title: Prostate cancer risk stratification via non-destructive 3D pathology with annotation-free gland segmentation and analysis

abstract:
Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. In current clinical practice, the microscopic architecture of the prostate glands is what forms the basis for prognostic grading by pathologists. Interpretation of these convoluted 3D glandular structures via visual inspection of a limited number of 2D histology sections is often unreliable, which contributes to the under- and over-treatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for non-destructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analog of standard H&E staining. Our analysis is based on interpretable glandular features, and is facilitated by the development of image-translation-assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep-learning-based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring real immunolabeling. To provide evidence of the translational value of a computational 3D pathology approach, we analyzed ex vivo biopsies (n = 300) extracted from archived radical-prostatectomy specimens (N = 50), and found that 3D glandular features are superior to corresponding 2D features for risk stratification of low-to intermediate-risk PCa patients based on their clinical biochemical recurrence (BCR) outcomes.

SignificanceWe present an end-to-end pipeline for computational 3D pathology of whole prostate biopsies, showing that non-destructive pathology has the potential to enable superior prognostic stratification for guiding critical oncology decisions.


title: Deficient auditory gamma-BOLD coupling in schizophrenia is related to sensory gating deficits

abstract:
BackgroundSchizophrenia is associated with aberrant gamma band power, hypothesized to reflect imbalance in the excitation-inhibition (E/I) ratio and undermine neural signal efficiency. Relationships between resting-state gamma, E/I balance, and regional hemodynamics from the fMRI BOLD signal are unknown.

MethodsWe recorded simultaneous EEG-fMRI at rest, with eyes open, in people with schizophrenia (n= 57) and people without a psychiatric diagnosis (n= 46) and identified gamma and aperiodic EEG parameters associated with E/I balance. Measures from all EEG channels were entered into a whole-brain, parametric modulation analysis followed by statistical correction for multiple comparisons. Sensory gating was assessed using the Sensory Gating Inventory, and psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.

ResultsAcross groups, gamma power modestly predicts a steeper aperiodic slope (greater inhibition), without group differences in either gamma power or aperiodic slope. In schizophrenia, gamma-BOLD coupling was reduced in bilateral auditory regions of the superior temporal gyri and inversely correlated with sensory gating deficits and symptom severity. Analysis of the spectral features of scanner sounds revealed distinct peaks in the gamma range, reflecting a rapidly repeating scanner pulse sound present throughout the resting state recording.

ConclusionRegional hemodynamic support for putative inhibitory and excitatory contributions to resting EEG are aberrant in SZ. Deficient gamma coupling to auditory BOLD may reflect impaired gating of fMRI-scanner sound.

category: psychiatry and clinical psychology


title: Predicting transitions between longitudinal classes of posttraumatic stress disorder, adjustment disorder, and well-being during the COVID-19 pandemic: Protocol of a latent transition model in a general Dutch sample

abstract:
BackgroundA growing body of literature shows profound effects of the COVID-19 pandemic on mental health, among which increased rates of posttraumatic stress disorder (PTSD) and adjustment disorder (AD). However, current research efforts have largely been unilateral, focusing on psychopathology and not including well-being, and are dominated by examining average psychopathology levels or on disorder absence/presence, thereby ignoring individual differences in mental health. Knowledge on individual differences, as depicted by latent subgroups, in the full spectrum of mental health may provide valuable insights in how individuals transition between health states and factors that predict transitioning from resilient to symptomatic classes. Our aim is to (1) identify longitudinal classes (i.e., subgroups of individuals) based on indicators of PTSD, AD, and well-being in response to the pandemic and (2) examine predictors of transitioning between these subgroups.

Methods and analysisWe will conduct a three-wave longitudinal online survey-study of n [≥] 2000 adults from the general Dutch population. The first measurement occasion takes place six months after the start of the pandemic, followed by two follow-up measurements with six months intervals. Latent transition analysis will be used for data-analysis.

Ethics and disseminationEthical approval has been obtained from four Dutch universities. Longitudinal study designs are vital to monitor mental health (and predictors thereof) in the pandemic to develop preventive and curative mental health interventions. This study is carried out by researchers who are board members of the Dutch Society for Traumatic Stress Studies and is part of a pan-European study (initiated by the European Society for Traumatic Stress Studies) examining the impact of the pandemic in eleven countries. Results will be published in peer-reviewed journals and disseminated at conferences, via newsletters, and media-appearance among (psychotrauma-)professionals and the general public.

Strengths and limitations of this studyO_LIThis is one of the first studies examining the mental health impact of the COVID-19 pandemic by focusing on negative and positive mental health in the general population.
C_LIO_LIA longitudinal research design is used, which enable us to examine predictors of transitioning between mental health classes over three time points.
C_LIO_LIA limitation of this study is that we used self-report measures, instead of clinical interviews, to assess mental health.
C_LI


title: Optimal and worst examination strategies for COVID-19

abstract: Coronavirus disease 2019 (COVID-19) is an emerging threat to the whole world, and every government is seeking an optimal solution. However, none of them have succeeded, and they have only provided series of natural experiments. Although simulation studies seem to be helpful, there is no model that addresses the how much testing to be conducted to minimise the emerging infectious disease outbreaks. In this study, we develop a testing susceptible, infectious, exposed, recovered, and dead (testing-SEIRD) model using two discrete populations inside and outside hospitals. The populations that tested positive were isolated. Through the simulations, we examined the infectious spread represented by the number of cumulative deaths, hospitalisations, and positive tests, depending on examination strategies, testing characteristics, and hospitalisation capacity. We found all-or-none responses of either expansion or extinction of the infectious spreads, depending on the rates of follow-up and mass testing, which represent testing the people identified as close contacts with infected patients using follow-up surveys and people with symptoms, respectively. We also demonstrated that there were optimal and worst examination strategies, which were determined by the total resources and testing costs. The testing-SEIRD model is useful in making decisions on examination strategies for the emerging infectious disease outbreaks.

category: public and global health


title: Development of a women empowerment framework to promote voluntary medical male circumcision uptake for HIV prevention in Zimbabwe

abstract:
IntroductionThis study aimed to develop a women empowerment framework to promote Voluntary Medical Male Circumcision (VMMC) uptake for human immune-deficiency virus (HIV) prevention, guided by the following objectives: To explore relevant literature on the role of women in promoting male circumcision uptake; To develop a women empowerment framework to promote male circumcision uptake; To describe the women empowerment framework to promote male circumcision uptake.

MethodsThe study used a theory-generation design to explore, describe and develop a women empowerment framework from a broad literature review.

ResultsA three-phase approach suitable for the framework development emerged from the literature review. Phase one involved exploring relevant literature on the role of women in male circumcision uptake, using the Population/problem, Intervention, Comparison and Outcome (PICO) method to identify and define the key concepts. Phase 2 adopted and adapted the model by Maibvise and Mavundla in identifying the following concepts: change agents as the health care providers, recipients as the women to influence men eligible for male circumcision, promoting male circumcision uptake and success of the male circumcision program. Phase 3 provided a detailed description of the framework including three key steps of empowerment of women, influencing positive perceptions of men and utilisation of male circumcision services.

ConclusionsThe identified concepts resulted in development of a women empowerment framework, which can be used as an education and advocacy tool in building the capacity of women in supporting the male circumcision programme to promote uptake. Further research is required to expand the utilisation of the framework in male circumcision healthcare services.


title: The association between influenza vaccination, all-cause mortality and cardiovascular mortality: a protocol for a living systematic review and prospective meta-analysis

abstract:
IntroductionInfluenza virus infection is known to increase the risk of cardiovascular events, especially in populations with pre-existing cardiovascular disease. Considering that influenza is vaccine preventable, international guidelines recommend high-risk populations with CVD receive an influenza vaccine every year, but there are various classifications of recommendations and levels of evidence. Previous systematic reviews concluded uncertain evidence on influenza vaccine efficacy for preventing cardiovascular events in the general population or in populations with pre-existing CVD. Limited safety data of influenza vaccines were reported for populations with pre-existing CVD. Randomized control trials with larger sample sizes relative to previous studies are emerging, the findings of these trials are likely to be highly influential on summary efficacy estimates.

Methods and analysisWe aim to perform a living systematic review and a prospective meta-analysis to evaluate the efficacy and safety of influenza vaccines compared to no vaccines or placebo for preventing mortality or cardiovascular disease events in the general population and in populations with pre-existing CVD.

Ethics and disseminationFormal ethical review is not required as this study does not need primary data collection. We will publish results of the living systematic review and prospective meta-analysis in a peer-reviewed journal. Findings will also be presented at relevant meetings.

PROSPERO registration numberCRD42021222519.

