title: Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis

abstract:
BackgroundIt was urgent and necessary to synthesize the evidence for vaccine effectiveness (VE) against SARS-CoV-2 variants of concern (VOC). We conducted a systematic review and meta-analysis to provide a comprehensive overview of the effectiveness profile of COVID-19 vaccines against VOC.

MethodsPublished and preprinted randomized controlled trials (RCTs), cohort studies, and case-control studies that evaluated the VE against VOC (Alpha, Beta, Gamma, or Delta) were searched until 31 August 2021. Pooled estimates and 95% confidence intervals (CIs) were calculated using random-effects meta-analysis. VE was defined as (1- estimate).

ResultsSeven RCTs (51,169 participants), 10 cohort studies (14,385,909 participants) and 16 case-control studies (734,607 cases) were included. Eight COVID-19 vaccines (mRNA-1273, BNT162b2, ChAdOx1, Ad26.COV2.S, NVX-CoV2373, BBV152, CoronaVac, and BBIBP-CorV) were included in this analysis. Full vaccination was effective against Alpha, Beta/Gamma, and Delta variants, with VE of 88.3% (95% CI, 82.4-92.2), 70.7% (95% CI, 59.9-78.5), and 71.6% (95% CI, 64.1-77.4), respectively. But partial vaccination was less effective, with VE of 59.0% (95% CI, 51.3-65.5), 49.3% (95% CI, 33.0-61.6), and 52.6% (95% CI, 43.3-60.4), respectively. mRNA vaccines seemed to have higher VE against VOC over others, significant interactions (pinteraction < 0.10) were observed between VE and vaccine type (mRNA vaccines vs. non-mRNA vaccines).

ConclusionsFull vaccination of COVID-19 vaccines is highly effective against Alpha variant, and moderate effective against Beta/Gamma and Delta variants. Partial vaccination has less VE against VOC. mRNA vaccines seem to have higher VE against Alpha, Beta/Gamma, and Delta variants over others.

category: infectious diseases


title: Assessing the impact of temperature and humidity exposures during early infection stages on case-fatality of COVID-19: a modelling study in Europe

abstract:
BackgroundAlthough associations between key weather indicators (i.e. temperature and humidity) and COVID-19 mortality has been reported, the relationship between these exposures among different timing in early infection stages (from virus exposure up to a few days after symptom onset) and the probability of death after infection (also called case fatality rate, CFR) has yet to be determined.

MethodsWe estimated the instantaneous CFR of eight European countries using Bayesian inference in conjunction with stochastic transmission models, taking account of delays in reporting the number of newly confirmed cases and deaths. The exposure-lag-response associations between fatality rate and weather conditions to which patients were exposed at different timing were obtained using distributed lag nonlinear models coupled with mixed-effect models.

ResultsOur results showed that the Odds Ratio (OR) of death is negatively associated with the temperature, with two maxima (OR=1.29 (95% CI: 1.23, 1.35) at -0.1{degrees}C; OR=1.12 (95% CI: 1.08, 1.16) at 0.1{degrees}C) occurred at the time of virus exposure and after symptom onset. Two minima (OR=0.81 (95% CI: 0.71, 0.92) at 23.2{degrees}C; OR=0.71 (95% CI: 0.63, 0.80) at 21.7{degrees}C) also occurred at these two distinct periods correspondingly. Low humidity (below 50%) during the early stages and high humidity (approximately 89%) after symptom onset were related to the lower fatality.

ConclusionEnvironmental conditions may affect not only the initial viral load when exposure to viruses but also individuals immunity response around symptom onset. Warmer temperatures and higher humidity after symptom onset were related to the lower fatality.

HighlightsO_LITemperature and humidity conditions that patients were exposed to during their early infection stages were associated with COVID-19 case fatality rate.
C_LIO_LIWarmer temperatures (> 20{degrees}C) at infection time or after symptom onset, but not during the incubation period, were associated with lower death risk. Low relative humidity (< 50%) during the early stages and high relative humidity (> 85%) after symptom onset were related to higher death risk.
C_LIO_LICreating optimal indoor conditions for cases who are under quarantine/isolation may reduce their risk of death.
C_LI


title: Assessing the impact of temperature and humidity exposures during early infection stages on case-fatality of COVID-19: a modelling study


title: Neutralizing efficacy of vaccines against the SARS-CoV-2 Mu variant

abstract: The rise of mutant strains of SARS-CoV-2 poses an additional problem to the existing pandemic of COVID-19. There are rising concerns about the Mu variant which can escape humoral immunity acquired from infections from previous strains or vaccines. We examined the neutralizing efficacy of the BNT162b2 mRNA vaccine against the Mu variant and report that the vaccine has 76% neutralizing effectiveness against the Mu compared to 96% with the original strain. We also show that Mu, similar to the Delta variant, causes cell-to-cell fusion which can be an additional factor for the variant to escape vaccine-mediated humoral immunity. Despite the rise in vaccine escape strains, the vaccine still possesses adequate ability to neutralize majority of the mutants.


title: Quantification and prognostic significance of interferon-γ secreting SARS-CoV-2 responsive T cells in hospitalised patients with acute COVID-19

abstract: Little is known about T-cell responses during acute coronavirus disease-2019 (COVID-19). We measured T-cell interferon gamma (IFN-{gamma}) responses to spike 1 (S1), spike 2 (S2), nucleocapsid (N) and membrane (M) SARS-CoV-2 antigens using the T-SPOT(R) Discovery SARS-CoV-2 assay, a proven EliSPOT technology, in 114 hospitalised adult COVID-19 patients and assessed their association with clinical disease phenotype. T-SPOT(R) Discovery SARS-CoV-2 responses were detectable within 2 days of a positive PCR and did not correlate with vaccination status or symptom duration. Higher responses to S1 protein associated with a higher symptom burden, and serum IL-6 levels. Despite treatment with dexamethasone this subgroup was also at greater risk of requiring continuous positive airway pressure (CPAP) in the days following sampling. Higher T-cell responses measured using T-SPOT(R) Discovery SARS-CoV-2 associate with progressive disease in acute COVID-19 disease and may have utility as a prognostic biomarker that should be evaluated in larger cohorts.


title: The COMBAT-TB Workbench: Making powerful M. tuberculosis bioinformatics accessible

abstract:
Whole Genome Sequencing (WGS) is a powerful method for detecting drug resistance, genetic diversity and transmission dynamics of Mycobacterium tuberculosis. Implementation of WGS in public health microbiology laboratories is impeded by a lack of user-friendly, automated and semi-automated pipelines. We present the COMBAT-TB workbench, a modular, easy to install application that provides a web based environment for Mycobacterium tuberculosis bioinformatics. The COMBAT-TB Workbench is built using two main software components: the IRIDA Platform for its web-based user interface and data management capabilities and the Galaxy bioinformatics workflow platform for workflow execution. These components are combined into a single easy to install application using Docker container technology. We implemented two workflows, for M. tuberculosis sample analysis and phylogeny, in Galaxy. Building our workflows involved updating some Galaxy tools (Trimmomatic, snippy and snp-sites) and writing new Galaxy tools (snp-dists, TB-Profiler, tb_variant_filter and TB Variant Report). The irida-wf-ga2xml tool was updated to be able to work with recent versions of Galaxy and was further developed into IRIDA plugins for both workflows. In the case of the M. tuberculosis sample analysis an interface was added to update the metadata stored for each sequence sample with results gleaned from the Galaxy workflow output. Data can be loaded into the COMBAT-TB Workbench via the web interface or via the command line IRIDA uploader tool. The COMBAT-TB Workbench application deploys IRIDA, the COMBAT-TB IRIDA plugins, the MariaDB database and Galaxy using Docker containers (https://github.com/COMBAT-TB/irida-galaxy-deploy).

