth was found to be associated with a significant difference in estimated lymphocyte and neutrophil counts. Early life environments influence the risk of developing mental health disorders later in life; however, this study provides no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.

category: genetic and genomic medicine


title: Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia

abstract: Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06, P = 2.83 x 10-9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.


title: Optimization of magnetic bead-based nucleic acid extraction for SARS-CoV-2 testing using readily available reagents

abstract:
The COVID-19 pandemic has highlighted the need for generic reagents and flexible systems in diagnostic testing. Magnetic bead-based nucleic acid extraction protocols using 96-well plates on open liquid handlers are readily amenable to meet this need. Here, one such approach is rigorously optimized to minimize cross-well contamination while maintaining sensitivity.

Article SummaryA scalable, non-proprietary, magnetic bead-based automated nucleic acid extraction protocol optimised for minimum cross-well contamination


title: A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk.

abstract: Parkinsons disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. A recent finding has suggested an association between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinsons Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinsons disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to healthy individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.


title: Maximisation of open hospital capacity under shortage of SARS-CoV-2 vaccines

abstract:
MotiveThe Covid-19 pandemic has led to the novel situation that hospitals must prioritise staff for a vaccine rollout while there is acute shortage of the vaccine. In spite of the availability of guidelines from state agencies, there is partial confusion about what an optimal rollout plan is. This study investigates effects in a hospital model under different rollout schemes.

MethodsA simulation model is implemented in VBA and studied for parameter variation. The implemented code is available as open access supplement.

Main resultsA rollout scheme assigning vaccine doses to staff primarily by staffs pathogen exposure maximises the predicted open hospital capacity when compared to a rollout based on hierarchical prioritisation. The effect increases under resource scarcity and increasing disease activity. Nursing staff benefits most from an exposure focused rollout.

ConclusionsThe model employs SARS-CoV-2 parameters; nonetheless, effects observable in the model are transferable to other infectious diseases. Necessary future prioritisation plans need to consider pathogen characteristics and social factors.

category: health economics


title: RubricOE: a learning framework for genetic epidemiology

abstract: Genetic epidemiology is a growing area of interest in the past years due to the availability of genetic data with the decreasing cost of sequencing. Machine learning (ML) algorithms can be a very useful tool to study the genetic factors on disease incidence or on different traits characterizing a population. There are many challenges that plagues the field of genetic epidemiology including the unbalanced case-control data sets, fallibility of standard genome wide association studies with single marker analysis, heavily underdetermined systems with millions of markers in contrast of a few thousands of samples, to name a few. Ensemble ML methods can be a very useful tool to tackle many of these challenges and thus we propose RubricOE, a pipeline of ML algorithms with error bar computations to obtain interpretable genetic and non-genetic features from genomic or transcriptomic data combined with clinical factors in the form of electronic health records. RubricOE is shown to be robust in simulation studies, detecting true associations with traits of interest in arbitrarily structured multi-ethnic populations.

category: health informatics


title: A Data-driven Framework for Learning and Visualizing Characteristics of Thrombotic Event Phenotypes from Clinical Texts

abstract: Automatically identifying thrombotic phenotypes based on clinical data, particularly clinical texts, can be challenging. Although many investigators have developed targeted information extraction methods for identifying thrombotic phenotypes from radiology notes, these methods can be time consuming to train, require large amounts of training data, and may miss subtle textual clues predictive of a thrombotic phenotype from notes beyond the radiology note. We developed a generalizable, data-driven framework for learning, characterizing, and visualizing clinical concepts from both radiology and discharge summaries predictive of thrombotic phenotypes.


title: Quantified Flu: an individual-centered approach to gaining sickness-related insights from wearable data

abstract:
BackgroundWearables have been used widely for monitoring health in general, and recent research results show that they can be used for predicting infections based on physiological symptoms. So far, the evidence has been generated in large, population-based settings. In contrast, the Quantified Self and Personal Science communities are composed of people interested in learning about themselves individually using their own data, often gathered via wearable devices.

ObjectiveWe explore how a co-creation process involving a heterogeneous community of personal science practitioners can develop a collective self-tracking system to monitor symptoms of infection alongside wearable sensor data.

MethodsWe engaged in a co-creation and design process with an existing community of personal science practitioners, jointly developing a working prototype of an online tool to perform symptom tracking. In addition to the iterative creation of the prototype (started on March 16, 2020), we performed a netnographic analysis, investigating the process of how this prototype was created in a decentralized and iterative fashion.

ResultsThe Quantified Flu prototype allows users to perform daily symptom reporting and is capable of visualizing those symptom reports on a timeline together with the resting heart rate, body temperature, and respiratory rate as measured by wearable devices. We observe a high level of engagement, with over half of the 92 users that engaged in the symptom tracking becoming regular users, reporting over three months of data each. Furthermore, our netnographic analysis highlights how the current Quantified Flu prototype is a result of an interactive and continuous co-creation process in which new prototype releases spark further discussions of features and vice versa.

ConclusionsAs shown by the high level of user engagement and iterative development, an open co-creation process can be successfully used to develop a tool that is tailored to individual needs, decreasing dropout rates.


title: Development and validation of a clinical and genetic model for predicting risk of severe COVID-19

abstract: Age, sex, and comorbidities are known risk factors for severe COVID-19 but are frequently considered independently and without accurate knowledge of the magnitude of their effects on risk. Single-nucleotide polymorphisms (SNPs) associated with risk of severe COVID-19 have appeared in the literature, but their application in predictive risk testing has not been validated. Reliance on age and sex alone to determine risk of severe COVID-19 will fail to accurately quantify risk. Here, we report the development and validation of a clinical and genetic model to predict risk of severe COVID-19 using confirmed SARS-CoV-2 positive participants from the UK Biobank. Our new model out-performed an age and sex model and had excellent discrimination and was well calibrated in the validation dataset. We also report validation studies of our prototype model and polygenic risk scores based on 8-SNP and 6-SNP panels identified in the literature. Accurate prediction of individual risk will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.

