title: Cell-mediated and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients

abstract:
ImportanceData on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited.

ObjectiveTo determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response.

DesignRetrospective observational cohort study.

SettingLarge healthcare system in Northern California.

ParticipantsThis study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection.

Exposure(s)Immunosuppressive diseases and therapies.

Main Outcome(s) and Measure(s)Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination.

Results496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (P<.001), sphingosine 1-phsophate (S1P) receptor modulators (P<.001), mycophenolate (P=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (P<.001) and mycophenolate (P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose.

Conclusions and RelevanceCellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.


title: Estimation of causal effects of a time-varying exposure at multiple time points through Multivariable Mendelian randomization

abstract: Mendelian Randomisation (MR) is a powerful tool in epidemiology to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilising genetic variants as instrumental variables (IVs) for the exposure. The effects obtained from MR studies are often interpreted as the lifetime effect of the exposure in question. However, the causal effects of many exposures are thought to vary throughout an individuals lifetime and there may be periods during which an exposure has more of an effect on a particular outcome. Multivariable MR (MVMR) is an extension of MR that allows for multiple, potentially highly related, exposures to be included in an MR estimation. MVMR estimates the direct effect of each exposure on the outcome conditional on all of the other exposures included in the estimation. We explore the use of MVMR to estimate the direct effect of a single exposure at different time points in an individuals lifetime on an outcome. We use simulations to illustrate the interpretation of the results from such analyses and the key assumptions required. We show that causal effects at different time periods can be estimated through MVMR when the association between the genetic variants used as instruments and the exposure measured at those time periods varies, however this estimation will not necessarily identify exact time periods over which an exposure has the most effect on the outcome. We illustrate the method through estimation of the causal effects of childhood and adult BMI on smoking behaviour.

category: epidemiology


title: Validation of a novel fluorescent lateral flow assay for rapid qualitative and quantitative assessment of total anti-SARS-CoV-2 S-RBD binding antibody units (BAU) from plasma or fingerstick whole-blood of COVID-19 vaccinees

abstract:
BackgroundLimited commercial LFA assays are available to provide a reliable quantitative measurement of the total binding antibody units (BAU/mL) against the receptor-binding domain of the SARS-CoV-2 spike protein (S-RBD).

AimTo evaluate the performance of FinecareTM2019-nCoV S-RBD LFA and its fluorescent reader (FinecareTM-FIA Meter) against the following reference methods (i) The FDA-approved Genscript surrogate virus-neutralizing assay (sVNT), and (ii) three highly performing automated immunoassays: BioMerieux VIDAS(R)3, Ortho VITROS(R), and Mindray CL-900i(R).

MethodsPlasma from 488 vaccinees were tested by all aforementioned assays. Fingerstick whole-blood samples from 156 vaccinees were also tested by FinecareTM.

Results and conclusionsFinecareTM showed 100% specificity as none of the pre-pandemic samples tested positive. Equivalent FinecareTM results were observed among the samples taken from fingerstick or plasma (Pearson correlation r=0.9, p<0.0001), suggesting that fingerstick samples are sufficient to quantitate the S-RBD BAU/mL. A moderate correlation was observed between FinecareTM and sVNT (r=0.5, p<0.0001), indicating that FinecareTM can be used for rapid prediction of the neutralization antibody post-vaccination. FinecareTM BAU results showed strong correlation with VIDAS(R)3 (r=0.6, p<0.0001), and moderate correlation with VITROS(R) (r=0.5, p<0.0001), and CL-900i(R) (r=0.4, p<0.0001), suggesting that FinecareTM be used as a surrogate for the advanced automated assays to measure S-RBD BAU/mL.

category: infectious diseases


title: Inherently explainable deep neural network-based interpretation of electrocardiograms using variational auto-encoders

abstract:
BackgroundDeep neural networks (DNNs) show excellent performance in interpreting electrocardiograms (ECGs), both for conventional ECG interpretation and for novel applications such as detection of reduced ejection fraction and prediction of one-year mortality. Despite these promising developments, clinical implementation is severely hampered by the lack of trustworthy techniques to explain the decisions of the algorithm to clinicians. Especially, currently employed heatmap-based methods have shown to be inaccurate.

MethodsWe present a novel approach that is inherently explainable and uses an unsupervised variational auto-encoder (VAE) to learn the underlying factors of variation of the ECG (the FactorECG) in a database with 1.1 million ECG recordings. These factors are subsequently used in a pipeline with common and interpretable statistical methods. As the ECG factors are explainable by generating and visualizing ECGs on both the model- and individual patient-level, the pipeline becomes fully explainable. The performance of the pipeline is compared to a state-of-the-art  black box DNN in three tasks: conventional ECG interpretation with 35 diagnostic statements, detection of reduced ejection fraction and prediction of one-year mortality.

FindingsThe VAE was able to compress the ECG into 21 generative ECG factors, which are associated with physiologically valid underlying anatomical and (patho)physiological processes. When applying the novel pipeline to the three tasks, the explainable FactorECG pipeline performed similar to state-of-the-art  black box DNNs in conventional ECG interpretation (AUROC 0{middle dot}94 vs 0{middle dot}96), detection of reduced ejection fraction (AUROC 0{middle dot}90 vs 0{middle dot}91) and prediction of one-year mortality (AUROC 0{middle dot}76 vs 0{middle dot}75). Contrary to state-of-the-art, our pipeline provided inherent explainability on which morphological ECG features were important for prediction or diagnosis.

InterpretationFuture studies should employ DNNs that are inherently explainable to facilitate clinical implementation by gaining confidence in artificial intelligence, and more importantly, making it possible to identify biased or inaccurate models.

FundingThis study was financed by the Netherlands Organisation for Health Research and Development (ZonMw, no. 104021004) and the Dutch Heart Foundation (no. 2019B011).

Research into ContextO_ST_ABSEvidence before this studyC_ST_ABSA comprehensive literature survey was performed for research articles on interpretable or explainable artificial intelligence (AI) for interpretation of raw electrocardiograms (ECGs) using PubMed and Google Scholar databases. Articles in English up to November 24, 2021, were included and the following key words were used: deep neural network (DNN), deep learning, convolutional neural network, artificial intelligence, electrocardiogram, ECG, explainability, explainable, interpretability, interpretable, and visualization. Many studies that used DNNs to interpret ECGs with high predictive performances were found, some focusing on tasks known to be associated with the ECG (e.g., rhythm disorders) and others identifying completely novel use cases for the ECG (e.g. reduced ejection fraction). All of these studies employed post-hoc explainability techniques, where the decisions of the  black box DNN were visualized after training, usually using heatmaps (i.e., using Grad-CAM, SHAP or LIME). In these studies, only some example ECGs were handpicked, as these heatmap-based techniques only work on single ECGs. Three studies also investigated the global features of the model by taking a summary measure of the heatmaps, by relating heatmaps to known ECG parameters (i.e., QRS duration) or by using prototypes. No studies investigated whether the features found using heatmaps were robust or reproducible.

Added value of this studyCurrently employed post-hoc explainability techniques, usually heatmap-based, have limited explainable value as they merely indicate the temporal location of a specific feature in the individual ECG. Moreover, these techniques have been shown to be unreliable, poorly reproducible and suffer from confirmation bias. To address this gap in knowledge, we designed a DNN that is inherently explainable (i.e. explainable by design instead of investigating post-hoc). This DNN is used in a pipeline that consists of three components: (i) a generative DNN (variational auto-encoder) that learned to encode the ECG into its underlying 21 continuous factors of variation (the FactorECG), (ii) a visualization technique to provide insight into these ECG factors, and (iii) a common interpretable statistical method to perform diagnosis or prediction using the ECG factors. Model-level explainability is obtained by varying the ECG factors while generating and plotting ECGs, which allows for visualization of detailed changes in morphology, that are associated with physiologically valid underlying anatomical and (patho)physiological processes. Moreover, individual patient-level explanations are also possible, as every individual ECG has its representative set of explainable FactorECG values, of which the associations with the outcome are known. When using the explainable pipeline for interpretation of diagnostic ECG statements, detection of reduced ejection fraction and prediction of one-year mortality, it yielded predictive performances similar to state-of-the-art  black box DNNs. Contrary to the state-of-the-art, our pipeline provided inherent explainability on which ECG features were important for prediction or diagnosis. For example, ST elevation was discovered to be an important predictor for reduced ejection fraction, which is an important finding as it could limit the generalizability of the algorithm to the general population.