ImportanceWhile the reduction in cost of WGS is making sequencing more affordable in Lower and Middle Income Countries, public health laboratories in these countries seldom have access to bioinformaticians and system support engineers adept at using the Linux command line and complex bioinformatics software. The COMBAT-TB Workbench provides an open source, modular, easy to deploy and use environment for managing and analysing M. tuberculosis WGS data and thereby makes WGS usable in practice in the LMIC context.


title: Development and validation of an electronic health records-based opioid use disorder algorithm by expert clinical adjudication

abstract:
BackgroundIn the US, over 200 lives are lost from opioid overdoses each day. Accurate and prompt diagnosis of opioid use disorders (OUD) may contribute substantially to prevention of overdose deaths. However, OUD research is limited, the specificity and sensitivity of OUD ICD codes are unknown, and the ICD codes are known to underestimate OUD prevalence. We developed and validated algorithms to identify OUD from EHR data and examine validity of ICD-based definitions for OUD.

MethodsThrough multiple iterations, we developed EHR-based algorithms to identify OUD. These algorithms and ICD-based OUD definition were validated against a total of 169 independent gold standard EHR chart reviews conducted by an expert adjudication panel of eight pain and addiction medicine clinical experts across four large healthcare systems. The experts relied on clinical judgement and current Diagnostic and Statistical Manual of Mental Disorders-5 criteria for making OUD diagnoses.

ResultsOf the 169 EHR charts, 81 (48%) were reviewed by more than one expert and exhibited 85% agreement between the reviewing experts. The OUD ICD codes alone had 10% sensitivity and 99% specificity, underscoring the strong potential for OUD underestimation in studies depending on ICD codes alone. In comparison, after four iterations, the algorithms identified OUD with a 23% sensitivity and 98% specificity.

Conclusions and RelevanceThis is the first study to evaluate the validity of OUD ICD codes and develop validated EHR-based algorithms to address OUD underestimation. This work has the potential to inform future research on early intervention and prevention of OUD.

category: addiction medicine


title: Social contacts and transmission of COVID-19 in British Columbia, Canada

abstract:
PurposeClose-contact rates are thought to be a significant driving force behind the dynamics of transmission for many infectious respiratory diseases. Efforts to control such infections typically focus on the practice of strict contact-avoidance measures. Yet, contact rates and their relation to transmission, and the impact of control measures, are seldom quantified. Here, we quantify the response of contact rates, transmission and new cases of COVID-19 to public health contact-restriction orders, and the associations among these three variables, in the Canadian province of British Columbia (BC) and within its two most densely populated regional health authorities: Fraser Health Authority (FHA) and Vancouver Coastal Health Authority (VCHA).

MethodsWe obtained time series for self-reported close-contact rates from the BC Mix COVID-19 Survey, new reported cases of COVID-19 from the BC Center for Disease Control, and transmission rates based on dynamic model fits to reported cases. Our study period was from September 13, 2020 to February 19, 2021, during which three public health contact-restriction orders were introduced (October 26, November 7 and November 19, 2020). We used segmented linear regression to quantify impacts of public health orders, Pearson correlation to assess the instantaneous relation between contact rates and transmission, and vector autoregressive modeling to study the lagged relations among the three variables.

ResultsOverall, declines in contact rates and transmission occurred concurrently with the announcement of public health orders, whereas declines in new cases showed a reporting delay of roughly two weeks. The impact of the first public health order (October 26, 2020) on contact rates and transmission was more pronounced than that of the other two health orders. Contact rates and transmission on the same day were strongly correlated (correlation coefficients = 0.64, 0.53 and 0.34 for BC, FHA, and VCHA, respectively). Moreover, contact rates were a significant time-series driver of COVID-19 and explained roughly 30% and 18% of the variation in new cases and transmission, respectively. Interestingly, increases in transmission and new cases were followed by reduced rates of contact: overall, average daily cases explained about 10% of the variation in provincial contact rates.

ConclusionWe show that close-contact rates were a significant driver of transmission of COVID-19 in British Columbia, Canada and that they varied in response to public health orders. Our results also suggest a possible feedback, by which contact rates respond to recent changes in reported cases. Our findings help to explain and validate the commonly assumed, but rarely measured, response of close contact rates to public health guidelines and their impact on the dynamics of infectious diseases.

category: epidemiology


title: Modeling the transmission of the SARS-CoV-2 delta variant in a partially vaccinated population

abstract:
In a population with ongoing vaccination, the trajectory of a pandemic is determined by how the virus spreads in unvaccinated and vaccinated individuals that exhibit distinct transmission dynamics based on different levels of natural and vaccine-induced immunity. We developed a mathematical model that considers both subpopulations and immunity parameters including vaccination rates, vaccine effectiveness, and a gradual loss of protection. The model forecasted the spread of the SARS-CoV-2 delta variant in the US under varied transmission and vaccination rates. We further obtained the control reproduction number and conducted sensitivity analyses to determine how each parameter may affect virus transmission. Our results show that a combination of strengthening vaccine-induced immunity and preventative behavioral measures will likely be required to deaccelerate the rise of infectious SARS-CoV-2 variants.

One-Sentence SummaryMathematical models considering vaccinated and unvaccinated individuals help forecast and manage the spread of new SARS-CoV-2 variants.


title: Who is at risk of poor mental health following COVID-19 outpatient management?

abstract:
BackgroundCOVID-19 convalescents are at risk of developing a de novo mental health disorder or of worsening of a pre-existing one. The objectives of our study was to phenotype individuals at highest risk of mental health disorders among COVID-19 outpatients.

MethodsWe conducted a binational online survey study with adult non-hospitalized COVID-19 convalescents (Austria/AT: n=1157, Italy/IT: n= 893). Primary endpoints were positive screening for depression and anxiety (PHQ-4, Patient Health Questionnaire) and self-perceived overall mental health and quality of life rated with 4 point Likert scales. Psychosocial stress was surveyed with a modified PHQ stress module. Associations of the mental health with socio-demographic variables, COVID-19 course and recovery data were assessed by multi-parameter random forest and serial univariable modeling. Mental disorder risk subsets were defined by self-organizing map and hierarchical clustering algorithms. The survey analyses are publicly available (https://im2-ibk.shinyapps.io/mental_health_dashboard/).