Strengths and limitations of this studyO_LIThe living systematic review will continually incorporate the latest research findings and keep the synthesized information updated. A prospective meta-analysis will better address this evolving evidence.
C_LIO_LISafety of influenza vaccines in populations with pre-existing cardiovascular diseases will be studied in particular to complete the current evidence base.
C_LIO_LIObservational studies may affect the overall quality of the study results. We will stratify the analysis by study design and present both randomized and non-randomized results.
C_LI


title: Ensemble model estimates of the global burden of measles morbidity and mortality from 2000 to 2019: a modeling study

abstract:
BackgroundMeasles remains a significant source of childhood morbidity and mortality worldwide. Two doses of measles containing vaccine are recommended for all children and delivered through a combination of routine and supplemental immunization activities. Uncertainty about the degree to which second dose opportunities reach previously unvaccinated children presents a challenge in the assessment of vaccination programs and the estimation of the global burden of measles disease and mortality.

MethodsWe fit an ensemble of models that represent alternative assumptions about the degree to which second dose opportunities reach previously unvaccinated children to routine measles surveillance from 100 countries. Using maximum likelihood we selected the best fit model for each country. We compare the resulting estimates of the burden of measles disease and mortality to existing methods for estimating the burden of measles that assume that second dose opportunities are independent of receipt of the first dose.

FindingsWe find that 78 of 100 countries are best-fit by a model that assumes that second doses that are delivered through supplemental campaigns are preferentially delivered to children who have received a first dose. Using a country-specific best-fit model we estimate that measles mortality has declined by 73% from 2000-2019 compared to an estimated decline of 83% using an assumption of independent doses in all countries.

InterpretationDespite large decreases in measles cases over the last two decades, the observed trajectories in most countries suggest that supplemental immunization activities are disproportionately reaching previously vaccinated children. To accelerate measles reduction goals efforts to reach unvaccinated children through supplemental activities and second dose opportunities should be intensified.

FundingBill and Melinda Gates Foundation, World Health Organization


title: Cardiovascular disease and all-cause mortality risk prediction from abdominal CT using deep learning

abstract: Cardiovascular disease is the number one cause of mortality worldwide. Risk prediction can help incentivize lifestyle changes and inform targeted preventative treatment. In this work we explore utilizing a convolutional neural network (CNN) to predict cardiovascular disease risk from abdominal CT scans taken for routine CT colonography in otherwise healthy patients aged 50-65. We find that adding a variational autoencoder (VAE) to the CNN classifier improves its accuracy for five year survival prediction (AUC 0.787 vs. 0.768). In four-fold cross validation we obtain an average AUC of 0.787 for predicting five year survival and an AUC of 0.767 for predicting cardiovascular disease. For five year survival prediction our model is significantly better than the Framingham Risk Score (AUC 0.688) and of nearly equivalent performance to method demonstrated in Pickhardt et al. (AUC 0.789) which utilized a combination of five CT derived biomarkers.

category: radiology and imaging


title: Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis

abstract:
BackgroundColorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity - a worldwide public health concern - is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner.

MethodsRNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas - Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; Body mass index (BMI) was calculated and categorized as normal, overweight, and obese.

ResultsWe observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing effects on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs.

ConclusionsThus, we conclude that obesity has CMS-specific effects on the CRC tumor transcriptome.

category: oncology


title: Predictive Classification of IBS-subtype: Performance of a 250-gene RNA expression panel vs. Complete Blood Count (CBC) profiles under a Random Forest model.

abstract: In this experiment, an R-script was developed to select the best performing machine learning (ML) predictive classification algorithm for IBS-subtype, and compare the performance of two datasets from the same clinical cohort - 1) The Complete Blood Count (CBC) results, and 2) A 250-gene Nanostring expression panel run on RNA from the "Buffy Coat" fraction. This publicly available data was compiled from open-source repositories and previously published supplementary data. Column labels were reformatted according to "tidy-data" standards. NA values in the data were imputed based on the mean value of the data column. Subject groups included Control (ie. healthy), IBS-D (diarrhea predominant), and IBS-C (constipation predominant) subtypes. These groups had unequal numbers in the original study, and so random re-sampling was used to make the group numbers equal for downstream linear regression-based analyses. The data was randomly split into training and validation subsets, and 5 classification algorithms were tested. Random Forest was clearly the best performing algorithm for both CBC and gene expression panel data, generally with >95% predictive accuracy, without additional tuning. The 250-gene RNA expression panel performed somewhat better than the CBC profile under a Random Forest model, however the CBC profiles had only 13 predictor variables vs. the 250 of the RNA expression panel. Some artifacts may result from the duplication of IBS-D and IBS-C rows from to the group-size balancing method, and so larger and more comprehensive datasets will be obtained for a follow-up analysis. The R-script and reformatted data are published as supplementary material here, and as a component of the  AnalyzeBloodworkv1.2 GitHub repository.

category: health informatics


title: Covid-19 Vaccine Effectiveness in Healthcare Personnel in six Israeli Hospitals (CoVEHPI)

abstract:
BackgroundMethodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate real-world VE in a closely monitored population.

MethodsWe conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples - at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fishers exact test.

FindingsOf the 1,567 HCP enrolled between December 27, 2020 and February 15, 2021, 1,250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR- confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant.

InterpretationOur prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 during a period of predominant alpha variant circulation.

FundingClalit Health Services

category: infectious diseases


title: Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution

abstract: The global effort to vaccinate people against SARS-CoV-2 in the midst of an ongoing pandemic has raised questions about the nature of vaccine breakthrough infections and the potential for vaccinated individuals to transmit the virus. These questions have become even more urgent as new variants of concern with enhanced transmissibility, such as Delta, continue to emerge. To shed light on how vaccine breakthrough infections compare with infections in immunologically naive individuals, we examined viral dynamics and infectious virus shedding through daily longitudinal sampling in a small cohort of adults infected with SARS-CoV-2 at varying stages of vaccination. The durations of both infectious virus shedding and symptoms were significantly reduced in vaccinated individuals compared with unvaccinated individuals. We also observed that breakthrough infections are associated with strong tissue compartmentalization and are only detectable in saliva in some cases. These data indicate that vaccination shortens the duration of time of high transmission potential, minimizes symptom duration, and may restrict tissue dissemination.


title: Modelling the potential role of super spreaders on COVID-19 transmission dynamics

abstract: Superspreading phenomenon has been observed in many infectious diseases and contributes significantly to public health burden in many countries. Superspreading events have recently been reported in the transmission of the COVID-19 pandemic. The present study uses a set of nine ordinary differential equations to investigate the impact of superspreading on COVID-19 dynamics. The model developed in this study addresses the heterogeineity in infectiousness by taking into account two forms of transmission rate functions for superspreaders based on clinical (infectivity level) and social or environmental (contact level). The basic reproduction number has been derived and the contribution of each infectious compartment towards the generation of new COVID-19 cases is ascertained. Data fitting was performed and parameter values were estimated within plausible ranges. Numerical simulations performed suggest that control measures that decrease the effective contact radius and increase the transmission rate exponent will be greatly beneficial in the control of COVID-19 in the presence of superspreading phenomena.

category: epidemiology


title: Pandemic-response adenoviral vector and RNA vaccine manufacturing

abstract: Rapid global COVID-19 pandemic response by mass vaccination is currently limited by the rate of vaccine manufacturing. This study presents a techno-economic feasibility assessment and comparison of three vaccine production platform technologies deployed during the COVID-19 pandemic: (1) adenovirus-vectored (AVV) vaccines, (2) messenger RNA (mRNA) vaccines, and (3) the newer self-amplifying RNA (saRNA) vaccines. Besides assessing the baseline performance of the production process, the impact of key design and operational uncertainties on the productivity and cost performance of these vaccine platforms were also evaluated using variance-based global sensitivity analysis. Cost and resource requirement projections were also computed for manufacturing multi-billion vaccine doses for covering the current global demand shortage and for providing annual booster immunizations. This model-based assessment provides key insights to policymakers and vaccine manufacturers for risk analysis, asset utilisation, directions for future technology improvements and future epidemic/pandemic preparedness, given the disease-agnostic nature of these vaccine production platforms.


title: Approbation of Self-directed Learning by first year medical students: a mixed method study

abstract:
BackgroundOne of the primary roles played by Indian medical graduates is to be a lifelong learner. For being a lifelong learner, the students should inculcate the habit of Self-Directed Learning (SDL). Lack of SDL skills among undergraduate medical students is a concern, hence the study was planned to introduce SDL in Physiology to phase-1 undergraduate medical students and assess its effectiveness through students and facultys perceptions.

MethodologyThe project was commenced after obtaining clearance from the Institutional Ethics Committee. The faculty members and students were sensitized on SDL. Feedback questionnaire was framed and the topics for SDL were selected. Six topics were covered as part of the project. The effectiveness of the sessions was evaluated by administering the feedback questionnaire to the students and recording perceptions of the students and faculty on SDL. The quantitative and qualitative analysis of the data was done.

