title: COVID-19 and acute kidney injury in German hospitals 2020

abstract:
IntroductionThe SARS-CoV-2 pandemic is a major challenge for patients, healthcare professionals, and populations worldwide. While initial reporting focused mainly on lung involvement, the ongoing pandemic showed that multiple organs can be involved, and prognosis is largely influenced by multi-organ involvement. Our aim was to obtain nationwide retrospective population-based data on hospitalizations with COVID-19 and AKI.

Materials & MethodsWe performed a query of G-DRG data for the year 2020 via the Institute for the hospital remuneration system (Institut fur das Entgeltsystem im Krankenhaus GmbH, InEK) data portal and therefore included hospitalizations with a secondary diagnosis of RT-PCR proven COVID-19 infection, aged over 15 years. We included hospitalizations with acute kidney injury (AKI) stages 1 to 3. Age-specific and age-standardized hospitalization and in-hospital mortality rates (ASR) per 100.000 person years were calculated, with the German population of 2011 as the standard.

ResultsIn 2020, there were 16.776.845 hospitalizations in German hospitals. We detected 154.170 hospitalizations with RT-PCR proven COVID-19 diagnosis. The age-standardized hospitalization rate for COVID-19 in Germany was 232,8 per 100.000 person years (95% CI 231,6-233,9). The highest proportion of hospitalizations associated with COVID-19 were in the age group over 80 years. AKI was diagnosed in 16.773 (10,9%) of the hospitalizations with COVID-19. The relative risk of AKI for males was 1,49 (95%CI 1,44-1,53) compared to females. Renal replacement therapy (RRT) was performed in 3.443 hospitalizations, 20,5% of the hospitalizations with AKI. For all hospitalizations with COVID-19, the in-hospital mortality amounted to 19,7% (n= 30.300). The relative risk for in-hospital mortality was 3,87 (95%CI 3,80-3,94) when AKI occurred. The age-standardized hospitalization rates for COVID-19 took a bimodal course during the observation period. The first peak occurred in April (ASR 23,95 per 100.000 person years (95%CI 23,58-24,33)), hospitalizations peaked again in November 2020 (72,82 per 100.000 person years (95%CI 72,17-73,48)). The standardized rate ratios (SRR) for AKI and AKI-related mortality with the overall ASR for COVID-19 hospitalizations in the denominator, decreased throughout the observation period and remained lower in autumn than they were in spring. In contrast to all COVID-19 hospitalizations, the SRR for overall mortality in COVID-19 hospitalizations diverged from hospitalizations with AKI in autumn 2020.

DiscussionOur study for the first time provides nationwide data on COVID-19 related hospitalizations and acute kidney injury in Germany in 2020. AKI was a relevant complication and associated with high mortality. We observed a less pronounced increase in the ASR for AKI-related mortality during autumn 2020. The proportion of AKI-related mortality in comparison to the overall mortality decreased throughout the course of the pandemic.

category: nephrology


title: COVID-19 vaccine-associated cerebral venous thrombosis in Germany: a descriptive study

abstract:
ObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.

MethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States.

ResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable.

ConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women.

category: neurology


title: COVID-19 vaccine-associated cerebral venous thrombosis in Germany


title: A polygenic score-based approach to identify gene-drug interactions stratifying breast cancer risk

abstract: An individuals genetics can dramatically influence breast cancer (BC) risk. While clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly-used medications are a promising set of modifiable factors, however no previous study has explored whether a range of widely-taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGS) that summarize BC genetic risk, and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a novel regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with a HR = 3.41 per-allele within corticosteroid users). Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk, and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.

category: genetic and genomic medicine


title: Disordered eating and self-harm as risk factors for poorer mental health during the COVID-19 pandemic: A population-based cohort study

abstract:
BackgroundYoung adults and especially those with pre-existing mental health conditions, such as disordered eating and self-harm, appear to be at greater risk of developing metal health problems during the COVID-19 pandemic. However, it is unclear whether this increased risk is affected by any changes in lockdown restrictions, and whether any lifestyle changes could moderate this increased risk.

MethodsIn a longitudinal UK-based birth cohort (The Avon Longitudinal Study of Parents and Children, ALSPAC) we assessed the relationship between pre-pandemic measures of disordered eating and self-harm and mental health during the COVID-19 pandemic in 2,657 young adults. Regression models examined the relationship between self-reported disordered eating, self-harm, and both disordered eating and self-harm at age 25 years and depressive symptoms, anxiety symptoms and mental wellbeing during a period of eased restrictions in the COVID-19 pandemic (May-July 2020) when participants were aged 27-29 years. Analyses were adjusted for sex, questionnaire completion date, pre-pandemic socioeconomic disadvantage and pre-pandemic mental health and wellbeing. We also examined whether lifestyle changes (sleep, exercise, alcohol, visiting green space, eating, talking with family/friends, hobbies, relaxation) in the initial UK lockdown (April-May 2020) moderated these associations.

ResultsPre-existing disordered eating, self-harm and comorbid disordered eating and self-harm were all associated with the reporting of a higher frequency of depressive symptoms and anxiety symptoms, and poorer mental wellbeing during the pandemic compared to individuals without disordered eating and self-harm. Associations remained when adjusting for pre-pandemic mental health measures. There was little evidence that interactions between disordered eating and self-harm exposures and lifestyle change moderators affected pandemic mental health and wellbeing.

ConclusionsYoung adults with pre-pandemic disordered eating, self-harm and comorbid disordered eating and self-harm were at increased risk for developing symptoms of depression, anxiety and poor mental wellbeing during the COVID-19 pandemic, even when accounting for pre-pandemic mental health. Lifestyle changes during the pandemic do not appear to alter this risk. A greater focus on rapid and responsive service provision is essential to reduce the impact of the pandemic on the mental health of these already vulnerable individuals.

Plain English summaryThe aim of this project was to explore the mental health of young adults with disordered eating behaviours (such as fasting, vomiting/taking laxatives, binge-eating and excessive exercise) and self-harm during the COVID-19 pandemic. We analysed data from an established study that has followed children from birth (in 1991 and 1992) up to present day, including during the pandemic when participants were 28 years old. We looked at the relationship between disordered eating and/or self-harm behaviours from before the pandemic and mental health problems (symptoms of depression and anxiety) and mental wellbeing during the pandemic. We also explored whether there were any lifestyle changes (such as changes in sleep, exercise, visiting green space) that might be linked to better mental health and wellbeing in young adults with disordered eating and self-harm. We found that young adults with prior disordered eating and/or self-harm had more symptoms of depression and anxiety, and worse mental wellbeing than individuals without prior disordered eating or self-harm. However, lifestyle changes did not appear to affect mental health and wellbeing in these young adults. Our findings suggest that people with a history of disordered eating and/or self-harm were at high risk for developing mental health problems during the pandemic, and they will need help from mental health services.

category: epidemiology


title: Disordered eating and self-harm as risk factors for poorer mental health during the COVID-19 pandemic: A UK-based birth cohort study


title: Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence

abstract: Esophageal squamous cell carcinoma (ESCC) shows a remarkable variation in incidence which is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. The mutational profiles of ESCC were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining the differences in ESCC incidence. APOBEC associated mutational signatures SBS2 and SBS13 were present in 88% and 91% of cases respectively and accounted for a quarter of the mutation burden on average, indicating that activation of APOBEC is a crucial step in ESCC tumor development.


title: City-wide school-located influenza vaccination: a retrospective cohort study

abstract:
BackgroundWe measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California.

MethodsWe conducted a retrospective cohort study among Kaiser Permanente Northern California (KPNC) members of all ages residing in either the intervention or a multivariate-matched comparison site from September 2011 - August 2017. Outcomes included medically attended acute respiratory illness (MAARI), influenza hospitalization, and Oseltamivir prescriptions. We estimated difference-in-differences (DIDs) in 2014-15, 2015-16, and 2016-17 using generalized linear models and adjusted for race, ethnicity, age, sex, health plan, and language.

ResultsPre-intervention member characteristics were similar between sites. Among school-aged children, SLIV was associated with lower Oseltamivir prescriptions per 1,000 (DIDs: -3.5 (95% CI -5.5, -1.5) in 2015-16; -4.0 (95% CI -6.5, -1.6) in 2016-17) but not with other outcomes. SLIV was associated with lower MAARI per 1,000 in adults 65+ years (2014-15: -13.2, 95% CI -23.2, -3.2; 2015-16: -21.5, 95% CI -31.1, -11.9; 2016-17: -13.0, 95% CI -23.2, -2.9). There were few significant associations with other outcomes among adults.

ConclusionsA city-wide SLIV intervention was associated with lower Oseltamivir prescriptions in school-aged children and lower MAARI among people over 65 years, suggesting possible indirect effects of SLIV among older adults.


title: Persistent neuropsychiatric symptoms after COVID-19: a systematic review and meta-analysis.

abstract:
BackgroundThe nature and extent of persistent neuropsychiatric symptoms after COVID-19 are not established. To help inform mental health service planning in the pandemic recovery phase, we systematically determined the prevalence of neuropsychiatric symptoms in survivors of COVID-19.

