title: Association between prenatal alcohol exposure and children's facial shape. A prospective population-based cohort study

abstract:
IMPORTANCEChildren exposed to a high level of prenatal alcohol exposure (PAE) are more likely to develop fetal alcohol spectrum disorder with adverse phenotypes on their faces. However, it is still poorly understood, which level of PAE is associated with facial manifestation and if such associations persist during childhood.

OBJECTIVETo examine the association between PAE and childrens facial phenotype in a prospective multi-ethnic population-based study.

DESIGN, SETTING, AND PARTICIPANTSThis study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. Children had a 3D facial image taken at ages 9 (n=3160) and 13 years (n=2492).

EXPOSURESWe defined 6 levels of PAE based on the frequency and dose of alcohol consumption, and defined three tiers based on the timing of alcohol exposure of the unborn child.

MAIN OUTCOMES AND MEASURESFor image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 endophenotypes representing facial morphology. These facial endophenotypes were used as dependent variables in a linear regression analysis to search for associations with PAE. Finally, to detect specific facial components associated with PAE, we mapped statistically significant endophenotypes back to the 3D facial shape. We generated heatmaps to display the facial changes associated with PAE. PAE prediction based on facial shape was also performed; the prediction accuracy was estimated by area under the receiver operating characteristic curve (AUC).

RESULTSA significant association between PAE and facial shape was found in the 9-year-old children, at all levels of alcohol exposure: the higher the level of exposure, the stronger the association. Moreover, PAE before and during pregnancy was associated with facial shape. The most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out jaw and turned-in lower-eyelid-related regions. For the 13-year-old children, the associations were weaker and the AUCs lower than those of the 9-years-old children.

CONCLUSIONS AND RELEVANCEPAE before and during pregnancy, even at low level, is associated with the facial shape of children, and these associations become weaker as children grow older.

Key pointsO_ST_ABSQuestionsC_ST_ABSWhich level of prenatal alcohol exposure (PAE) is associated with childrens facial shape at different lifetimes?

FindingsA 3D facial phenotype analysis of 9- (N=3160) and 13- (N=2492) year-old children was conducted. PAE before and during pregnancy, even at low level, associates with the childrens facial shape; the association becomes weaker as children grow older.

MeaningThe results suggest avoiding drinking alcohol at least three months before and during pregnancy is the safest option for the child. More research is needed to investigate the consequences of PAE on children; the discovered facial phenotypes could be used as a biomarker for further investigations.


title: The effect of transcranial direct current stimulation (tDCS) combined with cognitive training on EEG spectral power in adolescent boys with ADHD: a double-blind, randomised, sham-controlled trial

abstract: Transcranial direct current stimulation (tDCS) is a possible neurotherapeutic alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD). However, very little is known regarding the mechanisms of action of tDCS in children and adolescents with ADHD. We conducted the first multi-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC), a consistently under-functioning region in ADHD, combined with cognitive training (CT) in 50 children/adolescents with ADHD. This study investigated the underlying mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD (n, sham=10; anodal tDCS=13). We found no significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, no correlation between the QEEG and Go/No-Go Task performance, and no effect on clinical and cognitive outcome measures. These findings extend the null clinical or cognitive effects in our whole sample of 50 children/adolescents with ADHD. Our findings do not indicate multi-session anodal tDCS with CT over rIFC as a treatment for children/adolescents with ADHD. Larger RCTs should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD.

category: psychiatry and clinical psychology


title: Characterization of A Novel Autoimmune Encephalitis Associated Antibody against CRMP2

abstract:
ObjectiveAutoimmune encephalitis (AE) is a large category disorder urging antibody characterization. The aim was to identify a novel AE related autoantibody targeting an intracellular synaptic protein.

MethodsSuspected AE patients had negative conventional antibodies screening but strong immunolabel signals on rat brain sections with the serum and cerebrospinal fluid (CSF) samples were considered burdening unkown antibody. Immunoprecipitation from the rat brain protein lysate followed by mass spectrometry analysis was used to identify the targeting antigen. Western blotting and/or cell-based assay (CBA) with antigen-overexpressing HEK293T cells were used for antibody specificity, epitope and IgG subtype determination. Patients with similar immunostaining pattern on rat brain sections were retrospectively screened for the antibody.

ResultsThe antibody against collapsin response mediator protein 2 (CRMP2), a synaptic protein involved in axon guidance, was identified in a patient with suspected AE. The patient samples reactivated with HEK293T cell overexpressed CRMP2, rather than CRMP1, 3, 4, and 5. The patient samples mainly stained neuronal cytoplasm of the cortex, hippocampus and cerebellum Purkinje cells. This reactivity was eliminated by pre-immunoabsorption with CRMP2-overexpressing HEK293T cells. CRMP2 truncation experiments indicated that 536 amino acids at C-terminus was necessary for the epitope. Subtype analysis showed that anti-CRMP2 antibody was IgG4. Moreover, screening from 19 suspected AE patients led to identification of anti-CRMP2 antibody in another patient with a diagnosis of encephalomyelitis. The two patients responded to immunotherapy.

ConclusionsThis study discovered a novel anti-CRMP2 antibody associated with AE. Testing of the antibody might be promising for AE diagnosis and treatment.

category: neurology


title: Impact of SARS-CoV-2 variant on the severity of maternal infection and perinatal outcomes: Data from the UK Obstetric Surveillance System national cohort.

abstract:
BackgroundIn the UK, the Alpha variant of SARS-CoV-2 became dominant in late 2020, rapidly succeeded by the Delta variant in May 2021. The aim of this study was to compare the impact of these variants on severity of maternal infection and perinatal outcomes within the time-periods in which they predominated.

MethodsThis national, prospective cohort study collated data on hospitalised pregnant women with symptoms of confirmed SARS-CoV-2 infection and compared the severity of infection and perinatal outcomes across the Wildtype (01/03/20-30/11/20), Alpha (01/12/20-15/05/21) and Delta dominant periods (16/05/21-11/07/21), using multivariable logistic regression.

FindingsOf 3371 pregnant women, the proportion that experienced moderate to severe infection significantly increased between Wildtype and Alpha periods (24.4% vs. 35.8%; aOR1.75 95%CI 1.48-2.06), and between Alpha and Delta periods (35.8% vs. 45.0%; aOR1.53, 95%CI 1.07-2.17). Compared to the Wildtype period, symptomatic women admitted in the Alpha period were more likely to require respiratory support (27.2% vs. 20.3%, aOR1.39, 95%CI 1.13-1.78), have pneumonia (27.5% vs. 19.1%, aOR1.65, 95%CI 1.38-1.98) and be admitted to intensive care (11.3% vs. 7.7%, aOR1.61, 95%CI 1.24-2.10). Women admitted during the Delta period had further increased risk of pneumonia (36.8% vs. 27.5%, aOR1.64 95%CI 1.14-2.35). No fully vaccinated pregnant women were admitted between 01/02/2021 when vaccination data collection commenced and 11/07/2021. The proportion of women receiving pharmacological therapies for SARS-CoV-2 management was low, even in those critically ill.

InterpretationSARS-CoV-2 infection during Alpha and Delta dominant periods was associated with more severe infection and worse pregnancy outcomes compared to the Wildtype infection, which itself increased risk compared to women without SARS-CoV-2 infection.1 Clinicians need to be aware and implement COVID-specific therapies in keeping with national guidance. Urgent action to tackle vaccine misinformation and policy change to prioritise uptake in pregnancy is essential.

FundingNational Institute for Health Research HS&DR Programme (11/46/12).

category: obstetrics and gynecology


title: Assessing the effect of back exoskeletons on injury risk during material handling

abstract:
Low back disorders (LBDs) are a leading injury in the workplace. Back exoskeletons (exos) are wearable assist devices that complement traditional ergonomic controls and reduce LBD risks by alleviating musculoskeletal overexertion. However, there are currently no ergonomic assessment tools to evaluate risk for workers wearing back exos. Exo-LiFFT, an extension of the Lifting Fatigue Failure Tool, is introduced as a means to unify the etiology of LBDs with the biomechanical function of exos. We present multiple examples demonstrating how Exo-LiFFT can assess or predict the effect of exos on LBD risk without costly, time-consuming electromyography studies. For instance, using simulated and real-world material handling data we show an exo providing a 30 Nm lumbar moment is projected to reduce cumulative back damage by [~]70% and LBD risk by [~]20%. Exo-LiFFT provides a practical, efficient ergonomic assessment tool to assist safety professionals exploring back exos as part of a comprehensive occupational health program.

HIGHLIGHTSO_LIBack exos are wearable assist devices that complement ergonomic controls for reducing low back disorder (LBD) risks
C_LIO_LIHowever, no ergonomic assessment tools exist to evaluate LBD risks for workers wearing back exos
C_LIO_LIWe introduce Exo-LiFFT, an ergonomic assessment tool adapted from the Lifting Fatigue Failure Tool
C_LIO_LIExo-LiFFT is a practical tool that unifies the etiology of LBDs and biomechanical function of exos
C_LIO_LIExo-LiFFT can be used to assess or predict the effect of exos on LBD risk without EMG testing
C_LI

category: occupational and environmental health


title: An ergonomic assessment tool for evaluating the effect of back exoskeletons on injury risk


title: Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

abstract:
PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.

MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.

ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.

ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

category: genetic and genomic medicine


title: A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia

abstract: Pathogenic mutations in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose (PARP) inhibitors. In many countries, their detection includes patient prescreening with quantitative PCR (qPCR) identifying several founder mutations. In Russia, eight mutations are included in such tests, among which c.5266dup (5382insC) is the most frequently identified one. Here, we showed the distribution of 1406 pathogenic or likely pathogenic mutations in BRCA1/2 genes identified in ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most of mutations were detected with qPCR, for qPCR mutation negative samples, targeted next-generation sequencing (NGS) covering whole coding sequences of the genes was applied. As expected, the most abundant mutations were c.5266dupC (41.0%), c.4035delA (7.0%), c.1961delA (6.3%), c.181T>G (5.2%), c.3756_3759delGTCT (1.8%), c.3700_3704delGTAAA (1.5%), and c.68_69delAG (1.5%). However, we identified several mutations which were more frequent than the founder c.5946delT mutation (also known as 6174delT, 0.5% of participants): c.5152+1G>T (1.2%), c.1687C>T (1.0%), c.4689C>G (0.9%), c.1510delC (0.6%), c.2285_2286delGA (0.6%) in the BRCA1 gene; and c.5286T>G (1.2%), c.2808_2811delACAA (0.8%), c.658_659delGT (0.7%), c.7879A>T (0.6%), c.3847_3848delGT (0.6%) in the BRCA2 gene. Having developed an NGS-targeted panel on SNPs flanking BRCA2 c.5286T>G, we showed the founder effect for this mutation and suggested that it arose about 700 years ago that is twice later that it is thought for the c.5266dupC. The total occurrence of mutations identified in at least 10 participants (13 mutations) was only 70%. To our knowledge, eighty-nine mutations (identified in 8% of participants) have not been described previously. Thus, this study may help in improving prescreening qPCR tests and extend our knowledge about the BRCA1 and BRCA2 genes variability in ovarian cancer patients.


title: EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders.

abstract:
PurposeThe widespread adoption of genomic testing for individuals with ophthalmic disorders has increased demand on diagnostic genomic services for these conditions. Moreover, the clinical utility of a molecular diagnosis for individuals with inherited ophthalmic disorders is increasingly placing pressure on the speed and accuracy of genomic testing.

MethodsWe created EyeG2P, a publically available resource to assist diagnostic filtering of genomic datasets for ophthalmic conditions, utilising the Ensembl Variant Effect Predictor. We assessed the sensitivity of EyeG2P for 1234 individuals with a broad range of conditions, who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we also assessed the precision of EyeG2P in comparision to routine genomic diagnostic approaches.

ResultsWe observed that EyeG2P had a 99.5% sensitivity for genomic variants previously identified as a molecular diagnosis for 1234 individuals. EyeG2P enabled a significant increase in precision in comparison to routine testing strategies (p<0.001), with an increased precision in variant analysis of 35% per individual, on average.

ConclusionAutomated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders.


title: Comparison of gait speed reserve, usual gait speed, and maximum gait speed of adults aged 50+ in Ireland using explainable machine learning

abstract:
Gait speed is a measure of general fitness. Changing from usual (UGS) to maximum (MGS) gait speed requires a general effort across many body systems. The difference, MGS - UGS, is defined as gait speed reserve (GSR). In the present study, using 3925 participants aged 50+ from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA), we used a gradient boosted trees-based stepwise feature selection pipeline for the discovery of clinically relevant predictors of GSR, UGS, and MGS using a shortlist of 88 features across 5 categories (socio-demographics/anthropometrics/medical history; cardiovascular system; physical strength; sensory; and cognitive/psychological). The TreeSHAP explainable machine learning package was used to analyse the input-output relationships of the three models.

The mean [Formula] from 5-fold cross validation on training data and the [Formula] score on test data for the models are: 0.38 (0.04) and 0.41 for UGS; 0.45 (0.04) and 0.46 for MGS; and 0.19 (0.02) and 0.21 for GSR.

Features selected for the UGS model were: age, chair stands time, body mass index, grip strength, number of medications, resting state pulse interval, mean motor reaction time in the choice reaction time test, height, depression score, sit-to-stand difference in diastolic blood pressure, and left visual acuity.

The features selected for the MGS model were: age, grip strength, repeated chair stands time, body mass index, education, mean motor reaction time in the choice reaction time test, number of medications, height, the standard deviation of the mean reaction time in the sustained attention to response task, mean heart rate at resting state, fear of falling, MOCA errors, orthostatic intolerance during active stand, smoking status, total heart beat power during paced breathing, the root mean square of successive differences between heartbeats during paced breathing, and visual acuity.

Finally, the features chosen for the GSR model were: mean motor reaction time in the choice reaction time test, grip strength, education, chair stands time, MOCA errors, accuracy proportion in the sound induced flash illusion (two beeps and one flash with stimulus-onset asynchrony of +150 ms), fear of falling, height, age, sex, orthostatic intolerance, MMSE errors, and number of cardiovascular conditions.

MGS and UGS were more explainable than GSR. All three models contain features from all five categories. There were common features to all three models (age, grip strength, chair stands time, mean motor reaction time in the choice reaction time test, and height), but also some features unique to each of them. Overall, findings on all three models were clinically plausible and support a network physiology approach to the understanding of predictors of performance-based tasks. By employing an explainable machine learning technique, our observations may help clinicians gain new insights into the multisystem predictors of gait speed and gait speed reserve in older adults.

category: geriatric medicine


title: Prevention and Control of Acute Respiratory Viral Infections in Adult Population: A Systematic Review and Meta-Analysis on Ginseng-Based Clinical Trials.

abstract:
IntroductionAcute respiratory infections are continuously emerging. Discovered in Wuhan city, China in 2019, COV-SARS-2 and most viral respiratory diseases presently do not have a definitive cure. This paper aims to evaluate the therapeutic effectiveness of ginseng for prevention and control of acute respiratory illness including SARS-COV-2 in adult population.

MethodWe performed a systematic literature review using databases PubMed, Medline, Scopus, Google Scholar, Web of Science, and Cochrane library from 1st through the 27th of April 2020. All related articles that reported the use of Ginseng in COVID-19 patients were included in this analysis. Screening was done by 2-independent researchers. The meta-analysis was performed using comprehensive meta-analysis package.

Result596 articles were retrieved for the time frame. After screening, 5 articles with RCTs outcomes relevant to the review were selected. Ginseng was found to be effective in the reduction of risk by 38 % and 3-days shorter duration of acute respiratory illness (ARI) in all trials than placebo.

ConclusionAs the world continues to race to find a cure, it is important to consider the use of ginseng which has been proven over the years to be effective in the treatment of acute respiratory illnesses. Further studies should however be conducted to determine the right dosage to improve efficacy and prevent adverse events.

FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Highlight COVID-19 is very infectious ravaging the globe
 Millions have been infected and hundreds of thousands lost their lives to COVID-19
 Due to absence of vaccines, urgent search for vaccines and drugs is still underway
 Ginseng has been useful in similar respiratory viral infections in the past
 Current paper throws more light on the need to consider ginseng for COVID-19 control

category: infectious diseases


title: Willingness to receive vaccination against COVID-19: results from a large nationally representative Australian population survey

abstract: We surveyed 10,024 Australians regarding COVID-19 vaccine willingness. Overall, 59.9% indicated yes, 13.9% no and 26.3% unsure/dont know. Vaccine willingness was higher in males, and increased with increasing education and socioeconomic advantage. Results contrast with earlier, smaller Australian surveys regarding vaccination willingness and confirm the need for targeted vaccination information.


title: Characterization of SARS-CoV-2 Genetic Material in Wastewater

abstract: SARS-CoV-2 genetic material has been detected in raw wastewater around the world throughout the COVID-19 pandemic and has served as a useful tool for monitoring community levels of SARS-CoV-2 infections. SARS-CoV-2 genetic material is highly detectable in a patients feces and the household wastewater for several days before and after a positive COVID-19 qPCR test from throat or sputum samples. Here, we characterize genetic material collected from raw wastewater samples and determine recovery efficiency during a concentration process. We find that pasteurization of raw wastewater samples did not reduce SARS-CoV-2 signal if RNA is extracted immediately after pasteurization. On the contrary, we find that signal decreased by approximately half when RNA was extracted 24-36 hours post-pasteurization and [~]90% when freeze-thawed prior to concentration. As a matrix control, we use an engineered enveloped RNA virus. Surprisingly, after concentration, the recovery of SARS-CoV-2 signal is consistently higher than the recovery of the control virus leading us to question the nature of the SARS-CoV-2 genetic material detected in wastewater. We see no significant difference in signal after different 24-hour temperature changes; however, treatment with detergent decreases signal [~]100-fold. Furthermore, the density of the samples is comparable to enveloped retrovirus particles, yet, interestingly, when raw wastewater samples were used to inoculate cells, no cytopathic effects were seen indicating that wastewater samples do not contain infectious SARS-CoV-2. Together, this suggests that wastewater contains fully intact enveloped particles.

category: epidemiology


title: Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease.

abstract:
Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.

MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.

