title: LESSONS FROM THE COVID-19 THIRD WAVE IN CANADA: THE IMPACT OF VARIANTS OF CONCERN AND SHIFTING DEMOGRAPHICS

abstract:
ImportanceWith the emergence of more transmissible SARS-CoV-2 variants of concern (VOC), there is an urgent need for evidence about disease severity and the health care impacts of VOC in North America, particularly since a substantial proportion of the population have declined vaccination thus far.

ObjectiveTo examine 30-day outcomes in Canadians infected with SARS-CoV-2 in the first year of the pandemic and to compare event rates in those with VOC versus wild-type infection.

DesignRetrospective cohort study using linked healthcare administrative datasets.

SettingAlberta and Ontario, the two Canadian provinces that experienced the largest third wave in the spring of 2021.

ParticipantsAll individuals with a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction swab from March 1, 2020 until March 31, 2021, with genomic confirmation of VOC screen-positive tests during February and March 2021 (wave 3).

Exposure of InterestVOC versus wild type SARS-CoV-2

Main Outcomes and MeasuresAll-cause hospitalizations or death within 30 days after a positive SARS-CoV-2 swab.

ResultsCompared to the 372,741 individuals with SARS-CoV-2 infection between March 2020 and January 2021 (waves 1 and 2 in Canada), there was a shift in transmission towards younger patients in the 104,232 COVID-19 cases identified in wave 3. As a result, although third wave patients were more likely to be hospitalized (aOR 1.34 [1.29-1.39] in Ontario and aOR 1.53 [95%CI 1.41-1.65] in Alberta), they had shorter lengths of stay (median 5 vs. 7 days, p<0.001) and were less likely to die within 30 days (aOR 0.66 [0.60-0.71] in Ontario and aOR 0.74 [0.62-0.89] in Alberta). However, within the third wave, patients infected with VOC (91% Alpha) exhibited higher risks of death (aOR 1.52 [1.27-1.81] in Ontario and aOR 1.67 [1.13-2.48] in Alberta) and hospitalization (aOR 1.57 [1.47-1.69] in Ontario and aOR 1.88 [1.74-2.02] in Alberta) than those with wild-type SARS-CoV-2 infections during the same timeframe.

Conclusions and RelevanceOn a population basis, the shift towards younger age groups as the COVID-19 pandemic has evolved translates into more hospitalizations but shorter lengths of stay and lower mortality risk than seen in the first 10 months of the pandemic in Canada. However, on an individual basis, infection with a VOC is associated with a higher risk of hospitalization or death than the original wild-type SARS-CoV-2 - this is important information to address vaccine hesitancy given the increasing frequency of VOC infections now.


title: Cue-Induced Craving and Negative Emotion Disrupt Response Inhibition in Methamphetamine Use Disorder: Behavioral and fMRI Results from a Mixed Go/No-Go Task

abstract:
BackgroundDrug-related cue-reactivity, dysfunctional negative emotion processing, and response-disinhibition constitute three core aspects of methamphetamine use disorder (MUD). These phenomena have been studied independently, but the neuroscientific literature on their interaction in addictive disorders remains scant.

MethodsfMRI data were collected from 62 individuals with MUD when responding to the geometric Go or No-Go cues superimposed over blank, neutral, negative-emotional and drug-related background images. Neural correlates of drug and negative-emotional cue-reactivity, response-inhibition, and response-inhibition during drug and negative-emotional blocks were estimated, and methamphetamine cue-reactivity was compared between MUDs and 23 healthy controls (HCs). Relationships between clinical and behavioral characteristics and observed activations were subsequently investigated.

ResultsMUDs had longer reaction times and more errors in drug and negative-emotional blocks compared to neutral and blank ones. MUDs showed higher drug cue-reactivity than HCs across prefrontal regions, fusiform gyrus, and visual cortices (Z>3.1, p-corrected<0.05). Response-inhibition was associated with activations in the precuneus, inferior parietal lobule, and anterior cingulate, temporal and inferior frontal gyri (Z>3.1, p-corrected<0.05). Response-inhibition in drug cue blocks coincided with higher activations in the visual cortex and lower activations in the paracentral lobule and superior and inferior frontal gyri, while inhibition during negative-emotional blocks led to higher superior parietal, fusiform, and lateral occipital activations (Z>3.1, p-corrected<0.05).

ConclusionHigher visual cortical activations and lower parietal and prefrontal activations during drug-related response-inhibition suggest the down-regulation of inhibitory regions and up-regulation of bottom-up drug cue-reactivity. Our results suggest that drug and negative-emotional cue-reactivity influence response-inhibition, and the study of these interactions may aid mechanistic understandings of addiction and biomarker discovery.

category: addiction medicine


title: Direct Comparison of Antibody Responses to Four SARS-CoV-2 Vaccines in Mongolia

abstract: Different vaccines for SARS-CoV-2 are approved in various countries, but few direct comparisons of the antibody responses they stimulate have been reported. We collected plasma specimens in July 2021 from 196 Mongolian participants fully vaccinated with one of four Covid vaccines: Pfizer/BioNTech, AstraZeneca, Sputnik V and Sinopharm. Functional antibody testing with a panel of nine SARS-CoV-2 viral variant RBD proteins reveal marked differences in the vaccine responses, with low antibody levels and RBD-ACE2 blocking activity stimulated by the Sinopharm and Sputnik V vaccines in comparison to the AstraZeneca or Pfizer/BioNTech vaccines. The Alpha variant caused 97% of infections in Mongolia in June and early July 2021. Individuals who recover from SARS-CoV-2 infection after vaccination achieve high antibody titers in most cases. These data suggest that public health interventions such as vaccine boosting, potentially with more potent vaccine types, may be needed to control the COVID-19 pandemic in Mongolia and worldwide.

category: infectious diseases


title: A toolkit for quantification of biological age from blood-chemistry and organ-function-test data: BioAge

abstract: Methods to quantify biological aging are emerging as new measurement tools for epidemiology and population science and have been proposed as surrogate measures for healthy lifespan extension in geroscience clinical trials. Publicly available software packages to compute biological aging measurements from DNA methylation data have accelerated dissemination of these measures and generated rapid gains in knowledge about how different measures perform in a range of datasets. Biological age measures derived from blood chemistry data were introduced at the same time as the DNA methylation measures and, in multiple studies, demonstrate superior performance to these measures in prediction of healthy lifespan. However, their dissemination has been slow by comparison, resulting in a significant gap in knowledge. We developed a software package to help address this knowledge gap. The BioAge R package, available for download at GitHub (http://github.com/dayoonkwon/BioAge), implements three published methods to quantify biological aging based on analysis of chronological age and mortality risk: Klemera-Doubal Biological Age, PhenoAge, and homeostatic dysregulation. The package allows users to parametrize measurement algorithms using custom sets of biomarkers, to compare the resulting measurements to published versions of the Klemera-Doubal method and PhenoAge algorithms, and to score the measurements in new datasets. We applied BioAge to safety lab data from the CALERIE randomized controlled trial, the first-ever human trial of long-term calorie restriction in healthy, non-obese adults, to test effects of intervention on biological aging. Results contribute evidence that CALERIE intervention slowed biological aging. BioAge is a toolkit to facilitate measurement of biological age for geroscience.

category: epidemiology


title: COVID-19 infection among health care workers: Experience in Base Hospital Wathupitiwala,Sri Lanka.

abstract:
Coronavirus disease 2019 (COVID-19) is a serious global health pandemic resulting in high mortality and morbidity. Frontline health care workers (HCWs) are at an increased risk of the acquisition of severe acute respiratory syndrome coronavirus-2 infection (SARS CoV-2) due to their close interaction with infected patients (1, 2). Also, HCWs can serve as reservoirs of SARS CoV-2 cross-transmission both in community and hospital settings (1). However, the extent of COVID-19 infection among HCWs in Sri Lanka is understudied.

ObjectivesThis study determined the incidence, demographic characteristics, and risk exposure behavior of HCWs who tested positive for SARS CoV-2 at Base Hospital Wathupitiwala. Furthermore, the rate of acquisition of SARS CoV-2 following COVISHIELD/ChAdOx1 nCoV-19 and Sinopharm /BBIBP-CorV vaccines in HCWs were studied.

MethodsA retrospective cross-sectional descriptive analysis was conducted from May 2021 to August 2021 for a total of 818 HCWs.

ResultsHundred and twenty-four HCWs (15.16%) were tested positive for COVID-19. The mean age of infected HCWs was 46.27 years and the majority were females (74.19%). Among all infected persons, 54 (43.55%) were nurses/midwives, 39 (31.45%) were clinical supportive staff and 12(9.68%) were medical officers. The number of infected HCWs rapidly escalated and a total of 64(51.61%) HCWs got an infection during August/2021. No source was identified in most of them (34.68%) followed by community acquisition (33.87%). Thirty-five HCWs (28.23%) had acquired infection during a hospital setting or had a high-risk exposure in recent history. Among hospital-related infections, 37.91% of HCWs had shared meals or shared sleeping rooms with an infected workmate. The majority of the HCWs were tested by the infection control unit as symptomatic screening (70.16%) followed by contact tracing (20.16%). Fifty-six (45.16%) HCWs had a history of single or multiple comorbidities. The vast majority of HCWs (95.97%) presented as mild to asymptomatic disease that followed an uneventful recovery. Body aches, headache, fever, and sore throat were the most commonly reported symptoms among them. Among the five HCWs required therapeutic oxygen supplementation, two unvaccinated HCWs succumbed to the infection. The rate of breakthrough infection among HCWs was 8.93%. The acquisition of disease was significantly higher among unvaccinated HCWs than partially (p<0.0001) or fully vaccinated (p<0.0001) HCWs with either type of vaccine.