Implications of all the available evidenceA longstanding assumption was that the high-dimensional and non-linear  black box nature of the currently applied ECG-based DNNs was inevitable to gain the impressive performances shown by these algorithms on conventional and novel use cases. This study, however, shows that inherently explainable DNNs should be the future of ECG interpretation, as they allow reliable clinical interpretation of these models without performance reduction, while also broadening their applicability to detect novel features in many other (rare) diseases. The application of such methods will lead to more confidence in DNN-based ECG analysis, which will facilitate the clinical implementation of DNNs in routine clinical practice.

category: cardiovascular medicine


title: Factors Associated with COVID-19 Testing among People who Inject Drugs: Missed Opportunities for Reaching those Most at Risk

abstract: People who inject drugs (PWID) are vulnerable to SARS-CoV-2 infection. We examined correlates of COVID-19 testing among PWID in the U.S.-Mexico border region and described encounters with services or venues representing potential opportunities (i.e.,  touchpoints) where COVID-19 testing could have been offered. Between October, 2020 and September, 2021, participants aged [≥]18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month completed surveys and SARS-CoV-2, HIV, and HCV serologic testing. Logistic regression was used to identify factors associated with COVID-19 testing prior to enrollment. Of 583 PWID, 30.5% previously had a COVID-19 test. Of 172 PWID who tested SARS-CoV-2 seropositive in our study (30.1%), 50.3% encountered at least one touchpoint within the prior six months where COVID-19 testing could have been offered. Factors independently associated with at least two fold higher odds of COVID-19 testing were living in San Diego (versus Tijuana), having recently been incarcerated or attending substance use disorder (SUD) treatment and having at least one chronic health condition. In addition, recent homelessness, having had at least one COVID-19 vaccine dose and having been tested for HIV or HCV since the pandemic began were independently associated with COVID-19 testing. We identified several factors independently associated with COVID-19 testing and multiple touchpoints where COVID-19 testing could be scaled up for PWID, such as SUD treatment programs and syringe service programs. Integrated health services are needed to improve access to rapid, free COVID-19 testing in this vulnerable population.


title: The epidemiological impact of the Canadian COVID Alert App

abstract:
ObjectivesWe analyzed the effectiveness of the Canadian COVID Alert app on reducing COVID-19 infections and deaths due to the COVID-19 virus.

MethodsTwo separate, but complementary approaches, were taken. First, we undertook a comparative study to assess how the adoption and usage of the COVID Alert app compared to those of similar apps deployed in other regions. Next, we used data from the COVID Alert server and a range of plausible parameter values to estimate the numbers of infections and deaths averted in Canada using a model that combines information on number of notifications, secondary attack rate, expected fraction of transmissions that could be prevented, quarantine effectiveness, and expected size of the full transmission chain in the absence of exposure notification.

ResultsThe comparative analysis revealed that the COVID Alert app had among the lowest adoption levels among apps that reported usage. Our model indicates that use of the COVID Alert app averted between 6,284 and 10,894 infections across the six Canadian provinces where app usage was highest during the March - July 2021 period. This range is equivalent to 1.6%-2.9% of the total recorded infections across Canada in that time. Using province-specific case fatality rates, 57-101 deaths were averted during the same period. The number of cases and deaths averted was greatest in Ontario, whereas the proportion of cases and death averted was greatest in Newfoundland and Labrador. App impact measures were reported so rarely and so inconsistently by other countries that the relative assessment of impact is inconclusive.

ConclusionsWhile the nationwide rates are low, provinces with widespread adoption of the app showed high ratios of averted cases and deaths (upper bound was greater than 60% of averted cases). This finding suggests that the COVID Alert app, when adopted at sufficient levels, can be an effective public health tool for combatting a pandemic such as COVID-19.

category: public and global health


title: Neuropsychological and neuroanatomical features of patients with behavioral variant Alzheimer's disease (AD): a comparison to behavioral variant frontotemporal dementia and amnestic AD groups

abstract: An understudied non-amnestic variant of Alzheimers disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Subjects included 16 bvAD, 67 bvFTD, and 18 aAD patients, and 26 healthy controls. Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

category: neurology


title: Cortical and STN spectral changes during limb movements in PD patients with and without dystonia

abstract:
BackgroundDystonia is an under-studied motor feature of Parkinson disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.

ObjectivesTo investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in PD patients with and without dystonia.

MethodsWe examined the prevalence and distribution of dystonia in PD patients undergoing deep brain stimulation surgery and recorded intracranial electrophysiology from motor cortex and directional electrodes in subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.

ResultsDystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0{+/-}3.3 and 4.2{+/-}2.9 Hz peak frequencies for hand and foot movements respectively). PD patients with dystonia during DBS surgery displayed greater M1 beta power at rest and STN low frequency power during movements versus those without dystonia.

ConclusionsSpectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low frequency synchronization, especially in PD patients with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy.


title: Citizen Science and Public Health- Can eBird data inform relationships between public health and access to biodiversity?

abstract: The relationship between access to nature and public health outcomes has been well-studied and established in the literature. However, most studies use simple greenness indices as a proxy for access to nature, which ignores the "quality" of the nature since greenness indices are not able to predict biodiversity. My objective was to investigate the relationship between citizen scientist collected biodiversity data from the eBird platform, urban greenness and four human health outcomes (asthma, coronary heart disease, and self-assessed mental and physical health). I mapped and tested for correlations among eBird record species richness, greenness as NDVI and PLACES human health data in urban census tracts located in three metro areas/ecological zones (Albany, NY: eastern deciduous forest, Kansas City, MO: tallgrass prairie, and Phoenix, AZ: Sonoran Desert). eBird species richness was related to greenness, measures of urbanization and several human health factors; however, the correlations varied by metro area and in strength. Provided confounders are controlled for, eBird data could help to refine models surrounding relationships between public health and nature access.

category: occupational and environmental health


title: Surgical interventions targeting the nucleus caudalis: a systematic review and historical perspective.

abstract:
IntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.

MethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.

ResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.

ConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis.

category: pain medicine


title: Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review.


title: Hypothesis-free detection of gene-interaction effects on biomarker concentration in UK Biobank using variance prioritisation

abstract: Blood biomarkers include disease intervention targets that may interact with genetic and environmental factors resulting in subgroups of individuals who respond differently to treatment. Such interactions may be observed in genetic effects on trait variance. Variance prioritisation is an approach to identify genetic loci with interaction effects by estimating their association with trait variance, even where the modifier is unknown or unmeasured. Here, we develop and evaluate a regression-based Brown-Forsythe test and variance effect estimate to detect such interactions. We provide scalable open-source software (varGWAS) for genome-wide association analysis of SNP-variance effects (https://github.com/MRCIEU/varGWAS) and apply our software to 30 blood biomarkers in UK Biobank. We find 468 variance quantitative trait loci across 24 biomarkers and follow up findings to detect 82 gene-environment and six gene-gene interactions independent of strong scale or phantom effects. Our results replicate existing findings and identify novel epistatic effects of TREH rs12225548 x FUT2 rs281379 and TREH rs12225548 x ABO rs635634 on alkaline phosphatase and ZNF827 rs4835265 x NEDD4L rs4503880 on gamma glutamyltransferase. These data could be used to discover possible subgroup effects for a given biomarker during preclinical drug development.

category: genetic and genomic medicine


title: The impact of Mendelian sleep and circadian genetic variants in a population setting

abstract:
Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants of these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts.

We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data.

We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. We found no association of any of these variants with extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P=4x10-8; and had a 57-minute earlier midpoint sleep, P=5x10-7).

Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.


title: Towards Predicting 30-Day Readmission among Oncology Patients: Identifying Timely and Actionable Risk Factors

abstract:
1PurposePredicting 30-day readmission risk is paramount to improving the quality of patient care. Previous studies have examined clinical risk factors associated with hospital readmissions. In this study, we compare sets of patient, provider, and community-level variables that are available at two different points of a patients inpatient encounter (first 48 hours and the full encounter) to train readmission prediction models in order to identify and target appropriate actionable interventions that can potentially reduce avoidable readmissions.

MethodsUsing EHR data from a retrospective cohort of 2460 oncology patients, two sets of binary classification models predicting 30-day readmission were developed; one trained on variables that are available within the first 48 hours of admission and another trained on data from the entire hospital encounter. A comprehensive machine learning analysis pipeline was leveraged including preprocessing and feature transformation, feature importance and selection, machine learning modeling, and post-analysis.

ResultsLeveraging all features, the LGB (Light Gradient Boosting Machine) model produced higher, but comparable performance: (AUROC: 0.711 and APS: 0.225) compared to Epic (AUROC: 0.697 and APS: 0.221). Given features in the first 48-hours, the RF (Random Forest) model produces higher AUROC (0.684), but lower AUPRC (0.18) and APS (0.184) than the Epic model (AUROC: 0.676). In terms of the characteristics of patients flagged by these models, both the full (LGB) and 48-hour (RF) feature models were highly sensitive in flagging more patients than the Epic models. Both models flagged patients with a similar distribution of race and sex; however, our LGB and random forest models more inclusive flagging more patients among younger age groups. The Epic models were more sensitive to identifying patients with an average lower zip income. Our 48-hour models were powered by novel features at various levels: patient (weight change over 365 days, depression symptoms, laboratory values, cancer type), provider (winter discharge, hospital admission type), community (zip income, marital status of partner).