ResultsWe identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.

ConclusionWe have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.

category: gastroenterology


title: Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort

abstract:
Background and AimsLow pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users.

MethodsWe conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users.

ResultsOf 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes.

ConclusionAmong patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.


title: Mental Health of HBCU College Students during the COVID-19 Pandemic

abstract:
ObjectiveThis study investigated rates and predictors of mental health issues (e.g., depression and anxiety) in a sample of college students currently attending a historically Black college/university (HBCU) during the COVID-19 pandemic.

Participants/Methods98 undergraduate students (81 female and 17 male) completed an online survey containing questions about demographics, socioeconomic status, academic characteristics, and pandemic-related concerns. The survey also included PHQ-9 and GAD-7 questionnaires to evaluate depression and anxiety, respectively.

Results49% of students met the clinical cutoff for depression, 39% for anxiety, and 52% for depression and/or anxiety. Significant predictors of meeting the cutoffs included parental job loss/hour reduction, being a senior, and feeling that the pandemic negatively impacted daily life, among other factors. Demographic variables (age, gender, etc.) had no effect.

ConclusionHBCU students show high rates of depression and anxiety during the COVID-19 pandemic, which may be predicted based on the students academic, socioeconomic, and pandemic-related concerns.


title: Reduced dementia incidence following varicella zoster vaccination in Wales 2013--2020

abstract:
INTRODUCTIONChronic infection with herpes viruses is a potential contributing factor to the development of dementia. The introduction of nationwide shingles (varicella zoster) vaccination in Wales might therefore be associated with reduced incident dementia.

METHODSWe analyzed the association of shingles vaccination with incident dementia in Wales between 2013 and 2020 using retrospectively collected national health data.

RESULTSVaccinated individuals were at reduced risk of dementia (adjusted hazard ratio: 0.72; 95% CI: 0.69 to 0.75). The association was not modified by a reduction in shingles diagnosis and was stronger for vascular dementia than for Alzheimers disease. Vaccination was also associated with a reduction in several other diseases and all-cause mortality.

DISCUSSIONOur study shows a clear association of shingles vaccination with reduced dementia, consistent with other observational cohort studies. The association may reflect selection bias with people choosing to be vaccinated having a higher healthy life expectancy.


title: Cost-Effectiveness of Interventions to Improve HIV Pre-Exposure Prophylaxis Initiation, Adherence, and Persistence among Men Who Have Sex with Men

abstract:
BackgroundTo help achieve Ending the HIV Epidemic (EHE) goals of reducing new HIV incidence, pre-exposure prophylaxis (PrEP) use and engagement must increase despite multidimensional barriers to scale-up and limitations in funding. We investigated the cost-effectiveness of interventions spanning the PrEP continuum of care for men who have sex with men (MSM) in Atlanta, Georgia, a focal jurisdiction for the EHE plan.

MethodsUsing a network-based HIV transmission model, we simulated lifetime costs, quality-adjusted life years (QALYs), and infections averted for eight intervention strategies using a health sector perspective. Strategies included a status quo (no interventions), three distinct interventions (targeting PrEP initiation, adherence, or persistence), and all possible intervention combinations. Cost-effectiveness was evaluated incrementally using a $100,000/QALY gained threshold. We performed sensitivity analyses on PrEP costs, intervention costs, and intervention coverage.

FindingsStrategies averted 0.2-4.2% new infections and gained 0.0045%-0.24% QALYs compared to the status quo. Initiation strategies achieved 20%-23% PrEP coverage (up from 15% with no interventions) and moderate clinical benefits at a high cost, while adherence strategies were relatively low cost and low benefit. Under our assumptions, the adherence and initiation combination strategy was cost-effective with an incremental cost-effectiveness ratio of $86,927/QALY gained. Sensitivity analyses showed no strategies were cost-effective when intervention costs increased by 60% and the strategy combining all three interventions was cost-effective when PrEP costs decreased to $1,000/month.

InterpretationUnder reasonable assumptions of intervention uptake and cost, PrEP initiation interventions achieved moderate public health gains and could be cost-effective. However, these analyses demonstrate that substantial financial resources will be needed to improve the PrEP care continuum towards meeting EHE goals.

FundingUS National Institutes of Health

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles published between 2010-2020 using the term "(("Costs and Cost Analysis"[Mesh]) OR "Cost-Benefit Analysis"[Mesh] OR cost-effective* OR cost-utility OR "economic evaluation" OR "economic impact") AND ("HIV"[Mesh] OR HIV OR HIV/AIDS) AND (pre-exposure OR PrEP) AND (MSM OR gay OR bisexual OR GBM)," which yielded 79 results. PrEP (compared to no PrEP) for high-risk MSM is generally found to be cost-effective in the United States and other high-income countries, with some variation in findings. However, evidence on the cost and cost-effectiveness of interventions designed to address barriers to effective PrEP use are lacking. Current studies typically model hypothetical improvements that may not be realistically achieved.

Added value of this studyUsing a stochastic network-based model of HIV, we projected the potential costs, benefits, and cost-effectiveness of real-world interventions to improve PrEP use through increased initiation, adherence, and persistence among MSM in a US urban center. We found real-world interventions to improve PrEP use could be cost-effective, however they would be expensive and achieve only limited clinical gains.

Implications of all the available evidenceLower PrEP costs would improve the cost-effectiveness of expanding and improving PrEP use. Continued expansion of PrEP coverage beyond current levels will likely involve multiple interventions of increasing intensity and cost to engage harder-to-reach populations. Realistic efforts to end the HIV epidemic may require investments and interventions that are above currently accepted willingness-to-pay thresholds.

category: hiv aids


title: A spatio-temporal study of state-wide case-fatality risks during the first wave of the COVID-19 pandemic in Mexico

abstract: We study case-fatality risks (risks of dying in sick individuals) corresponding to the first wave of the COVID-19 pandemic in Mexico. Spatio-temporal analysis by state were performed, mainly from April to September 2020, including descriptive analyses through mapping and time series representations, and the fit of linear mixed models and time series clustering to analyze trends by state. The association of comorbidities and other variables with the risks were studied by fitting a spatial panel data linear model (splm). As results, we observed that on average the greatest risks were reached by July, and that highest risks were observed in some states, Baja California Norte, Chiapas, and Sonora; interestingly, some densely populated states, as Mexico City, had lower values. Different trends by state were observed, and a four-order polynomial, including fixed and random effects, was necessary to model them. The most general structure is one in which the risks increase and then decrease and was observed in states belonging to two clusters; however, there is a cluster corresponding to states with a retarded increase, and another in which increasing risks through time were observed. A cyclic behavior in terms of states having a second increasing trend was observed. Finally, according to the splm, percentage of men, being in the group of 50 years and over, chronic kidney disease failure, cardiovascular disease, asthma, and hypertension were positively associated with the case-fatality risks. This analysis may provide valuable insight into COVID-19 dynamics in future outbreaks, as well as the determinants of these trends at a state level; and, by combining spatial and temporal information, provide a better understanding of COVID-19 case-fatality.


title: Knowledge, attitude, and practices towards COVID-19 among the Rohingya refugees in Coxs Bazar, Bangladesh.

abstract: The Rohingya refugee population in Bangladesh has become more vulnerable to COVID-19 because of their living and environmental conditions. The current study represents an assessment of the Rohingya peoples COVID-19-related knowledge, attitude, and practices (KAP) at eight refugee camps in Coxs Bazar. This cross-sectional study was completed with a total of 400 responses between July and September of 2020. A questionnaire was created to assess demographic characteristics (5 items), knowledge (10 items), attitude (5 items), practices (5 items), and information sources (1 item). Aside from the total KAP scores, the scores are also presented based on demographic variables. The KAP of the respondents were not satisfactory, with scores of 5.8 {+/-}1.8, 2.2 {+/-} 1.0, and 0.9 {+/-} 0.7, respectively. We found significant differences only in the knowledge scores based on education and gender. In conclusion, this study emphasizes the importance of COVID-19 training that focuses on behavioral changes for the Rohingya people in Bangladesh.

category: public and global health


title: Challenges to self-isolation among contacts of cases of COVID-19: a national telephone survey in Wales

abstract:
ObjectivesTo identify the specific challenges of self-isolation experienced by population sub-groups to better target and tailor support.

DesignThe Contact Adherence Behavioural Insights Study (CABINS) was a 15-minute telephone survey of confirmed contacts of cases of COVID-19 identified through the national NHS Wales Test Trace Protect (TTP) database.

MethodsConfirmed contacts of cases of COVID-19 reached by TTP completed a 15-minute telephone survey (N = 2,027). Binary logistic regression models adjusted for age, gender, living alone, survey round, deprivation quintile (defined by the Welsh Index of Multiple Deprivation) and income precarity (financial security) determined which population sub-groups were more likely to experience challenges during self-isolation.

ResultsYounger people (aged 18-29 years) were 3 times more likely to report mental health concerns (Adjusted Odds Ratio [aOR]: 3.16, 95% Confidence Interval [CI]: 2.05-4.86) and 2 times more likely to report loneliness (aOR: 1.96, CI: 1.37-2.81) compared to people aged over 60 years. Women were 1.5 times more likely to experience mental health concerns (aOR: 1.51, 95% CI: 1.20-1.92) compared to men. People with high/very high levels of income precarity were 8 times more likely to report financial challenges (aOR: 7.73, CI: 5.10-11.74) and 3 times more likely to report mental health concerns than their more financially secure counterparts (aOR: 3.08, CI: 2.22-4.28).