ResultsA total of 96 phase-1 students participated in the study. Majority of the students felt that self-directed learning sessions have improved their SDL skills; they are more prepared and aware of their learning strengths and have started taking ownership of their learning. However some students felt the activity was not sufficient and SDL was not useful in improving their analytical skills. Both the students and the faculty were fairly satisfied by this teaching learning innovation.

ConclusionsStudents and faculty were satisfied with the SDL strategy. SDL has shown to make them independent learner, who are aware of their learning goals and capable of evaluating their learning.

category: medical education


title: Sparse canonical correlation to identify breast cancer related genes regulated by copy number aberrations

abstract: Background: Copy number aberrations (CNAs) in cancer affect disease outcomes by regulating molecular phenotypes, such as gene expressions, that drive important biological processes. To gain comprehensive insights into molecular biomarkers for cancer, it is critical to identify key groups of CNAs, the associated gene networks, regulatory modules, and their downstream effect on outcomes. Methods: In this paper, we demonstrate an innovative use of sparse canonical correlation analysis (sCCA) to effectively identify the ensemble of CNAs, gene networks and regulatory modules in the context of binary and censored disease endpoints. Our approach detects potentially orthogonal gene expression modules which are highly correlated with sets of CNA and then identifies the genes within these modules that are associated with the outcome. Results: Analyzing clinical and genomic data on 1,904 breast cancer patients from the METABRIC study, we found 14 gene modules to be regulated by groups of proximally located CNA sites. We validated this finding using an independent set of 1,077 breast invasive carcinoma samples from The Cancer Genome Atlas (TCGA). Our analysis on 7 clinical endpoints identified several novel and interpretable regulatory associations, highlighting the role of CNAs in key biological pathways and processes for breast cancer. Genes significantly associated with the outcomes were enriched for early estrogen response pathway, DNA repair pathways as well as targets of transcription factors such as E2F4, MYC and ETS1 that have recognized roles in tumor characteristics and survival. Subsequent meta-analysis across the endpoints further identified several genes through aggregation of weaker associations. Conclusions: Our findings suggest that sCCA analysis can aggregate weaker associations to identify interpretable and important genes, networks and pathways that are clinically consequential.


title: Establishment and validation of pre-therapy cervical vertebrae muscle quantification as a prognostic marker of sarcopenia in head and neck patients receiving definitive cancer surgery

abstract:
ImportanceSarcopenia, or diminished skeletal muscle mass, is prognostic for survival in patients with head and neck cancer (HNC). However, identification of this high-risk feature remains challenging for patients without computed tomography (CT) images that capture the abdomen or lower thorax.

ObjectivesTo (1) define sarcopenia thresholds at the C3 vertebral level using previously established thresholds derived from abdominal CT imaging and (2) determine if C3-defined sarcopenia is associated with survival in patients with HNC.

Design, setting, and participantsThis retrospective cohort study was conducted in consecutive patients with a squamous cell carcinoma of the head and neck with cross-sectional abdominal or neck imaging within 60 days prior to treatment and treated between January 2005 and December 2017. Data analysis was completed from December 2018 to April 2021.

ExposuresMeasurement of the cross-sectional muscle area at the third lumbar and cervical vertebral levels using CT imaging.

Main outcomes and measuresPrimary study outcome was overall survival.

ResultsIn a cohort of 253 HNC patients with CT imaging that captures both L3 and C3 vertebral levels, skeletal muscle cross-sectional area at C3 was strongly correlated with the L3 level in both men (n = 188; r = 0.77; p < 0.001) and women (n = 65; r = 0.80; p < 0.001), and C3-defined sarcopenia thresholds of 14.0 cm2/m2 (men) and 11.1 cm2/m2 (women) were best predictive of previously established L3-defined sarcopenia thresholds. Applying these defined C3 sarcopenia thresholds in a cohort of 536 HNC patients with neck imaging alone revealed that C3-defined sarcopenia was independently associated with reduced overall survival in men (HR = 2.63; 95% CI, 1.79, 3.85) but not women (HR = 1.18, 95% CI, 0.76, 1.85) with HNC.

Conclusions and relevanceThis study identifies sarcopenia thresholds at the C3 level that best predict L3-defined sarcopenia in both men and women. In HNC, C3-defined sarcopenia is associated with poor survival outcomes in men, but not women, suggesting sarcopenia may differentially affect men and women with HNC.

Key PointsO_ST_ABSQuestionC_ST_ABSIs cervical vertebrae muscle wasting a reliable predictor of sarcopenia-related mortality in patients with head and neck cancer (HNC)?

Findings(1) We established sex-specific sarcopenia thresholds (men, 14.0 cm2/m2; women, 11.1 cm2/m2) at the third cervical vertebrae (C3) level through statistical modelling that correlates with previously established lumbar thresholds. (2) Applying these defined C3 sarcopenia thresholds in a large cohort of HNC patients with neck imaging alone revealed that C3-defined sarcopenia was associated with reduced overall survival in men (HR = 2.63; 95% CI, 1.79, 3.85), but not women (HR = 1.18, 95% CI, 0.76, 1.85) with HNC.

MeaningThe C3 sarcopenia thresholds established herein may be a useful prognostic and risk-stratification tool; the influence of sarcopenia on patient outcomes should be assessed in a sex-specific manner.

category: otolaryngology


title: Deep immune profiling reveals early-stage and highly coordinated immune responses in mild COVID-19 patients

abstract: While immunopathology has been widely studied in severe COVID-19 patients, immunoprotective factors in non-hospitalized patients have remained largely elusive. We systematically analyzed 484 peripheral immune cell signatures, various serological parameters and TCR repertoire in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 control individuals. Within three days following PCR diagnosis, we observed coordinated responses of CD4 and CD8 T cells, various antigen presenting cells and antibody-secreting cells in mild, but not hospitalized COVID-19 patients. This early-stage SARS-CoV-2-specific response was predominantly characterized by substantially expanded clonotypes of CD4 and less of CD8 T cells. The early-stage responses of T cells and dendritic cells were highly predictive for later seroconversion and protective antibody levels after three weeks in mild non-hospitalized, but not in hospitalized patients. Our systemic analysis provides the first full picture and early-stage trajectory of highly coordinated immune responses in mild COVID-19 patients.


title: Estimating salt consumption in 49 low-and middle-income countries: Development, validation and application of a machine learning model

abstract:
BackgroundGlobal targets to reduce salt intake have been proposed but their monitoring is challenged by the lack of population-based data on salt consumption. We developed a machine learning (ML) model to predict salt consumption based on simple predictors, and applied this model to national surveys in low- and middle-income countries (LMICs).

MethodsPooled analysis of WHO STEPS surveys. We used 19 surveys with spot urine samples for the ML model derivation and validation; we developed a supervised ML regression model based on: sex, age, weight, height, systolic and diastolic blood pressure. We applied the ML model to 49 new STEPS surveys to quantify the mean salt consumption in the population.

ResultsThe pooled dataset in which we developed the ML model included 45,152 people. Overall, there were no substantial differences between the observed (8.1 g/day (95% CI: 8.0-8.2 g/day)) and ML-predicted (8.1 g/day (95% CI: 8.1-8.2 g/day)) mean salt intake (p= 0.065). The pooled dataset where we applied the ML model included 157,699 people; the overall predicted mean salt consumption was 8.1 g/day (95% CI: 8.1-8.2 g/day). The countries with the highest predicted mean salt intake were in Western Pacific. The lowest predicted intake was found in Africa. The country-specific predicted mean salt intake was within reasonable difference from the best available evidence.

ConclusionsA ML model based on readily available predictors estimated daily salt consumption with good accuracy. This model could be used to predict mean salt consumption in the general population where urine samples are not available.