category: infectious diseases


title: Wastewater Surveillance of SARS-CoV-2 across 40 U.S. states

abstract: Wastewater-based disease surveillance is a promising approach for monitoring community outbreaks. Here we describe a nationwide campaign to monitor SARS-CoV-2 in the wastewater of 159 counties in 40 U.S. states, covering 13% of the U.S. population from February 18 to June 2, 2020. Out of 1,751 total samples analyzed, 846 samples were positive for SARS-CoV-2 RNA, with overall viral concentrations declining from April to May. Wastewater viral titers were consistent with, and appeared to precede, clinical COVID-19 surveillance indicators, including daily new cases. Wastewater surveillance had a high detection rate (>80%) of SARS-CoV-2 when the daily incidence exceeded 13 per 100,000 people. Detection rates were positively associated with wastewater treatment plant catchment size. To our knowledge, this work represents the largest-scale wastewater-based SARS-CoV-2 monitoring campaign to date, encompassing a wide diversity of wastewater treatment facilities and geographic locations. Our findings demonstrate that a national wastewater-based approach to disease surveillance may be feasible and effective.


title: The BioNTech / Pfizer vaccine BNT162b2 induces class-switched SARS-CoV-2-specific plasma cells and potential memory B cells as well as IgG and IgA serum and IgG saliva antibodies upon the first immunization

abstract:
To treat the SARS-CoV-2 virus, that enters the body through the respiratory tract, different vaccines in particular against the SARS-CoV-2 spike (S)-protein have been developed or are in the development process. For the BioNTech / Pfizer mRNA vaccine BNT162b2, which is injected twice, protection against COVID-19 has been described for the first weeks after the second vaccination. The underlying mechanisms of defense and the long-term effectiveness of this vaccine against COVID-19 are currently under investigation.

In addition to the induction of systemic antibodies (Abs), Ab responses in the respiratory tract would help to form a first line of defense against SARS-CoV-2. Furthermore, protection depends on Fab-part-dependent neutralizing capacities, however, Fc-part-mediated effector mechanisms might also be important. Long-term defense would be based on the induction of long-lived antibody-producing plasma cells (PCs) and memory B cells.

Here, we established different assays to analyze anti-SARS-CoV-2-S IgG and IgA Abs in blood serum and saliva as well as SARS-CoV-2-S1-reactive IgG and IgA PCs and potential memory B cells in the blood of individuals upon their first immunization with BNT162b2.

We show that the vaccine induces in particular anti-SARS-CoV-2-S IgG1 and IgG3 as well as IgA1 and in some individuals also IgG2 and IgA2 serum Abs. In the saliva, we found no anti-SARS-CoV-2-S IgA, but instead IgG Abs. Furthermore, we found SARS-CoV-2-S reactive IgG+ blood PCs and potential memory B cells as well as SARS-CoV-2-S reactive IgA+ PCs and/or potential memory B cells in some individuals.

Our data suggest that the vaccine induces a promising CD4+ T cell-dependent systemic IgG1 and IgG3 Ab response with IgG+ PCs and potential memory B cells. In addition to the systemic IgG response, the systemic IgA and saliva IgG response might help to improve a first line of defense in the respiratory tract against SARS-CoV-2 and its mutants.


title: Case-control, diagnostic accuracy study of a non-sputum CD38-based TAM-TB test from a single milliliter of blood

abstract:
BackgroundCD4 T cell phenotyping-based blood assays have the potential to meet WHO target product profiles (TPP) of non-sputum-biomarker-based tests to diagnose tuberculosis (TB). Yet, substantial refinements are required to allow their implementation in clinical settings. This study assessed the real time performance of a simplified T cell activation marker (TAM)-TB assay to detect TB in adults from one millilitre of blood with a 24h turnaround time.

MethodsWe recruited 479 GeneXpert(R) positive cases and 108 symptomatic but GeneXpert(R) negative controls from presumptive adult TB patients in the Temeke District of Dar-es-Salaam, Tanzania. TAM-TB assay accuracy was assessed by comparison with a composite reference standard comprising GeneXpert(R) and solid culture. A single millilitre of fresh blood was processed to measure expression of CD38 or CD27 by CD4 T cells producing INF-{gamma} and/or TNF- in response to a synthetic peptide pool covering the sequences of Mycobacterium tuberculosis (Mtb) ESAT-6, CFP-10 and TB10.4 antigens on a 4-color FACSCalibur apparatus.

ResultsSignificantly superior to CD27 in accurately diagnosing TB, the CD38-based TAM-TB assay specificity reached 93.4% for a sensitivity of 82.2% with an area under the receiver operating characteristics curve of 0.87 (95% CI 0.84-0.91). The assay performance was not significantly affected by HIV status.

ConclusionsWe successfully implemented TAM-TB immunoassay routine testing with a 24h turnaround time at district level in a resource limited setting. Starting from one millilitre of fresh blood and being not influenced by HIV status, TAM-TB assay format and performance appears closely compatible with the optimal TPP accuracy criteria defined by WHO for a non-sputum confirmatory TB test.


title: Antimicrobial susceptibility patterns of respiratory Gram-negative bacterial isolates from COVID-19 patients in Switzerland

abstract:
BackgroundBacterial superinfections associated with COVID-19 are common in ventilated ICU patients and impact morbidity and lethality. However, the contribution of antimicrobial resistance to the manifestation of bacterial infections in these patients has yet to be elucidated.

MethodsWe collected 70 Gram-negative bacterial strains, isolated from the lower respiratory tract of ventilated COVID-19 patients in Zurich, Switzerland between March and May 2020. Species identification was performed using MALDI-TOF; antibiotic susceptibility profiles were determined by EUCAST disk diffusion and CLSI broth microdilution assays. Selected Pseudomonas aeruginosa isolates were analyzed by whole-genome sequencing.

ResultsP. aeruginosa (46%) and Enterobacterales (36%) comprised the two largest etiologic groups. Drug resistance in P. aeruginosa isolates was high for piperacillin/tazobactam (65.6%), cefepime (56.3%), ceftazidime (46.9%) and meropenem (50.0%). Enterobacterales isolates showed slightly lower levels of resistance to piperacillin/tazobactam (32%), ceftriaxone (32%), and ceftazidime (36%). All P. aeruginosa isolates and 92% of Enterobacterales isolates were susceptible to aminoglycosides, with apramycin found to provide best-in-class coverage. Genotypic analysis of consecutive P. aeruginosa isolates in one patient revealed a frameshift mutation in the transcriptional regulator nalC that coincided with a phenotypic shift in susceptibility to {beta}-lactams and quinolones.