ConclusionWe demonstrated that we could develop and validate models comparable to existing Epic 30-day readmission models, but provide several actionable insights that could create service interventions deployed by the case management or discharge planning teams that may decrease readmission rates over time.

category: health informatics


title: Effects of Varying Approaches to Lifting COVID-19 Pandemic Restrictions in the United States

abstract:
BackgroundPolicy approaches to lifting COVID-19 restrictions have varied significantly across the United States. An evaluation of the effects of state reopening policies on population health outcomes can inform ongoing and future pandemic responses. This study evaluates the approaches to lifting social distancing restrictions based on adherence to the Centers for Disease Control and Prevention (CDC) guidance established during the first wave of the COVID-19 pandemic.

MethodsWe performed a retrospective study using difference-in-differences analyses to examine the effects of reopening policies on COVID-19 outcomes with risk-adjustment for population density, temporal changes, and concurrent mask policy implementation. We examined the effects of reopening policies on per capita case rates and rates of severe COVID-19 outcomes, including hospitalizations and deaths.

ResultsAdherence to the CDCs reopening gating metrics and phased social distancing guidelines resulted in fewer COVID-19 cases, hospitalizations, and deaths. Phase one adherent states exhibited a 50-fold reduction in daily new cases and a 3-fold reduction in daily new deaths after reopening. Phase two adherent states experienced improvements in COVID-19 outcomes after reopening, while non-adherent states had a resurgence of worsening outcomes after lifting restrictions.

ConclusionsOur study findings indicate that adherence to the CDCs reopening guidance after implementing social distancing restrictions during the COVID-19 pandemic substantially prevents new cases, hospitalizations, and deaths. Following a stepwise reopening strategy and ensuring a sustained decline in case rates and test positivity rates before lifting restrictions can mitigate on a large scale the negative effects of a pandemic on population health outcomes.

category: health policy


title: Detection of fecal coliforms and SARS-CoV-2 RNA in sewage and recreational waters in the Ecuadorian Coast: a call for improving water quality regulation

abstract:
Wastewater surveillance represents an alternative approach for the diagnosis and early detection of infectious agents of public health importance. This study aimed to evaluate SARS-CoV-2 and other quality markers in oxidation lagoons, estuarine areas and seawater at Guayas and Santa Elena in Ecuador. Sample collections were conducted twice at 42 coastal sites and 2 oxidation lagoons during dry and rainy seasons (2020-2021). Physico-chemical and microbiological parameters were evaluated to determine organic pollution. Quantitative reverse transcription PCR was conducted to detect SARS-CoV-2. Results showed high levels of Escherichia coli and low dissolved oxygen concentrations. SARS-CoV-2 was detected in sea-waters and estuaries with salinity levels between 34.2-36.4 PSU and 28.8 {degrees}C-31.3 {degrees}C. High amounts of fecal coliforms were detected and correlated with the SARS-CoV-2 shedding. We recommend to decentralized autonomous governments in developing countries such as Ecuador to implement corrective actions and establish medium-term mechanisms to minimize a potential contamination route.

HIGHLIGHTSO_LISARS-CoV-2 RNA was detected in estuaries, bays and the wastewater treatment systems in Playas and Santa Elena.
C_LIO_LIHigh levels of fecal coliforms were detected along shorelines.
C_LIO_LIWater quality parameters revealed a negative impact on the beaches studied associated with human activities.
C_LI


title: T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all prior infected and vaccinated individuals

abstract: The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from infection and vaccine-induced antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. Here we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals ([~]21%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and reveal that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment. Booster vaccination substantially enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.


title: Containment of a multi-index B.1.1.7 outbreak on a university campus through a genomically-informed public health response

abstract: The first cluster of SARS-CoV-2 cases with lineage B.1.1.7 in the state of Michigan was identified through intensive university-led surveillance sampling and targeted sequencing. A collaborative investigation and response was conducted by the local and state health departments, and the campus and athletic medicine COVID-19 response teams, using S-gene target failure screening and rapid genomic sequencing to inform containment strategies. A total of 50 cases of B.1.1.7-lineage SARS-CoV-2 were identified in this outbreak, which was due to three coincident introductions of B.1.1.7-lineage SARS-CoV-2, all of which were genetically distinct from lineages which later circulated in the broader community. This investigation demonstrates the successful implementation of a genomically-informed outbreak response which can be extended to university campuses and other settings at high risk for rapid emergence of new variants.


title: Differential Effects of Race/Ethnicity and Social Vulnerability on COVID-19 Positivity, Hospitalization, and Death in the San Francisco Bay Area

abstract:
BACKGROUNDHigher COVID-19 incidence and morbidity have been documented for US Black and Hispanic populations but not as clearly for other racial and ethnic groups. Efforts to elucidate the mechanisms underlying racial health disparities can be confounded by the relationship between race/ethnicity and socioeconomic status.

OBJECTIVEExamine race/ethnicity and social vulnerability effects on COVID-19 out-comes in the San Francisco Bay Area, an ethnically and socioeconomically diverse region, using geocoded patient records from 2020 in the University of California, San Francisco Health system.

KEY RESULTSHigher social vulnerability, but not race/ethnicity, was associated with less frequent testing yet a higher likelihood of testing positive. Asian hospitalization rates (11.5%) were double that of White patients (5.4%) and exceeded the rates for Black (9.3%) and Hispanic patients (6.9%). A modest relationship between higher hospitalization rates and increasing social vulnerability was evident only for White patients. Hispanic patients had the highest years of expected life lost due to COVID-19.

CONCLUSIONSCOVID-19 outcomes were not consistently explained by greater social vulnerability. Asian individuals showed disproportionately high rates of hospitalization regardless of social vulnerability status. Study of the San Francisco Bay Area population not only provides valuable insights into the differential contributions of race/ethnicity and social determinants of health to COVID-19 outcomes but also emphasizes that all racial groups have experienced the toll of the pandemic, albeit in different ways and to varying degrees.


title: Heterologous vaccination with inactivated and mRNA vaccines increases B and T cell responses to SARS-CoV-2

abstract:
BackgroundThere has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines.

MethodsThe levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples.

ResultsA booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses.

ConclusionsHeterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron.

category: allergy and immunology


title: Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant


title: Multimodal repertoire analysis unveils B cell biology in health and immune-mediated diseases

abstract: Despite involvement of B cells in the pathogenesis of immune-mediated diseases, biological mechanisms underlying their function are scarcely understood. To overcome this gap, comprehensive analysis of the B cell repertoire is essential. Here, we cataloged and investigated the repertoire of five B cell subsets from 595 cases under immune-mediated diseases and health. CDR-H3 length among naive B cells was shortened among autoimmune diseases in an interferon signature-dependent manner. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of systemic lupus erythematosus patients with frequent usage of VDJ genes used mainly in naive B cells and not unswitched-memory B cells of healthy controls. We developed a scoring system for this skewing, and it correlated with peripheral helper T cell transcriptomic signatures and disease activity and decreased after belimumab treatment. Moreover, genetic association analysis identified three molecules possibly involved in somatic hyper-mutation processes in humans. Our multimodal repertoire analysis brings new insights to B cell biology.


title: Heart Block in patients with COVID-19

abstract:
BackgroundSince the emergence of the SARS COV-19 pandemic, multiple extrapulmonary manifestations of the virus have been reported from around the world. Cardiovascular complications including arrhythmias in patients with COVID-19 have been described in multiple studies. Our aim was to review various case reports detailing the new onset of heart block in COVID-19 patients and to summarise the clinical course of these patients.

MethodsWe systematically reviewed all reports published and indexed in PubMed, Scopus, and Embase between March 2020 to May 2021, analyzing the relation between the demographics of the patients, pre-existing comorbidities, and the progression of heart block in patients infected with COVID-19.

ResultsWe identified and included in this study 30 relevant articles describing 49 COVID-19 patients with heart block. Among them, 69.3% (n=34) of patients suffered from at least one comorbidity. 36.73% (n=18) of the patients showed spontaneous resolution of the heart block. Conversely, 63.26% (n=31) of the patients had persistent heart block, out of which 16.33% (n=8) and 42.86% (n=21) were implanted with a temporary and permanent pacemaker respectively. The reported mortality rate was 22.45% (n=11) during hospitalization. We noted that 45.45% (n=5) of the patients who died had complete heart block. 24.49% (n=12) of the patients in the studies we reviewed were suspected of having myocarditis. However, none were confirmed with MRI or cardiac biopsy.