FundingWellcome Trust (214185/Z/18/Z)


title: Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis: evidence for differential phenotypes in early and persistent psychosis

abstract: Cognitive impairments in psychosis are one of the strongest predictors of functional decline. Cortico-striatal dysfunction may contribute to both psychosis and cognitive impairment in psychotic illnesses. The decision-making processes underlying goal-directed action and serial reversal learning can be measured and are sensitive to changes reflecting cortico-striatal dysfunction. As such, changes in decision-making performance may assist with predicting functional decline in people with psychosis. We assessed decision-making processes in healthy controls (N=34), and those with early psychosis (N=15) and persistent psychosis (N=45). We subclassified subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with persistent psychosis were less deterministic in their decision-making. Those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. In contrast, the early psychosis group included a lower proportion of individuals with impaired goal-directed action (20%) and displayed a different cognitive phenotype from those with persistent psychosis. These findings suggest prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis while those with early psychosis have relatively intact decision-making processes compared to healthy controls. It is unclear if there is a progressive decline in decision-making processes in some individuals with psychosis or if the presence of decision-making processes in early psychosis is predictive of a persistent trajectory of illness.


title: Ensemble forecast of COVID-19 in Karnataka for vulnerability assessment and policy interventions

abstract: We present an ensemble forecast for Wave-3 of COVID-19 in the state of Karnataka, India, using the IISc Population Balance Model for infectious disease spread. The reported data of confirmed, recovered, and deceased cases in Karnataka from 1 July 2020 to 4 July 2021 is utilized to tune the models parameters, and an ensemble forecast is done from 5 July 2021 to 30 June 2022. The ensemble is built with 972 members by varying seven critical parameters that quantify the uncertainty in the spread dynamics (antibody waning, viral mutation) and interventions (pharmaceutical, non-pharmaceutical). The probability of Wave-3, the peak date distribution, and the peak caseload distribution are estimated from the ensemble forecast. Our analysis shows that the most significant causal factors are compliance to Covid-appropriate behavior, daily vaccination rate, and the immune escape new variant emergence-time. These causal factors determine when and how severe the Wave-3 of COVID-19 would be in Karnataka. We observe that when compliance to Covid-Appropriate Behavior is good (i.e., lockdown-like compliance), the emergence of new immune-escape variants beyond Sep  21 is unlikely to induce a new wave. A new wave is inevitable when compliance to Covid-Appropriate Behavior is only partial. Increasing the daily vaccination rates reduces the peak active caseload at Wave-3. Consequently, the hospitalization, ICU, and Oxygen requirements also decrease. Compared to Wave-2, the ensemble forecast indicates that the number of daily confirmed cases of children (0-17 years) at Wave-3s peak could be seven times more on average. Our results provide insights to plan science-informed policy interventions and public health response.


title: Change in force profile of the hardstyle kettlebell swing in older adults is small following 16 weeks of training and may not be required to improve physical function: findings from the BELL trial

abstract:
BackgroundHardstyle kettlebell training is characterised by the ballistic two-handed kettlebell swing with outcomes believed to be strongly influenced by swing proficiency. This study examines the effect of four months hardstyle kettlebell training on the force profile of the two-handed kettlebell swing, and peak ground reaction force during a kettlebell deadlift in older adults. These data will help inform healthcare providers and coaches about the use and prescription of kettlebell exercises with older adults.

MethodsFive males and five females <70 years of age who participated in the BELL trial were recruited. Two-handed hardstyle swings were performed with 8-16 kg, and deadlifts with 8-32 kg. Ground reaction force (GRF) was obtained from a floor-mounted force platform. Force-time curves (FTCs), peak force, forward force relative to vertical force, rate of force development (RFD), and swing cadence were investigated. Results were compared with the same data variables collected from the participants in an exploratory pre-intervention study, conducted approximately seven months before the present study. Participants completed approximately 90 kettlebell training sessions during a four-month training intervention.

ResultsParticipants used kettlebells to perform 3779 {+/-} 802 swings, 923 {+/-} 251 cleans, 825 {+/-} 309 snatches and 744 {+/-} 178 deadlifts during group-training sessions. Peak ground reaction force during kettlebell swings did not significantly change with any kettlebell weight. There was a significant 3% increase in the magnitude of forward force during 8 kg swings, and a significant 3% decrease in forward force during 16 kg swings. There were large significant improvements in swing cadence with a mean increase of three swings per minute and a small non-significant increase in RFD. Change in kettlebell swing force-time curve profiles were small. Change in peak ground reaction force during deadlifts were moderate to large. All participants increased in grip strength following training, with the magnitude of change greater than the minimum clinically important difference for seven participants. All participants had significant increases in multiple secondary outcomes.

ConclusionGroup-based and online kettlebell training is likely to be ineffective for improving the force profile of the hardstyle kettlebell swing in older adults. Insufficiently active older adults engaged in high-volume kettlebell training performed 3-5 times weekly, can however expect to see clinically meaningful improvements in health-related physical fitness irrespective of swing proficiency, and have increased confidence with heavy lifting tasks. Results of this study suggest that beyond safe and competent performance, striving to optimise hardstyle swing technique may provide no additional benefit to clinical outcomes in older adults.

category: sports medicine


title: Opt-out policies capacity to increase organ donors is limited

abstract:
ObjectivesTo increase post-mortem organ donation rates, several countries are adopting an opt-out (presumed consent) policy, meaning that individuals are deemed donors unless they expressly refused so. However, studies on the relative impact of opt-in or opt-out on deceased organ donation rates are inconclusive. Although opt-out countries tend to have higher donation rates, there is no conclusive evidence that this is caused by the policy itself. The main objective of this study is to better assess the impact of consent policies when considering the role of the family in decision-making.

DesignBy systematically combining the three components of the decision-making process --the default rule, the deceaseds preferences, and the familys preferences,-- we identify all situations that affect the retrieval outcome under opt-in and opt-out policies. Then, by gathering empirical data from a wide array of countries, we estimate the relative frequency of these situations.

Main outcome measuresWe measure the relative impact that opt-in and opt-out policies have per se on post-mortem organ retrieval.

ResultsOur analysis shows that opt-in and opt-out have strictly identical outcomes in eight out of nine situations. These policies only differ when neither the deceased nor the family have expressed a preference and defaults therefore apply. The actual impact of consent policies is typically circumscribed to a range of 0% to 5% of all opportunities for organ retrieval.

ConclusionsThis study may warn contemporary organ retrieval policy makers that, by emphasizing the need to introduce presumed consent, they might be overestimating the influence of policy defaults and underestimating the power granted to families in expressing their preferences and making decisions about organ donation. Governments should reassess the opportunity and effectiveness of adopting opt-out policies for organ retrieval.

O_TEXTBOXWhat is already known on this topicO_LIStudies on the relative impact of opt-in and opt-out on deceased organ donation rates are inconclusive.
C_LIO_LIThere is a correlation between presumed consent and higher rates of organ retrieval, but no evidence of a causal relationship.
C_LIO_LIMost studies overlook the role of the family in decision-making.
C_LI

What this study addsO_LIWhen the role of the family is taken into account, opt-in and opt-out policies have identical outcomes in eight out of nine situations.
C_LIO_LIThe situation where opt-in and opt-out actually differ from each other typically occurs in less than 5% of post-mortem organ retrieval opportunities.
C_LIO_LIMoving from opt-in to opt-out can only marginally increase the organ supply.
C_LI

Strenghts and limitations of this studyO_LIThe main strength of this study is the combination of analytical and empirical methods.
C_LIO_LIThis is the first study to analyse all situations that affect the retrieval outcome under both opt-in and opt-out policies when considering the role of the family in decision making.
C_LIO_LIData analysed in this study is the best empirical evidence available to date.
C_LIO_LIThe main limitation of our study is the heterogeneity of sources, sample sizes and time periods for the data collected, especially for the additional supporting evidence.
C_LIO_LIThis study only considers the direct effects of opt-out policies on organ retrieval rates, but not its indirect effects, such as organ preservation measures and psychological effects.
C_LI

C_TEXTBOX

category: transplantation


title: Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

abstract:
Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.

Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease.

We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

category: intensive care and critical care medicine


title: Quantification of the pace of biological aging in humans through a blood test: the DunedinPACE DNA methylation algorithm

abstract: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets. DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge. DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.


title: DunedinPACE: A DNA methylation biomarker of the Pace of Aging


title: The COVID-19 pandemic and ophthalmic care: a qualitative study of patients with neovascular age-related macular degeneration (nAMD)

abstract:
Background/aimsConcerns have been expressed about the relationship between reduced levels of health care utilisation and the COVID-19 pandemic. This study aimed to elicit and explore the views of patients with neovascular age-related macular degeneration (nAMD) regarding the COVID-19 pandemic and their ophthalmic care.

MethodsBetween April 29th and September 4th 2020, semi-structured telephone interviews were conducted with thirty-five patients with nAMD taking part in a larger diagnostic accuracy study of home-monitoring tests. Participants were recruited using maximum variation sampling to capture a range of key characteristics including age, gender and time since initial treatment. Transcribed interview data were analysed using a deductive and inductive thematic approach.

ResultsThree themes emerged from the analysis: i. access to eye clinic care. ii. COVID-19 mitigating factors and care delivery and iii. social and personal circumstances. Participants reported anxieties about cancelled or delayed appointments, limited communication from clinic-based services about appointments, and the impact of this on their ongoing care. Despite these concerns, there was apprehension about attending appointments due to infection risk and a perception that nAMD patients are a  high risk group. Views of those who attended clinics during the study period were, however, positive, with social distancing and infection control measures providing reassurance.

ConclusionsThese findings contribute to our understanding about experiences of patients with nAMD during the COVID-19 pandemic and have potential implications for future planning of care services. Innovative approaches may be required to address issues related to access to care, including concerns about delayed or cancelled appointments.

SynopsisPerspectives of patients with neovascular age-related macular degeneration regarding the COVID-19 pandemic identified important issues regarding access to, and experience of ophthalmic care. These findings have implications for future planning of services.

category: ophthalmology


title: Machine learning methods applied to genotyping data capture interactions between single nucleotide variants in late onset Alzheimer's disease

abstract:
INTRODUCTIONGenome-wide association studies (GWAS) in late onset Alzheimers disease (LOAD) provide lists of individual genetic determinants. However, GWAS are not good at capturing the synergistic effects among multiple genetic variants and lack good specificity.