ResultsIn the study cohorts, 4.6 (IT)/6% (AT) of participants reported depression and/or anxiety before to infection. At a median of 79 days (AT)/96 days (IT) post COVID-19 onset, 12.4 (AT)/19.3% (IT) of subjects were screened positive for anxiety and 17.3 (AT)/23.2% (IT) for depression. Over one-fifth of the respondents rated their overall mental health (AT: 21.8%, IT: 24.1%) or quality of life (AT: 20.3%, IT: 25.9%) as fair or poor. In both study collectives, psychosocial stress, high numbers of acute and persistent COVID-19 complaints and the presence of acute neurocognitive symptoms (impaired concentration, confusion, forgetfulness) were the strongest correlates of deteriorating mental health and poor quality of life. In clustering analysis, these variables defined a  high risk subset with particularly high propensity of post-COVID-19 mental health impairment and decreased quality of life. Pre-existing depression or anxiety was associated with an increased symptom burden during acute COVID-19 and recovery.

ConclusionOur study revealed a bidirectional relationship between COVID-19 symptoms and mental health. We put forward specific acute symptoms of the disease as  red flags of mental health deterioration which should prompt general practitioners to identify COVID-19 patients who may benefit from early psychological and psychiatric intervention.

Trial registrationClinicalTrials.gov: NCT04661462.


title: Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Breast Cancer Risk Prediction among Asian Women, Results from Asia Breast Cancer Consortium

abstract:
ImportancePolygenic risk scores (PRSs) have shown promises in breast cancer risk prediction; however, limited studies have been conducted among Asian women.

ObjectiveTo develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors.

DesignPRSs were developed using data from genome-wide association studies (GWAS) of breast cancer conducted among 123 041 Asian-ancestry women (including 18 650 cases) using three approaches (1) reported PRS for European-ancestry women; (2) breast cancer-associated single-nucleotide polymorphisms (SNPs) identified by fine-mapping of GWAS-identified risk loci; (3) genome-wide risk prediction algorithms. A nongenetic risk score (NgRS) was built including six well-established nongenetic risk factors using data from 1974 Asian women. Integrated risk scores (IRSs) were constructed using PRSs and the NgRS. PRSs were initially validated in an independent dataset including 1426 cases and 1323 controls and further evaluated, along with the NgRS and IRSs, in the second dataset including 368 cases and 736 controls nested withing a prospective cohort study.

SettingCase-control and prospective cohort studies.

Participants20 444 breast cancer cases and 106 450 controls from the Asia Breast Cancer Consortium.

Main Outcomes and MeasuresLogistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% confidence intervals (CIs) and area under the receiver operating characteristic curve (AUC).

ResultsIn the prospective cohort, PRS111, a PRS with 111 SNPs, developed using the fine-mapping approach showed a prediction performance comparable to a genome-wide PRS including over 855,000 SNPs. The OR per standard deviation increase of PRS111 was 1.67 (95% CI=1.46-1.92) with an AUC of 0.639 (95% CI=0.604-0.674). The NgRS had a limited predictive ability (AUC=0.565; 95% CI=0.529-0.601); while IRS111, the combination of PRS111 and NgRS, achieved the highest prediction accuracy (AUC=0.650; 95% CI=0.616-0.685). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and IRS111 were at a 3.84-folded (95% CI=2.30-6.46) and 4.25-folded (95% CI=2.57-7.11) elevated risk of breast cancer, respectively.

Conclusions and RelevancePRSs derived using breast cancer-associated risk SNPs have similar prediction performance in Asian and European descendants. Including nongenetic risk factors in models further improved prediction accuracy. Our findings support the utility of these models in developing personalized screening and prevention strategies.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the performance of breast cancer risk prediction models for Asian women incorporating polygenic risk scores (PRSs) and nongenetic risk factors?

FindingsA 111-genetic-variant PRS developed using data of 125 790 Asian women was significantly associated with breast cancer risk in an independent case-control study nested within a prospective cohort, with an odd ratio (OR) per standard deviation increase of 1.67 (95% confidence interval [CI]=1.46-1.92) and an area under the receiver operating characteristic curve (AUC) of 0.639 (95% CI=0.604-0.674). The prediction model including this PRS and six nongenetic risk factors improved the AUC to 0.650 (95% CI=0.616-0.685).

MeaningOur study provides strong supports for the utility of prediction models in identifying Asian women at high risk of breast cancer.


title: Is annual vaccination best? A modelling study of influenza vaccination strategies in children

abstract:
IntroductionAnnual vaccination of children against influenza is a key component of vaccination programs in many countries. However, past infection and vaccination may affect an individuals susceptibility to infection. Little research has evaluated whether annual vaccination is the best strategy. Using the United Kingdom as our motivating example, we assess the impact of different childhood vaccination strategies, specifically annual and biennial (every other year), on attack rate and expected number of infections.

Methods and FindingsWe present a multi-annual, individual-based, stochastic, force of infection model that accounts for individual exposure histories and disease/vaccine dynamics influencing susceptibility. We simulate birth cohorts that experience yearly influenza epidemics and follow them until age 18 to determine attack rates and the number of childhood infections. We perform simulations under baseline conditions, with an assumed vaccination coverage of 44%, to compare annual vaccination to no and biennial vaccination. We relax our baseline assumptions to explore how our model assumptions impact vaccination program performance.

At baseline, we observed more than a 50% reduction in the number of infections between the ages 2 and 10 under annual vaccination in children who had been vaccinated at least half the time compared to no vaccination. When averaged over all ages 0-18, the number of infections under annual vaccination was 2.07 (2.06, 2.08) compared to 2.63 (2.62, 2.64) under no vaccination, and 2.38 (2.37, 2.40) under biennial vaccination. When we introduced a penalty for repeated exposures, we observed a decrease in the difference in infections between the vaccination strategies. Specifically, the difference in childhood infections under biennial compared to annual vaccination decreased from 0.31 to 0.04 as exposure penalty increased.

ConclusionOur results indicate that while annual vaccination averts more childhood infections than biennial vaccination, this difference is small. Our work confirms the value of annual vaccination in children, even with modest vaccination coverage, but also shows that similar benefits of vaccination can be obtained by implementing a biennial vaccination program.

Author summaryMany countries include annual vaccination of children against influenza in their vaccination programs. In the United Kingdom, annual vaccination of children aged of 2 to 10 against influenza is recommended. However, little research has evaluated whether annual vaccination is the best strategy, while accounting for how past infection and vaccination may affect an individuals susceptibility to infection in the current influenza season. Prior work has suggested that there may be a negative effect of repeated vaccination. In this work we developed a stochastic, individual-based model to assess the impact of repeated vaccination strategies on childhood infections. Specifically, we first compare annual vaccination to no vaccination and then annual vaccination to biennial (every other year) vaccination. We use the UK as our motivating example. We found that an annual vaccination strategy resulted in the fewest childhood infections, followed by biennial vaccination. The difference in number of childhood infections between the different vaccination strategies decreased when we introduced a penalty for repeated exposures. Our work confirms the value of annual vaccination in children, but also shows that similar benefits of vaccination can be obtained by implementing a biennial vaccination program, particularly when there is a negative effect of repeated vaccinations.


title: Connecting Artificial Intelligence and Primary Care Challenges: Findings from a Multi-Stakeholder Collaborative Consultation

abstract:
Despite widespread advancements in and envisioned uses for artificial intelligence (AI), few examples of successfully implemented AI innovations exist in primary care (PC) settings.

