title: The Impact of Sampling Type, Frequency and Scale of Collection System on SARS-CoV-2 Quantification Fidelity

abstract:
With the rapid onset of the COVID-19 pandemic, wastewater-based epidemiology (WBE) sampling methodologies for SARS-CoV-2 were often implemented quickly and may not have taken the unique drainage catchment characteristics into account. One question of debate is the relevance of grab versus composite samples when surveying for SARS-CoV-2 at various catchment scales. This study assessed the impact of grab versus composite sampling on the detection and quantification of SARS-CoV-2 in catchment basins with flow rates ranging from high-flow (wastewater treatment plant influent), to medium-flow (neighborhood-scale micro-sewershed), to low-flow (city block-scale micro-sewershed) and down to ultra-low flow (building scale). At the high-flow site, grab samples were reasonably comparable to 24-h composite samples with the same non-detect rate (0%) and SARS-CoV-2 concentrations that differed by 32% on the Log10 scale. However, as the flow rates decreased, the percentage of false-negative grab samples increased up to 44% and the SARS-CoV-2 concentrations of grab samples varied by up to 1-2 orders of magnitude compared to their respective composite sample concentrations. At the ultra-low-flow site, increased sampling frequencies down to every 5 min led to composite samples with higher fidelity to the SARS-CoV-2 load. Thus, composite sampling is superior to grab sampling, especially as flow decreases.

SynopsisThe need for composite sampling to generate reliable SARS-CoV-2 wastewater based epidemiology results increases as the collection basin scale decreases.

Table of Content Art

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category: public and global health


title: Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust

abstract:
BackgroundWe aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity.

MethodsHCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99{middle dot}47%, specificity 99{middle dot}56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model.

FindingsAs of 12th June 2020, 24{middle dot}4% (n=311/1275) HCWs were seropositive. Of these, 39{middle dot}2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41{middle dot}1%, 95% CrI 30{middle dot}0-52{middle dot}9) and in Physiotherapists and Occupational Therapists (39{middle dot}2%, 95% CrI 24{middle dot}4-56{middle dot}5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those [≤]30 years.

InterpretationHCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for studies published up to March 6th 2021, using the terms "COVID", "SARS-CoV-2", "seroprevalence", and "healthcare workers", and in addition for articles of antibody titres in different age groups against coronaviruses using "coronavirus", "SARS-CoV-2, "antibody", "antibody tires", "COVID" and "age". We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised.

Added value of this studyIn this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 "Red Zones" and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity.

Implications of all the available evidenceThere are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates.

Author Contributions

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category: infectious diseases


title: BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in Systemic Lupus Erythematosus

abstract:
ObjectivesOur aims were to evaluate Systemic Lupus Erythematosus (SLE) disease activity and SARS-CoV-2 specific immune responses after BNT162b2 vaccination.

MethodsIn this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine, until day 15 after the second dose in 126 SLE patients. SARS-CoV-2 antibody responses were measured against wild-type spike antigen while serum-neutralizing activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T-cell responses were quantified by Interferon (IFN)-{gamma} release assay after the second dose.

ResultsBNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in SLE patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response ({beta}=-78; p=0.007, {beta}=-122; p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naive B cell frequencies ({beta}=2; p=0.018, {beta}=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.

ConclusionMMF, MTX and poor baseline humoral immune status, particularly: low naive B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up.

KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIBNT162b2 efficacy and safety has been described in studies mixing different RMDs
C_LI

What does this study add?O_LINo serious adverse effects, nor SLE flares have been documented after BNT162b2 in SLE patients.
C_LIO_LINot only MMF and MTX, but also a poor humoral immune status at baseline impair vaccine antibody response
C_LIO_LIAlbeit decreased, serum neutralizing activity against VOCs is conferred to vaccine-responders.
C_LI

How might this impact on clinical practice or future developments?O_LIThese parameters could be helpful for physicians to delineate which patients should have antibody measurement after full BNT162b2 vaccination and should be proposed a third injection of BNT162b2 vaccine.
C_LI


title: A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

abstract:
The locus coeruleus (LC) is the initial site of Alzheimers disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimers pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimers disease.

The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimers disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1 and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of A{beta}42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET.

Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1 and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in A{beta}42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment.

In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimers disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimers disease progression.

category: neurology


title: Neural Fragility of the Intracranial EEG Network Decreases after Surgical Resection of the Epileptogenic Zone

abstract: Over 15 million patients with epilepsy worldwide do not respond to medical therapy and may benefit from surgical treatment. In focal epilepsy, surgical treatment requires complete removal or disconnection of the epileptogenic zone (EZ). However, despite detailed multimodal pre-operative assessment, surgical success rates vary and may be as low as 30% in the most challenging cases. Here we demonstrate that neural fragility, a dynamical networked-system biomarker of epileptogenicity, decreases following successful surgical resection. Moreover, neural fragility increases or remains constant when seizure-freedom is not achieved. We demonstrate this retrospectively in a virtual patient with epilepsy using the Virtual Brain neuroinformatics platform, and subsequently on six children with epilepsy with pre- and post-resection intra-operative recordings. Finally, we compare neural fragility as a putative biomarker of epileptogenicity against established spectral metrics, such as high frequency oscillations and find that neural fragility is a superior biomarker of epileptogenicity.


title: Predicting Quality Adjusted Life Years in young people attending primary mental health services

abstract:
BackgroundQuality Adjusted Life Years (QALYs) are often used in economic evaluations, yet utility weights for deriving them are rarely directly measured in mental health services.

ObjectivesWe aimed to: (i) identify the best Transfer To Utility (TTU) algorithms and predictors for adolescent weighted Assessment of Quality of Life - six dimensions (AQoL-6D) health utility and (ii) assess ability of TTU algorithms to predict longitudinal change.

MethodsWe recruited 1107 young people attending Australian primary mental health services, collecting data at two time points, three months apart. Five linear and three generalised linear models were explored to identify the best TTU algorithm. Forest models were used to assess predictive ability of six candidate measures of psychological distress, depression and anxiety and linear / generalised linear mixed effect models were used to construct longitudinal predictive models for AQoL-6D change.

ResultsA depression measure (Patient Health Questionnaire-9) was the strongest independent predictor of health utility. Linear regression models with complementary log-log transformation of utility score were the best performing models. Between-person associations were slightly larger than within-person associations for most of the predictors.

ConclusionsAdolescent AQoL-6D utility can be derived from a range of psychological distress, depression and anxiety measures. TTU algorithms estimated from cross-sectional data can approximate longitudinal change but may slightly bias QALY predictions.

ToolkitsThe TTU models produced by this study can be searched, retrieved and applied to new data to generate QALY predictions with the Youth Outcomes to Health Utility (youthu) R package - https://ready4-dev.github.io/youthu.

category: health economics


title: Image and structured data analysis for prognostication of health outcomes in patients presenting to the Emergency Department during the COVID-19 pandemic

abstract:
BackgroundPatients admitted to the emergency department (ED) with COVID-19 symptoms are routinely required to have chest radiographs and computed tomography (CT) scans. COVID-19 infection has been directly related to development of acute respiratory distress syndrome (ARDS) and severe infections lead to admission to intensive care and can also lead to death. The use of clinical data in machine learning models available at time of admission to ED can be used to assess possible risk of ARDS, need for intensive care unit (ICU) admission as well as risk of mortality. In addition, chest radiographs can be inputted into a deep learning model to further assess these risks.

PurposeThis research aimed to develop machine and deep learning models using both structured clinical data and image data from the electronic health record (EHR) to adverse outcomes following ED admission.

Materials and MethodsLight Gradient Boosting Machines (LightGBM) was used as the main machine learning algorithm using all clinical data including 42 variables. Compact models were also developed using 15 the most important variables to increase applicability of the models in clinical settings. To predict risk of the aforementioned health outcome events, transfer learning from the CheXNet model was implemented on our data as well. This research utilized clinical data and chest radiographs of 3571 patients 18 years and older admitted to the emergency department between 9th March 2020 and 29th October 2020 at Loyola University Medical Center.

Main FindingsOur research results show that we can detect COVID-19 infection (AUC = 0.790 (0.746-0.835)) and predict the risk of developing ARDS (AUC = 0.781 (0.690-0.872), ICU admission (AUC = 0.675 (0.620-0.713)), and mortality (AUC = 0.759 (0.678-0.840)) at moderate accuracy from both chest X-ray images and clinical data.

Principal ConclusionsThe results can help in clinical decision making, especially when addressing ARDS and mortality, during the assessment of patients admitted to the ED with or without COVID-19 symptoms.

category: health informatics


title: Heparin for Moderately Ill Patients with Covid-19

abstract:
BackgroundHeparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.