ConclusionsAdditional research is necessary to unearth the mechanism of development of heart block in COVID-19 patients as well as its implications on the clinical course and prognosis. Physicians must be aware of the importance of monitoring patients hospitalized for COVID-19 for arrhythmias including heart blocks, especially in the presence of comorbidities. Early detection can improve the prognosis of the patient.


title: Waning Effectiveness of the BNT162b2 Vaccine Against Infection in Adolescents

abstract:
BackgroundThe short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, though, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months.

MethodsLeveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where two outcomes were evaluated separately: a documented SARS-CoV-2 infection (regardless of symptoms) and a symptomatic infection (COVID-19). Cases were defined as individuals aged 12 to 16 with a positive PCR test occurring between June 15 and December 8, 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously.

ResultsWe estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% and 90% effectiveness against SARS-CoV-2 infection and COVID-19, respectively. However, in line with previous findings for adults, waning of vaccine effectiveness was evident in adolescents as well. Long-term protection conferred by the vaccine was reduced to 75-78% against infection and symptomatic infection, respectively, 3 to 5 months after the second dose, and waned to 58% against infection and 65% against COVID-19 after 5 months.

ConclusionsLike adults, vaccine-induced protection against both SARS-CoV-2 infection and COVID-19 wanes with time, starting three months after inoculation and continuing for more than five months.


title: Meta-analysis of COVID-19 patients to understand the key predictors of mortality in the non-vaccinated groups in remote settings

abstract: Various studies have looked into the impact of the COVID-19 vaccine on large populations. However, very few studies have looked into the remote setting of hospitals where vaccination is challenging due to social structure, myths, and misconceptions. There is a consensus that elevated inflammatory markers such as CRP, ferritin, D-dimer correlate with increased severity of COVID-19 and are associated with worse outcomes. In the present study, through retrospective meta-analysis, we have looked into [~]20 months of SARS-COV2 infected patients with known mortality status and identified predictors of mortality concerning their comorbidities, various clinical parameters, inflammatory markers, superimposed infections, length of hospitalization, length of mechanical ventilation and ICU stay. Studies with larger sample sizes have covered the outcomes through epidemiological, social, and survey-based analysis--however, most studies cover larger cohorts from tertiary medical centers. In the present study, we assessed the outcome of non-vaccinated COVID 19 patients in a remote setting for 20 months from January 1, 2020, to August 30, 2021, at CHI Mercy Health in Roseburg, Oregon. We also included two vaccinated patients from September 2021 to add to the power of our cohort. The study will provide a comprehensive methodology and deep insight into multi-dimensional data in the unvaccinated group, translational biomarkers of mortality, and state-of-art to conduct such studies in various remote hospitals.


title: Development of the one-step qualitative RT-PCR assay to detect SARS-CoV-2 Omicron (B.1.1.529) variant in respiratory specimens

abstract: A new SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern has been emerging worldwide. We are seeing an unprecedented surge in patients due to Omicron in this COVID-19 pandemic. A rapid and accurate molecular test that effectively differentiates Omicron from other SARS-CoV-2 variants would be important for both epidemiologic value and for directing variant-specific therapies such as monoclonal antibody infusions. In this study, we developed a real-time RT-PCR assay for the qualitative detection of Omicron from routine clinical specimens sampling the upper respiratory tract. The limit of detection of the SARS-CoV-2 Omicron variant RT-PCR assay was 2 copies/l. Notably, the assay did not show any cross-reactivity with other SARS-CoV-2 variants including Delta (B.1.617.2). This SARS-CoV-2 Omicron variant RT-PCR laboratory-developed assay is sensitive and specific to detect Omicron in nasopharyngeal and nasal swab specimens.

category: pathology


title: Exploring the impact of shielding advice on the health and wellbeing of individuals identified as extremely vulnerable and advised to shield in Southwest England amid the COVID-19 pandemic: A mixed-methods evaluation

abstract:
ObjectiveExplore the impact and responses to public health advice on the health and wellbeing of individuals identified as clinically extremely vulnerable (CEV) and advised to shield (not leave home for 12 weeks at start of the pandemic) in Southwest England during the first COVID-19 lockdown.

DesignMixed-methods study; structured survey and follow-up semi-structured interviews.

SettingCommunities served by Bristol, North Somerset & South Gloucestershire Clinical Commissioning Group.

Participants204 people (57% female, 54% >69 years, 94% White British, 64% retired) in Southwest England identified as CEV and were advised to shield completed the survey. Thirteen survey respondents participated in follow-up interviews (53% female, 40% >69years, 100% White British, 61% retired).

ResultsReceipt of  official communication from NHS England or General Practitioner (GP) was considered by participants as the legitimate start of shielding. 80% of survey responders felt they received all relevant advice needed to shield, yet interviewees criticised the timing of advice and often sought supplementary information. Shielding behaviours were nuanced, adapted to suit personal circumstances, and waned over time. Few interviewees received community support, although food boxes and informal social support were obtained by some. Worrying about COVID-19 was common for survey responders (90%). Since shielding had begun, physical and mental health reportedly worsened for 35% and 42% of survey responders respectively. 21% of survey responders scored [≥]10 on the PHQ-9 questionnaire indicating possible depression and 15% scored [≥]10 on the GAD-7 questionnaire indicating possible anxiety.

ConclusionsThis research highlights the difficulties in providing generic messaging that is applicable and appropriate given the diversity of individuals identified as CEV and the importance of sharing tailored and timely advice to inform shielding decisions. Providing messages that reinforce self-determined action and assistance from support services could reduce the negative impact of shielding on mental health and feelings of social isolation.

O_TEXTBOXStrengths and limitations of this study

O_LIThe mixed-methods study examines the experiences of clinically extremely vulnerable (CEV) people at the height of the COVID-19 crisis, immediately after the first lockdown in England.
C_LIO_LIThe use of an existing list of individuals identified as needing to "shield" from Bristol, North Somerset & South Gloucestershire (BNSSG) Clinical Commissioning Group (CCG) allowed for access to key patient groups at the height of the crisis.
C_LIO_LIFindings may not be applicable to wider CEV populations due to demographic bias.
C_LI

C_TEXTBOX


title: Personal Resilience, Social Support, and Organizational Support Impact Burnout among Nurses During COVID-19

abstract:
BackgroundNurses have been under heavy workloads since the outbreak of COVID-19 and are at a high risk of infection, leading to a high level of psychosocial risk. This can adversely affect nurses both psychologically and physically. Burnout is caused by prolonged stress during work. In the nursing profession, burnout is common, potentially affecting the well-being of nurses and their productivity. The identification of factors that may contribute to maintaining mental health and reducing burnout among frontline nurses during a pandemic is essential.

PurposeThe purpose of this study was to explore how personal resilience, social support, and organizational support impact burnout among frontline staff nurses.

MethodsThis study involved 129 registered nurses from a COVID-19 designated hospital using four standardized scales.

ResultsThe mean age of the respondents was 29.46 years (standard deviation = 4.89). The mean number of years respondents worked in this organization was 5.60 years and the nursing profession was 4.16 years. Most of the respondents were female and held a bachelors degree in nursing. Multiple regression analysis was performed to predict burnout. Burnout was statistically significantly predicted by the multiple regression model (R2 = .420, F (3, 125) = 10.941, p < .0001; adjusted R2 = .406). Personal resilience, social support, and organizational support added statistically significantly to the prediction of burnout (p < .05).

ConclusionFindings from multiple regression analysis showed that nurses with low resilience and those who perceived inadequate social and organizational support had a higher risk of reporting more burnout. As a result of a bivariate analysis, there was no significant correlation between nurse variables and burnout level, except for age, which was negatively correlated with burnout level. Accordingly, young nurses tend to experience burnout, and nurse directors and managers must address this problem.

category: nursing


title: SARS-CoV-2 Genetic diversity and lineage dynamics of in Egypt

abstract: COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of national genomic surveillance, 1,027 SARS-CoV-2 near whole-genomes had been generated and published by the end of May 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analysed together with a representative set of global sequences within a phylogenetic framework. We show that a single lineage, C.36, introduced early in the pandemic was responsible for most cases in Egypt. Furthermore, we show that to remain dominant in the face of mounting immunity from previous infection and vaccination, this lineage evolved into various sub-lineages acquiring several mutations known to confer adaptive advantage and pathogenic properties. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and enforcement of public health measures to prevent expansion of existing lineages.


title: Timing of Breakthrough Infection Risk After Vaccination Against SARS-CoV-2

abstract:
BackgroundProvision of safe and effective vaccines has been a remarkable public health achievement during the SARS-CoV-2 pandemic. The effectiveness and durability of protection of the first two doses of SARS-CoV-2 vaccines is an important area for study, as are questions related to optimal dose combinations and dosing intervals.