MethodsFor this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750) we searched PubMed, EMBASE, CINAHL and PsycINFO to 20th February 2021, plus our own curated database. We included peer-reviewed studies reporting neuropsychiatric symptoms at post-acute or later time-points after COVID-19 infection, and in control groups where available. For each study a minimum of two authors extracted summary data. For each symptom we calculated a primary pooled prevalence using generalised linear mixed models. Heterogeneity was measured with I2. Subgroup analyses were conducted for COVID-19 hospitalisation, severity, and duration of follow-up.

FindingsFrom 2,844 unique titles we included 51 studies (n=18,917 patients). The mean duration of follow-up after COVID-19 was 77 days (range 14-182 days). Study quality was generally moderate. The most frequent neuropsychiatric symptom was sleep disturbance (pooled prevalence=27{middle dot}4% [95%CI 21{middle dot}4- 34{middle dot}4%]), followed by fatigue (24{middle dot}4% [17{middle dot}5-32{middle dot}9%]), objective cognitive impairment (20{middle dot}2% [10{middle dot}3-35{middle dot}7%]), anxiety (19{middle dot}1%[13{middle dot}3-26{middle dot}8%]), and post-traumatic stress (15{middle dot}7% [9{middle dot}9-24{middle dot}1%]). Only two studies reported symptoms in control groups, both reporting higher frequencies in Covid-19 survivors versus controls. Between-study heterogeneity was high (I2=79{middle dot}6%-98{middle dot}6%). There was little or no evidence of differential symptom prevalence based on hospitalisation status, severity, or follow-up duration.

InterpretationNeuropsychiatric symptoms are common and persistent after recovery from COVID-19. The literature on longer-term consequences is still maturing, but indicates a particularly high frequency of insomnia, fatigue, cognitive impairment, and anxiety disorders in the first six months after infection.

FundingJPR is supported by the Wellcome Trust (102186/B/13/Z).

IK is funded through the NIHR (Oxford Health Biomedical Research Facility, Development and Skills Enhancement Award) and the Medical Research Council (Dementias Platform UK and Deep and Frequent Phenotyping study project grants).

HH is funded by the German Research Foundation (DFG, Grant: HO 1286/16-1). The funders played no role in the design, analysis or decision to publish.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSNeuropsychiatric symptoms like cognitive impairment, fatigue, insomnia, depression and anxiety can be highly disabling. Recently there has been increasing awareness of persistent neuropsychiatric symptoms after COVID-19 infection, but a systematic synthesis of these symptoms is not available. In this review we searched five databases up to 20th February 2021, to establish the pooled prevalence of individual neuropsychiatric symptoms up to six months after COVID-19.

Added value of this studyThis study establishes which of a range of neuropsychiatric symptoms are the most common after COVID-19. We found high rates in general, with little convincing evidence that these symptoms lessen in frequency during the follow-up periods studied.

ImplicationsPersistent neuropsychiatric symptoms are common and appear to be limited neither to the post-acute phase, nor to recovery only from severe COVID-19. Our results imply that health services should plan for high rates of requirement for multidisciplinary services (including neurological, neuropsychiatric and psychological management) as populations recover from the COVID-19 pandemic.

category: psychiatry and clinical psychology


title: The Physiologic Response to COVID-19 Vaccination

abstract: Two mRNA vaccines and one adenovirus-based vaccine against SARS CoV-2 are currently being distributed at scale in the United States. Objective evidence of a specific individuals physiologic response to that vaccine are not routinely tracked but may offer insights into the acute immune response and personal and/or vaccine characteristics associated with that. We explored this possibility using a smartphone app-based research platform developed early in the pandemic that enabled volunteers (38,911 individuals between 25 March 2020 and 4 April 2021) to share their smartwatch and activity tracker data, as well as self-report, when appropriate, any symptoms, COVID-19 test results and vaccination dates and type. Of 4,110 individuals who reported at least one mRNA vaccination dose, 3,312 provided adequate resting heart rate data from the peri-vaccine period for analysis. We found changes in resting heart rate with respect to an individual baseline increased the days after vaccination, peaked on day 2, and returned to normal on day 6, with a much stronger effect after second dose with respect to first dose (average changes 1.6 versus 0.5 beats per minute). The changes were more pronounced for individuals who received the Moderna vaccine (on both doses), those who previously tested positive to COVID-19 (on dose 1), and for individuals aged <40 years, after adjusting for possible confounding factors. Taking advantage of continuous passive data from personal sensors could potentially enable the identification of a digital fingerprint of inflammation, which might prove useful as a surrogate for vaccine-induced immune response.

category: public and global health


title: The Effect of Combined Respiratory Muscle Training (cRMT) on dysarthric speech following single CVA: A retrospective pilot study

abstract:
BackgroundDysarthria frequently occurs as a result of stroke and adversely impacts speech sound production, making it more difficult for the listener to understand what the person with dysarthria is attempting to communicate. This in turn may lead to social isolation, depression, and increased cost of care. Some studies have underscored the importance of respiratory muscle strengthening as it relates to improvement of speech intelligibility, However, the benefits of respiratory muscle training on dysarthric speech following stroke have not been explored. This retrospective investigation examined the effects of a combined Respiratory Muscle Training (cRMT) protocol upon speech intelligibility in persons post single cerebrovascular accident (CVA).

MethodsThe clinical data of 10 patients who requested speech therapy at a pro bono outpatient clinic for the diagnosis and treatment of dysarthria following a single stroke was utilized for this study. The intervention group was treated with three 5-minute sessions with cRMT each day for 28 consecutive days. The control group received no cRMT and no other therapeutic exercise intervention during the time period. Respiratory function and speech intelligibility were assessed pre- and post-intervention in terms of peak expiratory flow, subject self-perception of intelligibility, and word level intelligibility.

ResultsAfter 28 days of cRMT, the intervention group exhibited significant gains compared to the control group in peak expiratory flow (PEF) (IG: 73.12% vs CG: 4.66%), Self-Perception of Intelligibility (IG: 72.38% vs CG: 0.83%), and the word task of the Assessment of Intelligibility of Dysarthric Speech (AIDS) (IG: 43.92% vs. CG: 0%).

ConclusionThese retrospective data demonstrate cRMT is a feasible and effective treatment for improving breath support and speech intelligibility in persons with dysarthric speech after single stroke.

category: rehabilitation medicine and physical therapy


title: Latin American Registry of renal involvement in COVID-19 disease. The relevance of assessing proteinuria throughout the clinical course.

abstract: The Latin American Society of Nephrology and Hypertension carried out a cohort prospective, multinational registry of patients with kidney impairment associated to COVID-19 in Latin America through open invitation in order to describe the characteristics of the disease in the region. A population of 870 patients from 12 countries were included. Median age was 63 years (54-74), most of patients were male (68.4%) and had comorbidities (87.2%). Acute kidney injury (AKI) was hospital-acquired in 64.7% and non-oliguric in 59.9%. Multiorgan dysfunction syndrome (MODS) due to COVID-19 and volume depletion were the main causes of AKI (59.2% and 35.7% respectively). Kidney replacement therapy was started in 46.2%. Non-recovery of renal function was observed in 65.3%. 71.5% of patients were admitted to ICU and 72.2% underwent mechanical ventilation. Proteinuria at admission was present in 62.4% of patients and proteinuria during hospital-stay occurred in 37.5%. Those patients with proteinuria at admission had higher burden of comorbidities, higher baseline sCr, higher mortality and MODS was severe. On the other hand, patients with de novo proteinuria had lower burden of comorbidities and near normal sCr at admission, but showed adverse course of disease and higher in-mortality. COVID-19 MODS was the main cause of AKI in both groups. All-cause mortality was 57.4%, and it was associated to age, chronic cardiac disease, fluid depletion, COVID-19 MODS, non-recovery of renal function, ICU admission, vasopressors, in-hospital complications and hospital stay. In conclusion, our study contributes to a better knowledge of this condition and highlights the relevance of the detection of proteinuria throughout the clinical course.


title: MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

abstract:
Rare variants in MAGEC3, members of the melanoma antigen gene family, are associated with BRCA-independent early onset ovarian cancers, while somatic mutations of this gene have been associated with kidney cancers. In this report, we quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in N=394 ovarian cancers and N=220 renal cell carcinomas. MAGEC3 protein levels fell into two categories - normal MAGEC3 and MAGEC3 loss - characterized by expression equivalent to normal tissue or significantly lower than normal tissue, respectively. Interestingly, cases with MAGEC3 loss demonstrated better overall survival in both ovarian cancers and renal cell carcinomas, which resembles patient outcomes with BRCA2 loss. MAGEC3 protein expression was associated with upregulation of pathways regulating G2/M checkpoint (NES: 4.13, FDR<0.001) and mitotic spindle formation (NES: 2.84, FDR<0.001). Increased CD8+ cell infiltration, coordinate expression of other cancer testis antigens, and tumor mutational burden were also associated with MAGEC3 expression. To emphasize the impact of these results, we built a prognostic RNA-based model using N=180 cancers of an independent cohort with matching transcriptomic data and tested its performance in two large public cohorts (N=282 ovary and N=606 kidney). Results based on predicted protein scores within these patients validated those discovered in patients with directly measured MAGEC3 protein. The RNA model was reproduced in independent cohorts implying a broader potential for MAGEC3-driven disease etiology and relevance to potential treatment selection.