MethodsWe randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.

ResultsAt 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).

ConclusionsIn moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days.

Trial registration numbers: NCT04362085; NCT04444700

category: hematology


title: REACT-1 round 13 interim report: acceleration of SARS-CoV-2 Delta epidemic in the community in England during late June and early July 2021

abstract:
BackgroundDespite high levels of vaccination in the adult population, cases of COVID-19 have risen exponentially in England since the start of May 2021 driven by the Delta variant. However, with far fewer hospitalisations and deaths per case during the recent growth in cases compared with 2020, it is intended that all remaining social distancing legislation in England will be removed from 19 July 2021.

MethodsWe report interim results from round 13 of the REal-time Assessment of Community Transmission-1 (REACT-1) study in which a cross-sectional sample of the population of England was asked to provide a throat and nose swab for RT-PCR and to answer a questionnaire. Data collection for this report (round 13 interim) was from 24 June to 5 July 2021.

ResultsIn round 13 interim, we found 237 positives from 47,729 swabs giving a weighted prevalence of 0.59% (0.51%, 0.68%) which was approximately four-fold higher compared with round 12 at 0.15% (0.12%, 0.18%). This resulted from continued exponential growth in prevalence with an average doubling time of 15 (13, 17) days between round 12 and round 13. However, during the recent period of round 13 interim only, we observed a shorter doubling time of 6.1 (4.0, 12) days with a corresponding R number of 1.87 (1.40, 2.45). There were substantial increases in all age groups under the age of 75 years, and especially at younger ages, with the highest prevalence in 13 to 17 year olds at 1.33% (0.97%, 1.82%) and in 18 to 24 years olds at 1.40% (0.89%, 2.18%). Infections have increased in all regions with the largest increase in London where prevalence increased more than eight-fold from 0.13% (0.08%, 0.20%) in round 12 to 1.08% (0.79%, 1.47%) in round 13 interim. Overall, prevalence was over 3 times higher in the unvaccinated compared with those reporting two doses of vaccine in both round 12 and round 13 interim, although there was a similar proportional increase in prevalence in vaccinated and unvaccinated individuals between the two rounds.

DiscussionWe are entering a critical period with a number of important competing processes: continued vaccination rollout to the whole adult population in England, increased natural immunity through infection, reduced social mixing of children during school holidays, increased proportion of mixing occurring outdoors during summer, the intended full opening of hospitality and entertainment and cessation of mandated social distancing and mask wearing. Surveillance programmes are essential during this next phase of the epidemic to provide clear evidence to the government and the public on the levels and trends in prevalence of infections and their relationship to vaccine coverage, hospitalisations, deaths and Long COVID.


title: Elucidating Post-COVID-19 manifestations in India

abstract:
BackgroundIn India, a large number of patients with coronavirus disease-2019 (COVID-19), presented with common symptoms including fever, dyspnea, cough, musculoskeletal symptoms (fatigue, myalgia, joint pain) and gastrointestinal symptoms. However, information is lacking on symptoms that persist after recovery from COVID-19. In this study we assessed symptoms that persisted in patients even after their recovery and discharged from the hospital after one month from COVID-19.

MethodsThis study is an observational cohort study. Participants in this study were enrolled between 30 to 40 days after recovery from COVID-19 of [≥]18 years of age, who were hospitalized with laboratory-confirmed RT-PCR COVID-19 disease. Outcomes from post COVID-19 participants were elicited through questionnaire that consisted of three main parts beginning from subjects demographical data, depicting about the status of COVID-19 and other co-morbidities of the subject, and about post-COVID-19 symptoms and manifestations.

ResultsAll subjects have reported some manifestation after recovery from COVID-19 whereas numerous symptoms and diseases were experienced by a great percentage of participants. Fatigue (56.25%), dyspnea (74.3%) and disturbed sleep (64.3%) were among the most common symptoms. However, more critical manifestations like renal failure and pulmonary fibrosis were reported by only a few percent of the subjects. Rating of worse physical and mental health after post-COVID recovery was also reported by subjects. There was a strong relationship found in between the presence of other co-morbidities before infection like diabetes, hypertension and in disease severity after infection. A total of 280 patients were enrolled and 160 completed the survey.

ConclusionsPost COVID-19 sufferers often experience symptoms that cause a disturbance in their physical health, mental health and their respiratory status for several weeks even after recovery from COVID-19. Therefore, all subjects after recovering from COVID-19 should undergo long-term monitoring programme for their symptoms and condition improvement.


title: Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis.

abstract:
IntroductionSepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis, as well as assessment of prognosis, is difficult. Aside from antibiotics-based treatment of the causative infection and circulation-supportive measures, treatment options remain limited. Better understanding of the immuno-pathophysiology of sepsis may lead to improved diagnostic and therapeutic solutions.

Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities were analyzed in whole blood samples from patients with sepsis.

MethodsA validated and previously published set of signal transduction pathway (STP) assays, determining immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGF{beta}, FOXO-PI3K, MAPK-AP1, and NF{kappa}B signal transduction pathways.

ResultsActivity of AR and TGF{beta} pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a PPV of 99% and NPV of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGF{beta} pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).

ConclusionThe AR and TGF{beta} pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.


title: Identification of Acute Respiratory Distress Syndrome subphenotypes denovo using routine clinical data: a retrospective analysis of ARDS clinical trials

abstract:
RationaleThe acute respiratory distress syndrome (ARDS) is a heterogenous condition, and identification of subphenotypes may help in better risk stratification.

ObjectivesIdentify ARDS subphenotypes using new simpler methodology and readily available clinical variables.

DesignRetrospective Cohort Study of ARDS trials.

SettingData from the U.S. ARDSNet trials and from the international ART trial.

Participants3763 patients from ARDSNet datasets and 1010 patients from the ART dataset.

Primary and secondary outcome measuresThe primary outcome was 60-day or 28-day mortality, depending on what was reported in the original trial. K-means cluster analysis was performed to identify subgroups. For feature selection, sets. Sets of candidate variables were tested to assess their ability to produce different probabilities for mortality in each cluster. Clusters were compared to biomarker data, allowing identification of subphenotypes.

ResultsData from 4,773 patients was analyzed. Two subphenotypes (A and B) resulted in optimal separation in the final model, which included nine routinely collected clinical variables, namely: heart rate, mean arterial pressure, respiratory rate, bilirubin, bicarbonate, creatinine, PaO2, arterial pH, and FiO2. Participants in subphenotype B showed increased levels of pro-inflammatory markers, had consistently higher mortality, lower number of ventilator-free days at day 28, and longer duration of ventilation compared to patients in the subphenotype A.

ConclusionsRoutinely available clinical data can successfully identify two distinct subphenotypes in adult ARDS patients. This work may facilitate implementation of precision therapy in ARDS clinical trials.

ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LILargest cohort of patients used to identify subphenotypes of ARDS patients.
C_LIO_LISubphenotypes were validated in the population of a large international ARDS randomized controlled trial.
C_LIO_LISubphenotypes were identified by using only routinely collected clinical data.
C_LIO_LIOur use of data exclusively from randomized controlled trials does not prove generalizability to unselected ARDS populations.
C_LIO_LIThe clinical utility of the subphenotypes have to be validated in a prospective study.
C_LI

category: intensive care and critical care medicine


title: Genome-Wide Association Meta-Analysis Using a Recessive Model Illuminates Genetic Architecture of Type 2 Diabetes

abstract:
ObjectiveMost genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered.

Research Design and MethodsWe conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We then used two additional cohorts, FinnGen and a Danish cohort, for replication. For the most significant recessive signal, we conducted a phenome-wide association study across hundreds of traits to make inferences about the pathophysiology underlying the increased risk seen in homozygous carriers.

ResultsWe identified 51 loci associated with type 2 diabetes, including five variants with recessive effects undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk. We replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1x10-16) and a stronger effect in men than in women (interaction P=7x10-7). Colocalization analysis linked this signal to reduced expression of the nearby PELO gene, and the signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides.

ConclusionsOur results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

category: endocrinology


title: A joint spatial marked point process model for dengue and severe dengue in Medellin, Colombia.

abstract:
The spatial distribution of surveillance-reported dengue cases and severity are usually analyzed separately, assuming independence between the spatial distribution of non-severe and severe cases. Given the availability of data for the individual geo-location of surveillance-notified dengue cases, we conducted a spatial analysis to model non-severe and severe dengue simultaneously, using a hierarchical Bayesian model. We fit a joint model to the spatial pattern formed by dengue cases as well as to the severity status of the cases. Results showed that age and socioeconomic status were associated with dengue presence, and there was evidence of clustering for overall cases but not for severity. Our findings inform decision making to address the preparedness or implementation of dengue control strategies at the local level.