METHODSWe applied tree-based machine learning algorithms (MLs) to discriminate LOAD (> 700 individuals) and age-matched unaffected subjects using single nucleotide variants (SNVs) from AD studies, obtaining specific genomic profiles with the prioritized SNVs.

RESULTSThe MLs prioritized a set of SNVs located in close proximity genes PVRL2, TOMM40, APOE and APOC1. The captured genomic profiles in this region showed a clear interaction between rs405509 and rs1160985. Additionally, rs405509 located in APOE promoter interacts with rs429358 among others, seemingly neutralizing their predisposing effect. Interactions are characterized by their association with specific comorbidities and the presence of eQTL and sQTLs.

DISCUSSIONOur approach efficiently discriminates LOAD from controls, capturing genomic profiles defined by interactions among SNVs in a hot-spot region.

category: genetic and genomic medicine


title: Wastewater-Based Epidemiology and Whole-Genome Sequencing for Community-Level Surveillance of SARS-CoV-2 in Selected Urban Communities of Davao City, Philippines: A Pilot Study

abstract:
ABSTRACT AND KEYWORDSO_ST_ABSBackgroundC_ST_ABSOver 50 countries have used Wastewater-Based Epidemiology (WBE) and Whole-Genome Sequencing (WGS) of SARS-CoV-2 for monitoring COVID-19 cases. COVID-19 surveillance in the Philippines relies on clinical monitoring and contact tracing, with both having limited use in early detection or prediction of community outbreaks. Thus, complementary public health surveillance methods that can provide community-level infection data faster and using lesser resources must be explored.

ObjectivesThis study piloted and assessed WBE and WGS as approaches for COVID-19 surveillance in low-resource and low-sanitation communities in Davao City, Philippines.

MethodsWeekly wastewater samples were collected from six barangay community sewer pipes or creeks from November to December 2020. Samples were concentrated using a PEG-NaCl precipitation method and analyzed by RT-PCR to detect the SARS-CoV-2 N, RdRP, and E genes. In addition, SARS-CoV-2 RNA-positive samples were subjected to WGS for genomic mutation surveillance. Public data from clinical surveillance were also reviewed to interpret WBE data.

ResultsTwenty-two of the 24 samples (91.7%) obtained from the six barangays tested positive for SARS-CoV-2 RNA. The cycle threshold (Ct) values were correlated with RNA concentration and attack rate. Thirty-two SARS-CoV-2 mutations were detected in WGS, including novel non-synonymous mutations or indels in seven SARS-CoV-2 genes and ten mutations previously reported in the Philippines.

DiscussionSARS-CoV-2 RNA was detected in community wastewater from the six barangays of Davao City, even when the barangays were classified as having a low risk of COVID-19 transmission and no new cases were reported. Despite the fragmented genome sequences analyzed, our genomic surveillance in wastewater confirmed the presence of previously reported mutations while identifying mutations not yet registered in clinical surveillance. The local context of a community must be considered when planning to adopt WBE and WGS as complementary COVID-19 surveillance methodologies, especially in low-sanitation and low-resource settings.


title: The Effective Coverage of Maternal and Child Primary Health Care Services and its Relationship with Health Expenditures: An Analysis at Sub-National Level in Iran

abstract:
BackgroundsMeasuring the effective coverage of essential health services is necessary for monitoring progress towards Universal Health Coverage (UHC). So, this study aimed to assess the geographic variations in key maternal and child indicators (as essential health services) provided at the primary health care (PHC) level in terms of their crude and effective coverage, and also to investigate the relationship between the effective coverage and health expenditures in the national and sub-national level of Iran.

MethodsThis study was a secondary analysis, which analyzed the spatial distribution of six key maternal and child health indicators using the latest available data of Demographic Health Survey-DHS (2010) across 31 provinces of Iran. Moreover, two composite indicators, the crude, and the effective coverage were calculated. The median cut-off was used to compare provinces situations. Furthermore, the relationship between coverage indicators and total health expenditure per capita was evaluated.

ResultsAt the national level, the crude and the effective composite coverage were 89.56 and 77.22%, respectively. Also, the medians of composite crude and effective service coverage in the provinces were 90.25 and 77.62%, respectively. There was no significant difference between urban and rural areas.

Conclusionsin this study, we found that there is a significant gap between crude and effective service coverage of the selected indicators. Overall, coverage indicators of maternal services were higher compared to those of children. In addition, geographic variations in key Indicators of maternal and child health services coverage among provinces were almost high. Although the services are free of charge in the rural areas, they did not have higher coverage than those of urban areas. PHC services in Iran are far away from reaching the desired coverage and achieving UHC.

O_TEXTBOXWhat is already known?O_LIIn Iran, primary health coverage(PHC) has a long history, even years before the adoption of Alma-ata declaration in1979.
C_LIO_LIIran is committed to implementing PHC programs in line with the Astana Declaration to accelerate access to universal health coverage.
C_LI

What are the new findings?O_LIthere is a significant gap between crude and effective coverage of maternal and child services, with high geographic variations among provenances.
C_LIO_LIHealth expenditures have no statistical relationship between coverage indicators; however, in low-coverage provinces, per capita health expenditure was lower
C_LI

What do the new findings imply?O_LIThe concept of the effective coverage of interventions has not received enough attention from health policy-makers in Iran, so it has not been incorporated into health system performance, yet.
C_LIO_LIDespite the long history of PHC in Iran, these services are still far away from reaching the appropriate targeted coverage; therefore, it is necessary to formulate and implement appropriate interventions in the provinces, based on their health needs and priorities.
C_LI

C_TEXTBOX


title: Tracking Covid-19 Cases and Deaths in the United States Distribution of Events by Day of Pandemic

abstract: In this paper, we analyze the progression of COVID-19 in the United States over a nearly one-year period beginning March 1, 2020, with a novel metric representing the partial-average day-of-event, where events are new cases and new deaths. The metric is calculated as a function of date and location to illustrate patterns of disease, showing growing or waning cases and deaths. The metrics enable the direct comparison of the time distribution of cases and deaths, revealing data coherence and how patterns varied over a one-year period. We also compare different methods of estimating actual infections and deaths to better understand on the timing and dynamics of the pandemic by state. We used three example states to graphically compare metrics as functions of date and also compared statistics derived from all 50 states. Over the period studied, average case day and average death day vary by two to five months among the 50 states, depending on data source, with the earliest averages in New York and surrounding states, as well as Louisiana. The average day of death has preceded the average day of case in Centers for Disease Control (CDC) data for most states and most dates since June of 2020. In contrast, "COVID-19 Projections" more closely align deaths and cases, which are similarly distributed.


title: Griffin: Framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA

abstract: Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we developed Griffin, a new method for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing (WGS) data. Griffin employs a novel GC correction procedure tailored to variable cfDNA fragment sizes, which improves the prediction of chromatin accessibility. Griffin achieved excellent performance for detecting tumor cfDNA in early-stage cancer patients (AUC=0.96). Next, we applied Griffin for the first demonstration of estrogen receptor (ER) subtyping in metastatic breast cancer from cfDNA. We analyzed 254 samples from 139 patients and predicted ER subtype with high performance (AUC=0.89), leading to insights about tumor heterogeneity. In summary, Griffin is a framework for accurate clinical subtyping and can be generalizable to other cancer types for precision oncology applications.


title: The impact of mental health and substance use issues on COVID-19 vaccine readiness: a cross sectional community-based survey in Ontario, Canada

abstract:
BackgroundCOVID-19 vaccines have been approved for use in Canada since December 2020. However, data about factors associated with vaccine hesitancy and the impact of mental health and/or substance use (MHSU) issues on vaccine uptake are currently not available. The goal of this study was to explore factors, particularly MHSU factors, that impact COVID-19 vaccination intentions in Ontario, Canada.

MethodsA community-based cross-sectional survey with recruitment based on age, gender, and geographical location (to ensure a representative population of Ontario), was conducted in February 2021. Multinomial logistic regression was used to test the relationship between COVID-19 vaccination status and plans and sociodemographic background, social support, anxiety about contracting COVID-19, and MHSU concerns.