MethodsWe performed a case-cohort study to generate real-world evidence on efficacy of first and second dose of SARS-CoV-2 vaccines, using a population-based case line list and vaccination database for the province of Ontario, Canada between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2% sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate.

ResultsFirst and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68%, 95% CI 67% to 69%; second dose efficacy 88%, 95% CI 87 to 88%). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95% CI 0.61 to 0.67) at 6-8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4-6 months after the second vaccine dose, but rose markedly thereafter.

InterpretationA case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination, particularly after the second dose of vaccine. However, this effect appeared to wane once more than 6 months had elapsed since vaccination. Heterologous vaccination and extended dosing intervals improved the durability of immune response.


title: Phylogeography of hepatitis B: The role of Portugal in the early dissemination of HBV worldwide

abstract: In 2015, 257 million people lived with chronic hepatitis B infection. In Portugal 1.4% of the population is chronically infected with hepatitis B virus. Limited information is available regarding the genetic diversity, origin of HBV in Portugal and its role in the dissemination of HBV worldwide. In this study, we aimed to investigate the epidemic history and transmission dynamics of HBV genotypes that are endemic in Portugal. HBV pol gene was sequenced from 130 patients followed in Lisbon. HBV genotype A (HBV/A) was the most prevalent genotype (n=54, 41.5%), followed by D [HBV/D; (n=44, 33.8%)], and E [HBV/E; (n=32, 24.6%)]. Spatio-temporal evolutionary dynamics were reconstructed using a Bayesian Markov Chain Monte Carlo method, as implemented in BEAST v1.10.4, with a GTR nucleotide substitution model, an uncorrelated lognormal relaxed molecular clock model under a Bayesian skyline plot and a continuous diffusion model. Our results indicate that HBV/D4 was the first subgenotype to be introduced in Portugal by the end of the XIX century, around 1857 (HPD 95% 1699 - 1931) followed by subgenotypes D3 and A2 a few decades later. Genotype E and subgenotype A1 were introduced in Portugal later, almost simultaneously. Our results also indicate a very important role of Portugal in the exportation of HBV subgenotypes D4 and A2 to Brazil and Cape Verde, respectively, in the beginning of the XX century. This work clarifies the epidemiological history of HBV in Portugal and show that Portugal had an important role in the global spread of this virus.


title: Sub-optimal Neutralisation of Omicron (B.1.1.529) Variant by Antibodies induced by Vaccine alone or SARS-CoV-2 Infection plus Vaccine (Hybrid Immunity) post 6-months

abstract:
BackgroundRapid expansion of the omicron SARS-CoV-2 variant of concern despite extensive vaccine coverage might be related to decreased neutralising ability of vaccine induced antibodies. The neutralising ability of different vaccines with or without natural SARS-CoV-2 infection against omicron is however not well known.

MethodsWe tested the ability of vaccine and natural infection induced antibodies to neutralise omicron variant in a live virus neutralisation assay. Four groups of individuals were included: (i) complete vaccination with ChAdOx1 nCoV-19 (n=20), (ii) complete vaccination with ChAdOx1 nCoV-19 plus prior SARS-CoV-2 infection during the delta variant driven surge (n=20), (iii) complete vaccination with inactivated whole virus vaccine (BBV152) (n=20), (iv) complete vaccination with BBV152 plus prior SARS-CoV-2 infection (n=20). Primary outcome was fold-change in the virus neutralisation ability of plasma against the omicron variant compared with ancestral and delta variant.

FindingsThe neutralisation geometric mean titre (GMT) was 384 (95% CI: 662, 223) against the ancestral virus with BBV152 vaccination alone and 383 (95% CI: 709, 207) with ChAdOx1 nCov-19 vaccination alone. The corresponding values for hybrid immunity groups were 795 (95% CI: 1302, 486) and 1424 (95% CI: 2581,786) respectively. Against the omicron variant, only 5 out of 20 in both BBV152 and ChAdOx1 nCoV-19 vaccine only groups, 5 out of 19 in BBV152 plus SARS-CoV-2 infection group, and 9 out of 20 in ChAdOx1 nCoV-19 plus SARS-CoV-2 infection group exhibited neutralisation titres above the lower limit of quantification (1:20) suggesting better neutralization in those with prior infection. The 50% neutralisation against ancestral strain and omicron demonstrated strong correlation with anti-RBD IgG levels [Pearson r: 0.94 (0.91, 0.96) p: <0.001 and 0.92 (0.88, 0.95) p:<0.001 respectively].

InterpretationOmicron variant shows significant reduction in neutralising ability of both vaccine induced and hybrid immunity induced antibodies which might explain immune escape and high transmission even in the presence of widespread vaccine coverage.

FundingDBT, India; GIISER-BMGF, USA

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe Omicron variant of SARS-CoV-2 is fast becoming the dominant circulating strain world-wide. We did a literature search on PubMed between 01 November 2020 to 04 January 2022 using the terms "Omicron" and "neutralisation" and found 11 results for virus neutralisation against omicron by vaccine/natural infection induced antibodies. We identified two published and one preprint articles relevant to omicron virus neutralisation using live virus neutralization. Preliminary reports suggest that omicron variant is significantly less susceptible to in-vitro neutralisation by antibodies among recipients of mRNA vaccines (BNT162b2 and mRNA-1273), adenovirus vectored vaccine (ChAdOx1 nCoV-19 vaccines) and no virus neutralization was observed in subjects who received Coronavac (inactivated virus vaccine). Data regarding immune escape among those with natural SARS-CoV2 infection and vaccination are not available.

Added value of this studyWe report here that the proportion of neutralisers (those who demonstrated a FRNT50 titre >1:20) was significantly reduced against the omicron variant as compared to the ancestral and delta variant. The geometric mean titre of neutralisation among the vaccinated individuals without a history of previous natural infection was significantly reduced against the omicron variant as compared with ancestral and delta variants. The titres among the those with a history of previous infection also followed the same pattern, but the neutralising ability was better in them than those who did not have previous infection.

Implications of all the available evidenceOmicron variant of SARS-CoV-2 is capable of escaping immunity provided by currently available vaccines and even natural infection due to significant mutations in its spike protein. The drop in neutralisation might be alarming, but the real-world impact of these reduced neutralisation titres on major public health indices like hospitalisation rates and mortality rates have to be interpreted along with the other factors such as inherent pathogenicity of the variant, immunization uptakes and seroprevalence from natural infection in different geographical regions and the expected role of cellular immune responses to the variant. Our data may guide policy on booster vaccination to deal with an impending public health emergency as a result of surge in omicron cases.


title: Lineage replacement and evolution captured by the United Kingdom Covid Infection Survey

abstract: The Office for National Statistics COVID-19 Infection Survey is a large household-based surveillance study based in the United Kingdom. Here, we report on the epidemiological and evolutionary dynamics of SARS-CoV-2 determined by analysing sequenced samples collected up until 13th November 2021. We observed four distinct sweeps or partial-sweeps, by lineages B.1.177, B.1.1.7/Alpha, B.1.617.2/Delta, and finally AY.4.2, a sublineage of B.1.617.2, with each sweeping lineage having a distinct growth advantage compared to their predecessors. Evolution was characterised by steady rates of evolution and increasing diversity within lineages, but with step increases in divergence associated with each sweeping major lineage, leading to a faster overall rate of evolution and fluctuating levels of diversity. These observations highlight the value of viral sequencing integrated into community surveillance studies to monitor the viral epidemiology and evolution of SARS-CoV-2, and potentially other pathogens, particularly as routine PCR testing is phased out or in settings where large-scale sequencing is not feasible.


title: Narrowing gap in regional and age-specific excess mortality in the first year and a half of COVID-19 in Hungary

abstract: In the first year and a half of the pandemic, the excess mortality in Hungary was 28,400, which was 1,700 lower than the official statistics on COVID-19 deaths. This discrepancy can be partly explained by protective measures instated during the COVID-19 pandemic that decreased the intensity of the seasonal flu outbreak, which caused on average 3,000 deaths per year. Compared to the second wave of the COVID-19 pandemic, the third wave showed a reduction in the differences in excess mortality between age groups and regions. The excess mortality rate for people aged 75+ fell significantly in the third wave, partly due to the vaccination schedule and the absence of a normal flu season. For people aged 40-77, the excess mortality rate rose slightly in the third wave. Between regions, excess mortality was highest in Northern Hungary and Western Transdanubia, and much lower in Central Hungary, where the capital is located. The excess mortality rate for men was almost twice as high as that for women in almost all age groups.


title: Comparison of Mammography Artificial Intelligence Algorithms for 5-year Breast Cancer Risk Prediction

abstract:
PURPOSETo examine the ability of 5 artificial intelligence (AI)-based computer vision algorithms, most trained to detect visible breast cancer on mammograms, to predict future risk relative to the Breast Cancer Surveillance Consortium clinical risk prediction model (BCSC v2).