HighlightsO_LIA model to jointly assess the spatial distribution of reported dengue and severity.
C_LIO_LIWe account for uncertainty in the surveillance-reported dengue while modelling severe cases.
C_LIO_LIWe assess spatial clustering of dengue and severe dengue cases in Medellin.
C_LIO_LINon-monotonic distribution of reported dengue cases across socioeconomic status.
C_LI

category: epidemiology


title: Association of socioeconomic and environmental factors with the spatio-temporal variability of suicide rates along a latitudinal gradient

abstract:
BackgroundSuicide results from complex interactions between biological, psychological, and socioeconomic factors. At the population level, the study of suicide rates and their environmental and social determinants allows us to disentangle some of these complexities and provides support for policy design and preventive actions.

ObjectivesTo evaluate the associations between environmental and socioeconomic factors and demographically stratified suicide rates on large temporal and spatial scales.

MethodThe dataset contains information about yearly suicides rates by sex and age from 2000 through 2017 along a 4,000 km latitudinal gradient. We used zero-inflated negative binomial models to evaluate the spatio-temporal influence of each environmental and socioeconomic variable on suicide rates at each sex/age combination.

ResultsOverall, we found differential patterns of associations between suicide rates and explanatory variables by age and sex. Suicide rates in men increases in middle and high latitude regions and intermediate age classes. For adolescent and adult women, we found a similar pattern with an increase in suicide rates at middle and high latitudes. Sex differences measured by the male/female suicide rate ratio shows a marked increase with age. We found that cloudiness has a positive effect on suicide rates in both men and women 24 years old or younger. Regional poverty shows a major impact on men in age classes above 35 years old, an effect that was absent in women. Alcohol and marijuana consumption showed no significant effect sizes.

ConclusionsOur findings support high spatio-temporal variability in suicide rates in interaction with extrinsic factors. Several strong differential impacts of environmental and socioeconomic variables on suicide rates depending on sex and age were detected. These results suggest that the design of public policies and interventions to mitigate the impact of the studied variables need to consider the local social and environmental contexts of target populations.


title: First detection of SARS-CoV-2 Delta variant (B.1.617.2) in the wastewater of (Ahmedabad), India

abstract:
Contrary to the conventional genomic surveillance based on clinical samples (symptomatic patients), the wastewater-based genomic surveillance can identify all the variants shed by the infected individuals in the population, as it does also include RNA fragmented shredded by clinically escaped asymptomatic patients. We analyzed four samples to detect key mutations in the SARS-CoV-2 genome and track circulating variants in Ahmedabad during the first wave (Sep/ Nov 2020) and before the second wave (in Feb 2021) of COVID-19 in India. The analysis showed a total of 35 mutations in the spike protein across four samples categorized into 23 types. We noticed the presence of spike protein mutations linked to the VOC-21APR-02; B.1.617.2 lineage (Delta variant) with 57% frequency in wastewater samples of Feb 2021. The key spike protein mutations were T19R, L452R, T478K, D614G, & P681R and deletions at 22029 (6 bp), 28248 (6 bp), & 28271 (1 bp). Interestingly, these mutations were not observed in the samples of Sep and Nov 2020 but appeared before the devastating second wave of COVID-19, which started in early April 2021 in India, caused rapid transmission and deaths all over India. We found the genetic traces of the B.1.617.2 in samples of early Feb 2021 i.e., more than a month before the first clinically confirmed case of the same variant in March 2021 in Ahmedabad, Gujarat. The present study tells about the circulating variants in Ahmedabad and suggests early prediction VOCs employing the wastewater genomic surveillance approach that must be exploited at a large scale for effective COVID-19 management.

HighlightsO_LIWhole-genome sequencing of SARS-CoV-2 from the WW samples was carried out.
C_LIO_LIVariant of Concern (VoC: VOC-21APR-02; B.1.617.2) were detected in WW samples.
C_LIO_LIWBE may detect prevalent SARS-CoV-2 variants and monitor their cryptic transmission
C_LIO_LIWW genomic surveillance can aid the decision-making system for public health policies.
C_LI


title: Impact of the national test strategy on the development of the Covid-19 pandemic in Denmark

abstract:
During the Covid-19 pandemic, Denmark has pursued a unique mass testing strategy culminating in testing of more than 8,000 citizens per 100,000 inhabitants per day in the Spring 2021. The strategy includes free access to Covid-19 testing and since 2021, compulsory documentation for negative test or vaccination for access to workplace, educational institutions, restaurants, and many other places.

In the present study we analysed the effect of the Danish mass testing strategy throughout relevant stages of the pandemic. Mass testing was found not to have impact on the number of hospitalizations during the pandemic. Furthermore, during the highest level of testing in the spring 2021 the fraction of positive tests increased slightly on comparable days indicating that mass testing at best, did not reduce the prevalence of Covid-19.

The relationship between positives in antigen testing and in PCR testing indicated that many patients are not tested early in their infection where the risk of transmission is highest.

A likely explanation for the lack of impact of mass testing on hospitalizations and infections is that the testing increases risk-behaviour of the tested persons and that a high fraction of false negatives at low Covid-19 prevalence combined with increased risk-behaviour outweighs beneficial effects of mass testing.


title: Modeling the emergence of vaccine-resistant variants with Gaussian convolution.COVID-19: Could the wrong strategy ruin vaccine efficiency?

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic, has been shown to mutate. In the absence of a vaccine, natural selection will favor variants with higher transmissibility rates. However, when a substantial portion of the population is vaccinated, natural selection will shift towards favoring variants that can resist the vaccine. These variants can therefore become dominant and even cancel out the benefit of the vaccine. This paper develops a compartmental model which simulates this phenomenon and shows how various vaccination strategies can lead to the emergence of vaccine-resistant variants.


title: Deaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data

abstract:
BackgroundDeaths in children and young people (CYP) following SARS-CoV-2 infection are rare. Quantifying the risk of mortality is challenging because of high relative prevalence of asymptomatic and non-specific disease manifestations. Therefore, it is important to differentiate between CYP who have died of SARS-CoV-2 and those who have died of an alternative disease process but coincidentally tested positive.

MethodsDuring the pandemic, the mandatory National Child Mortality Database (NCMD) was linked to Public Health England (PHE) testing data to identify CYP (<18 years) who died with a positive SARS-CoV-2 test. A clinical review of all deaths from March 2020 to February 2021 was undertaken to differentiate between those who died of SARS-CoV-2 infection and those who died of an alternative cause but coincidentally tested positive. Then, using linkage to national hospital admission data, demographic and comorbidity details of CYP who died of SARS-CoV-2 were compared to all other deaths. Absolute risk of death was estimated where denominator data were available.

Findings3105 CYP died from all causes during the first pandemic year in England. 61 of these deaths occurred in CYP who tested positive for SARS-CoV-2. 25 CYP died of SARS-CoV-2 infection; 22 from acute infection and three from PIMS-TS. 99{middle dot}995% of CYP with a positive SARS-CoV-2 test survived. The 25 CYP who died of SARS-CoV-2 equates to a mortality rate of 2/million for the 12,023,568 CYP living in England. CYP >10 years, of Asian and Black ethnic backgrounds, and with comorbidities were over-represented compared to other children.

InterpretationSARS-CoV-2 is very rarely fatal in CYP, even among those with underlying comorbidities. These findings are important to guide families, clinicians and policy makers about future shielding and vaccination.

FundingRH is in receipt of a fellowship from Kidney Research UK. JW is in receipt of a Medical Research Council Fellowship. LF is in receipt of funding from Martin House Childrens Hospice.

category: pediatrics


title: Preferential preservation of visuospatial memory over verbal memory in the Old Order Amish

abstract:
BackgroundWhile studying cognition in the Old Order Amish (OOA), we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuospatial memory in this population. Here, we investigate this by comparing the CPDR to the word list delayed recall (WLDR) within the OOA, as well as by comparing these results to a non-Amish cohort.

Method420 OOA individuals in Indiana/Ohio age 66-95 who had complete data for the CPDR and WLDR were included. From the non-Amish CERAD cohort, 401 individuals age 60-96 with the same tests were included. For both cohorts, education-adjusted Z-scores were calculated for the CPDR and WLDR. The difference between the CPDR Z-score and the WLDR Z-score was calculated as a measure of the preservation of visuospatial memory over verbal memory. T-tests were first used to compare the tests within both cohorts and then stratified by case/control status. Linear regression was then used to investigate the effects of age, sex, cognitive status, and cohort on the Z-scores and difference between Z-scores. Additional t-tests and regressions were then performed to further investigate the effect of sex and its interaction with cohort.