ConclusionsProtecting HCWs remains a challenge in resource-poor settings. The risk of infection fueled by very contagious circulating variants is continuously high even though vaccination has shown clear benefits in preventing mortality and severe infection. Therefore, all healthcare workers should be vaccinated while ensuring continuous infection control measures in the hospital setting.


title: Previous Infection Combined with Vaccination Produces Neutralizing Antibodies With Potency Against SARS-CoV-2 Variants

abstract:
SARS-CoV-2 continues to evolve in humans. Spike protein mutations increase transmission and potentially evade antibodies raised against the original sequence used in current vaccines. Our evaluation of serum neutralizing activity in both persons soon after SARS-CoV-2 infection (in April 2020 or earlier) or vaccination without prior infection confirmed that common spike mutations can reduce antibody antiviral activity. However, when the persons with prior infection were subsequently vaccinated, their antibodies attained an apparent biologic ceiling of neutralizing potency against all tested variants, equivalent to the original spike sequence. These findings indicate that additional antigenic exposure further improves antibody efficacy against variants.

LAY SUMMARYAs SARS-CoV-2 evolves to become better suited for circulating in humans, mutations have occurred in the spike protein it uses for attaching to cells it infects. Protective antibodies from prior infection or vaccination target the spike protein to interfere with its function. These mutations can reduce the efficacy of antibodies generated against the original spike sequence, raising concerns for re-infections and vaccine failures, because current vaccines contain the original sequence. In this study we tested antibodies from people infected early in the pandemic (before spike variants started circulating) or people who were vaccinated without prior infection. We confirmed that some mutations reduce the ability of antibodies to neutralize the spike protein, whether the antibodies were from past infection or vaccination. Upon retesting the previously infected persons after vaccination, their antibodies gained the same ability to neutralize mutated spike as the original spike, suggesting that the combination of infection and vaccination drove the production of enhanced antibodies to reach a maximal level of potency. Whether this can be accomplished by vaccination alone remains to be determined, but the results suggest that booster vaccinations may help improve efficacy against spike variants.


title: Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19

abstract: The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, mild to moderate infections are an important contributor to ongoing transmission. There remains a critical need to identify host immune biomarkers predictive of clinical and virologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial of Peginterferon Lambda for treatment of SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We define early immune signatures, including plasma levels of RIG-I and the CCR2 ligands (MCP1, MCP2 and MCP3), associated with control of oropharyngeal viral load, the degree of symptom severity, and immune memory (including SARS-CoV-2-specific T cell responses and spike (S) protein-binding IgG levels). We found that individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine had similar early immune trajectories to those observed in this natural infection cohort, including the induction of both inflammatory cytokines (e.g. MCP1) and negative immune regulators (e.g. TWEAK). Finally, we demonstrate that machine learning models using 8-10 plasma protein markers measured early within the course of infection are able to accurately predict symptom severity, T cell memory, and the antibody response post-infection.


title: Genetic and demographic predictors of general reading ability in two cohorts

abstract: Reading ability is a complex skill requiring multiple proficiencies (e.g., phonological awareness, decoding, and comprehension). Reading ability has genetic and environmental components that create the potential for significant gene-gene and gene-environment interactions, but the evidence for these interactions is limited. We used data from the Avon Longitudinal Study of Parents and Children and the Genes, Reading and Dyslexia Study to assess the contributions of genetic and demographic features to a continuous latent reading ability score. We then used this score as the phenotype on which to predicate genome-wide single nucleotide polymorph screening, followed by feature selection using an elastic net analysis. Results from the elastic net models showed that genetic and demographic features predicted reading ability for both cohorts. Five single nucleotide polymorphisms were associated with latent reading in the Avon Longitudinal Study of Parents and Children, as well as in the Genes, Reading and Dyslexia cohorts. For both cohorts, larger vocabularies were positively associated with latent reading ability. Genes within the neuron migration pathway were overrepresented in the Avon Longitudinal Study of Parents and Children cohort. We provide support that genes involved in early brain development have an impact on latent reading ability performance. Our findings also indicate high generalizability of genetic findings between cohorts, using our approach.

category: pediatrics


title: Novel Coronavirus Pandemic Impacts Children and Adolescents' Psychological Well-Being in Heavily Hit Chinese Provinces

abstract:
AbstractsIn light of the novel coronaviruss (COVID-19s) threat to public health worldwide, we sought to elucidate COVID-19s impacts on the mental health of children and adolescents in China. Through online self-report questionnaires, we aimed to discover the psychological effects of the pandemic and its associated risk factors for developing mental health symptoms in young people.

We disseminated a mental health survey through online social media, WeChat, and QQ in the five Chinese provinces with the most confirmed cases of COVID-19 during the late stage of the country-wide lockdown. We used a self-made questionnaire that queried children and adolescents aged 6 to 18 on demographic information, psychological status, and other lifestyle and COVID-related variables.

A total of 17,740 children and adolescents with valid survey data participated in the study. 10,022 (56.5%), 11,611 (65.5%), 10,697 (60.3%), 6,868 (38.7%), and 6,225 (35.1%) participants presented, respectively, more depressive, anxious, compulsive, inattentive, and sleep-related problems compared to before the outbreak of COVID-19. High school students reported a greater change in depression and anxiety than did middle school and primary school students. Despite the fact that very few children (0.1%) or their family members (0.1%) contracted the virus in this study, the psychological impact of the pandemic was clearly profound. Fathers anxiety appeared to have the strongest influence on a childrens psychological symptoms, explaining about 33% of variation in the childs overall symptoms. Other factors only explained less than 2% of the variance in symptoms once parents anxiety was accounted for.

The spread of COVID-19 significantly influenced the psychological state of children and adolescents. It is clear that children and adolescents, particularly older adolescents, need mental health support during the pandemic. The risk factors we uncovered suggest that reducing fathers anxiety is particularly critical to addressing young peoples mental health disorders in this time.

category: psychiatry and clinical psychology


title: Highly valued despite burdens: qualitative implementation research on rapid tests for hospital-based SARS-CoV-2 screening

abstract:
Antigen-based rapid diagnostic tests (RDTs) for SARS-CoV-2 have good reliability and have been repeatedly implemented as part of pandemic response policies, especially for screening in high-risk settings (e.g., hospitals and care homes) where fast recognition of an infection is essential, but evidence from actual implementation efforts is lacking.

We conducted a prospective qualitative study at a large tertiary care hospital in Germany where RDTs are used to screen incoming patients. We relied on semi-structured observations of the screening situation, as well as on 30 in-depth interviews with hospital staff (members of the regulatory body, department heads, staff working on the wards, staff training providers on how to perform RDTs, and providers performing RDTs as part of the screening) and patients being screened with RDTs.

Despite some initial reservations, RDTs were rapidly accepted and adopted as the best available tool for accessible and reliable screening. Decentralized implementation efforts resulted in different procedures being operationalized across departments. Procedures were continuously refined based on initial experiences (e.g., infrastructural or scheduling constraints), pandemic dynamics (growing infection rates), and changing regulations (e.g., screening of all external personnel). To reduce interdepartmental tension, stakeholders recommended high-level, consistently communicated and enforced regulations.

Despite challenges, RDT-based screening for all incoming patients was observed to be feasible and acceptable among implementers and patients, and merits continued consideration in the context of rising infections and stagnating vaccination rates.

category: public and global health


title: Child and caregiver mental health during COVID-19

abstract:
BackgroundThere are calls for research into the mental health consequences of living through the COVID-19 pandemic. Australias initial, effective suppression of COVID-19 offers insights into these indirect impacts in the relative absence of the disease. We aimed to describe the mental health experiences of Australian caregivers and children over 12 months, reporting differences related to demographic, socioeconomic and lockdown characteristics.

MethodsData were from Australias only nationally representative, repeated cross-sectional survey of caregivers with children (0-17 years). N=2020 caregivers participated in June 2020, N=1434 in September 2020, and N=2508 in July 2021. Caregivers reported their mental health (poor versus not, Kessler-6), and perceived impacts of the pandemic on theirs and their childrens mental health (negative versus none/positive). Data were weighted to approximate population distributions of caregiver age, gender, sole-caregiving, number and ages of children, state/territory and neighbourhood-level disadvantage.

ResultsPerceived impacts on mental health were more frequently negative for female (versus male) caregivers and older (versus younger) children. Poor caregiver mental health (K6) was more common for families experiencing socioeconomic adversity (especially financial), while perceived impacts were more frequently negative for more socially advantaged groups. Caregivers who experienced the least total lockdown reported similar K6 over time. Otherwise, poor mental health and perceived negative impacts increased over time with increasing total length of lockdown.

ConclusionDespite Australias low infection rates, the negative mental health experiences of the COVID-19 pandemic are real and concerning. Addressing poor mental health must be central to ongoing pandemic recovery efforts for families and children.

What is known about this topic?- The global evidence shows that, for general adult populations, psychological distress peaked in the first months of the COVID-19 pandemic before appearing to improve.
- Less is known about mental health over time of living through the pandemic, especially for caregivers and children. There are urgent calls for research.
- Due to low infection rates, Australias experience can provide insight into the mental health impacts of lockdown with minimal compounding harms of the virus.