ConclusionsConsiderable levels of antimicrobial resistance may have contributed to the manifestation of bacterial superinfections in ventilated COVID-19 patients, and may in some cases mandate consecutive adaptation of antibiotic therapy. High susceptibility to amikacin and apramycin suggests that aminoglycosides may remain an effective second-line treatment of ventilator-associated bacterial pneumonia, provided efficacious drug exposure in lungs can be achieved.


title: The Value of Rapid Antigen Tests to Identify Carriers of Viable SARS-CoV-2.

abstract: The search for effective methods to detect patients who excrete a viable virus is one of the urgent tasks of modern biomedicine. In the present study, we examined the diagnostic value of two antigen tests BIOCREDIT COVID-19 Ag (RapiGEN Inc., Korea) and SGTI-flex COVID-19 Ag (Sugentech Inc., Korea) for their diagnostic value in identifying patients who excrete viable SARS-CoV-2. As part of the study, we examined samples from 106 patients who had just been admitted to the hospital, who had undergone quantitative RT-PCR and assessment of viability of SARS-CoV-2 using cell culture. Sensitivity was 0.786 (0.492-0.953) for SGTI-flex COVID-19 Ag and 1 (0.768- 1) for Biocredit COVID-19 Ag. Specificity of rapid tests was significantly higher than that of RT-PCR and was 0.663 (0.557-0.758) and 0.674 (0.568-0.768) for SGTI-flex COVID-19 Ag and Biocredit COVID-19 Ag versus 0.304 (0.213-0.409) obtained for PCR. Thus, for tasks of identifying viable SARS-CoV-2 during screening of conditionally healthy people, as well as monitoring those quarantined, rapid tests show significantly better results.


title: Higher viral load drives infrequent SARS-CoV-2 transmission between asymptomatic residence hall roommates

abstract: In 2019-2020, the COVID-19 pandemic spread to over 200 countries in less than six months. To understand the basis of this aggressive spread, it is essential to determine the transmission rate and define the factors that increase the risk of transmission. One complication is the large fraction of asymptomatic cases, particularly in young populations: these individuals have viral loads indistinguishable from symptomatic people and do transmit the SARS-CoV-2 virus, but they often go undetected. As university students living in residence halls commonly share a small living space with roommates, some schools established regular, high density testing programs to mitigate on-campus spread. In this study, we analyzed longitudinal testing data of residence hall students at the University of Colorado Boulder. We observed that students in single rooms were infected at a lower rate than students in multiple occupancy rooms. However, this was not due to high rates of transmission between roommates, which only occurred approximately 20% of the time. Since these cases were usually asymptomatic at the time of diagnosis, this provides further evidence for asymptomatic transmission. Notably, individuals who likely transmitted to their roommates had an average viral load [~]6.5 times higher than individuals who did not. Although students were moved to separate isolation rooms after diagnosis, there was no difference in time to isolation between these cases with or without transmission. This analysis argues that inter-roommate transmission occurs in a minority of cases in university residence halls and provides strong correlative evidence that viral load can be proportional to the probability of transmission.


title: Global association of obesity and COVID-19 death rates

abstract:
ImportanceCOVID-19 was responsible for an enormous global death toll with large variation among countries.

ObjectiveTo examine the possible impact of obesity on COVID-19 death rates.

DesignMeasure associations between obesity rates in 2016 and COVID-19 deaths/million population through 2/25/2021, across countries.

SettingGlobal

Participants167 countries for which obesity and death data were available, grouped by population size, with multiples of 10 countries in each of 8 groups plus a group including all 57 countries with obesity rates <15%.

Outcome and measuresUsing Excel, COVID-19 deaths/million were regressed on the obesity rate for each country, based on obesity being a key factor in COVID hospitalizations and deaths. Using the least squares formula for the best fit for each model, R2, components of the formula, and the percentage of world population represented, were recorded for each group.

ResultsObesity rates ranged from 2.1% to 37.9% and death rates ranged from 0.4/million to 1,892/million for groups representing up to 91% of global population. Results for the 8 population groups had R2 from 0.30 to 0.90 with slopes of the fitted line ranging from 27.9-51.0. Countries with obesity rates <15% had consistently low death rates ([≤]233/million), R2 of 0.003 and slope of the line=1.01.

ConclusionsFor most countries about one-third of the difference in COVID death rates was due to obesity while in countries with obesity <15%, consistently low death rates were not associated with obesity. Reduced obesity rates could potentially have lowered the COVID death toll.


title: Analytical and clinical performances of a SARS-CoV-2 S-RBD IgG assay: comparison with neutralization titers

abstract:
BackgroundSARS-CoV-2 serology presents an important role in understanding the virus epidemiology, in vaccine prioritization strategies and in convalescent plasma therapy. Immunoassays performances have to be accurately evaluated and correlated with neutralizing antibodies to be used as a surrogate measure of neutralizing activity. We investigate the analytical and clinical performance of a SARS-CoV-2 RBD IgG assay, automated on a high throughput platform, and the correlation of the antibodies (Ab) levels with the plaque reduction neutralization (PRNT50) Ab titers.

MethodsA series of 546 samples were evaluated by SARS-CoV-2 RBD IgG assay (Snibe diagnostics), including 171 negative and 168 positive SARS-CoV-2 subjects and a further group of 207 subjects of the COVID-19 family clusters follow-up cohort.

ResultsAssay precision was acceptable at low and medium levels; linearity was excellent in all the measurement range. Considering specimens collected after 14 days post symptoms onset, overall sensitivity and specificity were 99.0% and 92.5%, respectively. A total of 281 leftover samples results of the PRNT50 test were available. An elevated correlation was obtained between the SARS-CoV-2 RBD IgG assay and the PRNT50 titer at univariate (rho = 0.689) and multivariate (rho = 0.712) analyses.