ObjectivesTo identify priority areas for AI and PC in Ontario, Canada.

MethodsA collaborative consultation event engaged multiple stakeholders in a nominal group technique process to generate, discuss, and rank ideas for how AI can support Ontario PC.

ResultsThe consultation process produced nine ranked priorities: 1) preventative care and risk profiling, 2) patient self-management of condition(s), 3) management and synthesis of information, 4) improved communication between PC and AI stakeholders, 5) data sharing and interoperability, 6-tie) clinical decision support, 6-tie) administrative staff support, 8) practitioner clerical and routine task support, and 9) increased mental health care capacity and support. Themes emerging from small group discussions about barriers, implementation issues, and resources needed to support the priorities included: equity and the digital divide; system capacity and culture; data availability and quality; legal and ethical issues; user-centered design; patient-centredness; and proper evaluation of AI-driven tool implementation.

DiscussionFindings provide guidance for future work on AI and PC. There are immediate opportunities to use existing resources to develop and test AI for priority areas at the patient, provider, and system level. For larger-scale, sustainable innovations, there is a need for longer-term projects that lay foundations around data and interdisciplinary work.

ConclusionStudy findings can be used to inform future research and development of AI for PC, and to guide resource planning and allocation.

SUMMARYO_ST_ABSWhat is already known?C_ST_ABS- The field of artificial intelligence and primary care is underdeveloped.

What does this paper add?- An environmental scan without geographic location restriction identified 110 artificial intelligence-driven tools with potential relevance to primary care that existed around the time of the study.
- A multi-stakeholder consultation session identified nine priorities to guide future work on artificial intelligence and primary care in Ontario, Canada.
- Priorities for artificial intelligence and primary care include provider, patient, and system level uses as well as foundational areas related to data and interdisciplinary communication.

category: primary care research


title: Structural and diffusion weighted brain imaging biomarkers for ADHD and its symptomology in very young (4-7-year-old) children

abstract: The current study aimed to identify the key neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD), as it relates to ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. To do so, we adapted a predictive modeling approach to identify the key structural and diffusion weighted brain imaging measures, and their relative standing with respect to teacher ratings of executive function - EF (measured by the Metacognition Index of the Behavior Rating Inventory of Executive Function- BRIEF), negativity and emotion regulation - ER (measured by the Emotion Regulation Checklist, ERC), in a critical young age range (ages 4 to 7, mean age 5.52 years, 82.2% Hispanic/Latino), where initial contact with educators and clinicians typically take place. Teacher ratings of EF and ER were predictive of both ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. Among the neural measures evaluated, the current study identified the critical importance of the largely understudied diffusion weighted imaging measures for the underlying neurobiology of ADHD and its associated symptomology. Specifically, our analyses implicated the inferior frontal gyrus, the pericallosal sulcus, and the caudate as critical predictors of ADHD diagnostic category and its associated symptomology, above and beyond teacher ratings of EF and ER. Collectively, the current set of findings have implications for theories of ADHD, the relative utility of neurobiological measures with respect to teacher ratings of EF and ER, and the developmental trajectory of its underlying neurobiology.

category: psychiatry and clinical psychology


title: Cross-sectional assessment of predictors for COVID-19 vaccine uptake: an online survey in Greece

abstract:
BackgroundA high level of COVID-19 vaccine uptake in the general population is essential to control the pandemic.

ObjectiveTo estimate the percentage of the general population vaccinated against the COVID-19 and to investigate the factors associated with COVID-19 vaccine uptake.

MethodsWe conducted an online cross-sectional study in Greece during August 2021. We included individuals over 18 years of age. Independent variables included socio-demographic data of the participants and attitudes towards COVID-19 vaccination and pandemic. Our outcome variable was COVID-19 vaccination status, measured through "yes/no" answers.

ResultsMost participants had been vaccinated against the COVID-19 (87.8%), while about half had been vaccinated against the influenza (52.5%). Multivariate analysis identified that increased age and higher level of education were associated with an increased likelihood of COVID-19 vaccination. Also, participants working in health services, participants without a previous COVID-19 diagnosis and those with previous seasonal influenza vaccination history had a greater probability to take a COVID-19 vaccine. Additionally, increased self-perceived severity of COVID-19, knowledge regarding COVID-19, and trust in COVID-19 vaccines and scientists were associated with COVID-19 vaccine uptake. On the other hand, the likelihood of vaccination was lower for participants who were more concerned about the side effects of COVID-19 vaccination.

ConclusionsUnderstanding the factors affecting individuals decision to take a COVID-19 vaccine is essential to improve the COVID-19 vaccination coverage rate. Policymakers and scientists should scale up their efforts to increase the COVID-19 vaccination rate among specific population groups such as young people, people with low level of education, people with negative attitudes towards vaccination, etc.

category: public and global health


title: Behavioral Markers for Deficits in Speed of Processing in Cerebrovascular Disease

abstract:
ObjectiveTo assess overlap and uniqueness of established behavioral markers of speed of processing for different aspects of visual information within a cerebrovascular disease cohort, and to examine the link between these speed of processing markers and functional behavior, specifically walking.

MethodsA cohort of 161 participants with cerebrovascular disease recruited to the Ontario Neurodegenerative Disease Research Initiative (ONDRI) were examined with three types of assessments: neuropsychology, saccadic eye movement and gait. Principal component analysis (PCA) and canonical correlation analysis (CCA) were performed on select variables from these assessments to reveal commonalities and discrepancies among the measures.

ResultsPCA analysis revealed different variable patterns between neuropsychology and saccade assessments, with the first component characterized primarily by neuropsychology, and the second and third components more influenced by the saccade assessments. CCA analysis did not reveal association between different types of assessments with the exception of a modest, but significant, positive association between speed of processing measures from the neuropsychological assessments and gait speed.

DiscussionNeuropsychological tests and the pro-saccade task can be used for assessment of speed of processing for two major features of visual information, visual perception vs. spatial location. Despite a general lack of association between different types of assessments, combining gait speed as an important contributor to the models reinforces the idea of the link between speed of processing and complex function such as walking, and provides support for the importance of attending to the potential consequences of changes in speed of processing after neurologic injury.

category: neurology


title: Relationship between support for workers with illness and work functioning impairment in Japan during the COVID-19 pandemic

abstract:
ObjectiveThis study examined the relationship between job accommodations for workers with poor health and work functioning impairment during the COVID-19 pandemic.

MethodsAn internet survey was conducted in December 2020. We included 24,429 subjects for analysis. One question was used to determine whether subjects needed job accommodations from their company to continue working in their current health condition. The odds ratios (ORs) of the necessity of job accommodations for sick workers associated with work functioning impairment were estimated using multilevel logistic regression analysis.

ResultsThe OR of work functioning impairment among sick workers not receiving job accommodations was 5.75 (95% confidence interval (CI) 5.34-6.20, p<0.001) and those receiving job accommodations was 1.88 (95% CI 1.69-2.08, p<0.001) compared to healthy workers.