STATEMENT OF TRANSLATIONAL RELEVANCEMAGEC3 protein is expressed in multiple tissues and is dysregulated in cancer. In this work, we show that ovarian and kidney cancer patients with loss of MAGEC3 protein have favorable prognosis, indicating that MAGEC3 protein level may be used as a prognostic biomarker. Integrative genomic analysis of patients spanning more than nine cancer types showed an association between MAGEC3 protein and genes affecting stress response, including those involved in cell cycle and DNA damage repair. Additionally, it is correlated with tumor mutational burden in patients with mutated oncogenes. These associations suggest that MAGEC3 protein levels may be used to identify patients with deficient DNA damage repair mechanisms that can be targeted by PARP inhibitors. To operationalize this idea, we use machine learning to predict MAGEC3 protein levels from RNA sequencing data which can facilitate the identification of patients for treatment stratification according to their MAGEC3 status.

category: oncology


title: Genetic overlap between major depression, bipolar disorder and Alzheimer's Disease

abstract:
BackgroundMood disorders, including major depression (MD) and bipolar disorder (BD), are risk factors for Alzheimers disease (AD) and possibly share an overlapping genetic architecture. However, few studies have investigated the shared loci and potential pleiotropy among these disorders.

MethodsWe carried out a systematic analytical pipeline using GWAS data and three complementary (genome-wide, single variant, and gene-level) statistical approaches to investigate the genetic overlap among MD, BD, and AD.

ResultsGWAS summary statistics data from 679,973 individuals were analyzed herein (59,851 MD cases and 113,154 controls; 20,352 BD cases and 31,358 controls; and 71,880 AD cases and 383,378 controls). We identified a significant positive genetic correlation between MD and AD (rG = 0.162; s.e. = 0.064; p = 0.012), and between BD and AD (rG = 0.162; s.e. = 0.068; p = 0.018). We also identified two pleiotropic candidate genes for MD and AD (TMEM106B and THSD7A) and three forBD and AD (MTSS2, VAC14, and FAF1), and reported candidate biological pathways associated with all three disorders.

DiscussionOur study identified genetic loci and mechanisms shared by mood disorders and AD. These findings could be relevant to better understand the higher risk for AD among individuals with mood disorders, and to propose new interventions.


title: A hemagglutination-based, semi-quantitative test for point-of-care determination of SARS-CoV-2 antibody levels

abstract: Serologic, point-of-care tests to detect antibodies against SARS-CoV-2 are an important tool in the COVID-19 pandemic. The majority of current point-of-care antibody tests developed for SARS-CoV-2 rely on lateral flow assays, but these do not offer quantitative information. To address this, we developed a new method of COVID-19 antibody testing employing hemagglutination tested on a dry card, similar to that which is already available for rapid typing of ABO blood groups. A fusion protein linking red blood cells (RBCs) to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein was placed on the card. 200 COVID-19 patient and 200 control plasma samples were reconstituted with O-negative RBCs to form whole blood and added to the dried protein, followed by a stirring step and a tilting step, 3-minute incubation, and a second tilting step. The sensitivity for the hemagglutination test, Euroimmun IgG ELISA test and RBD-based CoronaChek lateral flow assay was 87.0%, 86.5%, and 84.5%, respectively, using samples obtained from recovered COVID-19 individuals. Testing pre-pandemic samples, the hemagglutination test had a specificity of 95.5%, compared to 97.3% and 98.9% for the ELISA and CoronaChek, respectively. A distribution of agglutination strengths was observed in COVID-19 convalescent plasma samples, with the highest agglutination score (4) exhibiting significantly higher neutralizing antibody titers than weak positives (2) (p<0.0001). Strong agglutinations were observed within 1 minute of testing, and this shorter assay time also increased specificity to 98.5%. In conclusion, we developed a novel rapid, point-of-care RBC agglutination test for the detection of SARS-CoV-2 antibodies that can yield semi-quantitative information on neutralizing antibody titer in patients. The five-minute test may find use in determination of serostatus prior to vaccination, post-vaccination surveillance and travel screening.

category: infectious diseases


title: A Meta-analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation and Adverse Effects with Ivermectin Use in COVID-19 Patients

abstract:
ImportanceRepurposing Ivermectin, a known anti-parasitic agent, for treating COVID-19 has demonstrated positive results in several studies. We aim to evaluate the benefit and risk of Ivermectin in COVID-19.

MethodsWe conducted a systematic search for full-text manuscripts published from February 1, 2020, to August 15th, 2021 focusing on Ivermectin therapy against COVID-19. The primary outcomes were mortality, need for intensive care unit (ICU) admission; secondary outcomes were - adverse effects, need for mechanical ventilation, viral clearance, time to viral clearance, need for hospitalization, and length of hospital stay. Random-effects models were used for all analyses.

ResultsWe included a total of 52 studies (n=17561) in the qualitative analysis, out of these, 44 studies (n=14019) were included in the meta-analysis. In the mortality meta-analysis (N=29), odds of death were lower in the Ivermectin-arm compared to control (OR 0.54, p=0.009). Although lower odds of mortality were observed in various subgroup analyses of RCTs, they did not reach statistical significance: therapeutic RCTs: mild-moderate COVID-19 (OR 0.31, p=0.06), therapeutic RCTs: severe/critical COVID-19 (OR 0.86, p=0.56), inpatient RCTs: mild-moderate COVID-19 (OR 0.18, p=0.08), inpatient RCTs: severe/critical COVID-19 (OR 0.86, p=0.56). Ivermectin, mostly as adjuvant therapy, was associated with higher odds of viral clearance (N=22) (OR 3.52, p=0.0002), shorter duration to achieve viral clearance (N=8) (MD - 4.12, p=0.02), reduced need for hospitalization (N=6) (OR 0.34, p=008).

ConclusionOur meta-analysis suggests that the mortality benefit of Ivermectin in COVID-19 is uncertain. But as adjuvant therapy, Ivermectin may improve viral clearance and reduce the need for hospitalization.

HighlightsO_ST_ABSWhat We Already Know about This TopicC_ST_ABSO_LICOVID-19 is an ongoing global pandemic, for which Ivermectin has been tried on a therapeutic and prophylactic basis.
C_LIO_LIResults from several clinical trials and observational studies suggest that Ivermectin may improve survival and clinical outcomes with a good safety profile when compared with other treatments; however, the current evidence is limited..
C_LI

What This Article Tells Us That Is NewO_LIThis systematic review and meta-analysis provide a summary of the latest literature on the efficacy and safety of Ivermectin use for COVID-19.
C_LIO_LIBased on our analysis of the latest evidence, we found that Ivermectins benefit in reducing mortality cannot be concluded with confidence. However, as an adjuvant therapy it may help reduce the need for hospitalization, duration for viral clearance while increasing the likelihood of achieving viral clearance.
C_LIO_LIWe need more high-quality data for conclusive evidence regarding the benefit of Ivermectin in reducing the need for ICU admissions, mechanical ventilation and duration of hospital stay in COVID-19 patients.
C_LI


title: An Updated Systematic Review and Meta-Analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation, Adverse effects and other Clinical Outcomes of Ivermectin Treatment in COVID-19 Patients


title: Information and Communication Technology (ICT) in Medical Education: A Survey among Medical Students of Bangladesh.

abstract:
BackgroundBangladesh is declared as Digital Bangladesh however medical students are least acquainted with the necessary ICT knowledge in the context of medical education. We have conducted a survey to know about Digital Equipment Ownership, therefore, carried out a self-reported assessment of knowledge and Utilization of ICT in relation to educational and clinical development.

Materials and MethodsA cross-sectional, multi-centered questionnaire survey was conducted among the medical students during the period of October 2019.

Result & DiscussionsIn total 467 medical students responded to the questionnaire in which 92% of the students owned a Google android smart phone and accessed the internet on their devices. 69% student has (1-5) medical related apps in their device and drug formulary apps most commonly used 43%. 59% of students have gained their present computer knowledge by via self-learning. For study work with fellow student, 90% student preferred Facebook group, Whats app and Viber. While there was a range of variation in the usage of non-academic search engines 72% Google and no usages were found for more dedicated academic services such as PubMed and Medscape. According to 74% of students, inadequate integration of ICT knowledge into their syllabus culminated in insufficient future professional skills. All students were keen for a Basic ICT learning program at the beginning of their medical courses.

ConclusionThe study revealed that to prepare medical students for using ICT in their academic work adequately, introducing ICT training at the initial stage of the undergraduate program and designing the curriculum to develop a multiplicity of skills is essential in addition to an integrated teaching method.

category: medical education


title: Burdwan University Thalassemia Severity (BUTS) Scoring System: A numerical Method For Defining the Clinicopathological status of Thalassaemia Patient

abstract:
Background{beta}-haemoglobinopathies are the most common monogenic disorders worldwide. They present with extreme clinical heterogeneity, which makes generalized therapeutic approaches often ineffective. Currently available risk stratification approaches are either too complicated to be deployed at a primary healthcare level or are limited in their applicability across the spectrum of haemoglobinopathies. All current systems also classify patients into the three categories of mild, moderate and severe, where the moderate category is not well-characterized in terms of their expected prognosis.