ConclusionsSARS-CoV-2 S-RBD IgG assay achieves elevated analytical and clinical performances, and a strong correlation with sera neutralization activity.


title: An In-House ELISA for SARS-CoV-2 RBD uncovers elevatedimmune response at higher altitudes

abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reported in Wuhan has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) associated represents a challenge for health systems that had to quickly respond developing new diagnostic and therapeutic strategies. In the present work, we developed an "In House" ELISA with high sensitivity (92.2 %), specificity (100%) and precision (93.9%), with an area under the ROC curve (AUC) of 0.991, rendering the assay as an excellent serological test to correctly discriminate between SARS-COv-2 infected and non-infected individuals and study population seroprevalence. Among 758 patients evaluated for SARS-CoV-2 diagnosis in the province of Tucuman, Argentina, we found a Pearson correlation coefficient of 0.5048 between antibodies elicited against the RBD and the nucleocapsid (N) antigen. Additionally, 33.6% of individuals diagnosed with COVID-19 displayed mild levels of RBD-IgG antibodies, while 19% of the patients showed high antibody titers. Interestingly, patients with SARS-COV-2 infection over 60 years old elicited significantly higher levels of IgG antibodies against RBD compared to younger ones, while no difference was found between women and men. Surprisingly, individuals from a high altitude village displayed statistically significant higher and longer lasting anti-RBD antibodies compared to those from a city at a lower altitude, suggesting that a hypobaric hypoxia-adapted mechanism may act as a protective factor for COVID-19. To our knowledge, this is the first report correlating altitude with increased humoral immune response against SARS-Cov-2 infection.


title: A Recovery Algorithm and Pooling Designs for One-Stage Noisy Group Testing under the Probabilistic Framework

abstract:
Group testing saves time and resources by testing each pre-assigned group instead of each individual, and one-stage group testing emerged as essential for cost-effectively controlling the current COVID-19 pandemic. Yet, the practical challenge of adjusting pooling designs based on infection rate has not been systematically addressed. In particular, there are both theoretical interests and practical motivation to analyze one-stage group testing at finite, practical problem sizes, rather than asymptotic ones, under noisy, rather than perfect tests, and when the number of positives is randomly distributed, rather than fixed.

Here, we study noisy group testing under the probabilistic framework by modeling the infection vector as a random vector with Bernoulli entries. Our main contributions include a practical one-stage group testing protocol guided by maximizing pool entropy and a maximum-likelihood recovery algorithm under the probabilistic framework. Our findings high-light the implications of introducing randomness to the infection vectors - we find that the combinatorial structure of the pooling designs plays a less important role than the parameters such as pool size and redundancy.


title: Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalization rates in February 2021, Rio Grande do Sul, Southern Brazil

abstract: The emergence SARS-CoV-2 P.1 lineage has been coincidental with a rapid growth in hospitalization in the northern region of Brazil. An exponential growth of severe COVID-19 occurred in Rio Grande do Sul state, Southern Brazil in February-2021. Whole-genome sequencing revealed that the previously undetected P.1 lineage accounted for 88.9% of specimens collected from patients at a referral COVID-19 hospital. These findings raise concerns regarding a possible association between lineage P.1 and rapid growth in cases and hospitalizations.


title: Efficacy of SARS-CoV-2 Repeat Testing to Control Spread in Residential College Populations

abstract: AO_SCPLOWBSTRACTC_SCPLOWUniversities have turned to SARS-CoV-2 models to examine campus reopening strategies 1-9. While these studies have explored a variety of modeling techniques, all have relied on simulated data. Here, we use an empirical proximity network of college freshmen 10, ascertained using smartphone Bluetooth, to simulate the spread of the virus. We investigate the role of testing, isolation, mask wearing, and social distancing in the presence of implementation challenges and imperfect compliance. Here we show that while frequent testing can drastically reduce spread if mask wearing and social distancing are not widely adopted, testing has limited impact if they are ubiquitous. Furthermore, even moderate levels of immunity can significantly reduce new infections, especially when combined with other interventions. Our findings suggest that while testing and isolation are powerful tools, they have limited benefit if other interventions are widely adopted. If universities can attain high levels of masking and social distancing, they may be able to relax testing frequency to once every two to four weeks.


title: Examining SARS-CoV-2 Interventions in Residential Colleges Using an Empirical Network


title: Rapid screening for SARS-CoV-2 variants of concern in clinical and environmental samples using nested RT-PCR assays targeting key mutations of the Spike protein

abstract:
New SARS-CoV-2 mutations are constantly emerging, raising concerns of increased transmissibility, virulence or escape from host immune response.

We describe a nested RT-PCR assay ([~]1500 bps) to detect multiple key spike protein mutations distinctive of the major known circulating SARS-CoV-2 variants, including the three Variants of Concern (VOCs) 20I/501Y.V1 (United Kingdom), 20H/501Y.V2 (South Africa), and 20J/501Y.V3 (Brazil), as well as the 20E.EU1 variant (Spain), the CAL.20C recently identified in California, and the mink-associated variant (GR, lineage B.1.1.298). Prior to application to field samples, the discriminatory potential of this PCR assay was explored using GISAID and Nextclade. To extend variant detection to challenging matrices such as sewage, where the amplification of long fragments is problematic, two short nested RT-PCR assays ([~]300 bps) were also designed, targeting portions of the region spanned by the long nested assay.

The three newly-designed assays were then tested on field samples, including 7 fully-sequenced viral isolates from swab samples and 34 urban wastewater samples, some of which collected in areas where circulation of VOCs had been reported.

The long assay successfully amplified all the previously characterized viral isolates, allowing the correct identification of variants 20I/501Y.V1 and 20E.EU1 present in the panel. The sequences obtained using the short assays were consistent with those obtained with the long assay. Mutations characteristic of VOCs (UK and Brazilian variant) and of other variant (Spanish) were detected in sewage samples. To our knowledge, this is the first evidence of the presence of sequences harboring key mutations of 20I/501Y.V1 and 20J/501Y.V3 in urban wastewaters, highlighting the potential contribution of wastewater surveillance to explore SARS-CoV-2 diversity.

The developed nested RT-PCR assays can be used as an initial rapid screening test to select clinical samples containing mutations of interest. This can speed up diagnosis and optimize resources since it allows full genome sequencing to be done only on clinically relevant specimens. The assays can be also employed for a rapid and cost-effective detection of VOCs or other variants in sewage for the purposes of wastewater-based epidemiology. The approach proposed here can be used to better understand SARS-CoV-2 variant diversity, geographic distribution and impact worldwide.


title: Therapeutic Anticoagulation in Critically Ill Patients with Covid-19-Preliminary Report

abstract:
BackgroundThrombosis may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic anticoagulation would improve outcomes in critically ill patients with Covid-19.

MethodsWe conducted an open-label, adaptive, multiplatform, randomized, clinical trial. Patients with severe Covid-19, defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes, were randomized to receive therapeutic anticoagulation with heparin or pharmacological thromboprophylaxis as per local usual care. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21.