ResultWe found a significantly better performance on CPDR over WLDR in every cognitive status group in the OOA, but not in all groups of the CERAD cohort. After controlling for age, sex, and cognitive status, this preferential preservation remains significantly higher in the Amish, with being in the Amish cohort increasing the difference between Z-scores by an average of 0.615 units when compared to being in the CERAD cohort. When adjusting for age, sex, cognitive status, and cohort, the interaction between cohort and sex is significant, with the Amish males exhibiting a greater difference between Z-scores compared to other groups, with a significant interaction value of 0.676.

DiscussionOverall, these findings suggest that the OOA preferentially preserve visuospatial memory over verbal memory, regardless of cognitive status. This effect is particularly strong in OOA males. In summary, this study gives additional evidence that the Amish exhibit unique patterns of memory loss and aging, with a preferential preservation of visuospatial memory over verbal memory. Additional studies are needed to further explain this phenomenon.

category: psychiatry and clinical psychology


title: Symptomatic, Presymptomatic, and Asymptomatic Transmission of SARS-CoV-2

abstract:
ImportanceAsymptomatic and presymptomatic carriers of SARS-CoV-2 are an ongoing and significant risk for community spread of the virus, especially with the majority of the world still unvaccinated and new variants emerging.

ObjectiveTo quantify the presence and effects of symptom presentation (or lack thereof) on the community transmission of SARS-CoV-2.

DesignA cohort of 12,960 young adults participated in health reporting, contact tracing, and COVID-19 testing for 103 days between August 10 and November 20, 2020.

SettingA mid-sized university campus in Indiana, United States.

ParticipantsUniversity students, most of whom are 18-23 years old (67%) and living in congregate on-campus housing (60%). Of the 12,960 students, 1,556 (12.0%) tested positive for COVID-19 during the 103 day period. Of the positive cases, 1,198 reported sufficient health check data (7 days prior and 7 days post diagnosis) to be classified as asymptomatic or symptomatic.

Main OutcomeSecondary attack rate, based on presentation or absence of symptoms and type of symptoms calculated with respect to confirmed close contacts and a 14-day incubation period, varies on the type of symptom, timing of symptoms, and absence of symptoms. A quantifiable understanding of SAR on the longitudinal data of more than one thousand subjects in a university environment provides keen insights about developing strategies to respond to the continued prevalence of COVID-19 in the unvaccinated world and growth of variants.

Results32.5% of all cases reported no symptoms within a 15-day window centered on their positive test (7 days prior, the day of the positive test, and 7 days after). The secondary attack rate (SAR) of asymptomatic COVID-19 index cases was 19.1%. The SAR of symptomatic index cases was 25.4%, and while the onset timing of symptoms did not affect transmission, the presence of certain symptoms like fever, shortness of breath, and dry cough increased the SAR as high as 30.0%.

Conclusions and RelevanceAsymptomatic rates of transmission of SARS-CoV-2 are much higher than has been estimated in prior studies and continue to pose a significant and ongoing risk in the pandemic, especially with the prevalence of variants like the Delta variant. In addition, different symptoms are associated with varying rates of transmission, posing a significant challenge in how to diagnose or assess risk through mechanisms such as daily health checks for symptom reporting, a practice commonly in place for entry into schools, offices, restaurants, etc. Given the uncertain nature of symptoms and varied transmission rates, this study suggests a broader embrace of masking, social distancing and testing might be needed to counter the variants until higher global vaccination rates can be achieved.


title: Anxiety and Depression among Medical Doctors in Catalonia, Italy, and the UK during the COVID-19 Pandemic

abstract: Healthcare workers have had the longest and most direct exposure to COVID-19 and consequently may suffer from poor mental health. We conducted one of the first repeated multi-country analysis of the mental wellbeing of medical doctors (n=5,275) at two timepoints during the COVID-19 pandemic (June 2020 and November/December 2020) to understand the prevalence of anxiety and depression, as well as associated risk factors. Rates of anxiety and depression were highest in Italy (24.6% and 20.1%, June 2020), second highest in Catalonia (24.6% and 17.4%, June 2020), and lowest in the UK (11.7% and 13.7%, June 2020). Across all countries, higher risk of anxiety and depression symptoms are found among women, individuals below 60 years old, those feeling vulnerable/exposed at work, and those in poor health. We did not find systematic differences in mental health measures between the two rounds of data collection, hence we cannot discard that the mental health repercussions of the pandemic are persistent.


title: Automated lung sound analysis using the LungPass platform: A sensitive and specific tool for identifying lower respiratory tract involvement in COVID-19.

abstract:
BackgroundLower respiratory tract (LRT) involvement, observed in about 20% of patients suffering from coronavirus disease 2019 (COVID-19) is associated with a more severe clinical course, adverse outcomes and long-term sequelae. Early identification of LRT involvement could facilitated targeted and timely interventions that could alter the short- and long-term disease outcomes. The LungPass is an automated lung sound analysis platform developed using neural network technology and previously trained. We hypothesised that the LungPass could be used as a screening tool for LRT involvement in patients with COVID-19.

MethodsIn a prospective observational study involving 282 individuals with presenting in the emergency department with a strong clinical suspicion of COVID-19 and imaging findings consistent with COVID-19 LRT involvement (25.5% had concomitant hypoxia), and 32 healthy controls, we assessed the sensitivity and specificity of the LungPass in identifying LRT involvement in COVID-19. We also compared the auscultatory findings of the LungPass compared to a chest physician using a traditional, high-quality stethoscope.

ResultsAmong individuals with COVID-19 LRT involvement, the LungPass identified crackles in at least one auscultation site in 93.6% and in two or more points in 84%. Moreover, the LungPass identified any abnormal lung sound (crackles or wheeze) in at least one auscultation site in 98.6% and in at least two points in 94% of the participants. The respective percentages for the respiratory physicians were lower.

Considering the presence of any added abnormal sound (crackles or wheeze) in at least two auscultation points as evidence of LRT involvement, LungPass demonstrated a sensitivity of 98.6% (95% confidence intervals [CI]: 96.4%-99.6%) and a specificity of 96.9% (95% CI: 83.8%-99.9%) in identifying COVID-19 LRT involvement.

ConclusionThis exploratory study suggests the LungPass is a sensitive and specific platform for identifying LRT involvement due to COVID-19, even before the development of hypoxia.

category: respiratory medicine


title: Rapid vigilance and episodic memory decrements in COVID-19 survivors

abstract: Recent studies indicate that COVID-19 infection can lead to serious neurological consequences in a small percentage of individuals. However, in the months following acute illness, many more suffer from fatigue, low motivation, disturbed mood, poor sleep and cognitive symptoms, colloquially referred to as  brain fog. But what about individuals who had asymptomatic to moderate COVID-19 and report no concerns after recovering from COVID-19? Here we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial-visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation. However, they displayed significantly worse episodic memory (up to 6 months post-infection) and greater decline in vigilance with time on task (for up to 9 months). Overall, the results show that specific chronic cognitive changes following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after six-nine months, demonstrating evidence of recovery over time.


title: Demonstrating an approach for evaluating synthetic geospatial and temporal epidemiologic data utility: Results from analyzing >1.8 million SARS-CoV-2 tests in the United States National COVID Cohort Collaborative (N3C)

abstract:
ObjectiveTo evaluate whether synthetic data derived from a national COVID-19 data set could be used for geospatial and temporal epidemic analyses.

Materials and MethodsUsing an original data set (n=1,854,968 SARS-CoV-2 tests) and its synthetic derivative, we compared key indicators of COVID-19 community spread through analysis of aggregate and zip-code level epidemic curves, patient characteristics and outcomes, distribution of tests by zip code, and indicator counts stratified by month and zip code. Similarity between the data was statistically and qualitatively evaluated.

ResultsIn general, synthetic data closely matched original data for epidemic curves, patient characteristics, and outcomes. Synthetic data suppressed labels of zip codes with few total tests (mean=2.9{+/-}2.4; max=16 tests; 66% reduction of unique zip codes). Epidemic curves and monthly indicator counts were similar between synthetic and original data in a random sample of the most tested (top 1%; n=171) and for all unsuppressed zip codes (n=5,819), respectively. In small sample sizes, synthetic data utility was notably decreased.

DiscussionAnalyses on the population-level and of densely-tested zip codes (which contained most of the data) were similar between original and synthetically-derived data sets. Analyses of sparsely-tested populations were less similar and had more data suppression.