ConclusionsThis study suggests that providing job accommodations to workers with poor health may improve their work functioning impairment.

category: occupational and environmental health


title: Preliminary Report of Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application

abstract:
ObjectiveChimeric antigen receptor T (CAR-T) cell therapies already made an impact on the treatment of B cell malignancies. Although CAR-T cell therapies are promising, there are concerns with commercial products regarding their affordability and sustainability. In this preliminary study, results of the first productional and clinical data of academic CAR-T cell (ISIKOK-19) from Turkey are presented.

Materials and MethodsA pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy in patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. Production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusion is presented in this study.

ResultsNine patients were enrolled for the trial (ALL n=5 and NHL n=4) but only 7 patients could receive the treatment. Two out of three ALL patients and three out of four NHL patients had complete/partial response (ORR 72%). Four patients (57%) had CAR-T-related toxicities (CRS, CRES, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up.

ConclusionProduction efficacy and fulfilling the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles are acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19 positive tumors. The findings of this study need to be supported by the currently ongoing clinical trial of ISIKOK-19.

category: hematology


title: Antibody titers against the Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2 induced by BNT162b2 vaccination measured using automated chemiluminescent enzyme immunoassay

abstract:
BackgroundLevels of 50% neutralizing titer (NT50) reflect a vaccine-induced humoral immunity after the vaccination against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Measurements of NT50 are difficult to implement in large quantities. A high-throughput laboratory test is expected for determining the level of herd immunity against SARS-CoV-2.

MethodsWe analyzed samples from 168 Japanese healthcare workers who had completed two doses of the BNT162b2 vaccine. We analyzed immunoglobulin G (IgG) index values against spike protein (SP) using automated chemiluminescent enzyme immunoassay system AIA-CL and analyzed the background factors affecting antibody titer. SP IgG index was compared with 50% neutralization titers.

ResultsThe median SP IgG index values of the subjects (mean age = 43 years; 75% female) were 0.1, 1.35, 60.80, and 97.35 before and at 2, 4, and 6 weeks after the first dose, respectively. At 4 and 6 weeks after the first dose, SP IgG titers were found to have positive correlation with NT50 titer (r=0.7535 in 4 weeks; r=0.4376 in 6 weeks). Proportions of the SP IgG index values against the Alpha, Beta, Gamma, and Delta variants compared with the original strain were 2.029, 0.544, 1.017, and 0.6096 respectively. Older age was associated with lower SP IgG titer index 6 weeks after the first dose.

ConclusionsSP IgG index values were raised at 3 weeks after two doses of BNT162b2 vaccination and have positive correlation with NT50. SP IgG index values were lower in the older individuals and against Beta and Delta strain.


title: COVID-19 Vaccine Breakthrough Infections in the Veterans Health Administration.

abstract:
BackgroundVaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been accompanied by rising concern of vaccine breakthrough due to SARS-CoV-2 variants, waning protection over time, differential vaccine effectiveness, and regional resurgence of Coronavirus 2019 (COVID-19). Characterizing the frequency and drivers of vaccine breakthrough is necessary to inform COVID-19 control efforts.

MethodsWe performed a retrospective cohort study of vaccine breakthrough infections in fully vaccinated persons in Veterans Health Administration. We applied Cox proportional hazard models to estimate cumulative incidence, assess differences in outcomes by vaccine, and identify associations with individual characteristics as well as time-dependent geographic variation in COVID-19 incidence, proportion of delta variant, and vaccine coverage.

ResultsAmong 3,032,561 fully vaccinated persons, documented SARS-CoV-2 infection occurred in 11,197 (0.37%) and COVID-19 hospitalization occurred in 2,080 (0.07%). Compared to Ad26.COV2.S, BNT162b2 and mRNA-1273 had lower occurrence of documented SARS-CoV-2 infection (aHR 0.54, 95% confidence interval (CI) 0.51-0.58; aHR 0.36; 95% CI 0.33-0.38; respectively) and COVID-19 hospitalization (aHR 0.56, 95% CI 0.47-0.66; aHR 0.30; 0.25-0.35; respectively). Documented SARS-CoV-2 infection and COVID-19 hospitalization were associated with younger age, Hispanic or Latino ethnicity, number of comorbidities, and previous SARS-CoV-2 infection. Regional proportion of delta variant and county-level COVID-19 incidence were predictors of vaccine breakthrough events; county-level vaccine coverage was inversely associated.

ConclusionsVaccine breakthrough was rare among fully vaccinated persons. mRNA-1273 and BNT162b2 were more protective against documented SARS-CoV-2 infection and COVID-19 hospitalization compared to Ad26.COV2.S. Efforts to limit COVID-19 transmission and bolster vaccine coverage would also curtail vaccine breakthrough.


title: Sleep in the Intensive Care Unit through the Lens of Breathing and Heart Rate Variability: A Cross-Sectional Study

abstract:
BackgroundFull polysomnography, the gold standard of sleep measurement, is impractical for widespread use in the intensive care unit (ICU). Wrist-worn actigraphy and subjective sleep assessments do not measure sleep physiology adequately. Here, we explore the feasibility of estimating conventional sleep indices in the ICU with heart rate variability (HRV) and respiration signals using artificial intelligence methods.

MethodsWe used deep learning models to stage sleep with HRV (through electrocardiogram) and respiratory effort (through a wearable belt) signals in critically ill adult patients admitted to surgical and medical ICUs, and in covariate-matched sleep laboratory patients. We analyzed the agreement of the determined sleep stages between the HRV- and breathing-based models, computed sleep indices, and quantified breathing variables during sleep.

ResultsWe studied 102 adult patients in the ICU across multiple days and nights, and 220 patients in a clinical sleep laboratory. We found that sleep stages predicted by HRV- and breathing-based models showed agreement in 60% of the ICU data and in 81% of the sleep laboratory data. In the ICU, deep NREM (N2 + N3) proportion of total sleep duration was reduced (ICU 39%, sleep laboratory 57%, p<0.01), REM proportion showed heavy-tailed distribution, and the number of wake transitions per hour of sleep (median = 3.6) was comparable to sleep laboratory patients with sleep-disordered breathing (median = 3.9). Sleep in the ICU was also fragmented, with 38% of sleep occurring during daytime hours. Finally, patients in the ICU showed faster and less variable breathing patterns compared to sleep laboratory patients.