What this study adds- From June 2020 to July 2021, Australias lockdowns were detrimental for caregiver and child mental health.
- Negative mental health experiences differed by caregiver gender, child age and family socioeconomic characteristics.
- Pandemic response and recovery planning must consider both family mental health and socioeconomic security.


title: Child and caregiver mental health during 12 months of the COVID-19 pandemic in Australia


title: Child and caregiver mental health during 12 months of the COVID-19 pandemic in Australia: findings from national repeated cross-sectional surveys


title: Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

abstract:
BackgroundDiabetes is the leading cause of kidney disease, and heritability studies demonstrate a substantial, yet poorly understood, contribution of genetics to kidney complications in people with diabetes.

MethodsWe performed genome-wide association study (GWAS) meta-analyses using ten different phenotypic definitions of diabetic kidney disease (DKD), including nearly 27,000 individuals with diabetes, and integrated the results with various kidney omics datasets.

ResultsThe meta-analysis identified a novel low frequency intronic variant (rs72831309) in the TENM2 gene encoding teneurin transmembrane protein 2 associated with a lower risk of the combined chronic kidney disease (CKD; eGFR<60 ml/min/1.73 m2) and DKD (microalbuminuria or worse) phenotype ("CKD-DKD", odds ratio 2.08, p=9.8x10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A, and MFF, p<2.7x10-6). Integration of GWAS data with human glomerular and tubular expression data in a transcriptome-wide association study demonstrated higher tubular AKIRIN2 gene expression in DKD versus non-DKD controls (p=1.1x10-6). The lead SNPs within the DCLK1, AKIRIN2, SNX30 and three other gene regions significantly alterated the methylation at this region in kidneys (p<2.2x10-11). Expression of target genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes. For example, tubular TENM2 expression positively correlated with eGFR (p=2.3x10-9) and negatively with tubulointerstitial fibrosis (p=4.7x10-9), tubular DCLK1 expression positively correlated with fibrosis (p=1.6x10-12), and SNX30 level positively correlated with eGFR (p=7.6x10-13) and negatively with fibrosis (p<2x10-16).

ConclusionsGWAS meta-analysis and integration with renal omics data points to novel genes contributing to pathogenesis of DKD.

category: genetic and genomic medicine


title: Predicting brain amyloid-β PET phenotypes with graph convolutional networks based on functional MRI and multi-level functional connectivity

abstract: The detection of amyloid-{beta} (A{beta}) deposition in the brain provides crucial evidence in the clinical diagnosis of Alzheimers disease (AD). However, the efficiency of the current PET-based brain A{beta} examination suffers from both coarse, visual inspection-based bi-class stratification and high scanning cost and risks. In this work, we explored the feasibility of using non-invasive functional magnetic resonance imaging (fMRI) to predict A{beta}-PET phenotypes in the AD continuum with graph learning on brain networks. First, three whole-brain A{beta}-PET phenotypes were identified through clustering and their association with clinical phenotypes were investigated. Second, both conventional and high-order functional connectivity (FC) networks were constructed using resting-state fMRI and the network topological architectures were learned with graph convolutional networks (GCNs) to predict such A{beta}-PET phenotypes. The experiment of A{beta}-PET phenotype prediction on 258 samples from the AD continuum showed that our algorithm achieved a high fMRI-to-PET prediction accuracy (78.8%). The results demonstrated the existence of distinguishable brain A{beta} deposition phenotypes in the AD continuum and the feasibility of using artificial intelligence and non-invasive brain imaging technique to approximate PET-based evaluations. It can be a promising technique for high-throughput screening of AD with less costs and restrictions.

category: geriatric medicine


title: Analysis of daily reproduction rates of COVID-19 using Current Health Expenditure as Gross Domestic Product percentage (CHE/GDP) across countries

abstract:
(1) BackgroundImpact and severity of coronavirus pandemic on health infrastructure vary across countries. We examine the role percentage health expenditure plays in various countries in terms of their preparedness and see how countries improved their public health policy in the first and second wave of the coronavirus pandemic;

(2) MethodsWe considered the infectious period during the first and second wave of 195 countries with their Current Health Expenditure as Gross Domestic Product percentage (CHE/GDP). Exponential model was used to calculate the slope of the regression line while the ARIMA model was used to calculate the initial autocorrelation slope and also to forecast new cases for both waves. The relationship between epidemiologic and CHE/GDP data was used for processing ordinary least square multivariate modeling and classifying countries into different groups using PC analysis, K-means and Hierarchical clustering;

(3) ResultsResults show that some countries with high CHE/GDP improved their public health strategy against virus during the second wave of the pandemic;

(4) ConclusionsResults revealed that countries who spend more on health infrastructure improved in the tackling of the pandemic in the second wave as they were worst hit in the first wave. This research will help countries to decide on how to increase their CHE/GDP in order to tackle properly other pandemic waves of the present Covid-19 outbreak and future diseases that may occur. We are also opening up a debate on the crucial role socio-economic determinants play during the exponential phase of the pandemic modelling.

category: health economics


title: Prolonged SARS-CoV-2 infection in patients with lymphoid malignancies

abstract:
Coronavirus disease 2019 (COVID-19) infection results in high mortality rates in patients with hematologic malignancies. Persistent and/or recurrent COVID-19 has not yet been demonstrated in this population. We identified patients with B-cell lymphomas as having a particularly high risk for persistent SARS-CoV-2 positivity. Subsequent analysis of patients with lymphoid malignancies and COVID-19 identified discrete risk factors for severity of primary infection as compared to disease chronicity. Active therapy and diminished T-cell counts were key drivers of acute mortality in lymphoma patients with COVID-19 infection. Conversely, B-cell depleting therapy was the primary driver of re-hospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population.

Statement of SignificanceWe establish persistent symptomatic COVID-19 infection as a novel clinical syndrome in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8+ T-cell immunity.


title: A Systematic Review of the Protective Effect of Prior SARS-CoV-2 Infection on Repeat Infection

abstract:
IntroductionWe systematically reviewed studies to estimate the risk of SARS-CoV-2 reinfection among those previously infected with SARS-CoV-2.

MethodsFor this systematic review, we searched scientific publications on PubMed and, the pre-print server, MedRxiv through August 18, 2021. Eligible studies were retrieved on August 18, 2021. We used the following search term on PubMed: ((("Cohort Studies"[Majr]) AND ("COVID-19"[Mesh] OR "SARS-CoV-2"[Mesh])) OR "Reinfection"[Majr]) OR "Reinfection"[Mesh]. We used the following search term on MedRxiv: "Cohort Studies" AND "COVID-19" OR "SARS-CoV-2" AND "Reinfection". The search terms were broad to encompass all possibilities for applicable studies. There were no restrictions on the date of publication. Studies that did not describe cohorts with estimates of the risk of SARS-CoV-2 reinfection among those with previous infection were excluded. Studies that included vaccinated participants were either excluded or limited to sub-groups of non-vaccinated individuals. To identify relevant studies with appropriate control groups, we developed the following criteria for studies to be included in the systematic analysis: (1) baseline polymerase chain reaction (PCR) testing, (2) a negative comparison group, (3) longitudinal follow-up, (4) a cohort of human participants, i.e., not a case report or case series, and (5) outcome determined by PCR. The review was conducted following PRISMA guidelines. We assessed for selection, information, and analysis bias, per PRISMA guidelines.

ResultsWe identified 1,392 reports. Of those, 10 studies were eligible for our systematic review. The weighted average risk reduction against reinfection was 90.4% with a standard deviation of 7.7%. Protection against SARS-CoV-2 reinfection was observed for up to 10 months. Studies had potential information, selection, and analysis biases.

ConclusionsThe protective effect of prior SARS-CoV-2 infection on re-infection is high and similar to the protective effect of vaccination. More research is needed to characterize the duration of protection and the impact of different SARS-CoV-2 variants.


title: mRNA vaccines effectiveness against COVID-19 hospitalizations and deaths in older adults: a cohort study based on data-linkage of national health registries in Portugal

abstract:
BackgroundWe used electronic health registries to estimate the mRNA vaccine effectiveness (VE) against COVID-19 hospitalizations and deaths in older adults.

MethodsWe established a cohort of individuals aged 65 and more years, resident in Portugal mainland through data linkage of eight national health registries. For each outcome, VE was computed as one minus the confounder-adjusted hazard ratio, estimated by time-dependent Cox regression.

ResultsVE against COVID-19 hospitalization [≥]14 days after the second dose was 94% (95%CI 88 to 97) for age-group 65-79 years old (yo) and 82% (95%CI 72 to 89) for [≥]80 yo. VE against COVID-19 related deaths [≥] 14 days after second dose was 96% (95%CI 92 to 98) for age-group 65-79 yo and 81% (95%CI 74 to 87), for [≥]80 yo individuals. No evidence of VE waning was observed after 98 days of second dose uptake.

ConclusionsmRNA vaccine effectiveness was high for the prevention of hospitalizations and deaths in age-group 65-79 yo and [≥]80 yo with a complete vaccination scheme, even after 98 days of second dose uptake.


title: Automated diagnosis of atrial fibrillation in 24-hour Holter recording based on deep learning：a study with randomized and real-world data validation

abstract:
BackgroundWith the increasing demand for atrial fibrillation (AF) screening, clinicians spend a significant amount of time in identifying the AF signals from massive electrocardiogram (ECG) data in long-term dynamic ECG monitoring. In this study, we aim to reduce clinicians workload and promote AF screening by using artificial intelligence (AI) to automatically detect AF episodes and identify AF patients in 24 h Holter recording.