ResultsTherapeutic anticoagulation met the pre-defined criteria for futility in patients with severe Covid-19. The primary outcome was available for 1,074 participants (529 randomized to therapeutic anticoagulation and 545 randomized to usual care pharmacological thromboprophylaxis). Median organ support-free days were 3 days (interquartile range -1, 16) in patients assigned to therapeutic anticoagulation and 5 days (interquartile range -1, 16) in patients assigned to usual care pharmacological thromboprophylaxis (adjusted odds ratio 0.87, 95% credible interval (CrI) 0.70-1.08, posterior probability of futility [odds ratio<1.2] 99.8%). Hospital survival was comparable between groups (64.3% vs. 65.3%, adjusted odds ratio 0.88, 95% CrI 0.67-1.16). Major bleeding occurred in 3.1% of patients assigned to therapeutic anticoagulation and 2.4% of patients assigned to usual care pharmacological thromboprophylaxis.

ConclusionsIn patients with severe Covid-19, therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis.

Trial registration numbers NCT02735707, NCT04505774, NCT04359277, NCT04372589

category: intensive care and critical care medicine


title: Exploring provider perspectives on patients with atrial fibrillation who are not prescribed anticoagulation therapy

abstract:
BackgroundEvidence-based guidelines strongly recommend oral anticoagulants to prevent stroke in patients with non-valvular atrial fibrillation (AF). However, many patients are not prescribed guideline recommended anticoagulant therapy.

ObjectivesTo explore themes underlying anticoagulant prescribing or discontinuation in patients with AF and compare and contrast prescribing preferences between cardiologists and general practitioners.

MethodsProviders at the University of Utah Health system were recruited to participate in semi-structured interviews. An interview guide directed the 15-minute interviews with focus on anticoagulant prescribing practices for patients with AF. Interviews were transcribed verbatim. Two reviewers independently read transcripts and labeled passages of text corresponding with key concepts and themes.

ResultsOf the eleven practitioners interviewed, seven practiced in cardiology, two in internal medicine and two in family medicine. The most prominent reasons cited for not prescribing anticoagulation for stroke prevention in AF patients were concerns about intracranial bleeding, followed by gastrointestinal bleeding. Other common reasons were increased age, thrombocytopenia, chemotherapy, previous or concerns of noncompliance, and comorbidities. Providers believed patient refusal of anticoagulants was related to fear of bleeding, medication burden, or warfarins negative reputation. All prescribers reported similar prescribing strategies, including using risk stratification, shared decision making, and utilizing specialized anticoagulation clinics and pharmacists as resources.

ConclusionFear of bleeding was a common theme underlying anticoagulant underutilization in patients with AF. Identifying major reasons directly from providers can be utilized to develop patient education addressing common fears and misconceptions, promote shared decision making, and provide provider education and resources to achieve appropriate anticoagulant prescribing.

category: cardiovascular medicine


title: Validation of Automated Biventricular Myocardial Segmentation from Coronary Computed Tomographic Angiography for Multimodality Image Fusion

abstract:
PurposeImage fusion strategies of myocardial perfusion imaging (MPI) and coronary CT angiography (CCTA) have shown increased diagnostic power. However, their clinical feasibility is hindered by the lack of efficient algorithms for the extraction of cardiac anatomy from CCTA datasets. The aim of this work was to validate our previously published algorithm for automated cardiac segmentation of CCTAs in a larger cohort of subjects while testing its application in clinical settings.

MethodsThree borders were automatically and manually extracted on sixty-three clinical CCTAs: left and right endocardia (LV, RV) and the biventricular epicardium (EPI). Impact of image resolutions and inter-operator variability on accuracy and robustness of automated processing were evaluated. Automated algorithm accuracy was assessed with the Dice Similarity Coefficient (DSC) and the surface-to-surface distance metric. Relevant quantities were compared for automated versus manual segmentations: LV and RV volumes, myocardial mass and LV myocardial mass.

ResultsLower resolution images offered an acceptable trade-off for accuracy and processing time (45 sec). DSC for LV, RV, EPI borders were 0.88, 0.80 and 0.89. Automated versus manual correlation coefficients for LV and RV vol, myo and LV mass were 0.96, 0.73, 0.84 and 0.67 with inter-operator agreement > 0.93 for three variables. Consistent and improved results were evidenced at higher resolutions.

ConclusionOur algorithms allowed efficient automated cardiac segmentation from CT imagery with minimal user intervention, clinically acceptable times and accuracy. The reported results show promise for its use in a clinical environment, specifically in the context of image fusion.


title: Model Based Estimation of the SARS-CoV-2 Immunization Level in Austria and Consequences for Herd Immunity Effects

abstract: Several systemic factors indicate, that worldwide herd immunity against COVID-19 will probably not be achieved in 2021. Vaccination programs are limited by availability of doses, the number of people already infected is still too low to have a disease preventing impact and new emerging variants of the virus seem to partially neglect developed antibodies from previous infections. Nevertheless, after one year of COVID-19 observing high numbers of reported cases in most European countries, we might expect that the immunization level should have an impact on the spread of SARS-CoV-2. We used an agent-based simulation model to reproduce the COVID-19 pandemic in Austria to estimate the immunization level of the population as of February 2021. We ran several simulations of an uncontrolled epidemic wave with varying initial immunization scenarios to assess the effect on the effective reproduction number. We also used a classic differential equation SIR-model to cross-validate the simulation model. As of February 2021, 14.7% of the Austrian population has been affected by a SARS-CoV-2 infection which causes a 9% reduction of the effective reproduction number and a 24.7% reduction of the prevalence peak compared to a fully susceptible population. This estimation is now recomputed on a regular basis to publish model based analysis of immunization level in Austria also including the fast growing effects of vaccination programs. This provides substantial information for decision makers to evaluate the necessity of NPI-measures based on the estimated impact of natural and vaccinated immunization.

category: epidemiology


title: Evaluation of Measles Surveillance System amidst Covid 19 pandemic in Asutifi North District, Ahafo Region, Ghana.

abstract:
BackgroundMeasles is a disease of public health importance earmarked for elimination by all WHO Regions. Globally, more than 140 000 people died from Measles in 2018 affecting mostly children under 5 years, despite the availability of safe and effective vaccine.

MethodsA descriptive cross-sectional survey was conducted. Disease surveillance focal persons were interviewed using semi-structured questionnaire on the system operations and use of Measles case definitions. Measles case-based investigation forms from 2015 - 2020 were reviewed for its timeliness and data quality. CDC updated guidelines for surveillance system evaluation was used to assess its usefulness and attributes. Data was analyzed for frequencies and proportions and results presented in tables and graphs.