MethodsThe current study proposes a severity scoring scheme, utilizing five clinical parameters, viz., steady-state average pre-transfusion haemoglobin, age at presentation, transfusion interval, palpable splenomegaly and growth retardation to classify patients of various {beta}-haemoglobinopathies into severe and non-severe categories. The study then proceeds to validate this scoring scheme on a clinically heterogeneous cohort of 224 Eastern Indian {beta}-thalassaemia and {beta}-haemoglobinopathy patients, and evaluate the predictive performance of the proposed scheme against a clinical standard.

ResultsAll of the chosen parameters except steady-state haemoglobin display strong individual contribution to the final determination of severity, though steady-state haemoglobin conferred increased discriminatory power to the overall scheme. The proposed system achieved an accuracy of 94% against the clinical standard.

ConclusionsThe proposed risk stratification strategy, being almost entirely empirically-determined, should possess wider applicability across the spectrum of {beta}-haemoglobinopathies than currently existing systems, and should also be more suitable than said systems for studying genotype-phenotype correlations especially within the Eastern Indian {beta}-haemoglobinopathy population.


title: Tracking the emergence of disparities in the subnational spread of COVID-19 in Brazil using an online application for real-time data visualisation.

abstract:
BackgroundBrazil is one of the countries worst affected by the COVID-19 pandemic with over 20 million cases and 557,000 deaths reported. Comparison of real-time local COVID-19 data between areas is essential for understanding transmission, measuring the effects of interventions and predicting the course of the epidemic, but are often challenging due to different population sizes and structures.

MethodsWe describe the development of a new app for the real-time visualisation of COVID-19 data in Brazil at the municipality level. In the CLIC-Brazil app, daily updates of case and death data are downloaded, age standardised and used to estimate reproduction number (Rt). We show how such platforms can perform real-time regression analyses to identify factors associated with the rate of initial spread and early reproduction number. We also use survival methods to predict the likelihood of occurrence of a new peak of COVID-19 incidence.

FindingsAfter an initial introduction in Sao Paulo and Rio de Janeiro states in early March 2020, the epidemic spread to Northern states and then to highly populated coastal regions and the Central-West. Municipalities with higher metrics of social development experienced earlier arrival of COVID-19 (decrease of 11{middle dot}1 days [95% CI:13{middle dot}2,8{middle dot}9] in the time to arrival for each 10% increase in the social development index). Differences in the initial epidemic intensity (mean Rt) were largely driven by geographic location and the date of local onset.

InterpretationThis study demonstrates that platforms that monitor, standardise and analyse the epidemiological data at a local level can give useful real-time insights into outbreak dynamics that can be used to better adapt responses to the current and future pandemics.

FundingThis project was supported by a Medical Research Council UK (MRC-UK) -Sao Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0)


title: Tracking the emergence of disparities in the subnational spread of COVID-19 in Brazil using an online application for real-time data visualisation: a longitudinal analysis


title: Forecasting COVID-19 Spreading in Canada using Deep Learning

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe novel coronavirus disease 2019 (COVID-19) is disrupting all aspects of our lives as the global spread of the virus continues. In this difficult period, various research projects are taking place to study and analyse the dynamics of the pandemic. In the present work, we firstly present a deep overview of the main forecasting models to predict the new cases of COVID-19. In this context, we focus on univariate time series models in order to analyze the dynamic change of this pandemic through time. We secondly shed light on multivariate time series forecasting models using weather and daily tests data, to study the impact of exogenous features on the progression of COVID-19. In the final stage of this paper, we present our proposed approach based on LSTM and GRU ensemble learning model and evaluate the results using the MAE, RMSE and MAPE for the prediction of new cases. The results of our experiments using the Canadian dataset show that the ensemble model performs well in comparison to other models. In addition, this research provides us with a new outcome regarding the dynamic correlation between temperature, humidity and daily test data and its impact on the new contaminated cases.


title: Latest Generation Colonoscope Yields Improvements in Cecal Insertion Time and Adenoma Detection Rate: A Retrospective Comparison of Two Colonoscope Brands

abstract:
Background and AimsHigh quality colonoscopy remains the cornerstone of colon cancer prevention. Studies have shown that generational advances in colonoscopes result in more favorable clinical outcomes. Performance of various endoscopes is determined using objective quality measures. The aim of this study was to compare these measures between two colonoscope platforms.

MethodsThis study is a single center retrospective study of 3,761 patients undergoing initial screening colonoscopy between November 2013 and May 2020 using two different colonoscope platforms (Fujifilm EC-760R-V/L, n=2287 and Olympus CF and PCF 180 series, n= 1474). The primary outcomes measured were cecal insertion time, withdrawal time, and adenoma detection rate.

ResultsProcedures completed with the Fujifilm colonoscope had mean cecal insertion times that were 2.01 minutes shorter than procedures completed with Olympus (p<.0001). Procedures completed with Olympus brand colonoscopes had prolonged cecal insertion times ([≥]10 minutes) nearly three times as often compared to those performed with Fujifilm colonoscopes (p<.0001). Cecal withdrawal times were slightly longer for females performed with Fujifilm colonoscopes, but there was no difference when all procedures were included (p=.09). Procedures completed with Fujifilm colonoscopes had higher adenoma detection rates compared to those completed with Olympus colonoscopes (p<0.001).

ConclusionsIn this study, Fujifilm colonoscopes outperformed Olympus colonoscopes in screening colonoscopies with statistically and clinically significant shorter cecal insertion times and higher adenoma detection, though both platforms had similar withdrawal times.

category: gastroenterology


title: COVID-19 monitoring in rural communities: First comparison of lagoon and pumping station samples for wastewater-based epidemiology

abstract: Wastewater-based epidemiology/wastewater surveillance has been a topic of significant interest over the last year due to its application in SARS-CoV-2 surveillance to track prevalence of COVID-19 in communities. Although SARS-CoV-2 surveillance has been applied in more than 50 countries to date, the application of this surveillance has been largely focused on relatively affluent urban and peri-urban communities. As such, there is a knowledge gap regarding the implementation of reliable wastewater surveillance in small and rural communities for the purpose of tracking rates of incidence of COVID-19 and other pathogens or biomarkers. This study examines the relationships existing between SARS-CoV-2 viral signal from wastewater samples harvested from an upstream pumping station and from an access port at a downstream wastewater treatment lagoon with the communitys COVID-19 rate of incidence (measured as percent test positivity) in a small, rural community in Canada. Real-time quantitative polymerase chain reaction (RT-qPCR) targeting the N1 and N2 genes of SARS-CoV-2 demonstrate that all 24-hr composite samples harvested from the pumping station over a period of 5.5 weeks had strong viral signal, while all samples 24-hr composite samples harvested from the lagoon over the same period were below the limit of quantification. RNA concentrations and integrity of samples harvested from the lagoon were both lower and more variable than from samples from the upstream pumping station collected on the same date, indicating a higher overall stability of SARS-CoV-2 RNA upstream of the lagoon. Additionally, measurements of PMMoV signal in wastewater allowed to normalize SARS-CoV-2 viral signal for fecal matter content, permitting the detection of actual changes in community prevalence with a high level of granularity. As a result, in sewered small and rural communities or low-income regions operating wastewater lagoons, samples for wastewater surveillance should be harvested from pumping stations or the sewershed as opposed to lagoons.


title: COVID-19 wastewater surveillance in rural communities: Comparison of lagoon and pumping station samples


title: Progress, stasis, and regression through the hypertension care continuum: Longitudinal evidence from population-based cohort data in four populous middle-income countries

abstract:
BackgroundControlling and managing hypertension is a highly dynamic process yet, to our knowledge, existing evidence on hypertension control gaps in middle-income countries (MICs) is largely based on cross-sectional data. We provide the first longitudinal investigation of how individuals with hypertension move through the care continuum over time across multiple MICs.

MethodsWe used multiple waves of population-based longitudinal cohort data from China, Indonesia, Mexico and South Africa. Based on measured blood pressure and information on hypertension diagnosis and treatment status, we classified adults aged 40 + into four care stages at both the baseline and follow-up waves: undiagnosed; diagnosed and untreated; diagnosed, treated, but uncontrolled (systolic blood pressure (SBP) [≥] 140 mmHg or diastolic blood pressure (DBP) [≥] 90 mmHg); diagnosed, treated, and controlled (SBP < 140 mmHg and DBP < 90 mmHg). We estimated the probability of individuals progressing forward or regressing backwards through the continuum over a five-to nine-year between-wave period and investigated how these probabilities varied by age, sex, household location and educational attainment using Poisson regression models. We also estimated the probabilities of important clinical transitions (e.g. becoming diagnosed or treated; achieving blood pressure control; discontinuing treatment and losing blood pressure control).