ConclusionsSelf-isolation is particularly challenging for those with younger people, women and precarious incomes. Providing enhanced emotional, financial and social support and signposting to these groups is required to minimise the harms of self-isolation.

What is already known on this subject?O_LISelf-isolation after notification as a contact of a positive case of COVID-19 is essential to prevent the spread of the disease. However, self-isolation can be challenging and adherence is dependent upon a range of psychological, social and economic factors.
C_LIO_LIEmerging data suggests that the COVID-19 pandemic is having disproportionate impact on those on lower incomes and those of lower socio-economic status.
C_LI

What does this study add?O_LIThe most common challenges faced to self-isolation were wanting to see family and friends, followed by a lack of exercise.
C_LIO_LIIndividuals with some income precarity were more than 7 times more likely to report financial concerns and 3 times more likely to report mental health concerns as a challenge to self-isolation than those who were financially secure.
C_LIO_LIInterventions to support individuals to self-isolate needs to be targeted at groups most susceptible to experiencing challenges to self-isolation for infectious diseases. Our research suggests that the use of income precarity questions as a screening tool is important to direct financial and practical support through contact tracing systems.
C_LI


title: Antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19

abstract: There is a critical need for improved infectious disease diagnostics to enable rapid case identification in a viral pandemic and support targeted antimicrobial prescribing. Here we use high-resolution liquid chromatography coupled with mass spectrometry to compare the admission serum metabolome of patients attending hospital with a range of viral infections, including SARS-CoV-2, to those with bacterial infections, non-infected inflammatory conditions and healthy controls. We demonstrate for the first time that 3-Deoxy-3,4-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), is detectable in serum. ddhC acts as an accurate biomarker for viral infections, generating an area under the receiver operating characteristic curve of 0.954 (95% confidence interval 0.923-0.986) when comparing viral to non-viral cases. Gene expression of viperin, the enzyme responsible for ddhCTP synthesis, is highly correlated with ddhC, providing a biological mechanism for its increase during viral infection. These findings underline a key future diagnostic role of ddhC in the context of pandemic preparedness and antimicrobial stewardship.


title: Shocked-relaxed-tired: Mental health during the three waves of the Covid-19

abstract:
BackgroundSeveral recent studies reported that the Covid-19 pandemic induces significant mental distress. However, it remains unknown whether mental distress persists or subsides in response to consecutive Covid-19 waves. Therefore, we here examine mental distress before and across the three Covid-19 waves.

MethodsWe measured stress and depressive symptoms prior to and across the three Covid-19 waves in a well-established population-based sample. A total of 330 participants completed e-questionnaires prior to and during the Covid-19 waves. Friedmans repeated-measures and Wilcoxon rank-sum pairwise test with Bonferroni correction were used to investigate repeated-measure differences, while the Kruskal-Wallis test was used to assess the effect of behavioral and physiological parameters on mental health.

ResultsWe found significantly increased mental distress during each of the Covid-19 waves compared with the pre-Covid-19 period. Increased mental distress was more common in women and most pronounced during the 1st and in particular, the 3rd Covid-19 wave. The stress and depressive symptoms increased during the pandemic compared with the pre-Covid-19 period by a maximum of 1.58 and 3.63 times, respectively. Negative emotions and loneliness were identified as the most significant risk factors of Covid-19-induced mental distress, while resilience was found to be protective.

ConclusionsMental distress surged during all the Covid-19 waves without showing extinction. This pattern is mechanistically reminiscent of the post-traumatic stress disorder. Our results suggest that the Covid-19 pandemic underlies the development of a novel chronic mental health disorder and do not exclude possible further deterioration of mental health in the case of future Covid-19 waves.


title: Shocked, relaxed, tired: Mental health during the three waves of the Covid-19


title: A Multi-Site Analysis of the Prevalence of Food Security in the United States, before and during the COVID-19 Pandemic

abstract:
BackgroundThe COVID-19 pandemic profoundly affected food systems including food security. Understanding how the COVID-19 pandemic impacted food security is important to provide support, and identify long-term impacts and needs.

ObjectiveOur team- the National Food Access and COVID research Team (NFACT) was formed to assess food security over different U.S. study sites throughout the pandemic, using common instruments and measurements. Here we present results from 18 study sites across 15 states and nationally over the first year of the COVID-19 pandemic.

MethodsA validated survey instrument was developed and implemented in whole or part across the sites throughout the first year of the pandemic, representing 22 separate surveys. Sampling methods for each study site were convenience, representative, or high-risk targeted. Food security was measured using the USDA six-item module. Food security prevalence was analyzed using analysis of variance by sampling method to statistically significant differences.

ResultsIn total, more than 27,000 people responded to the surveys. We find higher prevalence of food insecurity (low or very low food security) since the COVID-19 pandemic, as compared to before the pandemic. In nearly all study sites, we find higher prevalence of food insecurity among Black, Indigenous, and People of Color (BIPOC), households with children, and those with job disruptions. We also demonstrate lingering food insecurity, with high or increased prevalence over time in sites with repeat surveys. We find no statistically significant differences between convenience and representative surveys, but statistically higher prevalence of food insecurity among high-risk compared to convenience surveys.

ConclusionsThis comprehensive multi-study site effort demonstrates higher prevalence of food insecurity since the beginning of the COVID-19 pandemic, which in multiple survey sites continues throughout the first year of the pandemic. These impacts were prevalent for certain demographic groups, and most pronounced for surveys targeting high-risk populations.

category: nutrition


title: A cross-sectional study of socioeconomic status and sickness presenteeism in Japanese workers during the COVID-19 pandemic

abstract:
BackgroundWe examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.

MethodsA cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.

ResultsThe odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.

ConclusionThe issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.


title: A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic


title: A cluster randomised trial of the impact of a policy of daily testing for contacts of COVID-19 cases on attendance and COVID-19 transmission in English secondary schools and colleges

abstract:
BackgroundSchool-based COVID-19 contacts in England are asked to self-isolate at home. However, this has led to large numbers of missed school days. Therefore, we trialled daily testing of contacts as an alternative, to investigate if it would affect transmission in schools.

MethodsWe performed an open-label cluster randomised controlled trial in students and staff from secondary schools and further education colleges in England (ISRCTN18100261). Schools were randomised to self-isolation of COVID-19 contacts for 10 days (control) or to voluntary daily lateral flow device (LFD) testing for school contacts with LFD-negative contacts remaining at school (intervention). Household contacts were excluded from participation.

Co-primary outcomes in all students and staff were symptomatic COVID-19, adjusted for community case rates, to estimate within-school transmission (non-inferiority margin: <50% relative increase), and COVID-19-related school absence. Analyses were performed on an intention to treat (ITT) basis using quasi-Poisson regression, also estimating complier average causal effects (CACE). Secondary outcomes included participation rates, PCR results in contacts and performance characteristics of LFDs vs. PCR.

FindingsOf 99 control and 102 intervention schools, 76 and 86 actively participated (19-April-2021 to 27-June-2021); additional national data allowed most non-participating schools to be included in the co-primary outcomes. 2432/5763(42.4%) intervention arm contacts participated. There were 657 symptomatic PCR-confirmed infections during 7,782,537 days-at-risk (59.1/100k/week) and 740 during 8,379,749 days-at-risk (61.8/100k/week) in the control and intervention arms respectively (ITT adjusted incidence rate ratio, aIRR=0.96 [95%CI 0.75-1.22;p=0.72]) (CACE-aIRR=0.86 [0.55-1.34]). There were 55,718 COVID-related absences during 3,092,515 person-school-days (1.8%) and 48,609 during 3,305,403 person-school-days(1.5%) in the control and intervention arms (ITT-aIRR=0.80 [95%CI 0.53-1.21;p=0.29]) (CACE-aIRR 0.61 [0.30-1.23]). 14/886(1.6%) control contacts providing an asymptomatic PCR sample tested positive compared to 44/2981(1.5%) intervention contacts (adjusted odds ratio, aOR=0.73 [95%CI 0.33-1.61;p=0.44]). Rates of symptomatic infection in contacts were 44/4665(0.9%) and 79/5955(1.3%), respectively (aOR=1.21 [0.82-1.79;p=0.34]).

InterpretationDaily contact testing of school-based contacts was non-inferior to self-isolation for control of COVID-19 transmission. COVID-19 rates in school-based contacts in both intervention and control groups were <2%. Daily contact testing is a safe alternative to home isolation following school-based exposures.


title: Proxalutamide Improves Inflammatory, Immunologic, and Thrombogenic Markers in Mild-to-Moderate COVID-19 Males and Females: an Exploratory Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial Early Antiandrogen Therapy (EAT) with Proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial)

abstract:
BackgroundThe androgen theory on COVID-19 is based on the fact that males, in particular when affected by androgenetic alopecia, and females with hyperandrogenic states are more severely affected by COVID-19, while chronic users of antiandrogens experiment lower rates of COVID-19 complications. The theory finds plausibility on the androgen-mediated transmembrane protease serine 2 (TMPRSS-2), a key protein for SARS-CoV-2 cell entry. We demonstrated reduction of hospitalization rate using a potent non-steroidal antiandrogen (NSAA), proxalutamide, in both females and males COVID-19 outpatients. In this joint exploratory analysis, we aimed to demonstrate whether the efficacy of proxalutamide on mild-to-moderate COVID-19 could be justified by improvements in inflammatory, immunologic, and thrombogenic responses.