ConclusionIn general, synthetic data were successfully used to analyze geospatial and temporal trends. Analyses using small sample sizes or populations were limited, in part due to purposeful data label suppression -an attribute disclosure countermeasure. Users should consider data fitness for use in these cases.


title: Following the science? Views from scientists on government advisory boards during the COVID-19 pandemic: a qualitative interview study in five European countries

abstract:
ObjectivesTo explore the views and experiences of scientists working on government advisory boards during the COVID-19 pandemic, with the aim to learn lessons for future pandemic management and preparedness.

DesignExplorative qualitative interview study.

ParticipantsTwenty one scientists with an official government advisory role during the COVID-19 pandemic in Belgium, the Netherlands, UK, Sweden or Germany.

MethodsOnline video or telephone semi-structured interviews took place between December 2020 and April 2021. They were audio recorded and transcribed, and analyzed using a combination of inductive and deductive thematic analysis techniques.

ResultsScientists found working on the advisory boards during the COVID-19 pandemic to be a rewarding experience. However, they identified numerous challenges including learning to work in an interdisciplinary way, ensuring that evidence is understood and taken on board by governments, and dealing with media and public reactions. Scientists found themselves taking on new roles, the boundaries of which were not clearly defined. Consequently, they received substantial media attention and were often perceived and treated as a public figure.

ConclusionsScientists working on advisory boards in European countries faced similar challenges, highlighting key lessons to be learnt. Future pandemic preparedness efforts should focus on building interdisciplinary collaboration within advisory boards; ensuring transparency in how boards operate; defining and protecting boundaries of the scientific advisor role; and supporting scientists to inform the public in the fight against disinformation, whilst dealing with potential hostile reactions.

O_TEXTBOXWhat is already known on this topicO_LITo tackle the COVID-19 pandemic, governments have established various types of scientific advisory boards to provide evidence and recommendations to policy makers.
C_LIO_LIWith science becoming a focal point of this pandemic, scientific advisors also found themselves in the public eye.
C_LIO_LIAs more attention is being paid to analysing what we can do to be better prepared for the next pandemic, the views of key actors, i.e. government scientific advisors, is still largely missing.
C_LI

What this study addsO_LIThe government scientific advisors working during the COVID-19 pandemic faced a number of challenges such as working in an interdisciplinary way with their peers on scientific boards, establishing a working relationship with government allowing evidence to be taken on board, and dealing with media and public reactions.
C_LIO_LIIt is crucial that we take on board key lessons shared by scientific advisors, which calls for building interdisciplinary collaboration within advisory boards; ensuring transparency in both how boards operate and clear boundaries of scientists-government relationship; and supporting scientists in their role of informing the public.
C_LI

C_TEXTBOX

category: health policy


title: Cross-sectional cycle threshold values reflect epidemic dynamics of COVID-19 in Madagascar

abstract: As the national reference laboratory for febrile illness in Madagascar, we processed samples from the first epidemic wave of COVID-19, between March and September 2020. We fit generalized additive models to cycle threshold (Ct) value data from our RT-qPCR platform, demonstrating a peak in high viral load, low-Ct value infections temporally coincident with peak epidemic growth rates estimated in real time from publicly-reported incidence data and retrospectively from our own laboratory testing data across three administrative regions. We additionally demonstrate a statistically significant effect of duration of time since infection onset on Ct value, suggesting that Ct value can be used as a biomarker of the stage at which an individual is sampled in the course of an infection trajectory. As an extension, the population-level Ct distribution at a given timepoint can be used to estimate population-level epidemiological dynamics. We illustrate this concept by adopting a recently-developed, nested modeling approach, embedding a within-host viral kinetics model within a population-level Susceptible-Exposed-Infectious-Recovered (SEIR) framework, to mechanistically estimate epidemic growth rates from cross-sectional Ct distributions across three regions in Madagascar. We find that Ct-derived epidemic growth estimates slightly precede those derived from incidence data across the first epidemic wave, suggesting delays in surveillance and case reporting. Our findings indicate that public reporting of Ct values could offer an important resource for epidemiological inference in low surveillance settings, enabling forecasts of impending incidence peaks in regions with limited case reporting.


title: Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States

abstract:
BackgroundAs SARS-CoV-2 vaccination coverage increases in the United States (US), there is a need to understand the real-world effectiveness against severe Covid-19 and among people at increased risk for poor outcomes.

MethodsIn a multicenter case-control analysis of US adults hospitalized March 11 - May 5, 2021, we evaluated vaccine effectiveness to prevent Covid-19 hospitalizations by comparing odds of prior vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with Covid-19 and hospital-based controls who tested negative for SARS-CoV-2.

ResultsAmong 1210 participants, median age was 58 years, 22.8% were Black, 13.8% were Hispanic, and 20.6% had immunosuppression. SARS-CoV-2 lineage B.1.1.7 was most common variant (59.7% of sequenced viruses). Full vaccination (receipt of two vaccine doses [≥]14 days before illness onset) had been received by 45/590 (7.6%) cases and 215/620 (34.7%) controls. Overall vaccine effectiveness was 86.9% (95% CI: 80.4 to 91.2%). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.3%; 95% CI: 78.9 to 99.7%). Among 45 patients with vaccine-breakthrough Covid hospitalizations, 44 (97.8%) were [≥]50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (59.2%; 95% CI: 11.9 to 81.1%) than without immunosuppression (91.3%; 95% CI: 85.5 to 94.7%).

ConclusionDuring March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing Covid-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.


title: Early initiation of corticosteroids in patients hospitalized with COVID-19 not requiring intensive respiratory support: cohort study

abstract:
ObjectivesTo determine whether early oral or parenteral corticosteroids compared to no corticosteroids are associated with decreased mortality in patients hospitalized with coronavirus disease 2019 (COVID-19) who are not on intensive respiratory support (IRS) within 48 hours of admission.

DesignObservational cohort study

SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated US national healthcare system

Participants9,058 patients admitted to a Veterans Affairs Medical Center between June 7, 2020-December 5, 2020 within 14-days after SARS-CoV-2 positive test; exclusion criteria include less than a 48 hour stay, receipt of prior systemic corticosteroids, and no indication of acute medical care for COVID-19.

Main outcome measure90-day all-cause mortality

ResultsOf 9,058 total patients (95% men, median age 71 years, 27% black), 6,825 (75%) were not on IRS within 48 hours. Among the 3,025 patients on no oxygen, 598 (20%) received corticosteroids and 283 (9%) died; of 3,800 patients on low-flow nasal cannula oxygen (NC), 2,808 (74%) received corticosteroids and 514 (13%) died. In stratified, inverse probability weighted Cox proportional hazards models comparing those who did and did not receive corticosteroids, patients on no oxygen experienced an 89% increased risk for 90-day mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.33 to 2.68); there was weak evidence of increased mortality among patients on NC (HR 1.21, 95% CI 0.94 to 1.57). Results were robust in subgroup analyses including restricting corticosteroids to dexamethasone, and in sensitivity analyses employing different modeling approaches.

ConclusionsIn patients hospitalized with COVID-19, we found no evidence of a mortality benefit associated with early initiation of corticosteroids among those on no oxygen or NC in the first 48 hours, though there was evidence of potential harm. These real-world findings support that clinicians should consider withholding corticosteroids in these populations and further clinical trials may be warranted.


title: AI-DRIVEN QUANTIFICATION OF GROUND GLASS OPACITIES IN LUNGS OF COVID-19 PATIENTS USING 3D COMPUTED TOMOGRAPHY IMAGING

abstract:
ObjectivesGround-glass opacity (GGO) -- a hazy, gray appearing density on computed tomography (CT) of lungs -- is one of the hallmark features of SARS-CoV-2 in COVID-19 patients. This AI-driven study is focused on segmentation, morphology, and distribution patterns of GGOs.

MethodWe use an AI-driven unsupervised machine learning approach called PointNet++ to detect and quantify GGOs in CT scans of COVID-19 patients and to assess the severity of the disease. We have conducted our study on the "MosMedData", which contains CT lung scans of 1110 patients with or without COVID-19 infections. We quantify the morphologies of GGOs using Minkowski tensors and compute the abnormality score of individual regions of segmented lung and GGOs.

ResultsPointNet++ detects GGOs with the highest evaluation accuracy (98%), average class accuracy (95%), and intersection over union (92%) using only a fraction of 3D data. On average, the shapes of GGOs in the COVID-19 datasets deviate from sphericity by 15% and anisotropies in GGOs are dominated by dipole and hexapole components. These anisotropies may help to quantitatively delineate GGOs of COVID-19 from other lung diseases.

ConclusionThe PointNet++ and the Minkowski tensor based morphological approach together with abnormality analysis will provide radiologists and clinicians with a valuable set of tools when interpreting CT lung scans of COVID-19 patients. Implementation would be particularly useful in countries severely devastated by COVID-19 such as India, where the number of cases has outstripped available resources creating delays or even breakdowns in patient care. This AI-driven approach synthesizes both the unique GGO distribution pattern and severity of the disease to allow for more efficient diagnosis, triaging and conservation of limited resources.