FindingsOur data included 8359 individuals with hypertension (China: N=1371, Indonesia: N= 3438, Mexico: N=1946, South Africa: N=1604). Across all countries, there was a less than 50% probability of forward progression through the care continuum over time. Just over one in four undiagnosed individuals became diagnosed (China 30% [95% CI 26-33%], Indonesia 30% [95% CI 28-32%], Mexico 27% [95% CI 25-29%], South Africa 37% [95% CI 34-39%]) and one in three diagnosed, untreated individuals became treated (Indonesia 17% [95% CI 14-21%], Mexico 30% [95% CI 28-32%], China 48% [95% CI 39-56%], South Africa 42% [95% CI 40-44%]). Importantly, there were very high probabilities of regressing to less advanced continuum stages: up to nine in ten treated and controlled individuals lost blood pressure control (Indonesia 92% [95% CI 88-95%], Mexico 77% [95% CI 72-81%], China 76% [95% CI 68-83%], South Africa 48% [95% CI 42-54%]) and up to three in four individuals discontinued treatment over the follow-up period (China 36% [95% CI 32-41%], Indonesia 70% [95% CI 67-73%], Mexico 34% [5% CI 32-36%], South Africa 25% [23-27%]). Individuals from rural households were disadvantaged in all countries but China, while females were more likely to progress through the continuum in Indonesia and Mexico.

InterpretationOur results uncover critical gaps in hypertension care in MICs in both early and late stages of the continuum. Adopting a longitudinal perspective reveals that policies solely aimed at improving diagnosis or initiating treatment may not lead to large improvements in control, as treatment initiation rates are low and achievement of blood pressure control and adherence to therapy are rarely sustained over time.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles published from database inception until January 1st, 2021 using variations of the search terms "blood pressure", "hypertension", "continuum", "cascade", "treatment", "diagnosis", "control", "treated", "diagnosed", "controlled" to screen titles and abstracts. The currently largest studies estimating nationally representative levels of hypertension diagnosis, treatment and control across multiple low- and middle-income countries (LMICs) are the Prospective Urban Rural Epidemiology (PURE) study from 2013, which included 140 000 individuals across 14 LMICs and a more recent study based on 1{middle dot}1 million adults in 44 LMICs from 2019. Both studies highlight important gaps in awareness, diagnosis, treatment and control of hypertension across populations in LMICs. However, these and smaller non-nationally representative or single country studies are all based on cross-sectional data and none capture the dynamic nature of chronic disease care and how individuals move through the hypertension care continuum over time.

Added value of this studyTo our knowledge, we provide the first longitudinal evidence on how individuals with hypertension in middle-income countries (MICs) move through the hypertension care continuum over time using country-wide, longitudinal cohort data from four MICs, which span three different continents and account for close to one-fourth of the world population. The longitudinal perspective provides new insights over existing cross-sectional cascades by capturing critical dynamic elements of chronic disease management, such as how individuals arrived at a specific continuum stage or whether they move forward or backward through continuum stages over time.

Implications of all available evidenceOur results reveal that individuals rarely sustain blood pressure control and that they tend to discontinue treatment over time. These results can inform efforts to improve hypertension control by revealing the need to move beyond policies aimed solely at screening and diagnosis to those that also aim to help individuals sustain blood pressure control over time.


title: Actigraphy Informs Distinct Patient-Centered Outcomes in Pre-COPD

abstract:
BackgroundActigraphy can clarify useful patient-centered outcomes for quantification of physical activity in the "real-world" setting.

MethodsTo characterize the relationship of actigraphy outputs with "in-laboratory" measures of cardiopulmonary function and respiratory symptoms in pre-COPD, we obtained actigraphy data for 8 hours/day for 5 consecutive days a week before in-laboratory administration of respiratory questionnaires, PFT, and CPET to a subgroup of subjects participating in the larger study of the health effects of exposure to secondhand tobacco smoke who had air trapping but no spirometric obstruction (pre-COPD). Using machine learning approaches, we identified the most relevant actigraphy predictors and examined their associations with symptoms, lung function, and exercise outcomes.

ResultsSixty-one subjects (age=66{+/-}7years; BMI=24{+/-}3kg/m2; FEV1/FVC=0.75{+/-}0.05; FEV1=103{+/-}17%predicted) completed the nested study. In the hierarchical cluster analysis, the activity, distance, and energy domains of actigraphy, including moderate to vigorous physical activity, were closely correlated with each other, but were only loosely associated with spirometric and peak exercise measures of oxygen consumption, ventilation, oxygen-pulse, and anaerobic threshold (VO2AT), and were divergent from symptom measures. Conversely, the sedentary domain clustered with respiratory symptoms, air trapping, airflow indices, and ventilatory efficiency. In Regression modeling, sedentary domain was inversely associated with baseline lung volumes and tidal breathing at peak exercise, while the activity domains were associated with VO2AT. Respiratory symptoms and PFT data were not associated with actigraphy outcomes.

DiscussionOutpatient actigraphy can provide information for "real-world" patient-centered outcomes that are not captured by standardized respiratory questionnaires, lung function, or exercise testing. Actigraphy activity and sedentary domains inform of distinct outcomes.

VISUAL ABSTRACT

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category: respiratory medicine


title: A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships

abstract:
BackgroundHuman male infertility has a notable genetic component, including well established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next generation sequencing technologies, and the absence of clear statements from leaders in the field as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility next generation sequencing studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the extent of evidence for reported GDRs.

Objective and rationaleIn 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of July 1st, 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.

Search methodsWe performed a literature search according to the PRISMA guidelines up until the 1st of July 2020 for publications in English, using search terms related to "male infertility" in combination with the word "genetics" in PubMed. Next, the quality and the extent of all evidence supporting selected genes was assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment, and functional evidence based on gene expression, mutant in vitro cell and in vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, as expressed by the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the ACMG-AMP guidelines and were recorded in spreadsheets for each GDR, which is available at imigc.org.

OutcomesThe primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.

Wider implicationsOur systematic review summarises and curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far past due. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility.


title: Transcriptome-wide and Stratified Genomic Structural Equation Modeling Identify Neurobiological Pathways Underlying General and Specific Cognitive Functions

abstract: Spearmans observation in 1904 that distinct cognitive functions--such as reasoning, processing speed, and episodic memory--are positively intercorrelated has given rise to over a century of speculation and investigation into their common and domain-specific mechanisms of variation. Here we develop and validate Transcriptome-wide Structural Equation Modeling (T-SEM), a novel method for studying the effects of tissue-specific gene expression within multivariate space. We apply T-SEM to investigate the shared and unique functional genomic characteristics of seven, distinct cognitive traits (N = 11,263-331,679). We identify 184 genes associated with general cognitive function (g), including 10 novel genes not identified in univariate analysis for the individual cognitive traits. We go on to apply Stratified Genomic SEM to identify enrichment for g within 29 functional genomic categories. This includes categories indexing the intersection of protein-truncating variant intolerant (PI) genes and specific neuronal cell types, which we also find to be enriched for the genetic covariance between g and a psychotic disorders factor.


title: Development of in-house, indirect ELISAs for the detection of SARS-CoV-2 spike protein-associated serology in COVID-19 patients in Panama.

abstract:
COVID-19 is the name of the acute respiratory disease caused by the new coronavirus SARS-CoV-2, a close relative of those that caused the severe outbreaks of SARS and MERS several years ago. Since first appearance on December of 2019, the COVID-19 pandemic has cause extremely high levels of mortality, morbidity, global economic breakdown and the consequent human suffering. While vaccination efforts are not extensive and rapid enough, the main tools to keep the virus under control are still keeping physical distancing, reinforce personal hygiene measures, using masks and early diagnosis of virus infected persons, either symptomatic or not. The main diagnostic test for the confirmation of symptomatic individuals is the detection of viral RNA by reverse transcriptase - quantitative real time PCR (RT-PCR). Additionally, serology techniques, such as ELISA are extremely useful to measure the antibodies generated in humans after virus contact, as well as the direct presence of viral antigens. In this study we aim to assemble and evaluate four ELISAs assays to measure the presence of IgG or IgM specific for the viral Spike protein in COVID-19 patients, using either the full recombinant SARS-CoV-2 Spike protein or the fragment corresponding to the receptor binding domain. As a control, we also analyzed a group of prepandemic serum samples obtained before 2017.

Strong reactivity was observed against both antigens. A few prepandemic samples displayed high OD values, suggesting the possibility of some crossreactivity. All four assays show very good repeatability, both intra- and inter-assay; however, no clear relationship could be detected between positivity and time of sample collection for serology. Receiver operating characteristic analysis allowed the definition of cutoffs and evaluation of performance for each ELISA by estimation of the area under the curve. This performance parameter was high for all tests (AUC range: 0.98-0.995). Multiple comparisons between tests revealed no significant difference between each other (P values: 0.24-0.95). Our results show that both antigens are very effective to reveal both specific IgG and IgM antibodies, with high sensitivity (range 0.929-0.99) and specificity (range 0.933-0.977). The estimated congruence with the RT-PCR test, as estimated by Cohens Kappa, indicates a high agreement in all cases (range 0.874-0.937). This test will allow health authorities to have a new tool to estimate seroprevalence, and to manage and improve the serious sanitary situation created by this virus.


title: Point of care testing for detection of coronaviruses including SARS-CoV-2 from saliva without treating RNA in advance

abstract:
Coronavirus disease 2019 (COVID-19) outbreak was reported to the WHO (World Health Organization) as an outbreak on end of 2019, afterwards pandemic on the worldwide in 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has be reported it to cause COVID-19, and highly transmissible. Therefore, it is important that it is rapidly and continuously detected and monitored on site so that the infection is prevented. Namely, POCT (point of care testing) may be important to control cross infection of SARS-CoV-2. At present, the routine confirmation of SARS-CoV-2 is based on detection of sequence unique in the virus RNA by nucleic acid amplification tests (NAATs) such as rRT-PCR. Taking POCT into account, it is clear that it takes time and labour very much or much. Thus, it was our purpose this time to contribute to develop POCT for microbes such as SARS-CoV-2, and thus needed to improve NAATs method.