MethodsThis is a joint post-hoc analysis of two double-blind, placebo-controlled two-arm randomized clinical trials (RCTs) on proxalutamide 200mg/day for seven days for female and male COVID-19 outpatients, respectively, compared to standard of care (SOC), of hematocrit, neutrophils lymphocytes, eosinophils, platelets, neutrophil-to-lymphocyte (N/L) ratio, ferritin, fibrinogen, D-dimer, ultrasensitive C-reactive protein (usCRP) lactate 1-hour erythrocyte sedimentation rate (1hESR), total testosterone, estradiol, sex hormone binding globulin (SHBG), oxygen saturation and heart rate measured on days 0, 1 and 7.

ResultsA total of 445 subjects were enrolled (268 males and 177 females) between October 21th 2020 and February 28th 2021, with similar baseline characteristics. Neutrophils were lower in proxalutamide group in Day 1 (p = 0.005) and Day 7 (p < 0.0001). Lymphocytes were higher in the proxalutamide group in Day 7 (p = 0.0001). Eosinophils were higher in the proxalutamide arm in Day 1 (p = 0.04) and Day 7 (p < 0.00010. In Day 7, platelets were higher in proxalutamide arm (p = 0.03). Ferritin levels were lower in proxalutamide arm in Day 7 (p = 0.03) Fibrinogen levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). D-dimer levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). UsCRP levels were reduced in proxalutamide group in Day 7 (p < 0.0001). 1hESR) was reduced in proxalutamide arm in Day 1 (p = 0.0009) and Day 7 (p < 0.0001). In males, testosterone levels were higher in proxalutamide group in Day 1 (p = 0.048) and Day 7 (p = 0.0001). In females, testosterone levels were higher in proxalutamide group in Day 7 (p = 0.018), and estradiol levels were higher in proxalutamide arm in Day 1 (p = 0.044). Oxygen saturation was higher in proxalutamide in Day 1 (p = 0.0006) and Day 7 (p < 0.0001).

ConclusionsThe substantial improvements observed in immunologic, inflammatory, thrombotic and oxygen markers with proxalutamide may support the reduction of hospitalization rate observed in both females and males with COVID-19 using proxalutamide, compared to standard of care.


title: Early multidrug treatment of SARS-CoV-2 (COVID-19) and decreased case fatality rates in Honduras

abstract:
INTRODUCTIONWithin 2 months of first detection of SARS-CoV-2 in Honduras, its government promoted nationwide implementation of multi-drug COVID-19 inpatient and outpatient treatment protocols. This was associated with a case fatality rate decrease from 9.33% to 2.97%. No decrease was seen in Mexico, a similar Latin American country that did not introduce multi-drug treatment protocols at that time.

OBJECTIVEThe primary objective of the study was to use statistical process control to assess the likelihood that the decrease in case fatality rate in Honduras was due to chance, using Mexico as a control country.

METHODSFourteen day running average COVID-19 case fatality rates in Honduras and Mexico were used to create Shewhart control charts during the first 6 months of the epidemic. The date of implementation in Honduras of the inpatient and outpatient multi-drug COVID-19 protocols were plotted on control charts, with a Mexican COVID-19 case fatality control chart for comparison.

RESULTSThe case fatality rate for COVID-19 in Honduras dropped below the lower control limit 9 days after implementation of an inpatient and outpatient multi-drug therapeutic protocol, from an average 9.33% case fatality rate to 5.01%. The Honduran COVID-19 case fatality rate again dropped below the lower control limit to 2.97%, 17 days after launching a substantial government program to make the protocol medications accessible to underserved areas. Shewhart control chart plots of case fatality rates in Honduras suggest a plausible temporal association between the implementation dates of both the initial protocol implementation on May 3, 2020, and the outreach effort on June 10, 2020, and statistically significant control chart anomalies. No control chart anomalies were seen during that time in Mexico.

CONCLUSIONDecreases in COVID-19 case fatality rates in Honduras were associated with both the initial publication a multi-drug COVID-19 therapeutic protocol and a subsequent outreach program.


title: Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18-59 years: interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial

abstract:
BackgroundLarge-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac.

MethodsIn this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 g per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 g), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2.

ResultsOverall, 540 participants received a third dose. In the 3 g group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 g group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination.

ConclusionsA third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)


title: Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study in Southeast Scotland

abstract:
BackgroundMGMT methylation in glioblastoma predicts response to temozolomide but dichotomising methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival.

MethodsWe included consecutive glioblastoma patients diagnosed (April 2012-May 2020) at a neuro-oncology centre. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumours were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, post-operative Karnofsky performance score, extent of resection, temozolomide regimen and radiotherapy.

FindingsThere were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%) and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46-0.79, p=0.005) and low (HR 0.67, 95%CI 0.50-0.89, p<0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation p=0.097; high methylation p=0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms p<0.001).

InterpretationQuantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.

category: oncology


title: Use of Indomethacin for mild and moderate Covid -19 patients. A Randomized Control Trial

abstract:
IntroductionIndomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been presented as a broad-spectrum antiviral agent. This randomised clinical trial in a hospital setting evaluated the efficacy and safety of this drug in RT-PCR-positive coronavirus disease 2019 (COVID-19) patients.

Materials & MethodsA total of 210 RT-PCR-positive COVID-19 patients, who provided consent were allotted, to control or case arm, based on block randomisation. The control arm received standard of care comprising paracetamol, ivermectin, and other adjuvant therapies. The patients in the case arm received indomethacin instead of paracetamol, with other medications retained. The primary endpoint was the development of hypoxia/desaturation with SpO2 [≤] 93, while time to become afebrile and time for cough and myalgia resolution were the secondary endpoints.

ResultsThe results of 210 patients were available, with 103 and 107 patients in the indomethacin and paracetamol arms, respectively. We monitored patient profiles along with everyday clinical parameters. Blood chemistry at the time of admission and discharge was assessed.

As no one in either of the arms required high-flow oxygen, desaturation with SpO2 level of 93 and below was an important goal. In the indomethacin group, none of the 103 patients developed desaturation. On the other hand, 20 of the 107 patients in the paracetamol arm developed desaturation. Patients who received indomethacin also experienced more rapid symptomatic relief than those in the paracetamol arm, with most symptoms disappearing in half the time. 56 patients out of 107 in the paracetamol arm had fever on the seventh day, while no patient in the indomethacin group had fever. Neither arm reported any adverse event. The fourteenth-day follow-up revealed that the paracetamol arm patients had faced several discomforts, including myalgia, joint pain, and tiredness; indomethacin arm patients mostly complained only of tiredness.

ConclusionIndomethacin is a safe and effective drug for treating patients with mild and moderate covid-19.


title: Indomethacin use for Mild & Moderate hospitalised Covid-19 patients: An open label randomised clinical trial


title: Safety and Immunogenicity of Nanocovax, a SARS-CoV-2 Recombinant Spike Protein Vaccine

abstract:
BackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant.

MethodsWe conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 microgram (mcg), 50 mcg, and 75 mcg doses, aluminum hydroxide adjuvanted). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2 which involved in 560 healthy adults, the primary outcomes are vaccine safety; and anti-S IgG antibody response. Secondary outcomes were surrogate virus neutralization, wild-type SARS-CoV-2 neutralization, and T-cell responses by intracellular staining (ICS) for interferon gamma (IFNg). We performed primary analyses at day 35 and day 42.

ResultsFor phase 1 study, no serious adverse events (SAE) were observed for all 60 participants. Most adverse events (AE) were grade 1 and disappeared shortly after injection. For phase 2 study, after randomization, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive placebo. Reactogenicity was absent or mild in the majority of participants and of short duration (mean, [≤]3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. There was no statistical difference in antibody responses among dose strengths on Day 42, in terms of anti S-IgG level and neutralizing antibody titer.