ResultsOf the total sample of 2528 respondents, 1932 (76.4%) were vaccine ready, 381 (15.1%) were hesitant, and 181 (7.1%) were resistant. Significant independent predictors of vaccine hesitancy compared with vaccine readiness included younger age (OR=2.11, 95%CI=1.62-2.74), female gender (OR=1.36, 95%CI=1.06-1.74), Black ethnicity (OR=2.11, 95%CI=1.19-3.75), lower education (OR=1.69, 95%CI=1.30-2.20), lower SES status (OR=.88, 95%CI=.84-.93), lower anxiety about self or someone close contracting COVID-19 (OR=2.06, 95%CI=1.50-2.82), and lower depression score (OR=.90, 95%CI=.82-.98). Significant independent predictors of vaccine resistance compared with readiness included younger age (OR=1.72, 95%CI=1.19-2.50), female gender (OR=1.57, 95%CI=1.10-2.24), being married (OR=1.50, 95%CI=1.04-2.16), lower SES (OR=.80, 95%CI=.74-.86), lower satisfaction with social support (OR=.78, 95%CI=.70-.88), lower anxiety about contracting COVID-19 (OR=7.51, 95%CI=5.18-10.91), and lower depression score (OR=.85, 95%CI=.76-.96).

InterpretationCOVID-19 vaccination intention is affected by sociodemographic factors, anxiety about contracting COVID-19, and select mental health issues.


title: Strengthening public COVID-19 response with private facilities in Kisumu, Kenya

abstract:
INTRODUCTIONIn Kenya approximately half of healthcare services are delivered through private sector providers. In line with our experience building rapid responses to HIV and to support and accelerate the public sectors COVID-19 response, we initiated a PPP project in Kisumu County, Kenya. In this manuscript we demonstrate this PPPs performance using digital tools as a replicable model for scaling the response to COVID-19 in similar resource-poor settings.

METHODSCOVID-19 diagnostic testing formed the basis for a PPP between KEMRI, Department of Health Kisumu County, PharmAccess Foundation, and local faith-based and private healthcare facilities, thus naming our PPP: COVID-Dx. COVID-Dx was implemented from June 01, 2020, to March 31, 2021, in Kisumu County, Kenya. Trained laboratory technologists in participating healthcare facilities collected nasopharyngeal and oropharyngeal samples from patients meeting the Kenyan MoH COVID-19 case definition. Samples were tested using RT-PCR at the central reference laboratory in KEMRI. Healthcare workers in participating facilities collected patient clinical data using a digitized MoH COVID-19 Case Identification Form. We shared aggregated results from these data via (semi-) live dashboard to all relevant stakeholders. We did descriptive statistical analyses using Stata 16 to inform project processes.

ResultsNine facilities participated in the project. A detailed collaboration schedule was developed, supported by a semi-real time digital dashboard. A total of 4,324 PCR tests for SARS-CoV-2 were added to the public response, with 425 positives. Geo-mapped and time-tagged information on incident cases was collected and fed back to policymakers. At the beginning of the pandemic, there a heavy focus on health workers within Kisumu County, with a total of 1009 tested consisting about 43% of all County health workforce.

CONCLUSIONWe demonstrate feasibility to rapidly increase the public health sector response to a COVID-19 epidemic outbreak in a resource-poor setting. Our complementary public-private intervention in Kisumu, Kenya was based on a joint testing strategy and demonstrated that digitalization of the healthcare system can gain efficiencies, link public and private healthcare efforts, increase transparency and inform local policy makers with semi-real time data supporting targeting interventions. The Kisumu model is currently being scaled to 13 additional western Kenyan counties.


title: Public-private partnership to strengthening COVID-19 response in Kisumu, Kenya


title: Investigating Presence of Ethnoracial Bias in Clinical Data using Machine Learning

abstract: An important target for machine learning research is obtaining unbiased results, which require addressing bias that might be present in the data as well as the methodology. This is of utmost importance in medical applications of machine learning, where trained models should be unbiased so as to result in systems that are widely applicable, reliable and fair. Since bias can sometimes be introduced through the data itself, in this paper we investigate the presence of ethnoracial bias in patients clinical data. We focus primarily on vital signs and demographic information and classify patient ethnoraces in subsets of two from the three ethnoracial groups (African Americans, Caucasians, and Hispanics). Our results show that ethnorace can be identified in two out of three patients, setting the initial base for further investigation of the complex issue of ehtnoracial bias.

category: medical ethics


title: The locus coeruleus shows a spatial pattern of structural disintegration in Parkinson's disease.

abstract:
BackgroundParkinsons disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. "Neuromelanin sensitive" magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo.

ObjectivesTo identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions.

Methods42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a "neuromelanin sensitive" magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also tested for correlations between CNRMTw and the severity of non-motor symptoms.

ResultsMean CNRMTw of LC was reduced in patients relative to controls. The attenuation of CNRMTw was not uniformly expressed in LC, but confined to the middle and caudal LC. CNRMTw attenuation in caudal LC scaled with the orthostatic drop in systolic blood pressure and apathy ratings. PCA identified a bilaterally expressed component that was more weakly expressed in patients. This component was characterized by a gradual change in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of non-motor symptoms.

ConclusionPD related structural disintegration of LC mainly affects its caudal part and may determine the individual expression of specific non-motor symptoms such as orthostatic dysregulation or apathy.

category: neurology


title: Lack of benefit of temozolomide for MGMT methylated patients with high vascular glioblastoma: a confirmatory study.

abstract:
In this study we evaluated the benefit on survival of the combination of MGMT methylation and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included at the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of temozolomide for MGMT methylated patients with high vascular glioblastomas. Preliminary results suggest that patients with moderate vascularity and methylated MGMT would benefit more from prolonged adjuvant chemotherapy.

Simple SummaryDespite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with MGMT methylation on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity. As well as the lack of benefit of temozolomide in patients with a highly vascular tumor.


title: Physical activity specifically evokes release of cell-free DNA from granulocytes thereby affecting liquid biopsy

abstract:
Cell-free DNA (cfDNA) methylation-based diagnostics is a promising approach in oncology and hematooncology. Exercise impacts immune homeostasis and leads to a rapid and marked increase of cfDNA levels in blood. Since the origin of cfDNA during exercise remains elusive, the implications for liquid biopsy are unknown. In this study, we identified the source of cfDNA in 10 healthy untrained individuals before, immediately after, and 30 min after exercise, and in 6 patients with myeloid neoplasms or acute leukemia under resting conditions. A pyrosequencing assay was used to analyze the methylation levels of four CpGs, representing DNA from granulocytes, lymphocytes, monocytes, and non-hematopoietic cells. After exercise, cfDNA was almost exclusively released from granulocytes, with cell type specific proportions increasing significantly from 54.1% to 90.2%. Exercise did not trigger the release of cfDNA from lymphocytes or other analyzed cell types, whereas a small amount of cfDNA was released from monocytes. Compared to healthy people, patients with hematological malignancies show significantly higher cfDNA levels at rest with 48.1 (19.1; 78) vs. 8.5 (8.2; 9.5) ng/ml, data expressed as median (25th; 75th percentiles), and considerably higher levels of lymphocyte specific hypomethylated cg17587997 (P<.001). Hence, exercise-induced cfDNA elevations can compromise diagnostic accuracy.

Key Points- cfDNA is a robust sample source for targeted bisulfite sequencing, enabling reliable mapping of the source cells.
- cfDNA methylation signatures differ between healthy people and patients with hematological malignancies.
- During intense exercise, cfDNA is almost exclusively derived from granulocytes, which can affect results of liquid biopsy.


title: Severe COVID-19 is characterised by inflammation and immature myeloid cells early in disease progression

abstract:
SARS-CoV-2 infection causes a wide spectrum of disease severity. Immune changes associated with severe disease include pro-inflammatory cytokine production and expansion of immature myeloid populations. The relative importance of the immunological changes in driving progression to severe disease remain poorly understood.

We aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19. We sought to use tests available in an on-site diagnostic hospital laboratory to identify an immunological signature for severe disease development which could be detected prior to peak severity thereby allowing initiation of therapeutic interventions. We used univariate and multivariate analysis, including unbiased machine learning, to investigate the relationships between clinical and demographic characteristics, inflammatory markers, and leukocyte immunophenotypes with progression to severe disease in 108 patients and to rank these in importance. A combination of four features (elevated levels of interleukin-6 and C-reactive protein, coupled with reduced monocyte HLA-DR expression and reduced neutrophil CD10 expression), were strongly predictive of severe disease with an average prediction score of 0.925.

HighlightsO_LISevere COVID-19 can be predicted by a combination of emergency myelopoiesis (CD10-neutrophils and HLA DR-monocytes) and inflammation (raised IL-6 and CRP)
C_LIO_LIThese changes can be identified from tests carried out prior to peak illness severity in a diagnostic laboratory
C_LIO_LIThis predictive model was derived from a cohort of patients with a wide range of ages, frailty and COVID-19 severity
C_LI

Graphical Abstract

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title: Sars-Cov-2 antibody titer 3 months post-vaccination is affected by age, gender, smoking and vitamin D.

abstract:
ContextVaccination against Sars-Cov-2 is in full swing during COVID-19 pandemic. One of the efficient methods to evaluate response to vaccination is the assessment of humoral immunity by measuring Sars-Cov-2 antibody titer. Identification of factors that affect the humoral response is important so as to ameliorate the responses to vaccination or identify vulnerable groups that may need vaccination boosters.