First, combining the mobile real-time RT-PCR (rRT-PCR) device PCR1100 with the appropriate rRT-PCR reagent, we found that it is possible to detect RNA of SARS-CoV-2 for less 14 minutes with equivalent accuracy to conventional devices. Next, we found that the above method made it possible for us to detect coronaviruses by direct rRT-PCR without pre-treatments. Furthermore, it also made clear that coronaviruses in saliva could be detected by the similar direct rRT-PCR method.

Hence, it was concluded that this method made it possible to detect virus in saliva without treating in advance (extraction, purification, concentration, etc.), and moreover, samples would be able to be collected with non-invasive. For this reason, we suggest that this method is useful for POCT of coronaviruses including SARS-CoV-2.


title: Infection Units: A novel approach to the modeling of COVID-19 spread

abstract: A novel mechanistic model describing the rate of COVID-19 spread is presented, that differs conceptually from previously published deterministic models. One of its main characteristics is that the pool of infected people is not assumed to be homogeneously mixed, but rather as a passage into which individuals enter upon contagion, move within it in a plug-flow manner and leave at recovery, within a fixed time period. So, the present model differs conceptually in the way it describes the dynamics of infection. An  infection unit is defined as the amount of COVID-19 virus that generates contagion, if it reaches a susceptible individual. This model separately considers various pools: symptomatic and asymptomatic infected patients; three different pools of recovered individuals; pools of assisted, hospitalized patients; the quarantined and, finally, those who died from COVID-19. The transmission of the disease from an infected person to others is described by an infection rate function, while an encounter frequency function modulates the frequency of effective encounters between the infected and the susceptible. The influence of the models parameters on the predicted results is presented. The effect of social restrictions and of quarantine policy on pandemic spread is shown. For model calibration, a set of experimental data is used. The model enables the calculation of the actual behaviour of the studied pools during pandemic spread.


title: Seizure likelihood varies with day-to-day variations in sleep duration in patients with refractory focal epilepsy: A longitudinal EEG investigation.

abstract:
BackgroundWhile the effects of prolonged sleep deprivation ([≥]24 hours) on seizure occurrence has been thoroughly explored, little is known about the effects of day-to-day variations in the duration and quality of sleep on seizure probability. A better understanding of the interaction between sleep and seizures may help to improve seizure management.

MethodsTo explore how sleep and epileptic seizures are associated, we analysed continuous intracranial EEG recordings collected from 10 patients with refractory focal epilepsy undergoing ordinary life activities. A total of 4340 days of sleep-wake data were analysed (average 434 days per patient). EEG data were sleep scored using a semi-automated machine learning approach into wake, stages one, two, and three non-rapid eye movement sleep, and rapid eye movement sleep categories.

FindingsSeizure probability changes with day-to-day variations in sleep duration. Logistic regression models revealed that an increase in sleep duration, by 1{middle dot}66 {+/-} 0{middle dot}52 hours, lowered the odds of seizure by 27% in the following 48 hours. Following a seizure, patients slept for longer durations and if a seizure occurred during sleep, then sleep quality was also reduced with increased time spent aroused from sleep and reduced REM sleep.

InterpretationOur results demonstrate that day-to-day deviations from regular sleep duration correlates with changes in seizure probability. Sleeping longer, by 1{middle dot}66 {+/-} 0{middle dot}52 hours, may offer protective effects for patients with refractory focal epilepsy, reducing seizure risk. Furthermore, the occurrence of a seizure may disrupt sleep patterns by elongating sleep and, if the seizure occurs during sleep, reducing its quality.

FundingAustralian National Health and Medical Research Council, US National Institutes of Health and Czech Technical University in Prague and Epilepsy Foundation of America Innovation Institute


title: Population Vaccine Effectiveness and its Implication for Control of the Spread of COVID-19 in the US

abstract: Realized vaccine efficacy in population is highly different from the individual vaccine efficacy measured in clinical trial. The realized vaccine efficacy in population is substantially affected by the vaccine age-stratified prioritization strategy, population age-structure, non-pharmaceutical intervention (NPI). We proposed a population vaccine efficacy which integrated individual vaccine efficacy, vaccine prioritization strategy and NPI to measure and monitor the control of the spread of COVID-19. We found that 11 states in the US had low population vaccine efficacy and 20 states had high population efficacy. We demonstrated that although the proportion of the population who received at least one dose of COVID-19 vaccine across 11 low population vaccine efficacy states, in general, was greater than that in 20 high population vaccine efficacy states, the 11 low population vaccine efficacy states experienced the recent COVID-19 surge, while the number of new cases in the 20 high population vaccine efficacy states exponentially decreased. We demonstrated that the proportions of adults in the population across 50 states were significantly associated with the forecasted ending date of the COVID-19. We show that it was recent low proportion of adults vaccinated in Michigan that caused its COVID-19 surge. Using population vaccination efficacy, we forecasted that the earliest COVID-19 ending states were Hawaii, Arizona, Arkansas, and California (in the end of June, 2021) and the last COVID-19 ending states were Colorado, New York and Michigan (in the Spring, 2022).


title: Effect of commuting on the risk of COVID-19 and COVID-19-induced anxiety

abstract:
BackgroundTo prevent the spread of coronavirus disease (COVID-19), it is important to avoid 3Cs (closed spaces, crowded places, and close-contact settings). However, the risk of contact with an unspecified number of people is inevitable while commuting to and from work. In this study, we investigated the relationship between commuting, and the risk of COVID-19 and COVID-19-induced anxiety.

MethodsAn internet-based questionnaire survey was conducted to obtain a dataset from 27036 respondents. One-way commuting time was evaluated using a five-case method. The commuting distance was estimated using zip codes of the home and workplace. Logistic regression analysis was performed with the following outcomes: COVID-19 risk, close contact, infection anxiety, and infection anxiety due to commuting. Commuting distance and commuting time were analyzed separately in the model. We excluded participants with incalculable commuting distance, commuting distance exceeding 300 km, commuting distance of 0 km, or who telecommuted at least once a week.

ResultsThe total number of participants included in the analysis was 14038. The adjusted odds ratios (aORs) of using public transportation for severe acute respiratory syndrome coronavirus 2 infection were 4.17 (95% confidence interval [CI]: 2.51-6.93) (commuting time) and 5.18 (95% CI: 3.06-8.78) (commuting distance). The aOR of COVID-19 diagnosis decreased significantly with increasing commuting distance. The aORs of using public transportation to infection anxiety were 1.44 (95% CI: 1.31-1.59) (commuting time) and 1.45 (95% CI: 1.32-1.60) (commuting distance). The longer the commuting time, the more the aOR increased..

ConclusionsCOVID-19 risk, close contact, and infection anxiety were all associated with the use of public transportation during commuting. Both commuting distance and time were associated with infection anxiety due to commuting, and the strength of the association increased with increase in commuting time distance. Since transportation by commuting is associated with COVID-19 risk and anxiety, we recommend the use of telecommuting and other means of work.

category: occupational and environmental health


title: Prevalence of anxiety, depression, and stress among teachers during the COVID-19 pandemic: Systematic review

abstract:
ObjectiveIdentifying the prevalence of anxiety, depression, and stress among teachers during the COVID-19 pandemic.

MethodsSystematic review of original studies published in any language. Protocol published in PROSPERO under number CRD42021240543. The search was carried out in the Web of Science, PsycINFO, Pubmed, Embase, LILACS, and SciELO databases, using the descriptors: anxiety, depression, stress, teacher, faculty, COVID-19, and their synonyms. Narrative synthesis was carried out in line with the synthesis without meta-analysis (SWiM) in systematic reviews.

ResultsOf the 1,372 records identified, six studies, all cross-sectional, were included in the review. The studies were carried out in China, Brazil, the United States of America, India, and Spain. Five studies included more women than men. The participants were aged from 24 to 60 years. Three studies included only school teachers, two included schools and universities teachers, and one only university teachers. Of the five studies, all dealt with remote activities and only one included teachers who returned to face-to-face classes one to two weeks ago. The prevalence of anxiety ranged from 10% to 49.4%, and depression from 15.9% to 28.9%, being considerably higher in studies with teachers who worked in schools. The prevalence of stress ranged from 12.6% to 50.6%.

ConclusionsThe prevalence of anxiety, depression, and stress was high among teachers during the pandemic, with great variation between studies. Anxiety and stress were more prevalent in the Spanish study. The results show the need for measures for the care of teachers mental health, especially when returning to face-to-face classes.

What is already known about this subject?[tpltrtarr] With remote classes during the COVID-19 pandemic, there were changes in the professional practice of teachers.
[tpltrtarr]Sudden changes in professional practice can result in increased levels of anxiety, depression, and stress.
[tpltrtarr]Returning to face-to-face classes can also result in increased levels of anxiety, depression, and stress.