ConclusionsCardiovascular and respiratory signals encode sleep state information, which can be utilized to measure sleep state in the ICU. Using these easily measurable variables can provide automated information about sleep in the ICU.

category: intensive care and critical care medicine


title: Evaluation Of A New All In One Sars-Cov-2 Antigen-Detecting Rapid Diagnostic Test And Self-Test: Diagnostic Performance And Usability On Child And Adult Population

abstract: The control of the COVID-19 epidemics has been one of top global health priorities for the last eighteen months. To that end, more reliable and easy-to-use diagnostic tests are necessary. Young children are still not eligible to vaccination and it is important to find a way to easily test this key population regularly. With that in mind, we evaluated a new innovative easy two-step self-test named COVID-VIRO ALL IN(R) developed by AAZ that uses a sampling nasal sponge instead of a classic nasal swab. Mirroring the previous study conducted on the first generation of COVID-VIRO(R) antigenic self-test, we first performed a multicentre, prospective study on 124 adults and children, in a point-of-care setting. Sensitivity, specificity and overall acceptance of the COVID-VIRO ALL IN(R) antigen self-test compared to RT-PCR on nasopharyngeal samples were evaluated at 93.02%, 100% and 97,5%, respectively. We then performed a multicentre, prospective, usability study to evaluate the ease of use of COVID-VIRO ALL IN(R) in real life on 68 laypersons, all adults. Globally, 99% of them considered the instructions material good, 98% executed the procedure well, and all of them interpreted the results correctly. The usability was then specifically investigated on 40 children and teenagers participants, comparing both COVID-VIRO(R) first generation and the new COVID-VIRO ALL IN(R). All of them found COVID-VIRO ALL IN(R) much easier to use and much more comfortable. For young children, the COVID-VIRO ALL IN(R) self-test appears to be safer (less risk of trauma compare to nasal swabs and no liquid exposure) easier to use than classic COVID self-tests and giving immediate result which is not the case for RT-PCR done on saliva samples (currently done in routine for kids in French schools). It could be an adapted tool for future mass screening campaigns in schools or at home under adult supervision for kids from the age of 3.


title: Xylazine Spreads Across the US: A Growing Component of the Increasingly Synthetic and Polysubstance Overdose Crisis

abstract:
BackgroundRecent sharp exacerbations of the US overdose crisis have been linked to systemic polysubstance use and potent synthetic compounds in numerous drug classes. Xylazine is a veterinary tranquilizer, long noted in the opioid supply of Puerto Rico, and more recently Philadelphia. Yet its national growth over time, geographic distribution, and potential role in the shifting US overdose risk environment are poorly characterized.

MethodsIn this sequential mixed methods study, xylazine was increasingly observed by our ethnographic team over many years of intensive participant observation fieldwork in Philadelphia among drug sellers and people who inject drugs (PWID). Subsequently, we systematically searched for records describing xylazine-involved overdose mortality across the US and assessed time trends and overlap with other drugs.

ResultsIn 10 jurisdictions--representing all 4 US Census Regions--xylazine was found to be increasingly implicated in overdose mortality, rising from 0.36% of deaths in 2015 to 6.7% in 2020. The highest xylazine prevalence in the recent data was observed in Philadelphia, (25.8% of deaths), followed by Maryland (19.3%) and Connecticut (10.2%). Illicitly-manufactured-fentanyls were present in 98.4% of xylazine-involved-overdose-deaths-- suggesting a strong ecological link--as well as cocaine (45.4%), benzodiazepines (28.4%), heroin (23.3%), and alcohol (19.7%). PWID in Philadelphia described xylazine as a sought-after adulterant that improves euphoria and lengthens the short duration of fentanyl injections, in particular. They also linked it to increased risk of soft tissue infection and overdose.

ConclusionsWe summarize evidence that xylazine is increasingly implicated in overdose deaths across the US and is linked to the proliferation of illicitly-manufactured-fentanyls. We document hypothesis-generating ethnographic accounts linking it to health risks for PWID. Nevertheless, many jurisdictions do not routinely test for xylazine, and it is not tracked in federal overdose statistics. Further efforts are needed to provide PWID with services that can help to minimize additional risks associated with a shifting drug supply.


title: SARS-CoV-2 vaccines breakthrough infection hospitalizations after one dose in Libya: cohort study

abstract: SARS-CoV-2 infection is widely spread over people, from youth to the elderly. Vaccination against SARS-CoV-2 is an important preventive measurement to help end the SARS-CoV-2 pandemic. From 30 April to 15 July, we collected the number of people infected with SARS-COV-2 and the mortality rate from daily reports issued by the National Center for Disease Control of Libya (NCDC). Approximately 445000 doses have been administered in Libya since 10 April, and 5 thousand doses are now being administered during this period on a daily basis. To estimate the rate of breakthrough vaccine infection of the SARS-COV-2 in Libya. We found that one dose of the three different types of vaccines had decreased the virus transmission across people and mortality rate until 10 weeks after the first dose. This study highlights the dramatic success of the early months of the nations coronavirus vaccines rollout.


title: Using genomic epidemiology of SARS-CoV-2 to support contact tracing and public health surveillance in rural Humboldt County, California.

abstract: During the COVID-19 pandemic within the United States, much of the responsibility for diagnostic testing and epidemiologic response has relied on the action of county-level departments of public health. Here we describe the integration of genomic surveillance into epidemiologic response within Humboldt County, a rural county in northwest California. Through a collaborative effort, 853 whole SARS-CoV-2 genomes were generated, representing [~]58% of the 1,449 SARS-CoV-2-positive cases detected in Humboldt County as of mid-March 2021. Phylogenetic analysis of these data was used to develop a comprehensive understanding of SARS-CoV-2 introductions to the county and to support contact tracing and epidemiologic investigations of all large outbreaks in the county. In the case of an outbreak on a commercial farm, viral genomic data were used to validate reported epidemiologic links and link additional cases within the community who did not report a farm exposure to the outbreak. During a separate outbreak within a skilled nursing facility, genomic surveillance data were used to rule out the putative index case, detect the emergence of an independent Spike:N501Y substitution, and verify that the outbreak had been brought under control. These use cases demonstrate how developing genomic surveillance capacity within local public health departments can support timely and responsive deployment of genomic epidemiology for surveillance and outbreak response based on local needs and priorities.


title: The Pandemic Brain: neuroinflammation in healthy, non-infected individuals during the COVID-19 pandemic

abstract:
SummaryO_ST_ABSBackgroundC_ST_ABSThe impact of COVID-19 on human health extends beyond the morbidity and death toll directly caused by the SARS-CoV-2 virus. In fact, accumulating evidence indicates a global increase in the incidence of fatigue, brain fog and depression, including among non-infected, since the pandemic onset. Motivated by previous evidence linking those symptoms to neuroimmune activation in other pathological contexts, we hypothesized that subjects examined after the enforcement of lockdown/stay-at-home measures would demonstrate increased neuroinflammation.

MethodsWe performed simultaneous brain Positron Emission Tomography / Magnetic Resonance Imaging in healthy volunteers either before (n=57) or after (n=15) the 2020 Massachusetts lockdown, using [11C]PBR28, a radioligand for the glial marker 18 kDa translocator protein (TSPO). First, we compared [11C]PBR28 signal across pre- and post-lockdown cohorts. Then, we evaluated the link between neuroinflammatory signals and scores on a questionnaire assessing mental and physical impacts of the pandemic. Further, we investigated multivariate associations between the spatial pattern of [11C]PBR28 post-lockdown changes and constitutive brain gene expression in post-mortem brains (Allen Human Brain Atlas). Finally, in a subset (n=13 pre-lockdown; n=11 post-lockdown), we also used magnetic resonance spectroscopy to quantify brain (thalamic) levels of myoinositol (mIns), another neuroinflammatory marker.