PATIENTS AND METHODSIn this case-cohort study, women who had a screening mammogram in 2016 at Kaiser Permanente Northern California with no evidence of cancer on final imaging assessment were followed through September 2021. Women with prior breast cancer or a known highly penetrant gene mutation were excluded. From the 329,814 total eligible women, a random subcohort of 13,881 women (4.2%) were selected, of whom 197 had incident cancer. All 4,475 additional incident cancers were also included. Continuous AI-predicted scores were generated from the index 2016 mammogram. Risk estimates were generated with the Kaplan-Meier method and time-varying area under the curve [AUC(t)].

RESULTSFor incident cancers at 0-1 year (interval cancer risk), BCSC demonstrated an AUC(t) of 0.62 (95% CI, 0.58-0.66), and the AI algorithms had AUC(t)s ranging from 0.66-0.71, all significantly higher than BCSC (P < .05). For incident cancers at 1 to 5 years (5-year future cancer risk), BCSC demonstrated an AUC(t) of 0.61 (95% CI, 0.60-0.62), and the AI algorithms had AUC(t)s ranging from 0.63 to 0.67, all significantly higher than BCSC. Combined BCSC and AI models demonstrated AUC(t)s for interval cancer risk of 0.67-0.73 and for 5-year future cancer risk of 0.66-0.68.

CONCLUSIONThe AI mammography algorithms we evaluated had significantly higher discrimination than the BCSC clinical risk model for interval and 5-year future cancer risk. Combined AI and BCSC models had slightly higher discrimination than AI alone.

category: radiology and imaging


title: Statistical learning in patients in the minimally conscious state

abstract: When listening to an unknown language, listeners could learn the transitional probability between syllables and group frequently co-occurred syllables into a whole unit. Such statistical learning ability has been demonstrated for both pre-verbal infants and adults, even during passive listening. Here, we investigated whether statistical learning occurred in patients in minimally conscious state (MCS) and patients emerged from the minimally conscious state (EMCS) using electroencephalography (EEG). We presented to participants an isochronous sequence of syllables, which were composed of either 2-word real phrases or 2-word artificial phrases that were defined by the transitional probability between words. An inter-trial phase coherence (ITPC) analysis revealed that the phrase-rate EEG response was weakened in EMCS patients compared with healthy individuals, and was even more severely weakened in MCS patients. Although weak, the phrase-rate response or its harmonics remained statistically significant in MCS patients, suggesting that the statistical learning ability was preserved in MCS patients. The word-rate response was also weakened with a decreased level of consciousness. The harmonics of the word-rate response, however, were more salient in MCS than EMCS patients in the alpha and beta bands. Together with previous studies, the current results suggest that MCS patients retain residual learning ability, which can potentially be harnessed to induce neural plasticity, and that different frequency bands are differentially related to the consciousness level.


title: Neurofeedback-guided kinesthetic motor imagery training in Parkinson's disease: Randomized trial

abstract:
BackgroundParkinsons disease (PD) causes difficulty with maintaining the speed, size, and vigor of movements, especially when they are internally generated. We previously proposed that the insula is important in motivating intentional movement via its connections with the dorsomedial frontal cortex (dmFC). We demonstrated that subjects with PD can increase the right insula-dmFC functional connectivity using fMRI-based neurofeedback (NF) combined with kinesthetic motor imagery (MI). The current study is a randomized clinical trial testing whether NF-guided kinesthetic MI training can improve motor performance and increase task-based and resting-state right insula-dmFC functional connectivity in subjects with PD.

MethodsWe assigned nondemented subjects with mild PD (Hoehn & Yahr stage [≤] 3) to the experimental kinesthetic MI with NF (MI-NF, n=22) and active control visual imagery (VI, n=22) groups. Only the MI-NF group received NF-guided MI training (10-12 runs). The NF signal was based on the right insula-dmFC functional connectivity strength. All subjects also practiced their respective imagery tasks at home daily for 4 weeks. Post-training changes in 1) task-based and resting-state right insula-dmFC functional connectivity were the imaging outcomes, and 2) MDS-UPDRS motor exam and motor function scores were the clinical outcomes.

ResultsThe MI-NF group did not show significant NF regulation and was not significantly different from the VI group in any of the imaging or clinical outcome measures. The MI-NF group reported subjective improvement in kinesthetic body awareness. There was significant and comparable improvement only in motor function scores in both groups. This improvement correlated with NF regulation of the right insula-dmFC functional connectivity only in the MI-NF group. Both groups showed specific training effects in whole-brain functional connectivity with distinct neural circuits supporting kinesthetic motor and visual imagery (exploratory outcome).

ConclusionsThe functional connectivity-based NF regulation was unsuccessful in our cohort with mild PD. However, kinesthetic MI practice by itself or in combination with other imagery techniques is a promising tool in motor rehabilitation in PD.

HighlightsO_LIParkinsons disease (PD) causes difficulty with sustained motor performance
C_LIO_LIInsula and dorsomedial frontal cortex (dmFC) are implicated in motivating movement
C_LIO_LIRegulation of insula-dmFC functional connectivity with neurofeedback (NF) failed
C_LIO_LIMotor imagery practice regardless of NF improved motor function and body awareness
C_LIO_LIMotor imagery is a promising strategy for motor rehabilitation in PD
C_LI


title: The chronic wound virome: phage diversity and associations with wounds and healing outcomes

abstract:
Two leading impediments to chronic wound healing are polymicrobial infection and biofilm formation. Recent studies have characterized the bacterial fraction of these microbiomes and have begun to elucidate compositional correlations to healing outcomes. However, the factors that drive compositional shifts are still being uncovered. The virome may play an important role in shaping bacterial community structure and function. Previous work on the skin virome determined that it was dominated by bacteriophages, viruses that infect bacteria. To characterize the virome, we enrolled 20 chronic wound patients presenting at an outpatient wound care clinic in a microbiome survey, collecting swab samples from healthy skin and chronic wounds before and after a single, sharp debridement procedure. We investigated the virome using a virus-like particle enrichment procedure, shotgun metagenomic sequencing, and a k-mer-based, reference-dependent taxonomic classification method. Taxonomic composition, diversity, and associations to covariates are presented. We find that the wound virome is highly diverse, with many phages targeting known pathogens, and may influence bacterial community composition and functionality in ways that impact healing outcomes.

ImportanceChronic wounds are an increasing medical burden. These wounds are known to be rich in microbial content, including both bacteria and bacterial viruses (phages). The viruses may play an important role in shaping bacterial community structure and function. We analyzed the virome and bacterial composition of 20 patients with chronic wounds. The viruses found in wounds are highly diverse compared to normal skin, unlike the bacterial composition, where diversity is decreased. These data represent an initial look at this relatively understudied component of the chronic wound microbiome.


title: Regulatory T-cells are central hubs for age-, sex- and severity-associated cellular networks during COVID-19

abstract: Using single-cell proteomics by mass cytometry, we investigate changes to a broad selection of over 10,000,000 immune cells in a cohort of moderate, severe, and critical Japanese COVID-19 patients and healthy controls with a particular focus on regulatory T-cells (Tregs). We find significant disruption within all compartments of the immune system and the emergence of atypical CTLA-4high CD4 T-cells and proliferating HLA-DRlowCD38high Tregs associated with critical patients. We also observed disrupted regulation of humoral immunity in COVID-19, with a loss of circulating T follicular regulatory T cells (Tfr) and altered T follicular helper (Tfh)/Tfr and plasma cell/Tfr ratios, all of which are significantly lower in male patients. Shifting ratios of CXCR4 and CXCR5 expression in B-cells provides further evidence of an autoimmune phenotype and dysregulated humoral immunity. These results suggest that Tregs are central to the changing cellular networks of a wide range of cells in COVID-19 and that sex specific differences to the balance of Tfr, Tfh and plasma cells may have important implications for the specificity of the humoral immune response to SARS-CoV-2.


title: Incidence and distribution of human leptospirosis in the Western Cape Province, South Africa, (2010-2019): A retrospective study.

abstract:
BackgroundLeptospirosis is an emerging zoonosis of global importance. In South Africa, the infection is an underreported public health concern, with limited information on its incidence and distribution. This study aimed to determine the incidence of human leptospirosis from 2010 to 2019 in Western Cape Province (WPC), and to compare the incidence based on seasonal and demographic factors.

MethodsA retrospective study was conducted with data on leptospirosis diagnoses by sex, age, season, and year in WCP obtained from the National Health Laboratory Services. With the provincial population sizes as the denominator, the incidence of leptospirosis was estimated and expressed as cases per 100,000 population. Negative binomial regression was used to estimate the effect of sex, season, and year on the incidence of leptospirosis.