ConclusionsUp to 42 days, Nanocovax vaccine was safe, well tolerated and induced robust immune responses. We propose using Nanocovax 25 mcg for Phase 3 to evaluate the vaccine efficacy. (Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04683484.)


title: The impact of large mobile air purifiers on aerosol concentration in classrooms and the reduction of airborne transmission of SARS-CoV-2

abstract: In the wake of the SARS-CoV-2 pandemic, an increased risk of infection by virus-containing aerosols indoors is assumed. Especially in schools, the duration of stay is long and the number of people in the rooms is large, increasing the risk of infection. This problem particularly affects schools without pre-installed ventilation systems that are equipped with filters and/or operate with fresh air. Here, the aerosol concentration is reduced by natural ventilation. In this context, we are investigating the effect of large mobile air purifiers (AP) with HEPA filters on particle concentration and their suitability for classroom use in a primary school in Germany. The three tested APs differ significantly in their air outlet characteristics. Measurements of the number of particles, the particle size distribution, and the CO2 concentration were carried out in the classroom with students (April/May 2021) and with an aerosol generator without students. In this regard, the use of APs leads to a substantial reduction in aerosol particles. At the same time, the three APs are found to have differences in their particle decay rate, noise level, and flow velocity. In addition to the measurements, the effect of various influencing parameters on the potential inhaled particle dose was investigated using a calculation model. The parameters considered include the duration of stay, particle concentration in exhaled air, respiratory flow rate, virus lifetime, ventilation interval, ventilation efficiency, AP volumetric flow, as well as room size. Based on the resulting effect diagrams, significant recommendations can be derived for reducing the risk of infection from virus-laden aerosols. Finally, the measurements were compared to computational fluid dynamics (CFD) modeling, as such tools can aid the optimal placement and configuration of APs and can be used to study the effect of the spread of aerosols from a source in the classroom.


title: Running related biomechanical risk factors for overuse injuries in distance runners: A systematic review considering injury specificity and the potentials for future research

abstract:
ObjectiveTo identify and evaluate the evidence of the most relevant running-related risk factors (RRRFs) for running-related overuse injuries (ROIs) and to suggest future research directions.

DesignSystematic review considering prospective and retrospective studies. (PROSPERO_ID: 236832)

Data sourcesPubmed. Connected Papers. The search was performed in February 2021.

Eligibility criteriaEnglish language. Studies on participants whose primary sport is running addressing the risk for the seven most common ROIs and at least one kinematic, kinetic (including pressure measurements), or electromyographic RRRF. An RRRF needed to be identified in at least one prospective or two retrospective studies.

ResultsSixty-two articles fulfilled our eligibility criteria. Levels of evidence for specific ROIs ranged from conflicting to moderate evidence. Running populations and methods applied varied considerably between studies. While some RRRFs appeared for several ROIs, most RRRFs were specific for a particular ROI. The biomechanical measurements performed in many studies would have allowed for consideration of many more RRRFs than have been reported, highlighting a potential for more effective data usage in the future.

ConclusionThis study offers a comprehensive overview of RRRFs for the most common ROIs, which might serve as a starting point to develop ROI-specific risk profiles of individual runners. Future work should use macroscopic (big data) approaches involving long-term data collections in the real world and microscopic approaches involving precise stress calculations using recent developments in biomechanical modelling. However, consensus on data collection standards (including the quantification of workload and stress tolerance variables and the reporting of injuries) is warranted.

category: orthopedics


title: Robust antibody levels in both diabetic and non-diabetic individuals after BNT162b2 mRNA COVID-19 vaccination

abstract: The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people that took two doses of BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. Their levels were 154{+/-}49.1 vs. 138{+/-}59.4BAU/mL for IgG and 87.1{+/-}11.6 vs. 79.7{+/-}19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95%CI: -27.08 to -0.64BAU/ml, p=0.041) less IgG antibodies and 4.42% (95%CI: -8.53 to -0.32%, p=0.036) less neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine; nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity.


title: Clinical echocardiography does not indicate cardiac dysfunction in critically ill Covid-19 patients

abstract:
ObjectiveWe aimed to investigate the acute cardiac effects of severe SARS-CoV-2.

MethodsThis is an observational study generated from the first 79 patients admitted to Uppsala intensive care due to respiratory failure with SARS-CoV-2 infection. 34 underwent echocardiography of which 25 were included in the study and compared to 44 non-echo patients. Exclusion was based on absence of normofrequent sinus rhythm and mechanical respiratory support. Biomarker analysis was carried out on all patients.

ResultsMortality was increased in the echo compared to non-echo group (44 % vs. 16%, p<0.05). Right sided dimensions and functional parameters were not affected. Tricuspid regurgitation velocity indicated how increased pulmonary artery pressure was associated with mortality (survivors (n=5): 2.51 {+/-} 0.01 m/s vs. non-survivors (n=5): 3.06 {+/-} 0.11 m/s, p<0.05). Cardiac markers and D-dimer correlated to initiation of echocardiography (hs-TnI (ng/L): echo (n=23): 133 {+/-} 45 vs. non-echo (n=41): 81.3 {+/-} 45, p<0.01; NTproBNP (ng/L): echo (n=25): 2959 {+/-} 573 vs. non-echo (n=42): 1641 {+/-} 420, p<0.001; D-dimer (mg/L): echo (n=25): 16.1 {+/-} 3.7 vs. non-echo (n=43: 6.1 {+/-} 1.5, p<0.01) and mortality (hs-TnI (ng/L): survivors (n=48): 59.1 {+/-} 21 vs. non-survivors (n=17): 211 {+/-} 105, p<0.0001; NT-proBNP (ng/L): survivors (n=47): 1310 {+/-} 314 vs. non-survivors (n=20): 4065 {+/-} 740, p<0.0001; D-dimer (mg/L): survivors (n=50): 7.2 {+/-} 1.5 vs. non-survivors (n=18): 17.1 {+/-} 4.8, p<0.01). All intervals refer to standard error of the mean. Tricuspid regurgitation velocity was correlated with troponin I (r=0.93, r2=0.74, p<0.001, n=10).

ConclusionsThese results suggest that there is no clear negative effect on cardiac function in critical SARS-CoV-2. There are indications that pulmonary pressure elevation carries a negative predictive outcome suggesting pulmonary disease as the driver of mortality. Cardiac biomarkers as well as D-dimer carry predictive value.

Trial registration numberPatients were included in "Clinical trials NCT04316884"

Article summaryO_ST_ABSStrength and limitations of this studyC_ST_ABS- The patient body is recruited from all patients admitted to ICU in need of mechanical respiratory support independent of background which makes it relevant to clinical practice.
- The echocardiographic image acquisition was carried out by hospital assigned agents on clinical indication, which makes the results applicable in a clinical setting.
- Since the image acquisition was carried out on a clinical indication, the results may be skewed towards the false positive if applied to all Covid19 patients.

category: cardiovascular medicine


title: Echocardiographic characterisation in critical Covid19 - an observational study


title: Breakthrough Symptomatic COVID-19 Infections Leading to Long Covid: Report from Long Covid Facebook Group Poll

abstract: Vaccines have been shown to be extremely effective in preventing COVID-19 hospitalizations and deaths. However, a question remains whether vaccine breakthrough cases can still lead to Post-Acute Sequelae of SARS-CoV-2 (PASC), also known as Long Covid. To address this question, the Survivor Corps group, a grassroots COVID-19 organization focused on patient support and research, posted a poll to its 169,900 members that asked about breakthrough cases, Long Covid, and hospitalizations. 1,949 people who self-report being fully vaccinated have responded to date. While robust data are needed in a larger, unbiased sample to extrapolate rates to the population, we analyzed the results of this public poll to determine what people were reporting regarding Long Covid after breakthrough infection and to prompt discussion of how breakthrough cases are measured. The poll was posted in the Survivor Corps Facebook group ([~]169,900 members). Of the 1,949 participants who responded to the poll, 44 reported a symptomatic breakthrough case and 24 of those reported that the case led to symptoms of Long Covid. 1 of these 24 cases was reported to have led to hospitalization in addition to Long Covid.


title: Geographical concentration of COVID-19 cases by social determinants of health in 16 large metropolitan areas in Canada - a cross-sectional study

abstract:
BackgroundThere is a growing recognition that strategies to reduce SARS-CoV-2 transmission should be responsive to local transmission dynamics. Studies have revealed inequalities along social determinants of health, but little investigation was conducted surrounding geographic concentration within cities. We quantified social determinants of geographic concentration of COVID-19 cases across sixteen census metropolitan areas (CMA) in four Canadian provinces.

MethodsWe used surveillance data on confirmed COVID-19 cases at the level of dissemination area. Gini (co-Gini) coefficients were calculated by CMA based on the proportion of the population in ranks of diagnosed cases and each social determinant using census data (income, education, visible minority, recent immigration, suitable housing, and essential workers) and the corresponding share of cases. Heterogeneity was visualized using Lorenz (concentration) curves.

ResultsGeographic concentration was observed in all CMAs (half of the cumulative cases were concentrated among 21-35% of each citys population): with the greatest geographic heterogeneity in Ontario CMAs (Gini coefficients, 0.32-0.47), followed by British Columbia (0.23-0.36), Manitoba (0.32), and Quebec (0.28-0.37). Cases were disproportionately concentrated in areas with lower income, education attainment, and suitable housing; and higher proportion of visible minorities, recent immigrants, and essential workers. Although a consistent feature across CMAs was concentration by proportion visible minorities, the magnitude of concentration by social determinants varied across CMAs.

InterpretationThe feature of geographical concentration of COVID-19 cases was consistent across CMAs, but the pattern by social determinants varied. Geographically-prioritized allocation of resources and services should be tailored to the local drivers of inequalities in transmission in response to SARS-CoV-2s resurgence.


title: A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes - a prospective study in three independent cohorts

abstract:
AimPeptide markers of inflammation have been associated with the development of type 2 diabetes. The role of upstream, lipid-derived mediators of inflammation such as eicosanoids, remains less clear. The aim was to examine whether eicosanoids are associated with incident type 2 diabetes.