MethodsWe used a total of 22 979 Holter recordings (24 h) from 22 757 adult patients and established accurate annotations for AF by cardiologists. First, a randomized clinical cohort of 3 000 recordings (1 500 AF and 1 500 non-AF) from 3000 patients recorded between April 2012 and May 2020 was collected and randomly divided into training, validation and test sets (10:1:4). Then, a deep-learning-based AI model was developed to automatically detect AF episode using RR intervals and was tested with the test set. Based on AF episode detection results, AF patients were automatically identified by using a criterion of at least one AF episode of 6 min or longer. Finally, the clinical effectiveness of the model was verified with an independent real-world test set including 19 979 recordings (1 006 AF and 18 973 non-AF) from 19 757 consecutive patients recorded between June 2020 and January 2021.

FindingsOur model achieved high performance for AF episode detection in both test sets (sensitivity: 0.992 and 0.972; specificity: 0.997 and 0.997, respectively). It also achieved high performance for AF patient identification in both test sets (sensitivity:0.993 and 0.994; specificity: 0.990 and 0.973, respectively). Moreover, it obtained superior and consistent performance in an external public database.

InterpretationOur AI model can automatically identify AF in long-term ECG recording with high accuracy. This cost-effective strategy may promote AF screening by improving diagnostic effectiveness and reducing clinical workload.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Google Scholar and PubMed for research articles on artificial intelligence-based diagnosis of atrial fibrillation (AF) published in English between Jan 1, 2016 and Aug 1, 2021, using the search terms "deep learning" OR "deep neural network" OR "machine learning" OR "artificial intelligence" AND "atrial fibrillation". We found that most of the previous deep learning models in AF detection were trained and validated on benchmark datasets (such as the PhysioNet database, the Massachusetts Institute of Technology Beth Israel Hospital AF database or Long-Term AF database), in which there were less than 100 patients or the recordings contained only short ECG segments (30-60s). Our search did not identify any articles that explored deep neural networks for AF detection in large real-world dataset of 24 h Holter recording, nor did we find articles that can automatically identify patients with AF in 24 h Holter recording.

Added value of this studyFirst, long-term Holter monitoring is the main method of AF screening, however, most previous studies of automatic AF detection mainly tested on short ECG recordings. This work focused on 24 h Holter recording data and achieved high accuracy in detecting AF episodes. Second, AF episodes detection did not automatically transform to AF patient identification in 24 h Holter recording, since at present, there is no well-recognized criterion for automatically identifying AF patient. Therefore, we established a criterion to identify AF patients by use of at least one AF episode of 6 min or longer, as this condition led to significantly increased risk of thromboembolism. Using this criterion, our method identified AF patients with high accuracy. Finally, and more importantly, our model was trained on a randomized clinical dataset and tested on an independent real-world clinical dataset to show great potential in clinical application. We did not exclude rare or special cases in the real-world dataset so as not to inflate our AF detection performance. To the best of our knowledge, this is the first study to automatically identifies both AF episodes and AF patients in 24 h Holter recording of large real-world clinical dataset.

Implications of all the available evidenceOur deep learning model automatically identified AF patient with high accuracy in 24 h Holter recording and was verified in real-world data, therefore, it can be embedded into the Holter analysis system and deployed at the clinical level to assist the decision making of Holter analysis system and clinicians. This approach can help improve the efficiency of AF screening and reduce the cost for AF diagnosis. In addition, our RR-interval-based model achieved comparable or better performance than the raw-ECG-based method, and can be widely applied to medical devices that can collect heartbeat information, including not only the multi-lead and single-lead Holter devices, but also other wearable devices that can reliably measure the heartbeat signals.

category: cardiovascular medicine


title: Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape

abstract: SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from infection- and vaccine-induced immunity. Much effort has been devoted to measuring these phenotypes, but predicting their impact on the course of the pandemic - especially that of immune escape - remains a challenge. Here, we use a mathematical model to simulate the dynamics of wildtype and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility easily rise to high frequency, whereas partial immune escape, on its own, often fails to do so. However, when these phenotypes are combined, enhanced transmissibility can carry the variant to high frequency, at which point partial immune escape may limit the ability of vaccination to control the epidemic. Our findings suggest that moderate immune escape poses a low risk unless combined with a substantial increase in transmissibility.


title: Physical Activity Moderates Inflammatory Gene Expression in Rheumatoid Arthritis

abstract:
BackgroundWhile general population studies have shown associations between greater physical activity and lower inflammatory markers, effects of physical activity on inflammatory pathways in rheumatoid arthritis (RA) remain unknown. We aimed to determine whether physical activity independently associates with differential expression of inflammatory genes in RA.

MethodsData derived from an observational RA cohort. Physical activity was measured with the GT9X ActiGraph Link device. RNA extraction from peripheral blood, sequencing library preparation and transcriptomic analyses were performed using established methods. Genes differentially expressed in the most versus least physically active groups (top versus bottom activity tertiles) were identified using DESeq2 after adjusting for sex, age, race/ethnicity, and disease activity. Ingenuity Pathway Analysis (IPA) was employed to identify canonical biological pathways and upstream regulating cytokines associated with physical activity.

Results35 participants were enrolled (mean age 56{+/-}12 years; 91% female; race/ethnicity 31% white, 9% African American, 9% Asian, 40% Hispanic). 767 genes were differentially expressed (padj<0.1) between high versus low activity groups. The high activity group exhibited downregulation of innate and adaptive immune signaling pathways, including CD40, STAT3, TREM-1, IL-17a, IL-8, toll-like receptor and interferon signaling. Upstream cytokine analysis demonstrated inhibition of TNF-alpha and interferon among individuals in the most active group.

ConclusionIn a racially diverse RA cohort, patients who were more physically active had lower expression of immune signaling pathways implicated in RA pathogenesis, even after adjusting for disease activity, suggesting a potential protective effect of physical activity in RA.

category: rheumatology


title: Associations between residential exposure to volatile organic compounds (VOCs) and liver injury markers

abstract: Occupational exposures to volatile organic compounds (VOCs) have been associated with numerous health complications including steatohepatitis and liver cancer. However, the potential impact of environmental/residential VOC exposures on liver health and function is largely unknown. To address this knowledge gap, the objective of this cross-sectional study is to investigate associations between VOCs and liver injury biomarkers in community residents. Subjects were recruited from six Louisville neighborhoods, and informed consent was obtained. Exposure biomarkers included 16 creatinine-adjusted urinary metabolites corresponding to 12 parent VOCs. Serological disease biomarkers measured included cytokertain-18 (K18 M65 and M30), liver enzymes and direct bilirubin. Associations between exposure and disease biomarkers were assessed using generalized linear models. Smoking status was confirmed through urinary cotinine levels. The population comprised of approximately 60% females and 40% males; White persons accounted 78% of the population; with more nonsmokers (n=413) than smokers (n=250). When compared to nonsmokers, Males (45%) and Black persons (26%) were more likely to be smokers. In the overall population, metabolites of acrolein, acrylonitrile, acrylamide, 1,3-butadiene, crotonaldehyde, styrene and xylene were positively associated with alkaline phosphatase (ALP). These associations persisted in smokers, with the exception of crotonaldehyde, and addition of N,N dimethylformamide and propylene oxide metabolites. Although no positive associations were observed for K18 M30, the benzene metabolite was positively associated with bilirubin, irrespective of smoking status. Taken together, the results demonstrated that selected VOCs were positively associated with liver injury biomarkers. These findings will enable better risk assessment and identification of populations vulnerable to liver disease.

category: toxicology


title: Training and Development Needs Assessment in a large NIHR Biomedical Research Centre: A Survey

abstract:
ObjectiveTo assess the training and development needs of researchers and support staff affiliated to the NIHR Oxford Biomedical Research Centre (BRC), one of the largest BRCs in England, and to find out about their past experiences of training.

DesignA cross-sectional online questionnaire survey.

Setting and ParticipantsA convenience sample of clinicians, nurses, midwives, allied health professionals, researchers and support staff (N=798) affiliated with the NIHR Oxford Biomedical Research Centre.

Primary and secondary outcome measuresThe primary outcome measure was the type of training and the secondary outcome measures were the duration, location and timing of training.

ResultsThe response rate was 24%. Of 189 respondents, 114 were women (60%) and 75 men (40%). Respondents included research scientists (31%), medical doctors and dentists (17%), nurses and midwives (16%) and research managers and administrators (16%). Seventy-one percent respondents (n=134) reported attending at least one training activity in the last year and the most wanted training was leadership skills (25%), followed by research grant and fellowship writing (18%) and statistical analysis (16%). An ideal length of a training course was half a day (41%), whole day (25%) and 1-2 hours (22%). The most preferred time of the day for training was morning (60%) and afternoon (22%) and the favoured delivery style of training was an interactive workshop (52%), lecture/talk (25%), online (9%) and practical activities (9%). The main barriers to attending training courses were the lack of time (n-18%), work commitments (13%), and childcare responsibilities (6%).

ConclusionsTranslational researchers and supporting affiliates want short, easily accessible, interactive training sessions, particularly leadership training skills and grant and fellowship writing. However, practical elements are important too e.g. in a convenient location during the working day. Work commitment is the biggest obstacle in doing training.