What are the new findings?[tpltrtarr] The prevalence of anxiety ranged from 10% to 49.4%, with higher rates recorded in female teachers, with comorbidities and working in schools.
[tpltrtarr]The prevalence of depression ranged from 15.9% to 28.9%, with higher rates identified in school teachers.
[tpltrtarr]The prevalence of stress varied from 12.6% to 50.6%, with higher rates observed among female teachers and those with chronic diseases.
[tpltrtarr]The only study that performed data collection during the return to face-to-face classes registered a higher prevalence of anxiety and stress than the other studies, in which the research was carried out during remote classes.

How might this impact policy or clinical practice in the foreseeable future?[tpltrtarr] Better training of teachers to handle the remote education model can contribute to preventing work overload and mental problems. Further, pedagogical and psychological support, especially for those who work in schools, can also prove effective.
[tpltrtarr]The return to face-to-face classes can increase stress and anxiety. Ensuring bio-safety protocols for safe return to face-to-face activities, can contribute to mitigating anxiety and stress about the risk of contracting the disease.
[tpltrtarr]There is insufficient evidence to determine a cause and effect relationship of the COVID-19 pandemic with anxiety, depression, and stress among teachers. Prospective cohort studies with control of confounding factors are necessary to infer that the pandemic has increased mental health problems in these professionals.


title: Manual curation of TCGA treatment data and identification of potential markers of therapy response.

abstract: The Cancer Genome Atlas (TCGA) represents a valuable source of genomic and clinical data across different tumor types. In this work, TCGA treatment response information have been manually curated in order to be computationally exploited. Drug names were manually corrected to remove typos and to unify commercial and molecule names. Moreover the drug therapy related information has been reorganized in a table to facilitate readability and analysis. The data were benchmarked with uni and multivariable statistical analyses to identify putative markers of response.


title: LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL

abstract:
BACKGROUNDSevere COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered(R) anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.

METHODSSubjects with COVID-19 (n=520), [≥]18 years, and [≤]94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.

RESULTSBaseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m2; mean CRP, 98.36 mg/L; CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54; 95%CI: 1.02-2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02-3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92; 1.20-3.07, nominal p=0.0067); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96; 1.63-5.37, nominal p=0.0003); and by 88% in subjects hospitalized [≤]2 days prior to randomization (1.88; 1.13-3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17; 1.04-4.54, nominal p=0.040).

CONCLUSIONLenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152


title: SARS-CoV-2 Seroprevalence and Risk Factors among Convalescents in Sichuan Province, China: a retrospective cohort study

abstract:
ObjectivesTo understand SARS-CoV-2 seroprevalence of convalescents and assess their the immunity. Furthermore, we intend to explore the association between antibody levels and with demographic factors.

Methods177 COVID-19 convalescents in Sichuan Province were voluntarily participated in our study. 363 serum samples were collected from June, 2020 to November, 2020. Duration of seroprevelance in these convalescents and their demographic characteristics were described, and the risk factors to antibody levels were analysed.

ResultsMen had more than twice the odds of having IgM antibody positive compared with women (OR=2.419, 95% CI:[1.232, 4.751]). Participants without symptoms were nearly 0.5 times IgG seropositive than those with symptoms (OR=0.455, 95% CI: [0.220, 0.940]). People aged[≥]60 years were nearly 3 times IgG seropositive than those who aged < 20 years (OR=2.986, 95% CI: [1.058, 8.432]). Seroprevalence in asymptomatic declined quicker than symptomatic.

ConclusionsAge and gender may affect the antibody levels and seroprevalence. Asymptomatic appeared more easier to turn to seronegative than symptomatic.


title: Smart Testing with Vaccination: A Bandit Algorithm for Active Sampling for Managing COVID-19

abstract: This paper presents methods to choose individuals to test for infection during a pandemic such as COVID-19, characterized by high contagion and presence of asymptomatic carriers. The smart-testing ideas presented here are motivated by active learning and multi-armed bandit techniques in machine learning. Our active sampling method works in conjunction with vaccination and quarantine policies and is adaptive to changes in real-time data. Using a data-driven agent-based model simulating New York City we show that the algorithm samples individuals to test in a manner that rapidly traces infected individuals. The results show that smart-testing is effective in significantly reducing infection and death rates as compared to current policies, with or without vaccination.


title: Prevalence use of nonsteroidal anti-inflammatory drugs in the general population with COVID-19 and associated COVID-19 risk, hospitalization, severity, death, and safety outcomes: A systematic review and meta-analysis

abstract:
IntroductionRecent reports of potential harmful effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with Corona Virus Disease 2019 (COVID-19) have provoked great concern. Therefore, the safety of NSAIDs is still questioned.

MethodsWe searched the PubMed, EMBASE, Cochrane Library and Web of Science databases from December 2019 to January 2021 to examine use prevalence for NSAIDs in general, as well as associated COVID-19 risk and outcomes. This study has been registered with PROSPERO (CRD42019132063)

ResultsWe included 25 studies with a total of 101,215 COVID-19 patients. The use of NSAIDs in COVID-19 patients reached 19%. Exposure to NSAIDs was not associated with significantly increased risk of developing COVID-19 (odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.78-1.24; I2=82%), hospitalization (OR=1.06, 95%CI: 0.76-1.48; I2=81%), mechanical ventilation (OR=0.71, 95%CI: 0.47-1.06; I2=38%), and length of hospital stay. Moreover, use of NSAIDs was significantly associated with better outcomes, including severity of COVID-19 (OR=0.79, 95%CI: 71-0.89; I2=0%) and death (OR=0.68, 95%CI: 0.52-0.89; I2=85%) in patients with COVID-19. Regarding safety outcomes, exposure to NSAIDs was associated with increased risk of stroke (OR=2.32, 95%CI: 1.04-5.2; I2=0%), but not with myocardial infraction (OR=1.49; p=0.66; I2=0%), overt thrombosis (OR=0.76, p=0.50; I2=28%) and major bleeding (p=0.61).

ConclusionBased on current evidence, exposure to NSAIDs is not linked to increased odds or exacerbation of COVID-19 in the general COVID-19 population. Furthermore, administration of NSAIDs might have better outcomes and survival benefits in the general COVID-19 population, although potentially increasing the risk of stroke. Use of NSAIDs might be safe and beneficial in COVID-19. Future observational and randomized control trials are needed for further confirmation.


title: Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials

abstract: Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.

category: cardiovascular medicine


title: Mapping evoked fields in primary motor and sensory areas via magnetoencephalography in tetraplegia

abstract: 1AO_SCPLOWBSTRACTC_SCPLOWDevices interfacing with the brain through implantation in cortical or subcortical structures have great potential for restoration and rehabilitation in patients with sensory or motor dysfunction. Typical implantation surgeries are planned based on maps of brain activity generated from intact function. However, mapping brain activity for planning implantation surgeries is challenging in the target population due to abnormal residual function and, increasingly often, existing MRI-incompatible implanted hardware. Here, we present methods and results for mapping impaired somatosensory and motor function in an individual with paralysis and an existing brain-computer interface (BCI) device. Magnetoencephalography (MEG) was used to directly map the neural activity evoked during transcutaneous electrical stimulation and attempted movement of the impaired hand. Evoked fields were found to align with the expected anatomy and somatotopic organization. This approach may be valuable for guiding implants in other applications, such as cortical stimulation for pain and to improve implant targeting to help reduce the craniotomy size.


title: A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

abstract: Autism Spectrum Disorder (ASD) is genetically complex, but specific copy number variants (CNVs; e.g., 1q21.1, 16p11.2) and genes (e.g., NRXN1, NLGN4) have been identified as penetrant susceptibility factors, and all of these demonstrate pleiotropy. Many ASD-associated CNVs are, in fact, genomic disorder loci where flanking segmental duplications lead to recurrent deletion and duplication events of the same region in unrelated individuals, but these lesions are large and involve multiple genes. To identify opportunities to establish a more specific genotype and phenotype correlation in ASD, we searched genomic data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 17 individuals from 15 unrelated families carrying a heterozygous guanine duplication (rs797044936; NM_033517.1; c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (at genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (6/7,521 or 0.08% of ASD-affected individuals studied by whole genome sequencing carried the p.Ala1227Glyfs*69 variant). This variant, which is predicted to cause a frameshift leading to a premature stop codon truncating the C-terminal region of the corresponding protein, was not reproducibly found in any of the control groups we analyzed. All probands identified carried de novo mutations with the exception of five individuals in three families who inherited it through somatic mosaicism. This same heterozygous variant in published mouse models leads to an ASD-like phenotype. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (16/16) formally tested for ASD carried a diagnosis, there was variable expression of core ASD features both within families and between families, underscoring the impact of as yet unknown modifiable factors affecting expressivity in autism.