MethodsIn the FINRISK 2002 study, a population-based sample of Finnish men and women aged 25-74 years, we used directed, non-targeted liquid chromatography - mass spectrometry to identify 545 eicosanoids and related oxylipins in the participants plasma samples (n=8,292). We used multivariable-adjusted Cox regression to examine associations between eicosanoids and incident type 2 diabetes. The findings were replicated in the Framingham Heart Study (FHS, n=2,886) and DILGOM 2007 (n=3,905). Together, these three cohorts had 1070 cases of incident type 2 diabetes.

Results76 eicosanoids were associated individually with incident type 2 diabetes. We identified three eicosanoids independently associated with incident type 2 diabetes using stepwise Cox regression with forward selection and a Bonferroni-corrected inclusion threshold. A three-eicosanoid risk score produced a hazard ratio (HR) of 1.56 (95% confidence interval 1.41-1.72) per one standard deviation (SD) increment for risk of incident diabetes. The HR for comparing the top quartile to the lowest was 2.80 (2.53-3.07). Meta-analysis of the three cohorts yielded a pooled HR per SD of 1.31 (1.05-1.56).

ConclusionPlasma eicosanoid profiles predict incident type 2 diabetes and the clearest signals replicate in three independent cohorts. Our findings give new information on the biology underlying type 2 diabetes and suggest opportunities for early identification of people at risk.


title: Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping

abstract:
Accurate tracing of epidemic spread over space enables effective control measures. We examined three metrics of infection and disease in a pediatric cohort (N {approx} 3,000) over two chikungunya and one Zika epidemic, and in a household cohort (N=1,793) over one COVID-19 epidemic in Managua, Nicaragua. We compared spatial incidence rates (cases/total population), infection risks (infections/total population), and disease risks (cases/infected population). We used generalized additive and mixed-effects models, Kulldorfs spatial scan statistic, and intracluster correlation coefficients. Across different analyses and all epidemics, incidence rates considerably underestimated infection and disease risks, producing large and spatially non-uniform biases distinct from biases due to incomplete case ascertainment. Infection and disease risks exhibited distinct spatial patterns, and incidence clusters inconsistently identified areas of either risk. While incidence rates are commonly used to infer infection and disease risk in a population, we find that this can induce substantial biases and adversely impact policies to control epidemics.

Article summary lineInferring measures of spatial risk from case-only data can substantially bias estimates, thereby weakening and potentially misdirecting measures needed to control an epidemic.


title: The U.S. COVID-19 Trends and Impact Survey, 2020-2021: Continuous real-time measurement of COVID-19 symptoms, risks, protective behaviors, testing and vaccination

abstract:
The U.S. COVID-19 Trends and Impact Survey (CTIS) is a large, cross-sectional, Internet-based survey that has operated continuously since April 6, 2020. By inviting a random sample of Facebook active users each day, CTIS collects information about COVID-19 symptoms, risks, mitigating behaviors, mental health, testing, vaccination, and other key priorities. The large scale of the survey - over 20 million responses in its first year of operation - allows tracking of trends over short timescales and allows comparisons at fine demographic and geographic detail. The survey has been repeatedly revised to respond to emerging public health priorities. In this paper, we describe the survey methods and content and give examples of CTIS results that illuminate key patterns and trends and help answer high-priority policy questions relevant to the COVID-19 epidemic and response. These results demonstrate how large online surveys can provide continuous, real-time indicators of important outcomes that are not subject to public health reporting delays and backlogs. The CTIS offers high value as a supplement to official reporting data by supplying essential information about behaviors, attitudes toward policy and preventive measures, economic impacts, and other topics not reported in public health surveillance systems.

Significance statementThe U.S. COVID-19 Trends and Impact Survey (CTIS) has operated continuously since April 6, 2020, collecting over 20 million responses. The largest public health survey ever conducted in the United States, CTIS was designed to facilitate detailed demographic and geographic analyses, track trends over time, and accommodate rapid response to emerging priorities. Using examples of CTIS results illuminating trends in symptoms, risks, mitigating behaviors, testing and vaccination in relation to evolving high-priority policy questions over 12 months of the pandemic, we illustrate the value of online surveys for tracking patterns and trends in COVID outcomes as an adjunct to official reporting, and showcase unique insights that would not be visible through traditional public health reporting.

category: health informatics


title: High throughput Next-Generation Sequencing Respiratory Viral Panel: A Diagnostic and Epidemiologic Tool for SARS-CoV-2 and Other Viruses.

abstract:
BackgroundIn the current phase of COVID-19 pandemic, we are facing two serious public health challenges that include deficits in SARS-CoV-2 variant monitoring, and neglect of other co-circulating respiratory viruses. Additionally, accurate assessment of the evolution, extent and dynamics of the outbreak are required to understand the transmission of the virus amongst seemingly unrelated cases and provide critical epidemiological information. To address these challenges, we evaluated a new high-throughput next-generation sequencing (NGS), respiratory viral panel (RVP) that includes 40 viral pathogens with the aim of analyzing viral subtypes, mutational variants of SARS-CoV-2, model to understand the spread of the virus in the state of Georgia, USA, and to assess other circulating viruses in the same population.

MethodsThis study evaluated a total of 522 samples that included 483 patient samples and 42 synthetic positive control material. The performance metrics were calculated for both clinical and reference control samples by comparing detection results with the RT-PCR assay. The limit of detection (LoD) studies were conducted as per the FDA guidelines. Inference and visualization of the phylogeny of the SARS-CoV-2 sequences were performed through the Nextstrain Command-Line Interface (CLI) tool, utilizing the associated augur and auspice toolkits.

ResultsThe performance metrics calculated using both the clinical samples and the reference controls revealed a PPA, NPA and accuracy of 95.98%, 85.96% and 94.4%, respectively. The LoD was determined to be 10 copies/ml with all 25 replicates detected across two different runs. The clade for pangolin lineage B that contains certain distant variants, including P4715L in ORF1ab, Q57H in ORF 3a and, S84L in ORF8 covarying with the D614G spike protein mutation were the most prevalent, early in the pandemic, in Georgia, USA. In our analysis, isolates from the same county formed paraphyletic groups, which indicated virus transmission between counties.

ConclusionThe study demonstrates the clinical and public health utility of the NGS-RVP to identify novel variants that can provide actionable information to prevent or mitigate emerging viral threats, models that provide insights into viral transmission patterns and predict transmission/ resurgence of regional outbreaks and provide critical information on co-circulating respiratory viruses that might be independent factors contributing to the global disease burden.


title: COVID-Q: validation of the first COVID-19 questionnaire based on patient-rated symptom gravity

abstract:
ObjectivesThe aim of the present study was to develop and validate the CoronaVirus Disease - 2019 (COVID-19) Questionnaire (COVID-Q), a novel symptom questionnaire specific for COVID-19 patients, to provide a comprehensive evaluation which may be helpful for physicians.. A secondary goal of the present study was to evaluate the performance of the COVID-Q in identifying subjects at higher risk of being tested positive for COVID-19.

Material and methodsConsecutive non-hospitalized adults who underwent nasopharyngeal and throat swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection at Treviso Hospital in March 2020, were enrolled. Subjects were divided into positive (cases) and negative (controls) in equal number. All of them gave consent and answered the COVID-Q. Patients not able to answer the COVID-Q due to clinical conditions were excluded.

Parallel Analysis and Principal Component Analysis were used to identify clusters of items measuring the same dimension. The Item Response Theory (IRT)-based analyses evaluated the functioning of item categories, the presence of clusters of local dependence among items, item fit within the model and model fit to the data.

ResultsAnswers obtained from 230 COVID-19 cases (113 males, and 117 females; mean age 55 years, range 20-99 years) and 230 controls (61 males, and 169 females; mean age 46 years, range 21-89) were analyzed. Parallel analysis led to the extraction of six components, which corresponded to as many clinical presentation patterns: asthenia, influenza-like symptoms, ear and nose symptoms, breathing issues, throat symptoms, and anosmia/ageusia. The final IRT models retained 27 items as significant for symptom assessment. The total score on the questionnaire was significantly associated with positivity to the molecular SARS-CoV-2 test: subjects with multiple symptoms were significantly more likely to be affected by COVID-19 (p < .001). Older age and male gender also represented risk factors. Presence of breathing issues and anosmia/ageusia were significantly related to positivity to SARS-CoV-2 (p < 0.001). None of the examined comorbidities had a significant association with COVID-19 diagnosis.

ConclusionAccording to the analyses, COVID-Q could be validated since the aspects it evaluated were overall significantly related to SARS-CoV-2 infection. The application of the novel COVID-Q to everyday clinical practice may help identifying subjects who are likely to be affected by COVID-19 and address them to a nasopharyngeal swab in order to achieve an early diagnosis.

What is already known about this topic?COVID-19 symptoms are widely known. Lots of studies have been published regarding self-administered questionnaires in order to characterize and know as much as possible regarding this disease. By the way, no specific questionnaires have been validated, yet, and there is no consensus regarding this topic.