ResultsA total of 254 cases of leptospirosis were reported between 2010 and 2019, with the highest number of cases being in 2015. The annual incidence ranged between 0.15 and 0.66/100,000 population with a 10-year average incidence of 0.40/100,000 population. The incidence was higher among males than in females (0.55 vs. 0.25/100,000 population; incidence rate ratio (IRR) 2.2, 95% CI: 1.66,3.03). The 18-44 age cohort and had the highest average incidence (0.56/100,000 population), while the [≤]17age cohort had the lowest incidence (0.07/100,000 population). The 18-44 (IRR 8.0, 95% CI: 4.65,15.15) and [≥]45 (IRR 7.4, 95% CI: 4.17,14.17) age cohorts were more at risk of infection compared to [≤]17age cohort. The average incidence of the infection was similar among seasons and there was no significant association between season and incidence of leptospirosis.

ConclusionsThe results highlight that leptospirosis is an important zoonosis within the province disproportionately affecting males and the productive age demographic groups. These findings should enhance targeted prevention and provoke further investigation on the importance of environmental and socioeconomic factors on leptospirosis burden.

Author SummaryLeptospirosis is an emerging zoonotic bacterial disease of global importance. Despite its wide distribution, the disease is largely underestimated because its clinical manifestations mimic certain commonly known febrile illnesses such as malaria, influenza, hepatitis, and yellow fever. Leptospirosis burden in South Africa has been suggested to be moderately high however studies on the burden of the infection are lacking. This study sought to determine the incidence and trends of leptospirosis in the Western Cape Province, South Africa between 2010 and 2019. Overall, leptospirosis average incidence was 0.4 cases per 100,000 population (ranging from 0.15 to 0.66 cases per 100,000 population). Leptospirosis incidence was highest among male individuals and among those who were aged 18-years and above, however, the incidence did not differ by seasons. These estimates highlight that leptospirosis is an important zoonotic disease within the province and potentially disproportionately affecting males and productive age demographic groups. Therefore, this indicates the need for an all-encompassing One Health Approach to obtain all relevant information concerning leptospirosis distribution and risk factors in South Africa and in Africa at large to effectively enhance leptospirosis prevention strategies.


title: A Composite Ranking of Risk Factors for COVID-19 Time-To-Event Data from a Turkish Cohort

abstract: Having a complete and reliable list of risk factors from routine laboratory blood test for COVID-19 disease severity and mortality is important for patient care and hospital management. It is common to use meta-analysis to combine analysis results from different studies to make it more reproducible. In this paper, we propose to run multiple analyses on the same set of data to produce a more robust list of risk factors. With our time-to-event survival data, the standard survival analysis were extended in three directions. The first is to extend from tests and corresponding p-values to machine learning and their prediction performance. The second is to extend from single-variable to multiple-variable analysis. The third is to expand from analyzing time-to-decease data with death as the event of interest to analyzing time-to-hospital-release data to treat early recovery as a meaningful event as well. Our extension of the type of analyses leads to ten ranking lists. We conclude that 20 out of 30 factors are deemed to be reliably associated to faster-death or faster-recovery. Considering correlation among factors and evidenced by stepwise variable selection in random survival forest, 10[~]15 factors seem to be able to achieve the optimal prognosis performance. Our final list of risk factors contain calcium, white blood cell and neutrophils count, urea and creatine, d-dimer, red cell distribution widths, age, ferritin, glucose, lactate dehydrogenase, lymphocyte, basophils, anemia related factors (hemoglobin, hematocrit, mean corpuscular hemoglobin concentration), sodium, potassium, eosinophils, and aspartate aminotransferase.


title: Protection afforded by prior infection against SARS-CoV-2 reinfection with the Omicron variant

abstract:
BACKGROUNDNatural SARS-CoV-2 infection elicits strong protection against reinfection with the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. However, the Omicron (B.1.1.529) variant harbors multiple mutations that can mediate immune evasion. We estimated effectiveness of prior infection in preventing reinfection (PES) with Omicron and other SARS-CoV-2 variants in Qatar.

METHODSPES was estimated using the test-negative, case-control study design, employing a methodology that was recently investigated and validated for derivation of robust estimates for PES. Cases (PCR-positive persons with a variant infection) and controls (PCR-negative persons) were exact-matched by sex, 10-year age group, nationality, and calendar time of PCR test, to control for known differences in the risk of exposure to SARS-CoV-2 infection in Qatar.

RESULTSPES against symptomatic reinfection was estimated at 90.2% (95% CI: 60.2-97.6) for Alpha, 84.8% (95% CI: 74.5-91.0) for Beta, 92.0% (95% CI: 87.9-94.7) for Delta, and 56.0% (95% CI: 50.6-60.9) for Omicron. Only 1 Alpha, 2 Beta, 0 Delta, and 2 Omicron reinfections progressed to severe COVID-19. None progressed to critical or fatal COVID-19. PES against hospitalization or death due to reinfection was estimated at 69.4% (95% CI: -143.6-96.2) for Alpha, 88.0% (95% CI: 50.7-97.1) for Beta, 100% (95% CI: 43.3-99.8) for Delta, and 87.8% (95% CI: 47.5-97.1) for Omicron.

CONCLUSIONSProtection afforded by prior infection in preventing symptomatic reinfection with Alpha, Beta, or Delta is robust, at about 90%. While such protection against reinfection with Omicron is lower, it is still considerable at nearly 60%. Prior-infection protection against hospitalization or death at reinfection appears robust, regardless of variant.


title: Vaccinating children against COVID-19: commentary and mathematical modelling

abstract: With the recent licensure of mRNA vaccines against COVID-19 in the 5-11 year old age group, the public health impact of a childhood immunization campaign is of interest. Using a mathematical epidemiological model, we project that childhood vaccination carries minimal risk and yields modest public health benefits. These include large relative reductions in child morbidity and mortality, although the absolute reduction is small because these events are rare. Furthermore, the model predicts "altruistic" absolute reductions in adult cases, hospitalizations, and mortality. However, vaccinating children to benefit adults should be considered from an ethical as well as a public health perspective. From a global health perspective, an additional ethical consideration is the justice of giving priority to children in high-income settings at low risk of severe disease while vaccines have not been made available to vulnerable adults in low-income settings.


title: The impact of demographic factors on numbers of COVID-19 cases and deaths in Europe and the regions of Ukraine

abstract: The accumulated numbers of COVID-19 cases and deaths per capita are important characteristics of the pandemic dynamics that may also indicate the effectiveness of quarantine, testing, vaccination, and treatment. The statistical analysis based on the number of cases per capita accumulated to the end of June 2021 showed no correlations with the volume of population, its density, and the urbanization level both in European countries and regions of Ukraine. The same result was obtained with the use of fresher datasets (as of December 23, 2021). The number of deaths per capita and per case may depend on the urbanization level. For European countries these relative characteristics decrease with the increase of the urbanization level. Opposite trend was revealed for the number of deaths per capita in Ukrainian regions.


title: Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients infected between March 2020 and November 2021

abstract:
BackgroundLong COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID-19 is not well understood. We determined whether vaccination was associated with the incidence of reporting long-term symptoms post-SARS-CoV-2 infection

MethodsWe invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-November 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected in terms of self-reported symptoms post-acute infection.

ResultsWe included 951 infected and 2437 uninfected individuals. Of the infected, 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, those who received two doses less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Those who received two doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection.

ConclusionsVaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.


title: Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and November 2021


title: Durability of Protection against COVID-19 Breakthrough Infections and Severe Disease by Vaccines in the United States

abstract: Background: Intrinsic durability of immune responses elicited by COVID-19 vaccines will drive vaccine effectiveness long-term across settings and may differ by vaccine type. We aimed here to determine durability of protection of three COVID-19 vaccines BNT162b2, mRNA-1273 and Ad26.COV2.S following primary vaccination against breakthrough infections, hospitalisations, and intensive care unit (ICU) admissions in the United States (US). Methods: Using national claims and laboratory data covering 168 million lives, we conducted a matched case-control study with fully vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing outcomes in months two through six following primary vaccination were estimated relative to the first month after primary vaccination for each vaccine separately. Results compare each vaccine to itself and are not directly comparative. Odds ratios were translated into vaccine effectiveness (VE) using assumptions about event rates in an unvaccinated cohort. Findings: Relative to its baseline, stable protection was observed for the single-shot Ad26.COV2.S against infections and severe disease. Relative to their baseline protection waned overtime against infections for BNT162b2 and mRNA-1273 and against hospitalisations for BNT162b2. No waning of baseline protection was observed at any time for ICU admissions for all three vaccines. Calculated baseline VE was consistent with the published literature. Interpretation: While the starting protection level provided by the primary series may differ by vaccine type and mechanism of action, this study demonstrated by comparing each vaccine to its own baseline protection that the three vaccines in three separate populations may have different durability profiles. Further investigation is required to fully characterize the durability profile of the three vaccines. Moreover, as the COVID-19 pandemic continues, and as more countries and populations implement a standard of care consisting of three doses of the mRNA vaccines or two doses of Ad26.COV2.S, further investigation is critical to understand the level of protection and the durability of response over longer periods, novel variants and in response to homologous and heterologous boosting.


title: Durability of protection post-primary COVID-19 vaccination in the US: a matched case-control study


title: Stability of plasma metabolomics over 10 years among women

abstract:
BackgroundIn epidemiological studies, samples are often collected long before disease onset or outcome assessment. Understanding the long-term stability of biomarkers measured in these samples is crucial. We estimated within-person stability over 10 years of metabolites and metabolite features (N=5938) in the Nurses Health Study (NHS): The primary dataset included 1880 women with 1184 repeated samples donated 10 years apart while the secondary dataset included 1456 women with 488 repeated samples donated 10 years apart.