FindingsBoth [11C]PBR28 and mIns signals were overall stable pre-lockdown, but markedly elevated after lockdown, including within brain regions previously implicated in stress, depression and "sickness behaviors". Moreover, amongst the post-lockdown cohort, subjects endorsing higher symptom burden showed higher [11C]PBR28 PET signal compared to those reporting little/no symptoms. Finally, the post-lockdown [11C]PBR28 signal changes were spatially aligned with the constitutive expression of several genes highly expressed in glial/immune cells and/or involved in neuroimmune signaling.

InterpretationOur results suggest that pandemic-related stressors may have induced sterile neuroinflammation in healthy individuals that were not infected with SARS-CoV-2. This work highlights the possible impact of the COVID-19 pandemic-related lifestyle disruptions on human brain health.

FundingR01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01, The Landreth Family Foundation.


title: COVID-19 L·OVE repository is highly comprehensive and can be used as a single source for COVID-19 studies

abstract:
ObjectiveCOVID-19 Living OVerview of Evidence (COVID-19 L{middle dot}OVE) is a public repository and classification platform for COVID-19 articles. The repository contains over 430,000 articles as of 20 September 2021 and intends to provide a one-stop shop for COVID-19 evidence. Considering that systematic reviews conduct high-quality searches, this study assesses the comprehensiveness and currency of the repository against the total number of studies in a representative sample of COVID-19 systematic reviews.

MethodsOur sample was generated from all the studies included in the systematic reviews of COVID-19 published during April 2021. We estimated the comprehensiveness of COVID-19 L{middle dot}OVE repository by determining how many of the individual studies in the sample were included in the COVID-19 L{middle dot}OVE repository. We estimated the currency as the percentage of studies that were available in the COVID-19 L{middle dot}OVE repository at the time the systematic reviews conducted their own search.

ResultsWe identified 83 eligible systematic reviews that included 2132 studies. COVID-19 L{middle dot}OVE had an overall comprehensiveness of 99.67% (2125/2132). The overall currency of the repository, that is, the proportion of articles that would have been obtained if the search of the reviews was conducted in COVID-19 L{middle dot}OVE instead of searching the original sources, was 96.48% (2057/2132). Both the comprehensiveness and the currency were 100% for randomised trials (82/82).

ConclusionThe COVID-19 L{middle dot}OVE repository is highly comprehensive and current. Using this repository instead of traditional manual searches in multiple databases can save a great amount of work to people conducting systematic reviews and would improve the comprehensiveness and timeliness of evidence syntheses. This tool is particularly important for supporting living evidence synthesis processes


title: High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing.

abstract: The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor and peripheral blood from 52 reportedly sporadic breast cancer patients, including breast-conserving surgery cases. Targeted resequencing of 542 cancer associated genes revealed mosaic somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3 and TSHR in the normal mammary gland, at considerable allelic frequencies (9x10-2 to 5.2x10-1) indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low level-mosaic (in 10-2 to 10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumor mammary gland tissue of breast-conserving surgery patients.

category: genetic and genomic medicine


title: Augmented mean arterial pressure supersedes STS-PROM risk score in predicting 1-year mortality in TAVR patients

abstract:
ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy.

category: cardiovascular medicine


title: A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality


title: Trends in Cognitive Function Pre- and Post- Stroke among Chinese Population

abstract:
IntroductionThe magnitude of changes in cognitive function after stroke among the Chinese population is not clear. We aimed to learn the trajectories of cognitive function before and after incident stroke among Chinese participants.

MethodsData were obtained from a nationally representative study. A total of 13311 Chinese participants aged 45 years or older and without a history of stroke were assessed at baseline between June 2011 and March 2012 and in at least one cognitive test between Wave 2 to Wave 4. Cognitive function was assessed by a global cognition score, which included episodic memory, visuospatial abilities, and executive function. A linear mixed model was developed to explore the repeated measurements.

ResultsDuring the seven-year follow-up, we observed 610 (4.6%) participants experienced the first stroke. The baseline mean (SD) age was 58.6 (9.2) years. 47.3% of them were male. There was no difference in the baseline cognitive function and decline rate of pre-stroke cognition between stroke survivors and stroke-free participants after adjusting for covariates. Among the stroke survivors, the acute decline was -0.123, -0.169, and -0.135 SD/y in cognitive domains of episodic memory, visuospatial ability, and global cognition, respectively. The executive function did not decline acutely after stroke. In the years following stroke, the decline rate of executive function was 0.056 SD/y faster than the rate before stroke. The decline rate of episodic memory, visuospatial ability, and global cognition did not accelerate after stroke.

ConclusionBefore stroke onset, the cognitive function of Chinese stroke survivors was similar to that of stroke-free participants. Incident stroke was associated with acute decline in global cognition, episodic memory, and visuospatial abilities, and accelerated decline in orientation, attention, and calculation abilities. The cognitive trajectories revealed by our study highlights the need to care for the cognitive decline among Chinese stroke survivors.


title: Oral Pre-exposure prophylaxis (PrEP) to prevent HIV: a systematic review and meta-analysis of clinical effectiveness, safety, adherence and risk compensation in all populations

abstract:
BackgroundThe objective of this study was to conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) of the effectiveness and safety of oral Pre-Exposure Prophylaxis (PrEP) to prevent HIV.

MethodsDatabases (PubMed, Embase and the Cochrane Register of Controlled Trials) were searched up to 5/7/2020. RCTs were included that compared oral tenofovir-containing PrEP to placebo, no treatment or alternative medication/dosing schedule. The primary outcome was the rate ratio (RR) of HIV infection using a modified intention-to-treat analysis. All analyses were stratified a priori by population: men who have sex with men (MSM), serodiscordant couples, heterosexuals and people who inject drugs (PWID).

The quality of individual studies was assessed using the Cochrane Risk-of-Bias tool and the certainty of evidence was assessed using GRADE.

ResultsOf 2,803 unique records, 15 RCTs met our inclusion criteria. Over 25,000 participants were included, encompassing 38,289 person-years of follow-up data.

PrEP was found to be effective in MSM (Rate Ratio [RR] 0.25, 95% CI: 0.1-0.61; Absolute Rate Difference [ARD] -0.03, 95% CI: -0.01 to -0.05), serodiscordant couples (RR 0.25, 95% CI: 0.14-0.46; ARD -0.01, 95% CI: -0.01 to -0.02) and PWID (RR 0.51, 95% CI: 0.29-0.92; ARD - 0.00, 95% CI: -0.00 to -0.01), but not in heterosexuals (RR 0.77, 95% CI: 0.46-1.29).

Efficacy was strongly associated with adherence (p<0.01). PrEP was found to be safe, however unrecognised HIV at enrolment increased the risk of viral drug mutations. Evidence for risk compensation or an increase in STIs was not found.

DiscussionPrEP is safe and effective in MSM, serodiscordant couples and PWID. Additional research is needed prior to recommending PrEP in heterosexuals. Data were limited by poor adherence in several studies. No RCTs were identified for other high-risk groups, such as trangender women and sex workers.