Key PointsOur approach to GGO analysis has four distinguishing features:

O_LIWe combine an unsupervised computer vision approach with convex hull and convex points algorithms to segment and preserve the actual structure of the lung.
C_LIO_LITo the best of our knowledge, we are the first group to use PointNet++ architecture for 3D visualization, segmentation, classification, and pattern analysis of GGOs.
C_LIO_LIWe make abnormality predictions using a deep network and Cox proportional hazards model using lung CT images of COVID-19 patients.
C_LIO_LIWe quantify the shapes and sizes of GGOs using Minkowski tensors to understand the morphological variations of GGOs within the COVID-19 cohort.
C_LI


title: Excess mortality analysis for Germany for all three COVID-19 waves in 2020 - 2021

abstract:
Background and AimsThe excess mortality has been used as a metric to estimate the impact of COVID-19 across countries. For Germany, we observe that during the second half of the first and second COVID-19 waves, the COVID-19 deaths are significantly higher than the excess mortality. We attribute the difference to the pre-dying effect. We then compare the excess mortality to the official COVID-19 death numbers and calculate the infection fatality rates (IFRs) and the percentage of infected individuals from excess mortality for different age bands. We also compare the impact of COVID-19 to past influenza waves and analyze the vaccination effect on excess mortality.

MethodsWe forecast the baseline mortality from official data on deaths in Germany. Distributing a part of excess mortality into the near future, we lower the baseline simulating the pre-dying effect. From the observed mortality deficit, we estimate the percentage of infected individuals and then estimate the age-dependent IFRs.

ResultsIn the first wave, we find an overall excess mortality of ca. 8 000. For the second wave, the overall excess mortality adds up to ca. 56 000. We find, that the pre-dying effect explains the difference between the official COVID-19 deaths and excess mortality in the second half of the waves to a high degree. Attributing the whole excess mortality to COVID-19, we find that the IFRs are significantly higher in the second wave. In the third wave, the overall excess mortality is ca. 5 000. We find an excess mortality in mid-age bands which cannot be explained by the official COVID-19 deaths. For the senior band 80+, we find results in favor of a strong and positive vaccination effect for the third COVID-19 wave.

ConclusionsWe conclude that in the first and second COVID-19 waves, the COVID-19 deaths explain almost all excess mortality when the pre-dying effect is taken into account. In the third wave in 2021, the excess mortality is not very pronounced for the 80+ age band, probably due to vaccination. The partially unvaccinated 40-80 age group experiences a pronounced excess mortality in the third wave while there are too few official COVID-19 deaths to explain the excess. The no-vaccination scenario for the 80+ age band results in a similarly high excess mortality as for the more younger age bands, suggesting a very positive vaccination effect on reduction of COVID-19 deaths.


title: Molecular epidemiology of carbapenem-resistant Acinetobacter baumannii strains in Belgian acute-care hospitals

abstract:
SynopsisO_ST_ABSObjectivesC_ST_ABSTo describe the genotypic epidemiological distribution and the antibiotic resistance mechanisms of recent carbapenem-resistant Acinetobacter baumannii (CRAb) strains recovered from clinical samples in Belgium.

MethodsA total of 40 clinical isolates of CRAb collected by the national reference center from 19 acute-care hospitals through national microbiological surveillance in 2014 and 2017 were analysed in this study. The isolates were tested for antimicrobial susceptibility by broth microdilution and determined for carbapenemase-encoding genes by multiplex PCR targeting major carbapenemases families. Isolates were subjected to whole-genome sequencing (WGS) with Illumina technology and the complete chromosomal sequences were de novo assembled. Genome analysis was performed to identify intrinsic and acquired resistance determinants and to characterize clonal lineage according to the sequence type (ST).

ResultsAll 40 isolates were resistant to carbapenems and exhibited extensively drug-resistant phenotype with blaOXA-23 (n=29) being the most abundant detected acquired AMR gene with 38 isolates encoding at least two different types of OXA enzymes. The majority of the isolates were globally disseminated clones of ST2 (n=25) while less frequent sequence types such as ST636 (n=6), ST1 (n=3), ST85 (n=2) and per one isolate from ST604, ST215, ST158 and ST78 were also detected.

ConclusionsWe have detected extensively drug-resistant globally occurring clones of A. baumannii ST1 and ST2 throughout Belgium as well as other sporadic ST including ST636 causing local outbreaks. Our results show the presence of high-risk clones of A. baumannii with common travel importation and the crucial need of constant surveillance.


title: Quantitative susceptibility mapping improves the detection of calcified carotid vessels by multi-contrast MRI using computed tomography angiography as the reference standard

abstract: The objective of this study was to evaluate initial feasibility and improvement in the detection of calcified carotid arteries by including quantitative susceptibility mapping (QSM) in the carotid vessel wall multi-contrast MRI (mcMRI) protocol using CTA as the reference standard. In a pilot cohort of ten patients with significant carotid artery stenosis, calcified vessel detection by mcMRI achieved 64.7% sensitivity and 100% specificity. Adding QSM to mcMRI improved sensitivity to 100% while not affecting specificity.

category: radiology and imaging


title: Developing a co-produced, systems-informed, sexually transmitted infection contact tracing intervention for gay and bisexual men who have sex with men and their one-off sexual partners

abstract:
ObjectiveGay and bisexual men who have sex with men (GBMSM) bear a disproportionate burden of sexually transmitted infections (STIs). Most STIS are asymptomatic and people infected wont know to seek care unless they are told about their exposure. Contact tracing, is the process of identifying and contacting sex partners of people with STIs for testing and treatment. Contact tracing is sometimes particularly challenging amongst GBMSM because of the kinds of sexual relationships which GBMSM enjoy. These include one-off partners who are particularly important for transmission dynamics as they contribute disproportionately to onwards transmission. The effectiveness of contact tracing interventions within sexual health are patterned by sexual-partner type. Contact tracing and management for  one-off partners is an on-going public health challenge. Low motivation amongst index patients, high resource burden on health care professionals and problems with contactability are key barriers to contact tracing. Using insights from complex adaptive systems thinking and behavioural science, we sought to develop an intervention which addressed both the upstream and down-stream determinants of contact tracing and change the system in which many inter-dependent contact tracing behaviours are embedded.

SettingUK community-recruited GBMSM, stakeholders, sexual hcp, dating app providers

MethodUsing the MRC complex intervention framework and insights from the INDEX study, a three-phase intervention development process was adopted to specify intervention content. Phase one consisted of an inter-professional and community-member stakeholder event (n=45) where small mixed groups engaged in exploratory systems-mapping and the identification of  hot spots for future intervention. Phase two used a series of focus groups with GBMSM (n=28) and interviews with representatives from key dating app providers (DAPs) (n=3) to further develop intervention ideas using the theoretical domains framework, the behaviour change wheel and the behaviour change technique taxonomy. In Phase 3 we again worked with key stakeholders expert health care professionals (HCPs) (n=5) and key workers from community-based organisations (CBOs) (n=6) to hone the intervention ideas and develop programme theory using the APEASE criteria.

ResultsThe co-produced intervention levers change simultaneously across the system within which contact tracing is embedded. Multiple change-agents (i.e., GBMSM, CBOs, HCPs) work together, sharing an overall vision to improve sexual health through contact tracing. Each make relatively modest changes that over time, synergistically combine to produce a range of multiple positively-reinforcing feedback loops to engender sustainable change around contact tracing. Agreed intervention elements included: a co-ordinated, co-produced mass and social media intervention to tip cultural norms and beliefs of GBMSM towards enabling more contact tracing and to challenge enduring STI- and sex-related stigmas; complementary CBO-co-ordinated, peer-led work to also focus on reducing STI stigma and enabling more contact tracing between one-off partners; priming GBMSM at the point of STI diagnosis to prepare for contact tracing interactions and reduce HCP and sexual health-service burden; changes to SHS environments and HCP-led interactions to systematically endorse contact tracing; changing national audits and monitoring systems to directly address one-off partner targets; delivering bespoke training to HCPs and CBO staff on one-off partners and the social and cultural context of GBMSM; DAPs active involvement in mass and social media promoting appropriate contact tracing messaging.