ObjectiveWe investigated the effect of anthropometric parameters (age, BMI), smoking, diabetes, statin use hypertension and levels of 25(OH)D and DHEAS to the Sars-Cov-2 antibody titer.

MethodsIn this longitudinal observational cohort study 712 subjects were tested for Sars-Cov-2 antibodies 3 months after the second dose of BNT162b2 vaccine. Multiple linear regression analysis was performed to identify which factors are associated with the antibody titer.

ResultsWe identified age to be negatively associated with antibody titer (p=0.0073) and male sex (p=0.0008). However, interaction of age and gender was significant (p<0.0001) highlighting the finding that only after the age of 40 years men had lower antibody levels than women. DHEAS, an aging marker, was not associated with the antibody titer. Smoking was also associated with low antibody titer (p=0.0008) while overweight or obese subjects did not have different antibody response compared to normal weight individuals. Although diabetic and hypertensive subjects trended towards lower antibody titer, this association was not statistically significant. Replete vitamin D levels were associated with higher antibody titers (p=0.00422).

ConclusionsAge, male sex and smoking negatively affects antibody titer while 25(OH)D is associated with increased Sars-Cov-2 antibody titers.


title: Immune response elicited from heterologous SARS-CoV-2 vaccination: Sinovac (CoronaVac) followed by AstraZeneca (Vaxzevria)

abstract: Limited COVID-19 vaccines in many countries have delayed mass-immunization. Although individuals fully vaccinated with Vaxzevria (AstraZeneca) have higher antibody levels than those with CoronaVac (Sinovac), heterologous prime-boost with CoronaVac-Vaxzevria yielded comparable antibody levels to two-dose Vaxzevria. Combination use of different available vaccines may be warranted in Thailand, which faces limited vaccine choice and supply.


title: Effectiveness of COVID-19 Vaccines Against SARS-CoV-2 Infection During a Delta Variant Epidemic Surge in Multnomah County, Oregon, July 2021

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) vaccines have been shown to be highly effective in preventing SARS-CoV-2 infection within controlled trials and real-world vaccine effectiveness (VE) studies. Recent reports have estimated reduced VE with the emergence and dissemination of the B.1.617.2 variant ("Delta variant"). We assess VE in Multnomah County, Oregon during a delta variant related epidemic expansion.

MethodsA test-negative design (TND) matched case-control analysis was performed to estimate the effectiveness of vaccination against SARS-CoV-2 infection during July 2021. Cases included a random sample of individuals that tested positive for SARS-CoV-2 and were reported by electronic laboratory report, were >15 years of age, and had no prior known SARS-CoV-2 infections. Controls were age and postal code matched individuals that tested negative for SARS-CoV-2 during July 2021. Immunization status was assessed using the Oregon ALERT Immunization Information system.

Results500 case-control pairs were matched (n=1000). 40.4% of cases were up-to-date on COVID-19 immunizations compared to 64.6% of controls. Effectiveness of any completed COVID-19 immunization was 73% (95% Confidence Interval [CI] 49-86%), 74% (95% CI 65-85%) for mRNA immunizations (BNT162b2, mRNA-1273), and 72% (95% CI 47-85%) for individuals partially immunized with mRNA immunizations.

ConclusionsOur findings estimate high, yet reduced, VE during Delta variant dissemination. These results highlight the importance of COVID-19 immunizations for reducing SARS-CoV-2 infection while juxtaposing the need for additional non-pharmaceutical interventions. Importantly, the reduced VE identified here may predict future reductions in vaccine performance in the context of ongoing viral genetic drift.


title: DNA methylation profiling of immune cells from tuberculosis-exposed individuals overlaps with BCG-induced epigenetic changes and correlates with the emergence of anti-mycobacterial 'corralling cells'

abstract: The mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Finally, we found evidence of an M. tuberculosis-triggered emergence of a non-macrophage cell population from BCG-trained macrophage cultures. These cells did not phagocytose M. tuberculosis, but  corralled the bacteria into focal points, resulting in limitation of bacterial growth. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG and suggests that the modifications promote transformation of macrophages (or an unknown progenitor) to establish a yet undescribed cellular defense mechanism which we term  corralling, based on the metaphorical resemblance to sheepdog herding.


title: Transcriptomics of acute DENV-specific CD8+ T cells does not support qualitative differences as drivers of disease severity.

abstract: While several lines of evidence suggest a protective role of T cells against disease associated with Dengue virus (DENV) infection, their potential contribution to immunopathology in the acute phase of DENV infection remains controversial, and it has been hypothesized that the more severe form of the disease (dengue hemorrhagic fever, DHF) is associated with altered T cell responses. To address this question, we determined the transcriptomic profiles of DENV-specific CD8+T cells in a cohort of 40 hospitalized DENV donors with either a milder form of the disease (dengue fever, DF) or a more severe disease form (dengue hemorrhagic fever, DHF). We found multiple transcriptomic signatures, one associated with DENV-specific Interferon-gamma responding cells, and two other gene signatures, one specifically associated with the acute phase, and the other with the early convalescent phase. Additionally, we found no differences in quantity and quality of DENV-specific CD8+T cells based on disease severity. Taken together with previous findings that did not detect altered DENV-specific CD4 T cell responses, the current analysis argues against alteration in DENV-specific T cell responses as being a correlate of immunopathology.

category: allergy and immunology


title: GENOME-WIDE ASSOCIATIONS OF AORTIC DISTENSIBILITY SUGGEST CAUSAL RELATIONSHIPS WITH AORTIC ANEURYSMS AND BRAIN WHITE MATTER HYPERINTENSITIES

abstract: Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We tested genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identified 102 loci (including 31 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlighted four signalling pathways associated with aortic distensibility (TGF-{beta}, IGF, VEGF and PDGF). We identified distinct sex-specific associations with aortic traits. We developed co-expression networks associated with aortic traits and applied phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggested a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

category: cardiovascular medicine


title: Mathematical modeling and adequate environmental sampling plans are essential for the public health assessment of COVID-19 pandemics: development of a monitoring indicator for SARS-CoV-2 in wastewater

abstract:
Since many infected people experience no or few symptoms, the SARS-CoV-2 epidemic is frequently monitored through massive virus testing of the population, an approach that may be biased and may be difficult to sustain in low-income countries. Since SARS-CoV-2 RNA can be detected in stool samples, quantifying SARS-CoV-2 genome by RT-qPCR in WWTPs1 has been proposed as an alternative tool to monitor virus circulation among human populations. However, measuring SARS-CoV-2 viral load in WWTPs can be affected by many experimental and environmental factors. To circumvent these limits, we propose here a novel indicator WWI2 that partly reduces and corrects the noise associated with the SARS-CoV-2 genome quantification in wastewater. This method has been successfully applied in the context of Obepine, a French national network that has been quantifying SARS-CoV-2 genome in a representative sample of French WWTPs since March 5th 2020. On August 26th, 2021, 168 WWTPs were monitored twice a week in the metropolitan and overseas territories of France. We detail the process of elaboration of this indicator, show that it is strongly correlated to the incidence rate and that the optimal time lag between these two signals is only a few days, making our indicator an efficient complement or even a credible alternative to the incidence rate. This alternative approach may be especially important to evaluate SARS-CoV-2 dynamics in human populations when the testing rate is low.

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title: Microbiota development in early life mediates association between mode of delivery and vaccine responses

abstract: The gut microbiota in early life, when critical immune maturation takes place, may influence the immunogenicity of childhood vaccinations. We assessed the association between mode of delivery, gut microbiota development in the first year of life, and mucosal antigen-specific immunoglobulin G (IgG) responses against pneumococcal and meningococcal conjugate vaccination at ages 12 and 18 months, respectively, in a prospective birth cohort of 120 infants. Birth by natural delivery was associated with higher IgG responses against both vaccines, which for the anti-pneumococcal IgG response could be explained by a gut microbial community composition with high abundances of Bifidobacterium and Escherichia coli in the first weeks of life. High E. coli abundance in the same period was also associated with higher anti-meningococcal IgG responses. Our results suggest that associations between mode of delivery and antibody responses to routine childhood vaccines are mediated by gut microbiota development.

category: pediatrics


title: Colorectal cancer and microbiota modulation for clinical use. A systematic review.

abstract:
Colorectal cancer is one of the top contributors to the global burden of cancer incidence and mortality with genetic and environmental factors contributing to its etiology. Modifiable or environmental factors can be the cause of up to 60% of the risk of developing colorectal cancer. Hence, there is a growing interest in specifically defining what can be improved in our lifestyle to reduce this risk, improve the effectiveness of treatments, reduce side effects, and decrease the risk of recurrence. One of the elements directly related to lifestyle is gut microbiota. The microbial ecosystem has a vital role in colorectal cancer prevention and antitumoral response through modulation of the immune system and production of short-chain fatty acids. Numerous approaches have been used to identify healthy microbiota that can reduce the risk of cancer development, improve treatment efficacy, and reduce side effects.