MethodsWe quantified plasma metabolomics using two liquid chromatography mass spectrometry platforms (lipids and polar metabolites) at the Broad Institute (Cambridge, MA). Intra-class correlations were used to estimate long-term stability (10 years) of metabolites and were calculated as the proportion of the total variability (within-person + between-person) attributable to between-person variability. Within-person variability was estimated among participants who donated two blood samples approximately 10 years apart while between-person variability was estimated among all participants.

ResultsIn the primary dataset, the median ICC was 0.43 (1st quartile [Q1]: 0.36; 3rd quartile [Q3]: 0.50) among known metabolites and 0.41 (Q1: 0.34; Q3: 0.48) among unknown metabolite features. The most stable (median ICCs: 0.54-0.57) metabolite classes were nucleosides, nucleotides and analogues, phosphatidylcholine plasmalogens, diglycerides, and cholesteryl esters. The least stable (median ICCs: 0.26-0.36) metabolite classes were lysophosphatidylethanolamines, lysophosphatidylcholines and steroid and steroid derivatives. Results in the secondary dataset were similar (Spearman correlation=0.87) to corresponding results in the primary dataset.

ConclusionWithin-person stability over 10 years is reasonable for lipid, lipid-related, and polar metabolites, and varies by metabolite class. Additional studies are required to estimate within-person stability over 10 years of other metabolites groups.


title: The Governance of Pandemics in Primary Health Care: The Governance Strategies Adopted by Health Facility Governing Committees in Times of COVID Pandemic in Tanzania

abstract:
The governance of COVID 19 in Lower and Middle-Income Countries (LMICs) is very critical for curbing its effects. However, it is unknown what governance strategies are adopted by Health Facility Governing Committees (HFGCs) s as a response to the pandemic. We employed an exploratory qualitative design to study the governance strategies adopted by HFGCs during the COVID19. Since COVID 19 is new, an inductive approach was used as it involves analyzing collected data with little or no predetermined theory for the study. A purposive sampling technique was employed in which multistage clustered sampling was used to select regions, councils, health facilities and respondents. In-depth interviews with HFGCs chairpersons and Focus Group Discussions with members of HFGCs were used to collect data. The data were analyzed based on the themes which emerged during data collection. We found five governance strategies that were found to be commonly adopted by many HFGCs which are financial allocation, re-planing, mobilization of resources, community sensitization and mobilization of stakeholders. however, these governance structures were not all adopted by all HFGCs. The HFGCs slowly adopted governance strategies in the times of COVID 19 pandemics because were unprepared. Despite being empowered by the Direct Health Facility Financing, still, the newest of the COVID 19 has been a challenge to many HFGCs. This calls for urgent capacity building for governance institutions on how to deal will pandemics in primary health facilities.

Key Questions Box O_TEXTBOXKey Questions

What is Already Known?[tpltrtarr] Governance of pandemics is very critical for minimizing its effects
[tpltrtarr]Government in Lower and Middle-Income Countries (LMICs) reacted differently to bring the COVID 19 pandemic under control
[tpltrtarr]Little is known on the governance strategies adopted by Health Facility Governing Committees (HFGCs) to control COVID 19 at the primary health care facilities in LMICs

What are the new findings?[tpltrtarr] HFGCs response to the COVID 19 is mixed as some HFGCs were so active and others were so slowly in instituting governance strategies to combat the pandemic
[tpltrtarr]The common governance strategies adopted were financial allocation, re-planning, embolization of resources, community sensitization and stakeholders mobilization
[tpltrtarr]HFGCs in LMICs were not well prepared for the pandemic at the community level

What do new findings imply?[tpltrtarr] Capacitated HFGCs in both soft and hard aspects cornerstone for effective governance of the pandemics in primary health care
[tpltrtarr]Preparedness of pandemics in LMICs needs to go beyond upper-level governance structures

C_TEXTBOX

category: primary care research


title: Severe and common mental disorders and risk of hospital admissions for Ambulatory Care Sensitive Conditions (ACSCs): prospective cohort study using UK Biobank

abstract:
BackgroundPeople with mental disorders have an excess chronic disease burden. One mechanism to potentially reduce the public health and economic costs of mental disorders is to reduce preventable hospital admissions. Ambulatory care sensitive conditions (ACSCs) are a defined set of chronic and acute illnesses not considered to require hospital treatment if patients receive adequate primary healthcare. We examined the relationship between both severe and common mental disorders and risk of emergency hospital admissions for ACSCs and factors associated with increased risk.

MethodsBaseline data from England (N=445,814) were taken from UK Biobank, which recruited participants aged 37-73 years during 2006 to 2010, and were linked to hospital admission records up to 31st December 2019. Participants were grouped into those who had a history of either schizophrenia, bipolar disorder, depression or anxiety, or no record of mental disorder. Cox proportional hazard models (for the first admission) and Prentice, Williams and Peterson Total Time models (PWP-TT, which account for all admissions) were used to assess the risk (using hazard ratios (HR)) of hospitalisation for ACSCs among those with mental disorders compared to those without, adjusting for factors in different domains, including sociodemographic (e.g. age, sex, ethnicity), socioeconomic (e.g. deprivation, education level), health and biomarkers (e.g. multimorbidity, inflammatory markers), health-related behaviours (e.g. smoking, alcohol consumption), social isolation (e.g. social participation, social contact) and psychological (e.g. depressive symptoms, loneliness).

ResultsPeople with schizophrenia had the highest risk of hospital admission for ACSCs compared to those with no mental disorder (HR=4.40, 95% CI: 4.04 - 4.80). People with bipolar disorder (HR=2.48, 95% CI: 2.28 - 2.69) and depression or anxiety (HR=1.76, 95% CI: 1.73 - 1.80) also had higher risk. Associations were more conservative when accounting for all admissions. Although adjusting for a range of factors attenuated the observed associations, they still persisted, with socioeconomic and health-related variables contributing most.

ConclusionsPeople with severe mental disorders had highest risk of preventable hospital admissions, with the risk also elevated amongst those with depression and anxiety. Ensuring people with mental disorders receive adequate ambulatory care is essential to reduce the large health inequalities experienced by these groups.


title: Adherence of SARS-CoV-2 delta variant to surgical mask and N95 respirators

abstract: The use of facial protection, including masks and respirators, has been adopted globally due to the COVID-19 pandemic. These products have been demonstrated to be effective in reducing the transmission of the virus. To determine whether or not the virus adheres to masks and respirators, we dissected four respirators and one surgical mask into layers. These individual layers were contaminated with the SARS-CoV-2 delta variant, and its release by vortexing was performed. Samples were used to infect Vero cells, and a plaque assay was used to determine to evaluate the adherence of the virus. Results showed that a cumulative log reduction of the layers reduced the load of the virus six-folds. Our study confirms the effectiveness of facial protection in reducing the transmission and or infection of the virus.


title: Mental health assessment of Israeli adolescents before and during the COVID-19 pandemic

abstract: The measures used to contain the COVID-19 pandemic caused severe disruption to the lives of children and adolescents, compromising their mental health and wellbeing. In this study we assessed the incidence rates of psychiatric diagnoses and drugs in Israeli adolescents before and during the COVID-19 pandemic. Analysis of health records data of over 200,000 12-17 years old adolescents identified a significant increase in all mental health diagnoses and most psychiatric drugs dispensation during the COVID-19 period compared to a corresponding pre-COVID period. A gender sub-analysis revealed that most of this increase was associated with adolescent girls. Girls exhibited increases of 68% in depression, 67% in eating disorders, 42% in anxiety and 29% in stress-related diagnoses during the COVID-19 period, which are significantly higher rates than those seen in boys and in the pre-COVID period. Sector sub-analysis showed that the increase was mainly in the general Jewish sector with almost no significant increases in the Arab and ultra-orthodox sectors. Our study highlights the mental health burden of Israeli adolescents during the pandemic and suggests that careful consideration should be given to it while deciding on measures to mitigate the pandemic.