ConclusionOur combination of multiple data sources, theoretical perspectives and diverse stakeholders have enabled us to develop an expansive, complex intervention that is firmly based in the priorities of those it will affect, and which has a solid theoretical foundation. Future work will assess if and how it will be possible to evaluate it. The resulting intervention is profoundly different than other ways of enhancing contact tracing, as it simultaneously addresses multiple, multi-levelled, upstream and social determinants of contact tracing.

category: sexual and reproductive health


title: POST-COVID-19 SYNDROME, INFLAMMATORY MARKERS AND SEX DIFFERENCES

abstract:
INTRODUCTION AND OBJECTIVEPost-COVID syndrome (PCS) is a poorly-known entity. Underlying low-grade inflammation (LGI) has been theorized as one of its pathophysiological mechanisms. We aimed to investigate a possible relationship between PCS and an increase in inflammation markers, in a sex-stratified analysis.

PARTICIPANTS AND METHODSMild cases of COVID-19 according to the WHO classification followed-up in a Primary Care Center, were included. We collected epidemiological data (age, sex, body mass index -BMI-, smoking, and comorbidities -Charlson index-), variables of the acute COVID-19 episode, and data at 3 months of follow-up (clinical manifestations and inflammatory markers). Serum C-reactive protein (CRP), neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), ferritin, fibrinogen, and D-dimer levels were analyzed. Low-grade inflammation (LGI) was defined as serum CRP between >0.3 and <1.0 mg/dL. Five composite indices were built combining the upper ranges of 4 markers. Bivariate and multivariate analyses (logistic regression and general linear models) were performed, stratified by sex.

RESULTSWe analyzed 121 subjects with mild COVID-19 (56.2% women; mean age 46 years). The most common symptom in the acute episode was fever (60.3%), while it was fatigue in PCS (42.8%). Prevalence of PCS was 35.8% in women and 20.8% in men (p = 0.07).

In women, after controlling for age, BMI, smoking, and comorbidities, the D1, D3, and D4 indices were consistently associated with PCS, with ORs of 5.14 (95% CI, 1.6-16.4), 4.20 (95% CI, 1.3-13.3), and 4.12 (95% CI, 1.3-13.1), respectively; in patients with post-COVID anosmia and ageusia, neutrophils were significantly elevated (3.43{+/-}0.3 vs 2.58{+/-}0.1; p = 0.014, and 3.89{+/-}0.3 vs 2.59{+/-}0.1; p = 0.002,respectively), after adjusting for confounders.

In men, the D2 and D5 indices were associated with PCS, with adjusted ORs of 10.1 (95% CI, 1.2-85) and 17.5 (95% CI, 2-153), respectively. Furthermore, serum CRP in the LGI range was associated with PCS [adjusted OR=12.9 (95% CI, 1.3-121)], and in post-COVID persistent fatigue, the neutrophil count was significantly elevated (4.68{+/-}0.6 vs 3.37{+/-}0.1; p = 0.041), after controlling for confounders.

CONCLUSIONSConsistent associations among PCS, anosmia, ageusia, and fatigue, with slight -but significant-elevated levels of inflammatory markers, have been observed. The neutrophil count was the most frequently involved marker. Sex-stratified analyses showed relevant differences between women and men concerning PCS and serum inflammatory markers.


title: Scoping Review and Interpretation of Myofascial Pain/Fibromyalgia Syndrome: An Attempt to Assemble a Medical Puzzle

abstract:
BackgroundMyofascial Pain Syndrome (MPS) is a common, overlooked, and underdiagnosed condition and has significant burden. MPS is often dismissed by clinicians while patients remain in pain for years. MPS can evolve into fibromyalgia, however, effective treatments for both are lacking due to absence of a clear mechanism. Many studies focus on central sensitization. Therefore, the purpose of this scoping review is to systematically search cross-disciplinary empirical studies of MPS, focusing on mechanical aspects, and suggest an organic mechanism explaining how it might evolve into fibromyalgia. Hopefully, it will advance our understanding of this disease.

MethodsSystematically searched multiple phrases in MEDLINE, EMBASE, COCHRANE, PEDro, and medRxiv, majority with no time limit. Inclusion/exclusion based on title and abstract, then full text inspection. Additional literature added on relevant side topics. Review follows PRISMA-ScR guidelines. PROSPERO yet to adapt registration for scoping reviews.

Findings799 records included. Fascia can adapt to various states by reversibly changing biomechanical and physical properties. Trigger points, tension, and pain are a hallmark of MPS. Myofibroblasts play a role in sustained myofascial tension. Tension can propagate in fascia, possibly supporting a tensegrity framework. Movement and mechanical interventions treat and prevent MPS, while living sedentarily predisposes to MPS and recurrence.

ConclusionsMPS can be seen as a pathological state of imbalance in a natural process; manifesting from the inherent properties of the fascia, triggered by a disrupted biomechanical interplay. MPS might evolve into fibromyalgia through deranged myofibroblast in connective tissue ("fascial armoring"). Movement is an underemployed requisite in modern lifestyle. Lifestyle is linked to pain and suffering. The mechanism of needling is suggested to be more mechanical than currently thought. A "global percutaneous needle fasciotomy" that respects tensegrity principles may treat MPS/fibromyalgia more effectively. "Functional-somatic syndromes" can be seen as one entity (myofibroblast-generated-tensegrity-tension), sharing a common rheuma-phycho-neurological mechanism.

category: rheumatology


title: Screening power of STIR muscle MRI in Critical illness myo-neuropathy and GBS in the ICU

abstract:
IntroductionCritical illness myo-neuropathy [CIMN] or ICU acquired weakness [CIMN] is a common cause of weakness in ICU patients. It is diagnosed by clinical features, nerve conduction studies and muscle/nerve biopsies.

MethodsThe MRI muscle STIR images of 7 patients with suspected CIMN and 7 GBS patients were reviewed.

ResultsAll 7 patients with CIMN showed diffuse muscle edema, predominating in the lower limbs. Only one patient with GBS showed abnormal MRI changes (14%) and MRI was normal in 86%. The sensitivity of MRI to detect CIMN was 100%, whereas the specificity was 85.7%. Thus, the positive predictive value of MRI in this situation was 87.5% and the negative predictive value was 100%.

ConclusionsMuscle STIR imaging may help to differentiate between CIMN and GBS and can modify the diagnostic algorithm of CIMN.


title: Simplified point-of-care full SARS-CoV-2 genome sequencing using nanopore technology

abstract:
BackgroundThe scale of the ongoing SARS-CoV-2 pandemic warrants the urgent establishment of a global decentralized surveillance system to recognize local outbreaks and the emergence of novel variants-of-concern. Among available deep-sequencing technologies, nanopore-sequencing could be an important cornerstone, since it is mobile, scalable and costs-effective. Therefore, streamlined nanopore-sequencing protocols need to be developed and optimized for SARS-CoV-2 variants identification.

ResultsWe adapted and simplified existing workflows using the  midnight 1,200 bp amplicon split primer sets for PCR, which produce tiled overlapping amplicons covering almost the entire SARS-CoV-2 genome. Subsequently, we applied Oxford Nanopore Rapid Barcoding and the portable MinION Mk1C sequencer combined with the interARTIC bioinformatics pipeline. We tested a simplified and less time-consuming workflow using SARS-CoV-2-positive specimens from clinical routine and identified pre-analytical parameters, which may help to decrease sequencing failures rates. Complete pipeline duration was approx. 7 hrs for one specimen and approx. 11 hrs for 12 multiplexed barcoded specimens.

ConclusionsThe adapted protocol contains less processing steps and can be completely conducted within one working-day. Diagnostic CT values are principal criteria for specimen selection.


title: Three-step rhythmic breathing exercise and COVID-19: A cross-sectional study

abstract:
IntroductionThe present study assessed the prevalence of COVID-19 among people practicing three-step rhythmic breathing (3SRB) exercise and those who were not practicing any breathing exercises, including 3SRB exercise.

MethodsA community-based cross-sectional observational study was conducted. Data was collected using a self-constructed online google survey tool from July 2020 to August 2020.

ResultsOut of a total 1083 sample, a higher proportion of the participants (41.3%) belonged to the 34-49 years age group, followed by the age group of 50-65 (32.5%). The sample was almost equally distributed; about 51.9% of the population was male, and 48.4% were female. The COVID-19 positivity was recorded almost double (3.1%) in groups not practicing 3SRB exercises compared to a group (1.3%) practicing 3SRB exercises. Furthermore, the practice of 3SRB was significantly associated with a lower percentage of COVID-19 infection (p=0.046).