title: Does the Data Tell the True Story? A Modelling Study of Early COVID-19 Pandemic Suppression and Mitigation Strategies in Ghana

abstract: This paper uses publicly available data and various statistical models to estimate the basic reproduction number (R0) and other disease parameters for the early COVID-19 pandemic outbreak in Ghana. We also test the effectiveness of government imposition of public health measures to reduce the risk of transmission and impact of the pandemic, especially in the early phase. R0 is estimated from the statistical model as 3.21 using a 0.147 estimated growth rate [95% C.I.: 0.137-0.157] and a 15-day time to recovery after COVID-19 infection. This estimate of the initial R0 is consistent with others reported in the literature from other parts of Africa, China and Europe. Our results also indicate that COVID-19 transmission reduced consistently in Ghana after the imposition of public health interventions - such as border restrictions, intra-city movement, quarantine and isolation - during the first phase of the pandemic from March to May 2020. However, the time-dependent reproduction number (Rt) beyond mid-May 2020 does not represent the true situation given there was not a consistent testing regime in place. This is also confirmed by our Jack-knife bootstrap estimates which show that the positivity rate over-estimates the true incidence rate from mid-May 2020. Given concerns about virus mutations, delays in vaccination and a possible new wave of the pandemic, there is a need for systematic testing of a representative sample of the population to monitor the reproduction number. There is also an urgent need to increase the availability of testing for the general population to enable early detection, isolation and treatment of infected individuals to reduce progression to severe disease and mortality.

category: health policy


title: Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient: a source of immune escape variants

abstract: The recent emergence of SARS-CoV-2 variants showing increased transmissibility and immune escape is a matter of global concern. Their origin remains unclear, but intra-host virus evolution during persistent infections could be a contributing factor. Here, we studied the long-term SARS-CoV-2 infection in an immunosuppressed organ transplant recipient. Frequent respiratory specimens were tested for variant viral genomes by RT-qPCR, next-generation sequencing (NGS), and virus isolation. Late in infection, several virus variants emerged which escaped neutralization by COVID-19 convalescent and vaccine-induced antisera and had acquired genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil. Importantly, infection of susceptible hACE2-transgenic mice with one of the patients escape variants elicited protective immunity against re-infection with either the parental virus, the escape variant or the South African variant of concern, demonstrating broad immune control. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results indicate that immunocompromised patients are an alarming source of potentially harmful SARS-CoV-2 variants and open up new avenues for the updating of COVID-19 vaccines.


title: Serological Response in Lung Transplant Recipients after Two Doses of SARS-CoV-2 mRNA Vaccines

abstract: The immunological effectiveness of SARS-CoV-2 mRNA vaccines in lung transplant (LT) recipients is largely unknown. Thus, we assessed the effect of Pfizer-BioNTech and Moderna mRNA vaccines two-dose (2D) regimen on humoral responses in immunocompromised lung transplant (LT) recipients. About 25% (18/73) of SARS-CoV-2 uninfected-LT patients generated positive spike-IgG response following 2D of vaccines, with 36% (9/25) in the Moderna cohort and only 19% (9/48) in the Pfizer cohort. 2D in LT patients elicited significantly lesser median IgGSP response (1.7 AU/mL, 95% CI: 0.6-7.5 AU/mL) compared to non-transplanted, uninfected naive subjects (14209 AU/mL, 95% CI: 11261-18836 AU/mL) (p<0.0001). In LT patients, Moderna-evoked seropositivity trend was higher by 23-fold than Pfizer. 2D COVID-19 vaccination elicits a dampened serological response in LT patients. Whether assessing other arms of host immunity combined with higher vaccine dose can better capture and elicit improved immunogenicity in this immunocompromised population warrants investigation.


title: Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase 1, dose-escalating, randomised controlled study

abstract:
BackgroundAGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.

MethodsWe undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses.

ResultsOf 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild ([≤]grade 2). The probability of [≥]30% excess toxicity over controls at 800mg was estimated at 0.9%.

ConclusionMolnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.

category: pharmacology and therapeutics


title: An Audit of Use and Monitoring of ACE-inhibitors in General Practice

abstract:
IntroductionACE-inhibitors are one of the most widely prescribed drugs in general practice for the treatment of hypertension. They are also one of the most frequent drugs associated with preventable drug-related morbidity incidents and guidelines are in place regarding the monitoring of renal function during treatment with these drugs.

AimTo assess the pattern of prescribing and monitoring of ACE-inhibitors in a general practice setting.

MethodsA retrospective medical records review was undertaken in a general practice in the Kerry region. Data collected included the indication for the ACE-inhibitor and whether blood pressure, electrolytes, renal function and glomerular filtration rate were measured within three months after initiation and in the period from January 2010 to June 2011. Data was entered into Microsoft Excel and analysed using SPSS.

ResultsData on 285 patients was analysed and showed that 78.2% of patients were on ACE-inhibitors for treatment of blood pressure. Following initiation of the ACE-inhibitor, 94.8% of patients had their blood pressure checked within 3 months, while 37.1% of patients had electrolytes checked, 51% of patients had their renal function checked and 31% of people had their glomerular filtration rate checked in the same time period. In the months from January 2010 to June 2011, 91.2% of patients had their blood pressure checked with 73% having electrolytes checked, 80.4% having their renal function checked and 54.7% had their glomerular filtration rate checked. Of those who had their renal function checked 26.1% had an abnormal creatinine level.

ConclusionFollow up of monitoring blood pressure, renal function, electrolytes and glomerular filtration rate within 3 months initiation of the ACE-inhibitor was poor but annual check up scored highly. Having a recall system in place within the practice for reminding patients to get their blood levels checked may help to increase all percentages to 100%.

category: primary care research


title: Preventing COVID-19 Outbreaks Through Surveillance Testing in Healthcare Facilities - A Modelling Study

abstract: Surveillance testing within healthcare facilities provides an opportunity to prevent severe outbreaks of coronavirus disease 2019 (COVID-19). However, the quantitative impact of different available surveillance strategies is not well-understood. Our study adds to the available body of evidence by examining different strategies for their potential to decrease the probability of outbreaks in these facilities. Based on our findings, we propose determinants of successful surveillance measures. To this end, we establish an individual-based model representative of a mental health hospital yielding generalizable results. Attributes and features of this facility were derived from a prototypical hospital, which provides psychiatric, psychosomatic and psychotherapeutic treatment. We estimate the relative reduction of outbreak probability for three test strategies (entry test, once-weekly test and twice-weekly test) relative to a symptom-based baseline strategy. We found that fast diagnostic test results and adequate compliance of the clinic population are mandatory for conducting effective surveillance. The robustness of these results towards uncertainties is demonstrated via comprehensive sensitivity analyses. In summary, we robustly quantified the efficacy of different surveillance scenarios and conclude that active testing in mental health hospitals and similar facilities successfully reduces the number of COVID-19 outbreaks.


title: Impaired everyday executive functions and cognitive strategy use on the Weekly Calendar Planning Activity in individuals with stroke undergoing acute inpatient rehabilitation

abstract: Executive dysfunction is common in stroke patients undergoing acute inpatient rehabilitation. However, comprehensive neuropsychological evaluation of executive functions is often not feasible in this setting. Objective, standardized, and performance-based measures of cognitively-based instrumental activities of daily living (C-IADL) can capture everyday executive functions and inform rehabilitation planning and interventions. The goal of this study was to compare performance of individuals with stroke to healthy age-matched adults in performance on the 10-item Weekly Calendar Planning Activity (WCPA). 77 stroke inpatients undergoing rehabilitation and 77 healthy control participants completed the WCPA, a C-IADL measure involving scheduling appointments that requires planning, working memory, shifting, and inhibitory control. Compared to the control group, stroke patients had significantly worse accuracy, made more errors, used fewer cognitive strategies, followed fewer rules, took more time to complete the task, and were less efficient. 83% of stroke patients were less accurate than predicted by their age, and 64% used less strategies than their age prediction. Among 28 participants who screened as having "normal" cognitive function on the Montreal Cognitive Assessment, the majority had deficits on the WCPA. Our results indicate that the WCPA is sensitive to executive dysfunction in stroke patients undergoing acute inpatient rehabilitation and underscores deficits in C-IADL accuracy, efficiency, and strategy use at this stage of stroke recovery. The WCPA may be a useful measure to ascertain executive dysfunction and to incorporate in cognitive rehabilitation.


title: Changes in work and health of Australians during the COVID-19 pandemic: a longitudinal cohort study

abstract:
ObjectivesTo determine the long-term effects of work loss on health during the COVID-19 pandemic, and whether any effects are persistent upon returning to work.

MethodsA prospective longitudinal cohort study of 2603 participants across Australia monitored changes in health and work during between March and December 2020, with participants completing surveys at baseline and 1, 3 and 6 months later. Outcomes described psychological distress, and mental and physical health. Linear mixed regression models examined associations between changes in health and experiences of work loss, and return to work, over time.

ResultsLosing work during the early stages of the pandemic was associated with long-term poorer mental health, which began to recover over time as some returned to work. Physical health deteriorated over time, greater for people not working at baseline. Being out of work was associated with poorer mental health, but better physical health. These effects were larger for people that had recently lost work than for people with sustained work loss, and retaining employment played a protective role. Generally, returning to work resulted in poorer physical health and improvements in mental health, although this depended on the broader context of changes in work.

ConclusionsWork cessation during the pandemic led to poor health outcomes and had long-lasting effects. Returning to work benefits mental health but may reduce physical activity in the short-term. We encourage the provision of accessible mental health supports and services immediately following loss of work, and for people with prolonged forms of work loss.