Strengths and limitations of this studyO_LIThis survey was done to develop and revamp the NIHR Oxford BRCs training programme that met the training and development needs of our researchers and research support staff.
C_LIO_LILeadership skills, research grant and fellowship writing, statistical analysis were the most wanted training.
C_LIO_LIThe lack of time, work commitments, and childcare responsibilities were the main barriers to attending training courses.
C_LIO_LIOur findings have limited generalisability because the study is based on the responses of participants who are affiliated with only one NIHR BRC; hence, these findings could not be generalised to other NIHR BRCs.
C_LIO_LIThese findings might inform the training and development programmes in other NIHR BRCs in the country.
C_LI

category: medical education


title: Thalamic deep brain stimulation modulates circadian and infradian cycles of seizure risk in epilepsy

abstract: Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (infradian) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and infradian cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and infradian IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and infradian (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.

category: neurology


title: Predictors of eviction and quality of tenant-landlord relationships during the 2020-2021 eviction moratorium in the U.S.

abstract: In 2020, the Centers for Disease Control and Prevention (CDC) issued several agency orders that put into effect a national moratorium on evictions for over one year to limit transmission of Coronavirus Disease 2019 (COVID-19). Little is known about landlord and tenant behaviors during the eviction moratorium. The current study used three waves of data from May 2020-April 2021 from a nationally representative sample of U.S. middle- and low-income tenants (n= 3,393 in Wave 1, n= 1,311 in Wave 2, and 814 in Wave 3) to examine tenants who were evicted during the eviction moratorium and the reported effects of the moratorium on tenant rental payments and tenant-landlord relationships. Across three Waves, 4.3% of tenants reported experiencing an eviction during the moratorium and 6-23% of tenants reported delaying paying rent because of the moratorium. Multivariable analyses found that tenants who delayed paying their rent, were female, or had a history of mental illness or substance use disorder were significantly more likely to report the eviction moratorium had a negative effect on the relationship with their landlord. Analyses also revealed that testing positive for COVID-19 was not a significant predictor of eviction but tenants with a history a homelessness were more than 9 times as likely to report an eviction than those without such a history. Together, these findings suggest the eviction moratorium has had some unintended consequences on rent payments and tenant-landlord relationships that need to be considered in the aftermath of the COVID-19 pandemic.

category: health policy


title: Current attitudes towards HIV viral load self-testing: thematic analysis of a consultation with potential end-users

abstract:
BackgroundHIV viral load (VL) is key to monitoring response to antiretroviral therapy. A number of point-of-care HIV VL tests are in development. These tests could be repurposed for HIV VL self-testing.

MethodsWe held a patient and public involvement (PPI) consultation for people living with HIV to explore the prospect of HIV viral load self-testing. We conducted a thematic analysis on the data from this consultation.

ResultsKey themes were access, convenience, usability, technical aspects, technology potential, connectivity and confidentiality. Attendees expressed significant appetite for decentralised HIV care, including HIV VL self-testing.

ConclusionsThis PPI consultation can help researchers developing HIV viral load self-testing technology to better understand the needs of potential end users. Our findings will help guide the development and implementation of HIV VL self-testing.

category: hiv aids


title: Antibodies anti-SARS-CoV2 time-course in patients and vaccinated subjects: an evaluation of the harmonization of two different methods

abstract:
The time-course of antibodies anti SARS-CoV2 is not yet well elucidated, especially in people who underwent a vaccination campaign. In this study we measured antibodies anti-S1 and anti-RBD with two different methods both in patients and in vaccinated subjects.

108 specimens from 48 patients diagnosed as COVID-19 affected (time from the onset of symptoms from 3 to 368 days) and 60 specimens from 20 vaccinated subjects (collected after 14 days from the first dose, 14 days and 3 months after a second dose of Comirnaty) were evaluated.

We used an ELISA method that measure IgG against anti-Spike 1 and a chemiluminescence immunoassays that measure IgG anti-RBD.

In the patients, antibodies concentrations tend to decline after a few months with both methods, but persist relatively high up to nearly a year after symptoms.

In vaccinated subjects, antibodies were already detectable after the first dose, but after the booster they show a significant increase. However, the decrease is rapid, given that after 3 months after the second vaccination they are reduced to less than a quarter.

The conversion of the results into BAU units improves the relationship between the two methods. However, in vaccinated subjects there was no evidence of proportional error after the conversion, while in the patients the difference between the two methods remained significant.


title: Differential expression of genes influencing mitotic processes in cord blood mononuclear cells after a pre-conceptional micronutrient-based randomized controlled trial: Pune Rural Intervention in Young Adolescents (PRIYA)

abstract:
In the Pune Maternal Nutrition Study, low maternal vitamin B12 and high folate concentrations during pregnancy predicted adiposity and insulin resistance (diabesity) in the children. Based on these findings, we designed an RCT (PRIYA) to provide these nutrients pre-conceptionally to reduce diabesity in the offspring. The interventions included: 1) vitamin B12+multi-micronutrients and protein supplement (B12+MMN), 2) vitamin B12 alone, and 3) placebo. A total of 149 women became pregnant and delivered in the trial. We report results of RNA sequencing in the cord-blood mononuclear cells in 88 deliveries. Gene expression analysis revealed 20 differentially expressed genes (FDR <0.1, a discovery threshold) between the B12+MMN and placebo groups. The enriched biological processes included: chromosome segregation, nuclear division and organelle fission. A cell cycle checkpoint gene Claspin (CLSPN) was expressed less in the B12+MMN group but proliferation markers did not differ. No difference was observed between the B12 alone and placebo groups. The B-complex vitamins are essential for nucleotide synthesis and generation of S-Adenosyl Methionine, a universal cellular methyl donor and thereby may contribute to the regulation of gene expression. Vitamins A and D, and zinc in MMN may also influence gene expression. We propose that the multi-micronutrient intervention influenced rate of progression of specific phases of cell cycle without affecting proliferation. Vitamin B12 alone was not sufficient.

We highlight a novel molecular mechanism for the effect of multi-micronutrients during fetal development, and a plausible mechanism for intergenerational nutritional programming. Follow up studies will help understand their implications on the future phenotype.


title: COVID-19-associated hospitalizations among vaccinated and unvaccinated adults >=18 years - COVID-NET, 13 states, January 1 - July 24, 2021

abstract:
BackgroundAs of August 21, 2021, >60% of the U.S. population aged [≥]18 years were fully vaccinated with vaccines highly effective in preventing hospitalization due to Coronavirus Disease-2019 (COVID-19). Infection despite full vaccination (vaccine breakthrough) has been reported, but characteristics of those with vaccine breakthrough resulting in hospitalization and relative rates of hospitalization in unvaccinated and vaccinated persons are not well described, including during late June and July 2021 when the highly transmissible Delta variant predominated.

MethodsFrom January 1-June 30, 2021, cases defined as adults aged [≥]18 years with laboratory-confirmed Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection were identified from >250 acute care hospitals in the population-based COVID-19-Associated Hospitalization Surveillance Network (COVID-NET). Through chart review for sampled cases, we examine characteristics associated with vaccination breakthrough. From January 24-July 24, 2021, state immunization information system data linked to both >37,000 cases representative cases and the defined surveillance catchment area population were used to compare weekly hospitalization rates in vaccinated and unvaccinated individuals. Unweighted case counts and weighted percentages are presented.

ResultsFrom January 1 - June 30, 2021, fully vaccinated cases increased from 1 (0.01%) to 321 (16.1%) per month. Among 4,732 sampled cases, fully vaccinated persons admitted with COVID-19 were older compared with unvaccinated persons (median age 73 years [Interquartile Range (IQR) 65-80] v. 59 years [IQR 48-70]; p<0.001), more likely to have 3 or more underlying medical conditions (201 (70.8%) v. 2,305 (56.1%), respectively; p<0.001) and be residents of long-term care facilities [37 (14.5%) v. 146 (5.5%), respectively; p<0.001]. From January 24 - July 24, 2021, cumulative hospitalization rates were 17 times higher in unvaccinated persons compared with vaccinated persons (423 cases per 100,000 population v. 26 per 100,000 population, respectively); rate ratios were 23, 22 and 13 for those aged 18-49, 50-64, and [≥]65 years respectively. For June 27 - July 24, hospitalization rates were [≥]10 times higher in unvaccinated persons compared with vaccinated persons for all age groups across all weeks.

ConclusionPopulation-based hospitalization rates show that unvaccinated adults aged [≥]18 years are 17 times more likely to be hospitalized compared with vaccinated adults. Rates are far higher in unvaccinated persons in all adult age groups, including during a period when the Delta variant was the predominant strain of the SARS-CoV-2 virus. Vaccines continue to play a critical role in preventing serious COVID-19 illness and remain highly effective in preventing COVID-19 hospitalizations.


title: The effectiveness of SARS-CoV-2 vaccination in preventing severe illness and death- real-world data from a cohort of patients hospitalized with COVID-19.

abstract:
BackgroundDue to the unprecedented speed of SARS-CoV-2 vaccine development, their efficacy trials and issuance of emergency use approvals and marketing authorizations, additional scientific questions remain that need to be answered regarding vaccine effectiveness, vaccination regimens and the need for booster doses. While long-term studies on the correlates of protection, vaccine effectiveness, and enhanced surveillance are awaited, studies on breakthrough infections help us understand the nature and course of this illness among vaccinated individuals and guide in public health preparedness.

MethodsThis observational cohort study aimed at comparing the differences in clinical, biochemical parameters and the hospitalization outcomes of 53 fully vaccinated individuals with those of unvaccinated (1,464) and partially vaccinated (231) individuals, among a cohort of 2,080 individuals hospitalized with SARS-CoV-2 infection.

ResultsCompleting the course of vaccination protected individuals from developing severe COVID-19 as evidence by lower proportions of those with hypoxia, abnormal levels of inflammatory markers, requiring ventilatory support and death compared to unvaccinated and partially vaccinated individuals. There were no differences in these outcomes among patients who received either vaccine type approved in India.