ResultsMeasles surveillance system was timely as 100% (69/69) of the suspected cases were reported on time. Also, the level of representativeness was good as all the 14 health facilities in the District were participating in the Measles Surveillance system. Majority 73.1 (44/60) of the case-based investigation forms filled were incomplete with some columns wrongly filled.

ConclusionDespite the outbreak of Covid - 19 with most districts battling with how to contain the virus, measles surveillance system was still meeting its objectives of early detection and prompt reporting but with poor data quality.


title: Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris, France: the SEROCOV prospective cohort study

abstract:
BackgroundWith the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern.

MethodsIn this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression.

ResultsAmong 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3.

ConclusionThe rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.

Key messagesO_LIDuring the first epidemic wave, 14.6% of 1,062 first-line Health Care Workers had a positive serology and/or RT-PCR test for SARS-CoV-2.
C_LIO_LIMost infections occurred early
C_LIO_LIRisk was increased by working in infectious diseases (OR 4.22, 95% confidence interval [0.92; 18.28]), emergency (3.91 [0.83; 18.43]) and intensive care units (1.80, [0.38; 8.58])
C_LIO_LIBeing an active smoker was protective (0.36 [0.21; 0.3]).
C_LI


title: Temporal Aspects of the Association between Exposure to the World Trade Center Disaster and Risk of Skin Melanoma

abstract: Rescue/recovery workers who responded to the World Trade Center (WTC) attacks on 9/11/2001 were exposed to known/suspected carcinogens. Studies have identified an increased risk of skin melanoma in this population, but the temporal aspects of the association have not been investigated. A total of 44,540 non-Hispanic White workers from the WTC Combined Rescue/Recovery Cohort were observed between 3/12/2002 and 12/31/2015. Cancer data were obtained via linkages with 13 state registries. Poisson regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), using the New York State population as reference; change points in the HRs were estimated using profile likelihood. We observed 247 incident cases of skin melanoma. No increase in incidence was detected between 2002 and 2004. Beginning in 2005, the HR was 1.34 (95% CI 1.18-1.52). A dose-response relationship was observed according to time worked on the WTC effort. Risk of melanoma among non-Hispanic White WTC rescue/recovery workers was elevated, beginning in 2005. While WTC-related exposure to ultraviolet radiation or other agents might have contributed to this result, exposures other than the WTC effort and enhanced medical surveillance cannot be discounted. Our results support the continued surveillance of this population for melanoma.


title: Vaccine confidence and timeliness of childhood immunisation by health information source, maternal, socioeconomic, and geographic characteristics in Albania

abstract:
BackgroundAlbania is facing decreasing childhood immunisation coverage and timeliness despite a growing economy and universal health insurance. Our aim is to estimate vaccine confidence and timeliness of childhood immunisation by health information source, maternal, socioeconomic, and geographic characteristics in Albania.

MethodsWe used the 2017-2018 Albania Demographic and Health Survey to analyse vaccine confidence, measured via the proxy of vaccine timeliness, among 2,156 mothers of under-5-year-old children using simple and multivariable logistic regression.

Results77.9% [74.2, 81.2] of mothers had confidence in vaccines. Immunisation delay was reported by 21.5% [18.3, 25.3] of mothers, but a majority (65.7%) were caused by the infants sickness at the time of vaccination, while a minority (8.7%) due to mothers concerns about vaccine safety and side effects. Among 1.7% of mothers who ever refused vaccination of their children, the main concerns were about vaccine safety (35.9%) and adverse events (42.7%). Factors associated with lower vaccine confidence were using the Internet/social media as the main health information source compared to other sources (AOR=0.66 [0.47, 0.94], p=0.020), mothers work outside the home (AOR=0.65 [0.47, 0.91], p=0.013), lack of maternal education (AOR=0.14 [0.03, 0.67], p=0.014), and living in AL02-Qender (AOR=0.38 [0.23, 0.63]) and AL03-Jug regions (AOR=0.36 [0.24, 0.53]) in comparison to AL01-Veri region (p<0.0001).

ConclusionsReinforcement of scientific evidence-based online communication about childhood immunisation and monitoring anti-vaccination movements on the Internet/social media would be beneficial in improving vaccine confidence and timeliness in Albania, together with traditional ways of promoting vaccination by healthcare professionals who enjoy confidence as trusted sources of information.


title: Environmental drivers of SARS-CoV-2 lineage B.1.1.7 transmission in England, October to December 2020

abstract: Previous work has shown that environment affects SARS-CoV-2 transmission, but it is unclear whether emerging strains show similar responses. Here we show that, like other SARS-CoV-2 strains, lineage B.1.1.7 spread with greater transmission in colder and more densely populated parts of England. However, we also find evidence of B.1.1.7 having a transmission advantage at warmer temperatures compared to other strains. This implies that spring and summer conditions are unlikely to slow B.1.1.7s invasion in Europe and across the Northern hemisphere - an important consideration for public health interventions.


title: Environmental drivers of SARS-CoV-2 lineage B.1.1.7 transmission intensity


title: Genomic epidemiology of SARS-CoV-2 in the United Arab Emirates reveals novel virus mutation, patterns of co-infection and tissue specific host responses

abstract: To unravel the source of SARS-CoV-2 introduction and the pattern of its spreading and evolution in the United Arab Emirates, we conducted meta-transcriptome sequencing of 1,067 nasopharyngeal swab samples collected between May 9th and Jun 29th, 2020 during the first peak of the local COVID-19 epidemic. We identified global clade distribution and eleven novel genetic variants that were almost absent in the rest of the world defined five subclades specific to the UAE viral population. Cross-settlement human-to-human transmission was related to the local business activity. Perhaps surprisingly, at least 5% of the population were co-infected by SARS-CoV-2 of multiple clades within the same host. We also discovered an enrichment of cytosine-to-uracil mutation among the viral population collected from the nasopharynx, that is different from the adenosine-to-inosine change previously reported in the bronchoalveolar lavage fluid samples and a previously unidentified upregulation of APOBEC4 expression in nasopharynx among infected patients, indicating the innate immune host response mediated by ADAR and APOBEC gene families could be tissue-specific. The genomic epidemiological and molecular biological knowledge reported here provides new insights for the SARS-CoV-2 evolution and transmission and points out future direction on host-pathogen interaction investigation.