Scientific literature in this subject is growing exponentially and, therefore, systematic reviews and meta-analysis are required to ensure that appropriate recommendations are given to patients.

This work aimed to perform a systematic analysis of the published literature to elucidate whether microbiota modulation through pre-, pro-, symbiotic treatment and/or nutritional intervention can be beneficial for patients diagnosed with colorectal cancer.

Detailed analysis of published studies shows that some prebiotics, such as inulin and resistant starch, probiotics such as lactic strains producers of short-chain fatty acids, and consumption of unprocessed plant products, can be effective recommendations for patients diagnosed with colorectal cancer. This advice should always be individually tailored and followed up by a healthcare professional with expertise in the field.


title: Multi-task deep learning-based survival analysis on the prognosis of late AMD using the longitudinal data in AREDS

abstract: Age-related macular degeneration (AMD) is the leading cause of vision loss. Some patients experience vision loss over a delayed timeframe, others at a rapid pace. Physicians analyze time-of-visit fundus photographs to predict patient risk of developing late-AMD, the most severe form of AMD. Our study hypothesizes that 1) incorporating historical data improves predictive strength of developing late-AMD and 2) state-of-the-art deep-learning techniques extract more predictive image features than clinicians do. We incorporate longitudinal data from the Age-Related Eye Disease Studies and deep-learning extracted image features in survival settings to predict development of late-AMD. To extract image features, we used multi-task learning frameworks to train convolutional neural networks. Our findings show 1) incorporating longitudinal data improves prediction of late-AMD for clinical standard features, but only the current visit is informative when using complex features and 2) "deep-features" are more informative than clinician derived features. We make codes publicly available at https://github.com/bionlplab/AMD_prognosis_amia2021.


title: Characteristics associated with COVID-19 vaccine uptake among adults in England (08 December to 17 May 2021)

abstract:
ObjectiveTo determine characteristics associated with COVID-19 vaccine coverage among individuals aged 50 years and above in England since the beginning of the programme.

DesignObservational cross-sectional study assessed by logistic regression and mean prevalence margins.

SettingCOVID-19 vaccinations delivered in England from 08 December 2020 - 17 May 2021.

Participants30,624,257/ 61,967,781 (49.4%) and 17,360,045/ 61,967,781 (28.1%) individuals in England were recorded as vaccinated in the National Immunisation Management System with a first dose and a second dose of a COVID-19 vaccine, respectively.

InterventionsVaccination status with COVID-19 vaccinations.

Main Outcome MeasuresProportion, adjusted odds ratios and mean prevalence margins for individuals not vaccinated with dose 1 among those aged 50-69 years old and dose 1 and 2 among those aged 70 years old and above.

ResultsAmong individuals aged 50 years and above, Black/African/Caribbean ethnic group was the least likely of all ethnic groups to be vaccinated with dose 1 of the COVID-19 vaccine. However, among those aged 70 years and above, the odds of not having dose 2 was 5.53 (95% CI 5.42 to 5.63) and 5.36 (90% CI 5.29 to 5.43) greater among Pakistani and Black/African/Caribbean compared to White British ethnicity, respectively. The odds of not receiving dose 2 was 1.18 (95% CI 1.16 to 1.20) higher among individuals who lived in a care home compared to those who did not. This was the opposite to that observed for dose 1, where the odds of not being vaccinated was significantly higher among those not living in a care home (0.89 (95% CI 0.87 to 0.91)).

ConclusionsWe found that there are characteristics associated with low COVID-19 vaccine coverage. Inequalities, such as ethnicity are a major contributor to suboptimal coverage and tailored interventions are required to improve coverage and protect the population from SARS-CoV-2.

Article summaryO_ST_ABSStrengths and Limitations of this studyC_ST_ABSO_LIThis is the is the first study assessing characteristics associated with COVID-19 vaccine coverage for all individuals aged 50 years and above in England.
C_LIO_LIThis study uses data from the National Immunisation Management System (NIMS) which is based on all individuals in England with a registered NHS number.
C_LIO_LIThis centralised national system captures individual level data for both vaccination status and demographic characteristics and allows for linkage to other datasets such as health care worker and care home resident status.
C_LIO_LIThis study does not include those without an NHS number and, therefore, it is possible we have underestimated the number of vaccines delivered and odds of not being vaccinated for characteristics such as ethnic groups where we have seen the greatest impact.
C_LIO_LIResidual errors in data entry on the point of care apps at the vaccination sites may have also occurred, though these errors are not likely to be widespread.
C_LI


title: Impact and effectiveness of social distancing for COVID-19 mitigation -- A transnational and transregional study

abstract: We present an analysis of the relationship between SARS-CoV-2 infection rates and a social distancing metric from data for all the states and most populous cities in the United States and Brazil, all the 22 European Economic Community countries and the United Kingdom. We discuss why the infection rate, instead of the effective reproduction number or growth rate of cases, is a proper choice to perform this analysis when considering a wide span of time. We obtain a strong Spearmans rank order correlation between the social distancing metric and the infection rate in each locality. We show that mask mandates increase the values of Spearmans correlation in the United States, where a mandate was adopted. We also obtain an explicit numerical relation between the infection rate and the social distancing metric defined in the present work.


title: A transnational and transregional study of the impact and effectiveness of social distancing for COVID-19 mitigation


title: The pitfalls of inferring virus-virus interactions from co-detection prevalence data: Application to influenza and SARS-CoV-2

abstract: There is growing experimental evidence that many respiratory viruses--including influenza and SARS-CoV-2--can interact, such that their epidemiological dynamics may not be independent. To assess these interactions, standard statistical tests of independence suggest that the prevalence ratio--defined as the ratio of co-infection prevalence to the product of single-infection prevalences--should equal unity for non-interacting pathogens. As a result, earlier epidemiological studies aimed to estimate the prevalence ratio from co-detection prevalence data, under the assumption that deviations from unity implied interaction. To examine the validity of this assumption, we designed a simulation study that built on a broadly applicable epidemiological model of co-circulation of two respiratory viruses causing seasonal epidemics. By focusing on the pair influenza-SARS-CoV-2, we first demonstrate that the prevalence ratio systematically under-estimates the strength of interaction, and can even misclassify antagonistic or synergistic interactions that persist after clearance of infection. In a global sensitivity analysis, we further identify properties of viral infection--such as a high reproduction number or a short infectious period--that blur the interaction inferred from the prevalence ratio. Altogether, our results suggest that epidemiological studies based on co-detection prevalence data provide a poor guide to assess interactions among respiratory viruses.


title: COVID-19 mortality in children and young people in Mexico

abstract:
ObjectiveTo estimate COVID-19 and pre-pandemic low respiratory infection (LRI) mortality in children and young people in Mexico.

Material and methodsWe estimated the percentage of total mortality attributable to COVID-19 (95% confidence intervals; 95%CI) and corresponding estimates for pre-pandemic LRI mortality.

ResultsIn 2019, LRIs represented 8.6% (95%CI 8.3, 8.9) of deaths in children 0-9 years and 2.0% (95%CI 1.8, 2.3) in those aged 10-19 years. In 2020, corresponding estimates for COVID-19 were 4.4% (95%CI 4.1, 4.6) and 3.7% (95%CI 3.4, 4.1).

ConclusionsRelative to LRI, COVID-19 may be exerting considerable mortality burden, particularly in older children and adolescents.


title: Evaluation of Primary Prescription Nonadherence Post-discharge from an Inpatient Psychiatry Unit at a Large Urban Community Hospital -an Observational Study

abstract:
IntroductionHere, we aimed to evaluate primary prescription nonadherence post-discharge from an acute inpatient psychiatric unit. Prescription nonadherence is a concern across all patient care settings, with primary nonadherence defined as not picking up prescribed medication from the pharmacy or not delivering prescriptions to the pharmacy. Secondary nonadherence, defined as filling a prescription but not taking the medication as prescribed, was not tracked in this study. The incidence of nonadherence can vary widely across settings and has been reported to range from 3- 86%. This is a particular concern in patients with a primary psychiatric diagnosis both in an outpatient and inpatient setting.

DesignThe prescription fill rate of eligible patients was tracked on days 7 and 21 post-discharge from acute inpatient psychiatric units of an acute care multispecialty urban community teaching hospital.

ResultsIn total, 72 patients aged 18 and above (44%, women) were analyzed. A primary nonadherence incidence of 43% was found, which did not vary significantly across the analyzed variables of age, sex, or primary diagnosis.

ConclusionPrimary nonadherence is a significant issue in this population. Strategies, such as the implementation of "med-to-bed" programs and use of longer acting injectables when appropriate, would help in increasing adherence. Further research, including the evaluation of other variables that affect nonadherence, is needed to identify and develop steps to overcome the obstacles to adherence.

category: psychiatry and clinical psychology