ConclusionWith a current rate of only 9.5% of the Indian population being fully vaccinated, efforts should be made to improve the vaccination rates as a timely measure to prepare for the upcoming waves of this highly transmissible pandemic. Vaccination rates of the communities may also guide in the planning of the health needs and appropriate use of medical resources.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe Government of India started vaccinating its citizens from the 16th of January 2021, after emergency use authorization had been received for the use of two vaccines, BBV152, a COVID-19 vaccine based on the whole-virion SARS-CoV-2 vaccine strain NIV-2020-770, (Covaxin) and the recombinant replication-deficient chimpanzee adenovirus vector encoding the spike protein ChAdOx1 nCoV-19 Corona Virus Vaccine (Covishield). These have been approved by the Indian regulatory authority based on randomized controlled studies. In these studies, was found that the vaccines led to more than 90% reduction in symptomatic COVID-19 disease. However, there is scarce evidence of the efficacy of these vaccines in real-world scenarios. A few studies have looked at vaccinated cohorts such as health care workers in whom the vaccines had an efficacy similar to the RCTs. In a study of patients with SARS-CoV-2 infection admitted to a tertiary care hospital in New Delhi, it was found that mortality in fully vaccinated patients was 12.5% as compared to 31.5% in the unvaccinated cohort.

Added-value of this studyThis cohort of hospitalized patients with SARS-CoV-2 infection was studied during the peak of the second wave of COVID-19 in India during which the delta variant of concern was the predominant infecting strain and had 26% patients who were partially vaccinated and 71.4% who were unvaccinated. Only 3% of the patients were fully vaccinated and developed a breakthrough infection. At the time of presentation, 13% of the individuals with breakthrough infection and 48{middle dot}5% in the non-vaccinated group were hypoxic. Inflammatory markers were significantly lower in the completely vaccinated patients with breakthrough infection. The need for use of steroids and anti-viral agents such as remdesivir was also significantly low in the breakthrough infection group. A significantly less proportion of the individuals with breakthrough infection required oxygen supplementation or ventilatory support. Very few deteriorated or progressed to critical illness during their hospital stay. Only 3 individuals (5.7%) out of the 53 who developed breakthrough infection succumbed to illness while case fatality rates were significantly higher in the unvaccinated (22.8%) and partially vaccinated (19.5%) groups. Propensity score weighted multivariate logistic regression analysis revealed lower odds of developing hypoxia, critical illness or death in those who were completely vaccinated.

Implications of all the available evidenceThe real-world effectiveness of the vaccines against SARS-CoV-2 seems to be similar to the randomized controlled trials. The vaccines are very effective in reducing the incidence of severe COVID-19, hypoxia, critical illness and death. The reduced need for oxygen supplementation, mechanical ventilation and the requirement of corticosteroids or other expensive medications such as anti-viral drugs could go a long way in redistributing scarce health care resources. All nations must move forward and vaccinate the citizens, as the current evidence suggests that  prevention is better than cure.


title: Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial

abstract:
BackgroundOpaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. The objective of the study was to evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen.

MethodsThis Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n=23) or placebo (n=19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo.

ResultsThe relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. The incidence of [≥] Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group.

ConclusionsIn this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib required less supplementary oxygen and had earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.

SummaryUpon receiving opaganib, patients with COVID-19 pneumonia who were hospitalized and required supplemental oxygen showed symptomatic clinical improvement compared to placebo, with less supplemental oxygen requirement, resulting in earlier hospital discharge, and no safety concerns arising.


title: Intramuscular SARS-CoV-2 vaccines elicit varying degrees of plasma and salivary antibody responses as compared to natural infection

abstract: Vaccination induced antibody and T-cell immune responses are important for systemic protection from COVID-19. Because SARS-CoV-2 infects and is transmitted by oral-pharyngeal mucosa, we wished to test mucosal antibodies elicited by natural infection or intramuscular vaccine injection. In a non-randomized observational study, we measured antibodies against the SARS-CoV-2 RBD in plasma and saliva from convalescent or vaccinated individuals and tested their neutralizing potential using a replication competent rVSV-eGFP-SARS-CoV-2. We found IgG and IgA anti-RBD antibodies as well as neutralizing activity in convalescent plasma and saliva. Two doses of mRNA vaccination (BNT162b2 or mRNA-1273) induced high levels of IgG anti-RBD in saliva, a subset of whom also had IgA, and significant neutralizing activity. We detected anti-RBD IgG and IgA with significant neutralizing potential in the plasma of single dose Ad26.COV2.S vaccinated individuals, and we detected slight amounts of anti-RBD antibodies in matched saliva. The role of salivary antibodies in protection against SARS-CoV-2 infection is unknown and merits further investigation. This study was not designed to, nor did it study the full kinetics of the antibody response or protection from infection, nor did it address variants of SARS-CoV-2.

category: allergy and immunology


title: Whole-genome analysis of monozygotic twins discordant for type 1 narcolepsy

abstract: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. To contribute to the understanding of NT1 genetic causes, here we describe a whole-genome analysis of a monozygotic twin pair discordant for NT1. Our study revealed that although both twins have the same pathogenic mutations in NT1 associated genes (such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01) the unaffected twin has mutations in genes outside the HLA loci that could be suppressing the NT1 phenotype. These results support the notion that NT1 has an immunological basis but that protective mutations in non-HLA might interfere with the clinical manifestation of the disease.


title: Evaluation of Residual Disinfectant Levels in Public Drinking Water Distribution Systems in Relation to an Acanthamoeba Keratitis Outbreak - Illinois, 2002-2009

abstract: Acanthamoeba keratitis (AK) is a painful, potentially blinding eye disease associated with contact lens use and corneal injury. AK, caused by the free-living amoeba Acanthamoeba, is ubiquitous in the environment and has been isolated from municipal water supplies. It can be tolerant of normal chlorine levels in drinking water. An AK outbreak investigated in 2003-2005 in five Illinois counties showed a lower AK age-standardized rate ratio in Cook County than in surrounding counties and was hypothesized to be due in part to reductions in residual disinfectant levels (RDLs) in drinking water. We evaluated RDLs in public water systems in the same five Illinois counties over eight years (2002-2009) using a multivariable model of water system RDL measurements. Fitted RDLs for each county were in the acceptable range by United States Environmental Protection Agency standards for the entire study period. After correcting for multiple testing, two of the surrounding counties had fitted RDLs that differed from Cook County for one year--this pattern differed from the epidemiologic pattern of cases observed in the AK outbreak. Our findings do not support the hypothesis that the development of AK was associated with changes in RDLs in the five Illinois counties.


title: Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: An Updated Systematic Review and Meta-Analysis

abstract:
BackgroundThe increase in the number of available biologic agents for psoriasis has led to an urgent need to evaluate their associated risk of serious infections to help inform clinical decisions.

MethodologyWe systematically searched PubMed, Medline, Embase, and Cochrane databases for biologics targeting TNF (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/23 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, risankizumab, and tildrakizumab) for the primary outcome serious infections, at 10- 16 weeks, 1 year and 3 years. Petos method (fixed effect model) was used to estimate the pooled odds ratio (OR) in meta-analyses comparing biologics with one another, methotrexate, or placebo.

ResultsForty-three publications (49 trials) consisting of 29,724 participants met our inclusion criteria. Serious infections across all studies were low (n=97) at 10-16 weeks and did not show an increased risk with biologic therapies compared with placebo. Seven head-to-head RCTs were identified, most of which showed no significant difference in the risk of serious infections at 10-16 weeks and at 1 year. Adalimumab was not associated with a significant increased risk of serious infections compared with methotrexate in children at 10-16 weeks.

ConclusionsBiologics for psoriasis were not associated with an increased risk of serious infections compared with placebo or one another at 10-16 weeks. Longer-term, real-world data with larger sample sizes are warranted.

category: dermatology


title: Time In Range as measured by continuous glucose monitor as a predictor of microvascular complications in type 2 diabetes: A systemic review

abstract:
AimContinuous glucose monitoring (CGM) derived times in range (TIR) correlates with hemoglobin A1c (A1c) among patients with type 2 diabetes mellitus (T2DM); however, there is a paucity of data evaluating its association with microvascular complications. We conducted this systematic review to examine the association between TIR and microvascular complications of diabetic retinopathy (DR), diabetic nephropathy (DN) and peripheral diabetic neuropathy (DPN).

MethodWe conducted a comprehensive literature search on online database of PubMed, Scopus, and Web of Science following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Full texts original articles that evaluated association between CGM-derived TIR and risk of microvascular complications which were published between 2010 and June 2021, were included in our systematic review. The quality of included studies were evaluated using National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data were analyzed using qualitative synthesis.

ResultEleven studies were included in the systematic review. The mean sample size, baseline A1c, and diabetes duration were 1271 (105-5901), 8.2 % (SD 0.5 %) and 11.3 years, respectively. Majority of studies were conducted in Asia (10 out 11). Four studies evaluated the relationship between CGM-derived TIR and DR and CGM-derived TIR and DN, while seven studies evaluated the relationship between CGM-derived TIR and DPN. A 10 % increase in TIR was associated with a reduction in albuminuria, severity of diabetic retinopathy, and prevalence of diabetic peripheral nephropathy and cardiac autonomic neuropathy. In addition, an association was observed between urinary albumin-to-creatinine ratio but not with estimated glomerular filtration rate.

ConclusionThis review summarizes recent evidence supporting an association between CGM-derived TIR and microvascular complications among patients with T2DM. A larger{square}scale multi-center investigation that includes more diverse participants is warranted to further validate the utility of TIR as a predictor for diabetic microvascular complications.

category: endocrinology


title: Can tracking mobility be used as a public health tool against COVID-19 following the expiration of stay-at-home mandates?

abstract:
BackgroundConsidering the emergence of SARS-CoV-2 variants and low vaccine access and uptake, minimizing human interactions remains an effective strategy to mitigate the spread of SARS-CoV-2. The aim of this study was to create a novel multidimensional mobility index to capture the complexity of human interaction and evaluate its utility as an early indicator of surges in COVID-19 cases.