title: Genomic epidemiology of SARS-CoV-2 in the United Arab Emirates reveals novel virus mutation, patterns of co-infection and tissue specific host innate immune response


title: COVID-19: Optimal Allocation of Ventilator Supply under Uncertainty and Risk

abstract: This study presents a new risk-averse multi-stage stochastic epidemics-ventilator-logistics compartmental model to address the resource allocation challenges of mitigating COVID-19. This epidemiological logistics model involves the uncertainty of untested asymptomatic infections and incorporates short-term human migration. Disease transmission is also forecasted through a new formulation of transmission rates that evolve over space and time with respect to various non-pharmaceutical interventions, such as wearing masks, social distancing, and lockdown. The proposed multi-stage stochastic model overviews different scenarios on the number of asymptomatic individuals while optimizing the distribution of resources, such as ventilators, to minimize the total expected number of newly infected and deceased people. The Conditional Value at Risk (CVaR) is also incorporated into the multi-stage mean-risk model to allow for a trade-off between the weighted expected loss due to the outbreak and the expected risks associated with experiencing disastrous pandemic scenarios. We apply our multi-stage mean-risk epidemics-ventilator-logistics model to the case of controlling the COVID-19 in highly-impacted counties of New York and New Jersey. We calibrate, validate, and test our model using actual infection, population, and migration data. The results indicate that short-term migration influences the transmission of the disease significantly. The optimal number of ventilators allocated to each region depends on various factors, including the number of initial infections, disease transmission rates, initial ICU capacity, the population of a geographical location, and the availability of ventilator supply. Our data-driven modeling framework can be adapted to study the disease transmission dynamics and logistics of other similar epidemics and pandemics.


title: Immune response during lactation after anti-SARS-CoV2 mRNA vaccine

abstract:
BackgroundData regarding adverse events observed in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines.

MethodsFrom a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers 2nd dose).

ResultsNo severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period. PEGylated proteins, were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation.

ConclusionsCOVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.

category: pediatrics


title: COVID-19 mRNA Vaccination in Lactation: Assessment of adverse effects and transfer of anti-SARS-CoV2 antibodies from mother to child


title: COVID-19 mRNA Vaccination in Lactation: Assessment of adverse events and vaccine related antibodies in mother-infant dyads


title: Feasibility of Social Media Recruitment for Orofacial Cleft Genetic Research

abstract:
ObjectiveThis study assessed the feasibility of unpaid social media (SM) advertising to recruit participants affected with an orofacial cleft (OFC) for a genetic study.

DesignThis paper is a retrospective analysis of study recruitment based on enrollment and participation in a genetic study. Participants completed a series of enrollment surveys, provided saliva samples for genetic analysis, and completed post-participation feedback surveys.

ParticipantsParticipants signed up for the study following SM advertisement. Participants were eligible if: they or a minor in their care were affected by an OFC, the affected participant was not adopted, and the mother of the affected individual had not taken anti-seizure medication during pregnancy. 313 individuals completed initial screening surveys; 306 participants were eligible. 263 individuals completed all online surveys and were sent DNA sample kits. 162 subject DNA samples were returned.

Main Outcome MeasuresSuccess of recruitment was evaluated as number of enrolled participants and return rate for DNA samples.

Results263 OFC-affected individuals completed the screening process in the first 12 months of recruitment. 162 of 263 affected subject DNA samples were returned within 12 months of sending, for a return rate of 62%. Approximately two-thirds (66.3%) of all returned samples were sent back within the first 6 weeks after receiving DNA kits.

ConclusionsUnpaid SM advertising enabled the recruitment of a large cohort of participants in a short time (12 months). SM recruitment was inexpensive and effective for recruiting participants for a genetic study.


title: Infections in childhood and subsequent diagnosis of autism spectrum disorders and intellectual disability: a register-based cohort study

abstract:
ObjectiveTo explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID) and their co-occurrence.

MethodsThe association between specialized care for any infection, defined by ICD-codes and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders childrens characteristics, family socioeconomic factors, obstetric complications, and parental histories of both treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with exclusion of congenital causes of ASD/ID and documented risk for infections were also performed.

ResultsCrude estimates indicated that infections during childhood were associated with later ASD and ID with largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later  ASD without ID (HR 1.24, 95%CI 1.15-1.33),  ASD with ID (1.57, 1.35-1.82) and  ID without ASD (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID.

ConclusionsInfections during childhood cannot be excluded in the etiology of ASD, particularly ASD with co-occurring ID.

category: psychiatry and clinical psychology


title: The impact of the UK's first COVID-19 lockdown on rates of violence and aggression on psychiatric inpatient wards

abstract:
AimsInpatient life in UK mental health hospitals was profoundly altered during the first wave of the COVID-19 pandemic. We analysed whether these changes impacted the rate of violent and aggressive incidents across acute adult wards and psychiatric intensive care units in a South London NHS Mental Health Trust during the first UK lockdown.

MethodsWe used an interrupted time series analysis to assess whether the rate of violent and aggressive incidents changed during the lockdown period from 23rd March 2020 to 15th June 2020. We used a quasi-poisson general additive model to model the weekly rate of violent incidents as a function of a seasonal trend, time trend, and impact of lockdown, using data from 1st January 2017 to 27th September 2020.

ResultsThere was a 35% increase in the rate of incidents of violence and aggression [IR = 1.35, 95% CI: 1.15 - 1.58, p < 0.001] between March 23rd 2020 and June 15th 2020. In addition, there was strong evidence of temporal (p < 0.001) and seasonal trends (p < 0.001).

ConclusionsOur results suggest that restrictions to life increased the rate of violent incidents on the mental health wards studied here.


title: Acceptability of contact management and care of simple cases of COVID-19 at home: a mixed-method study in Senegal

abstract:
IntroductionIn mid-2020, due to the health system challenges from increased COVID-19 cases, the Ministry of Health and Social Action in Senegal opted for contact management and care of simple cases at home. The studys objective was to determine the acceptability of contact management, home care of simple cases of COVID-19, and its associated factors.

MethodThis was a sequential mixed-method study. We collected data from June 11, 2020, to July 10, 2020, for the quantitative survey (N=813) and from August 24 to September 16, 2020, for the qualitative survey (N=30). We carried out a sampling strategy using marginal quotas at the national level. We collected data using a structured questionnaire in a telephone interview for the quantitative survey and using an interview guide formulated from the quantitative surveys initial results for the qualitative data. We assessed acceptability using binomial logistic regression combined with content analysis.