ConclusionsPractice of 3SRB is significantly associated with a lower percentage of COVID-19 infection. A future study with a robust methodology is warranted to validate the findings of this study and determine the effects of 3SRB on physiological and biological markers.


title: Aorta-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

abstract:
BackgroundBicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

MethodsA comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

ResultsProtein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

ConclusionsThe aorta-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

FundingNational Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

category: cardiovascular medicine


title: RISK OF ON JOB NON COMPLIANCE TOWARDS VARIOUS COVID-19 STANDARD & TRANSMISSION BASED INFECTION PREVENTION & CONTROL MEASURES/PRECAUTIONS AMONG THE HEALTHCARE WORKS WORKING IN OPD SETTINGs OF PUBLIC SECTOR TERTIORY CARE HOSPITALS OF QUETTA BALOCHISTAN. (Prospective cohort study).

abstract:
BackgroundCOVID-19 Pandemic is still circulating within the human population and proving to be a deadlier disease with mortality rate ranging from 0.5 to 7%8. Since COVID-19 is a highly transmissible disease; there is always a probability for its out ward spread towards general public and community from the hospitals and healthcare facilities where they come to seek treatment.

MethodologyA prospective cohort study design was used, considering the limited available resources and time __ A total of 200 healthcare workers (Including Doctors, Nurses, Para-Medical staff, Janitorial staff, Reception staff & Pharmacists) working in the OPDs of the two major Public sector hospitals of Quetta were made part of this study. The study participants were selected using simple random sampling technique. The study participants from "Hospital-A" were first of all educated and trained on various COVID-19 IPC measures later on various COVID-19-IEC materials; written in simple Urdu language, were displayed clearly everywhere in the OPD. Similarly hand washing station along with Hand sanitizers/Soaps and surgical face masks were also made available free of cost for all the study participants of Hospital-A. More over the importance and effectiveness of COVID-19 IPC measures were continuously announced in the OPD gallery of Hospital-A, these announcements used Simple wording in local languages (i.e. Urdu, Pashto, Balochi & Brahvi). On the other hand in the OPD of "Hospital-B" no such interventions were made. The study participants of both the hospitals were followed for one month and observations like-which group showed more on-job non compliance towards various COVID-19 IPC measures were recorded. The data was recorded on daily bases (From 1st May-to-31st May 2021) after observing the study participants and checklist was used for recording various findings. Lastly all the data was analyzed using Microsoft Excel 2007 version.

ResultsThe major findings of this study are almost in line with the set objectives, the study results are clearly showing the Risk ratio (R.R) as 0.27, indicating that the intervention group participants were only 27% as likely to develop On-job non-compliance for various COVID-19 IPC measures compare to the non-intervention group.

ConclusionThe best suggestion and intervention for the developing countries that could at least address the spread of COVID-19 in a cost effective manner at health facility levels remains to be adoption of various Standard and Transmission based non-pharmacological measures of Infection prevention and Control (IPC)5.


title: Lung function from school age to adulthood in primary ciliary dyskinesia

abstract:
Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents, and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the international PCD Cohort (iPCD) and calculated z-scores for forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1 and FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores) but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low BMI was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty, or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialized centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

Take home messageLung function in children with PCD is reduced by age 6 years and further declines during the growth period. It is essential to develop strategies to improve prognosis.


title: Monitoring SARS-CoV-2 variants alterations in Nice neighborhoods by wastewater nanopore sequencing

abstract:
BackgroundWastewater surveillance has been proposed as an epidemiological tool to define the prevalence and evolution of the SARS-CoV-2 epidemics. However, most implemented SARS-CoV-2 wastewater surveillance projects were relying on qPCR measurement of virus titers and did not address the mutational spectrum of SARS-CoV-2 circulating in the population.

MethodsWe have implemented a nanopore RNA sequencing monitoring system in the city of Nice (France, 550,000 inhabitants). Between October 2020 and March 2021, we monthly analyzed the SARS-CoV-2 variants in 113 wastewater samples collected in the main wastewater treatment plant and 20 neighborhoods.

FindingsWe initially detected the lineages predominant in Europe at the end of 2020 (B.1.160, B.1.177, B.1.367, B.1.474, and B.1.221). In January, a localized emergence of a variant (Spike:A522S) of the B.1.1.7 lineage occurred in one neighborhood. It rapidly spread and became dominant all over the city. Other variants of concern (B.1.351, P.1) were also detected in some neighborhoods, but at low frequency. Comparison with individual clinical samples collected during the same week showed that wastewater sequencing correctly identified the same lineages as those found in COVID-19 patients.

InterpretationWastewater sequencing allowed to document the diversity of SARS-CoV-2 sequences within the different neighborhoods of the city of Nice. Our results illustrate how sequencing of sewage samples can be used to track pathogen sequence diversity in the current pandemics and in future infectious disease outbreaks.


title: A Highly Accurate Ensemble Classifier for the Molecular Diagnosis of ASD at Ages 1 to 4 Years

abstract:
ImportanceASD diagnosis remains behavior-based and the median age of the first diagnosis remains unchanged at [~]52 months, which is nearly 5 years after its first trimester origin. Long delays between ASDs prenatal onset and eventual diagnosis likely is a missed opportunity. However, accurate and clinically-translatable early-age diagnostic methods do not exist due to ASD genetic and clinical heterogeneity. There is a need for early-age diagnostic biomarkers of ASD that is robust against its heterogeneity.

ObjectiveTo develop a single blood-based molecular classifier that accurately diagnoses ASD at the age of first symptoms.

Design, Setting, and ParticipantsN=264 ASD, typically developing (TD), and language delayed (LD) toddlers with their clinical, diagnostic, and leukocyte RNA data collected. Datasets included Discovery (n=175 ASD, TD subjects), Longitudinal (n=33 ASD, TD subjects), and Replication (n=89 ASD, TD, LD subjects). We developed an ensemble of ASD classifiers by testing 42,840 models composed of 3,570 feature selection sets and 12 classification methods. Models were trained on the Discovery dataset with 5-fold cross validation. Results were used to construct a Bayesian model averaging-based (BMA) ensemble classifier model that was tested in Discovery and Replication datasets. Data were collected from 2007 to 2012 and analyzed from August 2019 to April 2021.

Main Outcomes and MeasuresPrimary outcomes were (1) comparisons of the performance of 42,840 classifier models in correctly identifying ASD vs TD and LD in Discovery and Replication datasets; and (2) performance of the ensemble model composed of 1,076 models and weighted by Bayesian model averaging technique.

ResultsOf 42,840 models trained in the Discovery dataset, 1,076 averaged AUC-ROC>0.8. These 1,076 models used 191 different feature routes and 2,764 gene features. Using weighted BMA of these features and routes, an ensemble classifier model was constructed which demonstrated excellent performance in Discovery and Replication datasets with ASD classification AUC-ROC scores of 84% to 88%. ASD classification accuracy was comparable against LD and TD subjects and in the Longitudinal dataset. ASD toddlers with ensemble scores above and below the ASD ensemble mean had similar diagnostic and psychometric scores, but those below the ASD ensemble mean had more prenatal risk events than TD toddlers. Ensemble features include genes with immune/inflammation, response to cytokines, transcriptional regulation, mitotic cell cycle, and PI3K-AKT, RAS, and Wnt signaling pathways.

Conclusions and RelevanceAn ensemble ASD molecular classifier has high and replicable accuracy across the spectrum of ASD clinical characteristics and across toddlers aged 1 to 4 years, which has potential for clinical translation.

Key PointsO_ST_ABSQuestionC_ST_ABSSince ASD is genetically and clinical heterogeneous, can a single blood-based molecular classifier accurately diagnose ASD at the age of first symptoms?

FindingsTo address heterogeneity, we developed an ASD classifier method testing 42,840 models. An ensemble of 1,076 models using 191 different feature routes and 2,764 gene features, weighted by Bayesian model averaging, demonstrated excellent performance in Discovery and Replication datasets producing ASD classification with the area under the receiver operating characteristic curve (AUC-ROC) scores of 84% to 88%. Features include genes with immune/inflammation, response to cytokines, transcriptional regulation, mitotic cell cycle, and PI3K-AKT, RAS and Wnt signaling pathways.

MeaningAn ensemble gene expression ASD classifier has high accuracy across the spectrum of ASD clinical characteristics and across toddlers aged 1 to 4 years.


title: Modulating amygdala activation to traumatic memories with a single ketamine infusion

abstract: NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be stored in an altered form. This concept might have significant clinical implications in treating PTSD. Using amygdala activity as a major biomarker of fear response, we tested the potential of a single subanesthetic intravenous infusion of ketamine (NMDA receptor antagonist) to enhance post-retrieval extinction of PTSD trauma memories. Post-extinction, ketamine recipients (vs midazolam) showed a lower amygdala and hippocampus reactivation to trauma memories. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus, with no change in amygdala-vmPFC connectivity, which suggests that ketamine may enhance post-retrieval extinction of PTSD trauma memory in humans. These findings demonstrate the capacity to rewrite human traumatic memories and to modulate the fear response for at least 30 days post-extinction.