MethodsWe used publicly available anonymous cell phone data compiled by SafeGraph, from all counties in Illinois, Ohio, Michigan and Indiana between January 1st to December 8, 2020. Six metrics of mobility were extracted for each county. Changes in mobility were defined as a time-updated 7-day rolling average. We used an unsupervised machine learning method known as functional principal component analysis (fPCA) to construct the latent mobility index (MI) using the six metrics of mobility. Associations between our MI and COVID-19 cases were estimated using a quasi-Poisson hierarchical generalized additive model adjusted for population density and the COVID-19 community vulnerability index.

ResultsIndividual mobility metrics varied significantly by counties and by calendar time. More than 50% of the variability in the data was explained by the first principal component by each state, indicating good dimension reduction. Following the expiration of stay-at-home orders, mobility increased across all counties and this was particularly evident on weekends. While an individual metric of mobility was not associated with surges of COVID-19, our MI was independently associated with COVID-19 cases in all four states given varying time-lags.

ConclusionFollowing the expiration of stay-at-home orders, a single metric of mobility was not sensitive enough to capture the complexity of human interactions. Monitoring mobility can be an important public health tool, however, it should be modelled as a multidimensional construct.

category: epidemiology


title: A machine learning approach for identification of gastrointestinal predictors for the risk of COVID-19 related hospitalization

abstract:
Background and aimCOVID-19 can be presented with various gastrointestinal symptoms. Shortly after the pandemic outbreak several machine learning algorithms have been implemented to assess new diagnostic and therapeutic methods for this disease. Aim of this study is to assess gastrointestinal and liver related predictive factors for SARS-CoV-2 associated risk of hospitalization.

MethodsData collection was based on questionnaire from the COVID-19 outpatient test center and from the emergency department at the University hospital in combination with data from internal hospital information system and from the mobile application used for telemedicine follow-up of patients. For statistical analysis SARS-CoV-2 negative patients were considered as controls to three different SARS-CoV-2 positive patient groups (divided based on severity of the disease).

ResultsTotal of 710 patients were enrolled in the study. Presence of diarrhea and nausea was significantly higher in emergency department group than in the COVID-19 outpatient test center. Among liver enzymes only aspartate transaminase (AST) has been significantly elevated in the hospitalized group compared to patients discharged home. Based on random forest algorithm, AST has been identified as the most important predictor followed by age or diabetes mellitus. Diarrhea and bloating have also predictive importance although much lower than AST.

ConclusionSARS-CoV-2 positivity is connected with isolated AST elevation and the level is linked with the severity of the disease. Furthermore, using machine learning random forest algorithm, we have identified elevated AST as the most important predictor for COVID-19 related hospitalizations.

category: gastroenterology


title: Exploring Vaccine Hesitancy in Care Home Employees in North West England: A Qualitative Study

abstract:
ObjectivesCare homes have experienced a high number of COVID-19 outbreaks, and it is therefore important for care home employees to receive the COVID-19 vaccine. However, there is vaccine hesitancy at a greater rate among this group than in the wider community. We aimed to understand barriers and facilitators to getting the COVID-19 vaccine, as well as views on potential mandatory vaccination policies.

DesignSemi-structured interviews.

SettingCare home employees in North West England. Interviews conducted in April 2021.

Participants10 care home employees (aged 25 to 61 years old) in the North West, who had been invited to have, but had not yet received, the COVID-19 vaccine.

ResultsWe analysed the interviews using a framework analysis. Our analysis identified eight themes: perceived risk of COVID-19, efficacy of the vaccine, concerns about the vaccine, mistrust in authorities, facilitators to getting the vaccine, views on potential mandatory COVID-19 vaccination policies, negative experiences of care work during the COVID-19 pandemic, and communication challenges.

ConclusionsThe care home employees interviewed at the time of this study reported a low perceived risk of COVID-19, alongside concerns over the efficacy of the vaccine, side effects, and speed of vaccine development, which is exacerbated by mistrust in authorities. Facilitators to getting the vaccine included wanting to protect others, perceived severity of COVID-19, and workplace norms. Making COVID-19 vaccination a condition of deployment may not result in increased willingness to get the COVID-19 vaccination, with most care home employees in this study favouring leaving their job rather than getting vaccinated. At a time when many of the workers already had negative experiences of care work during the pandemic due to perceived negative judgment from others and a perceived lack of support facing care home employees, policies that require vaccination as a condition of deployment were not positively received.


title: Machine learning-based prediction of motor status in glioma patients using diffusion MRI metrics along the corticospinal tract

abstract: Along tract statistics enables white matter characterization using various diffusion MRI (dMRI) metrics. Here, we applied a machine learning (ML) method to assess the clinical utility of dMRI metrics along corticospinal tracts (CST), investigating whether motor glioma patients can be classified with respect to their motor status. The ML-based analysis included developing models based on support vector machine (SVM) using histogram-based measures of dMRI-based tract profiles (e.g., mean, standard deviation, kurtosis and skewness), following a recursive feature elimination (RFE) method based on SVM (SVM-RFE). Our model achieved high performance (74% sensitivity, 75% specificity, 74% overall accuracy and 77% AUC). Incorporating the patients demographics and clinical features such as age, tumor WHO grade, tumor location, gender and resting motor threshold (RMT) into our designed models demonstrated that these features were not as effective as microstructural measures. The results revealed that ADC, FA and RD contributed more than other features to the model.

category: radiology and imaging


title: Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

abstract:
BackgroundResponses to conventional donor lymphocyte infusion (DLI) for post-allogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.

MethodsWe initiated this ongoing phase 1 trial of adoptively transferred cytokine induced memory-like (CIML) NK cells in patients with myeloid malignancies relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5-10 x million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High resolution profiling with mass cytometry and single cell RNA sequencing characterized the expanding and persistent NK cells subpopulations in a longitudinal manner after infusion. In vitro functional studies of infused CIML NK cells were complemented with in vivo evaluation of NK trafficking to disease sites using multiparameter immunofluorescence.

ResultsIn the first 5 patients on the trial, infusion of CIML NK cells led to a rapid 10 to 50-fold in vivo expansion that was sustained over months. The infusion was well-tolerated, with fever and pancytopenia as the most common adverse events. Responses were attained in 4 of 5 patients at day +28. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires. AML relapse after initial response to CIML NK cell therapy was associated with low transcript expression of CD2 ligands, including CD48/SLAMF2 and CD58/LFA3.

ConclusionGiven their rapid expansion and long-term persistence in an immune compatible environment, CIML NK cells serve as a promising platform for the treatment of post-transplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T-cells and tumor targets will lead to the development of novel cell-based immunotherapies.

category: transplantation


title: Predictive factors of response to 3rd dose of COVID-19 mRNA vaccine in kidney transplant recipients

abstract: Only a minority of kidney transplant recipients (KTRs) develop protective neutralizing titers of anti-receptor binding domain of spike protein (RBD) IgG after two doses of mRNA COVID-19 vaccine. Administration of a third dose of mRNA vaccine to KTRs with sub-optimal response increase anti-RBD IgG titers but with high inter-individual variability. Patients with the higher response rate to the third dose of vaccine can be identified by the presence of low anti-RBD IgG titers and spike-specific CD4+ T cells in their circulation 14 days after the second dose.


title: Analysis of Mutational Profile of Hypopharyngeal and Laryngeal Head and Neck Cancers Identifies KMT2C as a Potential Tumor Suppressor

abstract: Hypopharyngeal cancer represents one of worst types of head and neck tumors with only few studies focusing on the genomic profile of this type of cancer. Using targeted next-generation sequencing we analyzed 48 HPV-negative tumor samples including 23 originating from hypopharynx, and 25 from larynx. Among genes previously described as significantly mutated, TP53, FAT1, NOTCH1, KMT2C and CDKN2A were found to be most frequently mutated. We also found that more than three-fourths of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 head and neck cancers from other sites and found no prominent differences in mutational frequency except for CASP8 and HRAS genes. Since we observed relatively frequent mutations of KTM2C (MLL3) in our dataset, we analyzed their role in vitro by generating KMT2C-mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrate that KMT2C loss-of-function results in increased colony formation and proliferation, in concordance with its previously published results. In summary, our results show that mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrate for the first time that KMT2C gene may play a role of tumor suppressor in head and neck cancer, which opens new possibilities in the search for new targeted treatment approaches.

category: genetic and genomic medicine


title: CLINICAL OPPORTUNITIES FOR GERMLINE PHARMACOGENETICS AND MANAGEMENT OF DRUG-DRUG INTERACTIONS IN PATIENTS WITH ADVANCED SOLID CANCERS

abstract:
PURPOSEPrecision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit advanced cancer patients who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer.

PATIENTS AND METHODSMedication data were collected from the electronic health records (EHRs) for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes.

RESULTSApproximately 60% of subjects were prescribed at least one medication with CPIC recommendations, and [~]14% of subjects had an instance for actionable PGx, defined as prescription of a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, [~]40% of subjects had at least one opportunity for a precision medicine-based intervention and [~]98% of subjects had an actionable phenotype for at least one CYP enzyme.