What does this article add?This paper shows the COVID-Q, a novel symptom questionnaire specific for COVID-19 patients. The aim is to provide a comprehensive evaluation that may be helpful to clinicians in order to suspect SARS-CoV-2 infection or not.


title: Novel risk factors for Coronavirus disease-associated mucormycosis (CAM): a case control study during the outbreak in India

abstract:
BackgroundThe epidemiology of the Coronavirus-disease associated mucormycosis (CAM) syndemic is poorly elucidated. We aimed to identify risk factors that may explain the burden of cases and help develop preventive strategies.

MethodsWe performed a case-control study comparing cases diagnosed with CAM and those who had recovered from COVID-19 without developing mucormycosis (controls). Information on comorbidities, glycemic control, and practices related to COVID-19 prevention and treatment was recorded.

Results352 patients (152 cases and 200 controls) diagnosed with COVID-19 during April-May 2021 were included. In the CAM group, symptoms of mucormycosis began a mean 18.9 (SD 9.1) days after onset of COVID-19, and predominantly rhino-sinus and orbital involvement was present. All, but one, CAM cases carried conventional risk factors of diabetes and steroid use. On multivariable regression, increased odds of CAM were associated with the presence of diabetes (adjusted OR 3.5, 95%CI 1.1-11), use of systemic steroids (aOR 7.7,95% CI 2.4-24.7), prolonged use of cloth and surgical masks (vs no mask, aOR 6.9, 95%CI 1.5-33.1), and repeated nasopharyngeal swab testing during the COVID-19 illness (aOR 1.6,95% CI 1.2-2.2). Zinc therapy, probably due to its utility in immune function, was found to be protective (aOR 0.05, 95%CI 0.01-0.19). Notably, the requirement of oxygen supplementation or hospitalization did not affect the risk of CAM.

ConclusionJudicious use of steroids and stringent glycemic control are vital to preventing mucormycosis. Use of clean masks, preference for N95 masks if available, and minimizing swab testing after the diagnosis of COVID-19 may further reduce the incidence of CAM.


title: Online user comments responding to deemed consent organ donor legislation in Nova Scotia: a divided public or a few loud voices?

abstract:
BackgroundThe Canadian province of Nova Scotia recently became the first jurisdiction in North America to pass deemed consent organ donation legislation. This change in legislation generated substantial online discussion, which we analyzed to provide insights on public perception.

MethodsWe performed directed content analysis on 2663 user-generated comments appearing on two widely-shared Canadian Broadcasting Company (CBC) articles published online in April 2019. We determined levels of support and opposition in comments and described the specific rhetoric used for doing so. We also performed one-way ANOVA and Pearson chi-square tests to determine how the comments were being received and engaged by other users.

ResultsA range of commentary was present in both support and opposition to the changes in legislation. There were more negative than positive comments, and negative commentary generated more replies. Positive comments were received more positively by other users, while negative comments were received more negatively. The total sum of negative comments was greatly influenced by a small number of very active participants. Negative commentary focused more on broad concepts and principles related to government, power, and individual rights rather than specific issues in the Nova Scotian context. Substantial issues of trust in the government and healthcare system were evident.

ConclusionsThere were strong positive and negative sentiments expressed in the comments, but the total sum of negativity in the comments was significantly influenced by a small number of commentators. Analysis on the presumed consent concerns can be helpful to inform public outreach efforts.

Implication StatementThis research is the first to examine the robust online commentary regarding reactions to Nova Scotias recently-passed deemed consent organ donation law. Our analysis provides extensive detail on the commentary in favour and in opposition to the new law, which has relevance for understanding public perception and designing public outreach.

category: transplantation


title: Protection afforded by the BNT162b2 and mRNA-1273 COVID-19 vaccines in fully vaccinated cohorts with and without prior infection

abstract: Effect of prior SARS-CoV-2 infection on vaccine protection remains poorly understood. Here, we investigated whether persons vaccinated after a prior infection have better protection against future infection than those vaccinated without prior infection. Effect of prior infection was assessed in Qatars population, where the Alpha (B.1.1.7) and Beta (B.1.351) variants dominate incidence, using two national retrospective, matched-cohort studies, one for the BNT162b2 (Pfizer-BioNTech) vaccine, and one for the mRNA-1273 (Moderna) vaccine. Incidence rates of infection among BNT162b2-vaccinated persons, with and without prior infection, were estimated, respectively, at 1.66 (95% CI: 1.26-2.18) and 11.02 (95% CI: 9.90-12.26) per 10,000 person-weeks. The incidence rate ratio was 0.15 (95% CI: 0.11-0.20). Analogous incidence rates among mRNA-1273-vaccinated persons were estimated at 1.55 (95% CI: 0.86-2.80) and 1.83 (95% CI: 1.07-3.16) per 10,000 person-weeks. The incidence rate ratio was 0.85 (95% CI: 0.34-2.05). Prior infection enhanced protection of those BNT162b2-vaccinated, but not those mRNA-1273-vaccinated. These findings may have implications for dosing, interval between doses, and potential need for booster vaccination.


title: Can we clinically identify pre-symptomatic and asymptomatic COVID-19?

abstract:
ObjectivesCOVID-19 has had a severe impact on morbidity and mortality among nursing home (NH) residents. Earlier detection of SARS-CoV-2 may position us to better mitigate risk of spread. Both asymptomatic or pre-symptomatic transmission are common in outbreaks, and threshold temperatures, such as 38C, for screening for infection could miss timely detection in the majority.

DesignRetrospective cohort study using electronic health records

MethodsWe hypothesized that in long-term care residents, temperature trends with SARS-CoV-2 infection could identify infection in pre-symptomatic and asymptomatic individuals earlier. We collected information about age and other demographics, baseline temperature, and specific comorbidities. We created standardized definitions, and an alternative hypothetical model to test measures of temperature variation and compare outcomes to the VA reality.

Settings and participantsOur subjects were 6,176 residents of the VA NHs who underwent SARS-CoV-2 trigger testing.

ResultsWe showed that a change from baseline of >0.4C identifies 47% of the SARS-CoV-2 positive NH residents early, and achieves earlier detection by 42.2 hours. Range improves early detection to 55% when paired with a 37.2C cutoff, and achieves earlier detection by 44.4 hours. Temperature elevation >0.4C from baseline, when combined with a 0.7C range, would detect 52% early, leading to earlier detection by more than 3 days in 22% of the residents. This earlier detection comes at the expense of triggering 57,793 tests, as compared to the number of trigger tests ordered in the VA system of 40,691.

Conclusion and implicationsOur model suggests that current clinical screening for SARS-CoV-2 in NHs can be substantially improved upon by triggering testing using a patient-derived baseline temperature with a 0.4C degree relative elevation or temperature variability of 0.7C trigger threshold for SARS-CoV2 testing. Such triggers could be automated in facilities that track temperatures in their electronic records.


title: The Costs and Benefits of Covid-19 Lockdowns in New Zealand

abstract: This paper considers the costs and benefits of New Zealands Covid-19 nation-wide lockdown strategy relative to pursuit of a mitigation strategy in March 2020. Using data available up to 28 June 2021, the estimated additional deaths from a mitigation strategy are 1,750 to 4,600, implying a Cost per Quality Adjusted Life Year saved by locking down in March 2020 of at least 13 times the generally employed threshold figure of $62,000 for health interventions in New Zealand; the lockdowns do not then seem to have been justified by reference to the standard benchmark. Using only data available to the New Zealand government in March 2020, the ratio is similar and therefore the same conclusion holds that the nation-wide lockdown strategy was not warranted. Looking forwards from 28 June 2021, if a new outbreak occurs that cannot be suppressed without a nation-wide lockdown, the death toll from adopting a mitigation strategy at this point would be even less than had it done so in March 2020, due to the vaccination campaign and because the period over which the virus would then inflict casualties would now be much less than the period from March 2020; this would favour a mitigation policy even more strongly than in March 2020. This approach of assessing the savings in quality adjusted life years and comparing them to a standard benchmark figure ensures that all quality adjusted life years saved by various health interventions are treated equally, which accords with the ethical principle of equity across people.

category: health economics


title: A significant increase in Tuberculosis diagnosis is required to mitigate the impact of COVID-19 on its future burden

abstract: The ongoing COVID-19 pandemic has greatly disrupted our everyday life, forcing the adoption of non-pharmaceutical interventions in many countries worldwide and putting public health services and healthcare systems worldwide under stress. These circumstances are leading to unintended effects such as the increase in the burden of other diseases. Here, using a data-driven epidemiological model for Tuberculosis (TB) spreading, we describe the expected rise in TB incidence and mortality that can be attributable to the impact of COVID-19 on TB surveillance and treatment in four high-burden countries. Our calculations show that the reduction in diagnosis of new TB cases due to the COVID-19 pandemic could result in 824250 (CI 702416-940873) excess deaths in India, 288064 (CI 245932-343311) in Indonesia, 145872 (CI 120734-171542) in Pakistan, and 37603 (CI 27852-52411) in Kenya. Furthermore, we show that it is possible to revert such unflattering TB burden scenarios by increasing the pre-covid diagnosis capabilities at least a 75% during 2 to 4 years. This would prevent almost all TB-related excess mortality caused by the COVID-19 pandemic, which will be observed if nothing is done to prevent it. Our work therefore provides guidelines for mitigating the impact of COVID-19 on tuberculosis epidemic in the years to come.