ResultsThe care of simple cases of COVID-19 at home was well accepted (78.5%). This result was justified for some (saturation of the health system) but not for others (risk of contamination). The use of home contact management was less accepted (51.4%), with risk limitation as the main reason given. The acceptability of home-based care for simple cases was positively associated with knowledge of the modes of transmission of the virus (ORaj: 1.55 [95%CI: 1.04,2.28]), regular research into COVID-19 (ORaj: 2.12 [95%CI: 1.45,3.12]), belief in the existence of treatment (ORaj: 1.82 [95%CI: 1.19,2.83]), and confidence in institutional information (ORaj: 2.10 [95%CI: 1.43,3.10]). The acceptability of home-based contact management was positively associated with knowledge of the modes of transmission of the virus (ORaj: 1.77 [95%CI: 1.27,2.48]), regular research for information on COVID-19 (ORaj: 2.39 [95%CI: 1.76,3.26]), and confidence in the government in the fight against the epidemic (ORaj: 1.51 [95%CI: 1.10,2.08]).

ConclusionRegular information on the disease, knowledge of its mode of transmission and trust in institutions are factors in accepting COVID-19 management at the community level. Authorities should take these factors into account for better communication to improve the acceptability of home-based care.


title: An Extended COVID-19 Epidemiological Model with Vaccination and Multiple Interventions for Controlling COVID-19 Outbreaks in the UK

abstract: For controlling the first wave of the UK COVID-19 pandemic in 2020, a plethora of hypothetical COVID-19 models has been developed for simulating how diseases spread under different non-pharmaceutical interventions like suppression and mitigation and providing useful guidance to UK policymakers. While many models demonstrate their effectiveness on predicting and controlling the spread of COVID-19, they rarely consider consequence of incorporating the effects of potential SARS-CoV-2 variants and implementing vaccine interventions in large-scale. By December 2020, the second wave in the UK appeared to be much more aggressive with many more cases as one potentially more contagious SARS-CoV-2 variant was detected in the UK since September 2020. Meanwhile, UK has begun their first mass vaccination campaign on 8 December 2020, where three vaccines were in use including Pfizer, BioNTech and Moderna. Thus, these new issues pose an emergent need to build up advanced models for accessing effectiveness of taking both vaccination and multiple interventions for controlling COVID-19 outbreaks and balancing healthcare demands. Targeting at this problem, we conducted a feasibility study by defining a new mathematical model SEMCVRD (Susceptible [S], Exposed [E] (infected but asymptomatic), Mild [M] and Critical [C] (mild cases, severe and critical cases), [V] (vaccinated), Recovered [R] and Deceased [D]), containing two importantly new features: the combined infection of the mutant strain and the original strain and the addition of a new group who have been vaccinated. The model was fitted and evaluated with a public COVID-19 dataset including daily new infections, new deaths and daily vaccination in the UK from February 2020 to February 2021. Based on the simulation results, 1) we find under the assumption that the vaccine is equivalently effective against both the original strain and new variants of COVID-19, if the UK government implements insensitive suppression intervention for 13 weeks, COVID-19 epidemic will be controlled by the first week of April 2021 and nearly ended by the first week of May 2021. It shows that taking both vaccine and suppression interventions can effectively inhibit the spread and infection of the new mutant virus. 2) we suggest implementing a 3-weeks phased and progressive lifting intervention strategy up to a low intensity mitigation level for effectively controlling COVID-19 outbreaks in the UK. By implementing this strategy, the total number of infections in the UK will be limited to 4.2 million and the total number of deaths in the UK is 135 thousand, by the end of June 2021. The epidemic will nearly end in the early of June 2021, and the UK will not experience a shortage of medical resources. 3) On the assumption that UK has a capability of providing 600 thousand vaccinations every day, a 3-weeks phased and progressive lifting intervention strategy up to a moderate intensity mitigation level can end the epidemic by the end of May 2021. This strategy would reduce the overall infections and deaths of COVID-19 outbreaks, and balance healthcare demand in the UK.


title: Individual's daily behaviour and intergenerational mixing in different social contexts of Kenya

abstract: Which are the characteristics of contact patterns in diverse social contexts in sub-Saharan Africa, and which types of individuals and daily behaviours may play a pivotal role in infection transmission to the most vulnerable, such as older adults? We address these questions using novel survey data on social contacts and time use from a sample of 1407 individuals from rural, urban, and slum settings in Kenya. In the rural setting, we observed the highest number of daily social contacts (11.56, SD = 0.23) and the highest share of intergenerational mixing with older adults (7.5% vs. around 4% in the urban settings). Intergenerational mixing with older adults was mainly reported by individuals spending their day mostly in the general community (around 8%) or at home (5.1%), rather than at work (1.5%) or at school (3.6%). These results are essential to define effective interventions to control infection transmission in the African context.


title: Rationale and design of the brain magnetic resonance imaging protocol for FutureMS: a longitudinal multi-centre study of newly diagnosed patients with relapsing-remitting multiple sclerosis in Scotland

abstract:
IntroductionMultiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. MRI can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression. This paper provides an overview of MRI data acquisition, management and processing in FutureMS.

Methods and analysisMRI is acquired at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures.

Ethics and disseminationThe study received ethical approval from the South East Scotland Research Ethics Committee 02 (reference 15/SS/0233). Results will be made available to study participants and funders.

STRENGTHS AND LIMITATIONS OF THE STUDYO_LIBrain imaging acquired within six months after relapsing-remitting multiple sclerosis (RRMS) diagnosis allows for detection of abnormalities at a very early stage of disease.
C_LIO_LILongitudinal structural and microstructural brain MRI are integrated with multi-modal clinical, blood biomarker, genetic and retinal imaging data to allow comprehensive evaluation of early RRMS stratifiers.
C_LIO_LIMR protocol optimization was implemented mid-study to improved image quality and protocol harmonization, resulting in some between-subject protocol variation.
C_LIO_LIMultiplatform MRI acquisition required to allow access for a large MS population across Scotland introduces inevitable inter-site data variance.
C_LIO_LIContrast enhanced MRI was not acquired, limiting imaging evaluation of active inflammatory lesions.
C_LI

category: radiology and imaging


title: A phase 2 study of the inhaled pan-JAK inhibitor TD-0903 in severe COVID-19: Part 1

abstract:
BackgroundLung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD-0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.

MethodsPart 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics.

ResultsTwenty-five patients were randomised to receive TD-0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths.

ConclusionsIn Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.

category: respiratory medicine