CONCLUSIONOur findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.


title: Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis

abstract: Clinical heterogeneity is common in Mendelian disease, but small sample sizes make it difficult to identify specific contributing factors. However, if a rare disease represents the severely affected extreme of a spectrum of phenotypic variation, then modifier effects may be apparent within a larger subset of the population. Analyses that take advantage of this full spectrum could have substantially increased power. To test this, we developed cryptic phenotype analysis (CPA), a model-based approach that uses symptom data to infer latent quantitative traits that capture disease-related phenotypic variability. By applying this approach to 50 Mendelian diseases in two large cohorts of patients, we found that these quantitative traits reliably captured disease severity. We then conducted genome-wide association analyses for five of the inferred cryptic phenotypes, uncovering common variation that was predictive of Mendelian disease-related diagnoses and outcomes. Overall, this study highlights the utility of computationally derived phenotypes and biobank-scale cohorts for investigating the complex genetic architecture of Mendelian diseases.


title: Predicting the impact of low influenza activity in 2020 on population immunity and future influenza season in the United States

abstract:
BackgroundsThe influenza season of 2020-21 was remarkably low, likely due to implementation of public health preventive measures such as social distancing, mask-wearing, and school closure and due to decreased international travel. This leads to a key public health question: what will happen in the 2021-22 influenza season? To answer this, we developed a multi-season influenza model that accounted for residual immunity from prior infection.

MethodWe built a multi-strain, non-age structured compartmental model that captures immunity over multiple influenza seasons. By the end of the influenza season, we sorted the population based on their experience of natural infection and/or vaccination, which determines the susceptibility to influenza infection in the following season. Because the exact parameters of transmission rates and immunity are unknown, we implemented Bayesian calibration against the observed influenza epidemics (influenza hospitalization rates from 2012 to 2020 in the US) to estimate those parameters. In forward projections, we simulated low influenza activity in 2020-21 season by lowering transmission rate by 20%. Compared to the counterfactual case, in which influenza activity remained at the normal level in 2020-21, we estimated the change in the number of hospitalizations in the following seasons with varying level of vaccine uptake and effectiveness. We measured the change in population immunity over time by varying the number of seasons with low influenza activity.

ResultWith the low influenza activity in 2020-21, the model estimated 102,000 [95% CI: 57,000-152,000] additional hospitalizations in 2021-22, without change in vaccine uptake and effectiveness. The expected change in hospitalization varied depending on the level of vaccine uptake and effectiveness in the following year. Achieving 50% increase in one of two measures (1.5X vaccine uptake with 1X vaccine efficacy or 1.5X vaccine efficacy with 1X vaccine uptake) was necessary to avert the expected increase in hospitalization in the next influenza season. Otherwise, increases in both measures by 25% averted the expected increase in influenza-hospitalization. If the low influenza activity seasons continue, population immunity would remain low during those seasons, with 48% the population susceptible to influneza infection.

ConclusionWe predicted a large compensatory influenza season in 2021-2 due to a light season in 2020-21. However, higher influenza vaccine uptake would reduce this projected increase in influenza.

category: infectious diseases


title: Randomized trials on non-pharmaceutical interventions for COVID-19 as of August 2021: a meta-epidemiological analysis

abstract:
BackgroundNumerous non-pharmaceutical interventions (NPIs) were taken worldwide to contain the spread of the COVID-19 pandemic. We aimed at providing an overview of randomized trials assessing NPIs to prevent COVID-19.

MethodsWe included all randomized trials assessing NPIs to prevent COVID-19 in any country and setting registered in ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform using the COVID-evidence platform (until 17 August 2021). We searched for corresponding publications in MEDLINE/PubMed, Google Scholar, the Living Overview of Evidence platform (L-OVE), and the Cochrane COVID-19 registry as well as for results posted in registries.

ResultsWe identified 41 randomized trials. Of them, 11 were completed (26.8%) including 7 with published results. The 41 trials planned to recruit a median of 1,700 participants (IQR, 588 to 9,500, range 30 to 35,256,399) with a median planned duration of 8 months (IQR, 3 to 14, range 1 to 24). Most came from the United States (n=11, 26.8%). The trials mostly assessed protective equipment (n=11, 26.8%), COVID-19-related information and education programs (n=9, 22.0%), access to mass events under specific safety measures (n=5, 12.2%), testing and screening strategies (n=5, 12.2%), and hygiene management (n=5, 12.2%).

ConclusionsWorldwide, 41 randomized trials assessing NPIs have been initiated with published results available to inform policy decisions for only 7 of them. A long-term research agenda including behavioral, environmental, social, and systems level interventions is urgently needed to guide policies and practices in the current and future public health emergencies.


title: AEROSOL GENERATION DURING COUGHING - QUANTITATIVE DEFINITION FOR AEROSOL GENERATING PROCEDURES: OBSERVATIONAL STUDY

abstract:
AimThe purpose of the study was to determine aerosol exposure generated by coughing in operation room environments to create a quantitative limit value for high-risk aerosol-generating medical procedures.

BackgroundCoughing is known to produce a significant amount of aerosols and is thus commonly used as a best reference for high-risk aerosol-generation. Accordingly, procedures during which aerosol generation exceeds the amount of aerosol generated in instances of coughing are seen as high-risk aerosol generating procedures. However, no reliable quantitative values are available for high-risk aerosol-generation.

MethodsCoughing was measured from 37 healthy volunteers in the operating room environment. Aerosol particles generated during coughing within the size range of 0.3-10 {micro}m were measured with Optical Particle Sizer from 40cm, 70cm, and 100cm distances. The distances reflected potential exposure distances where personnel are during surgeries.

ResultsA total of 306 coughs were measured. Average aerosol concentration during coughing was 1.580 {+/-} 13.774 particles/cm3 (range 0.000 - 195.528).

DiscussionThe aerosol concentration measured in this study can be used as a limit for high-risk aerosol generation in the operating room environment when assessing the aerosol generating procedures and the risk of operating room staffs exposure for aerosol particles.


title: The Association Between Platelet Transfusion and Mortality Rate Among Preterm Neonates in the Eastern Province, Saudi Arabia

abstract:
Platelet transfusion is the main mode of management of thrombocytopenia. However, some studies link frequent and high-threshold platelet transfusions with an incremental increase of mortality rate.

AimThis study aims to assess the association between the frequency and the threshold of platelet transfusions, with the mortality rate among preterm neonates.

MethodsA retrospective cohort study design was used. This study was conducted at maternity and childrens hospitals in Al-Ahasa, Saudi Arabia. The sample size includes 154 preterm neonates, included in the study by the use of the convenience sampling technique.

ResultThere is a significant relationship found between the gestational age and the birth weight of the preterm neonates with the survival rates among both groups. In contrast, there is no significant relationship found between transfusion frequency, transfusion threshold, and the survival rates of the group which received platelet transfusion.

Implications for Practice and ResearchThe current study found that mortality is mainly associated with lower gestational ages, and not platelet transfusions. More studies are needed to fill the remaining gaps of knowledge, and to optimise platelet transfusion practices among preterm neonates.

category: intensive care and critical care medicine


title: A novel Vascular Leak Index identifies sepsis patients with a higher risk for in-hospital death and fluid accumulation

abstract:
PurposeSepsis is a leading cause of morbidity and mortality worldwide and is characterized by vascular leak syndrome. Treatment for sepsis, specifically intravenous fluids, may worsen deterioration in the context of vascular leak.

MethodsWe performed a retrospective cohort study of sepsis patients in four ICU databases in North America, Europe, and Asia. We developed an intuitive vascular leak index (VLI) and determined the relationship between VLI and in-hospital death and 36h-84h fluid balance using generalized additive models (GAM).

ResultsUsing GAM, we found that increased VLI is associated with an increased risk of in-hospital death. Patients with a VLI in the highest quartile (Q4), across the four datasets, had a 1.61-2.31 times increased odds of dying in the hospital compared to patients with a VLI in the lowest quartile (Q1). VLI Q2 and Q3 were also associated with increased odds of dying. The relationship between VLI, treated as a continuous variable, and in-hospital death and 36h-84h death was statistically significant in the three datasets with a large number of patients. Specifically, we observed that as VLI increased, there was increase in the risk for in-hospital death and 36h-84h fluid balance. For the few patients with a positive VLI, this relationship differed across databases.

ConclusionsOur VLI identifies groups of patients who may be at higher risk for in-hospital death and for fluid accumulation early in the ICU course. This relationship persisted in models developed to control for severity of illness and chronic comorbidity burden.


title: IgA deficiency destabilizes immunological homeostasis towards intestinal microbiota and increases the risk of systemic immune dysregulation

abstract:
Mammals produce large quantities of mucosal and systemic antibodies that maintain the intestinal barrier, shape the intestinal microbiome and promote lifelong mutualism with commensal microbes. Here, we developed an integrated host-commensal approach combining microbial flow cytometry and 16s rRNA gene sequencing to define the core microbes that induce mucosal and systemic antibodies in pediatric selective Immunoglobulin A (IgA) deficient and household control siblings with CyTOF analysis to determine the impacts of IgA deficiency on host cellular immune phenotype. In healthy controls, mucosal secretory IgA and IgM antibodies coat an overlapping subset of microbes, predominantly Firmicutes and Proteobacteria. Serum IgG antibodies target a similar consortium of fecal microbes, revealing connections between mucosal and systemic antibody networks. Unexpectedly, IgM provides limited compensation for IgA in children lacking intestinal IgA. Furthermore, we find broad systemic immune dysregulation in a subset of children and mice lacking IgA, including enhanced IgG targeting of fecal microbiota, elevated levels of inflammatory and allergic cytokines and alterations in T cell activation state. Thus, IgA tunes systemic interactions between the host and commensal microbiota. Understanding how IgA tunes baseline immune tone has implications for predicting and preventing autoimmune, inflammatory and allergic diseases broadly, as well as providing improved prognostic guidance to patients with IgA deficiency.

One Sentence SummaryIgA deficiency impairs immune homeostasis toward microbiota in children, increasing the risk of immune dysregulation.