PROSPERO IDCRD42017065937

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIA systematic review and meta-analysis of RCTs was conducted of the efficacy and safety of oral PrEP to prevent HIV following best practice guidelines (PRISMA guidelines and GRADE framework)
C_LIO_LIObservational studies were excluded from this review, and as such, PrEP effectiveness may be lower in real-world settings
C_LIO_LIChange in sexual behaviour, or  risk compensation, is difficult to ascertain based on RCT evidence alone
C_LIO_LIDue to substantial variation in adherence across studies, findings should be interpreted with caution.
C_LI

category: hiv aids


title: Age-Specific Changes in Virulence Associated with SARS-CoV-2 Variants of Concern

abstract:
BackgroundNovel variants of concern (VOCs) have been associated with both increased infectivity and virulence of SARS-CoV-2. The virulence of SARS-CoV-2 is closely linked to age. Whether relative increases in virulence of novel VOCs is similar across the age spectrum, or is limited to some age groups, is unknown.

MethodsWe created a retrospective cohort of people in Ontario, Canada testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and August 30, 2021 (n=233,799). Cases were classified as N501Y-positive VOC, probable Delta VOC, or VOC undetected. We constructed age-specific logistic regression models to evaluate the effects of N501Y-postive or Delta VOC infections on infection severity, using hospitalization, intensive care unit (ICU) admission, and death as outcome variables. Models were adjusted for sex, time, health unit, vaccination status, comorbidities, immune compromise, long-term care residence, healthcare worker status, and pregnancy.

ResultsInfection with either N501Y-positive or Delta VOCs was associated with significant elevations in risk of hospitalization, ICU admission, and death in younger and older adults, compared to infections where a VOC was not detected. Delta VOC increased hospitalization risk in children under 10 by a factor of 2.5 (adjusted odds ratio, 95% confidence interval: 1.2 to 5.1) compared to non-VOC. For most VOC-outcome combinations there was no heterogeneity in adverse outcomes by age. However, there was an inverse relationship between age and relative increase in risk of death with delta VOC, with younger age groups showing a greater relative increase in risk of death than older individuals.

InterpretationSARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.


title: Lasting changes to circulating leukocytes in people with mild SARS-CoV-2 infections

abstract: Survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae. Whether survivors of mild or asymptomatic infections can expect any long-term health consequences is not yet known. Herein we investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n=22) compared to those that had recovered from other mild respiratory infections (n=11). Individuals who had mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1-3 months after symptom onset, and changes in phenotype and function of circulating T cells that were not apparent in individuals 6-9 months post-symptom onset. Markers of monocyte activation and expression of adherence and chemokine receptors indicative of altered migratory capacity were also higher at 1-3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6-9 months post-infection. Perhaps most surprisingly, polyclonal activation of T cells was higher in individuals who had recently experienced a mild SARS-CoV-2 infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for up to three months after mild or asymptomatic SARS-CoV-2 infections.


title: COVID-19 attack ratio among children critically depends on the time to removal and activity levels

abstract: The attack ratio in a subpopulation is defined as the total number of infections over the total number of individuals in this subpopulation. Using a methodology based on modified age-stratified transmission dynamics model, we estimated the attack ratio of COVID-19 among children (individuals 0-11 years) in Ontario, Canada when a large proportion of individuals eligible for vaccination (age 12 and above) are vaccinated to achieve herd immunity among this subpopulation, or the effective herd immunity with additional physical distancing measures (hence effective herd immunity). We describe the relationship between this attack ratio among children, the time to remove infected individuals from the transmission chain and the children-to-children daily contact rate, while considering the increased transmissibility of virus variants (using the Delta variant as an example). We further illustrate the generality and applicability of the methodology established by performing an analysis of the attack ratio of COVID-19 among children in the Canadian population. The clinical attack ratio, the number of symptomatic infections over the total population can be informed from the attack ratio, and both can be reduced substantially via a combination of higher vaccine coverage in the vaccine eligible population, reduced social mixing among children, and rapid testing and isolation.


title: Lower probability and shorter duration of infections after Covid-19 vaccine correlate with anti-SARS-CoV-2 circulating IgGs

abstract: The correlation between immune responses and protection from SARS-CoV-2 infections and its duration remains unclear. We performed a sanitary surveillance at the European Institute of Oncology (IEO) in Milan over a 17 months period. Pre-vaccination, in 1,493 participants, we scored 266 infections (17.8%) and 8 possible reinfections (3%). Post-vaccination, we identified 30 infections in 2,029 vaccinated individuals (1.5%). We report that the probability of infection post-vaccination is i) significantly lower compared to natural infection, ii) associated with a significantly shorter median duration of infection than that of first infection and reinfection, iii) anticorrelated with circulating antibody levels.


title: Descriptive characteristics of continuous oximetry measurement in moderate to severe COVID-19 patients

abstract: Non-invasive oxygen saturation (SpO2) is a central vital sign that supports the management of COVID-19 patients. However, reports on SpO2 characteristics are scarce and none has analysed high resolution continuous SpO2 in COVID-19. We provide the first analysis of high resolution SpO2 across the spectrum of COVID-19 disease severity and respiratory support. A total of 367 COVID-19 patients recordings, comprising 27K hours of continuous SpO2 data, could be retrieved from patients hospitalized at the Rambam Health Care Campus. Using oximetry digital biomarkers (OBM), we quantified SpO2 characteristics and showed that the percentage of time under 93% oxygen saturation threshold is the best single OBM discriminating between critical and non-critical patients. OBMs traditionally used in the field of sleep medicine research, were informative for assessing the patients response to respiratory support. In addition, periodicity and hypoxic burden biomarkers were affected up to several hours before the initiation of the mechanical ventilation. Characteristics from high resolution SpO2 signal may enable to anticipate clinically relevant events, monitoring of treatment response and may be indicative of future deterioration.x


title: Yellow fever disease severity is driven by an acute cytokine storm modulated by an interplay between the human gut microbiome and the metabolome

abstract: Infection with Yellow Fever (YF) can lead to multiple outcomes ranging from death from total organ failure to clearance of viremia and survival. The mechanisms underlying these differences in clinical outcomes have yet to be defined. We had access to a cohort of YF infected subjects that showed these range of outcomes. An unbiased integrated OMICs approach was used to identify pathways and effector molecules that drive the severe disease and death as compared to resolution of infection. We used the MELD and SIC score as objective markers of disease severity. We show that a specific signature of upregulated innate pro-inflammatory cytokines significantly demarcates subjects with severe disease leading to death from subjects who clear virus. Pathogen sequencing showed heightened levels of proteolytic bacteria at the i.e Actinobacteria and these were correlated to lower levels of tryptophan and tyrosine amino acids measured by untargeted metabolomics. These two features were significantly associated to MELD scores synonymous of milder disease. Propionate a bacterial metabolite that triggers Treg differentiation that can as well limit the hyperimmune activation associated to severe outcome was also associated to improved outcome. Our results suggest a model whereby proteolytic bacteria limit the availability of the aromatic amino acid pool available for cytokine production thereby preventing the induction of the cytokine storm that is associated to severe disease and death.

category: allergy and immunology


title: pIVW: A novel Mendelian Randomization Method Accounting for Weak Instruments and Horizontal Pleiotropy with Applications to the COVID-19 Outcomes

abstract: SO_SCPLOWUMMARYC_SCPLOWMendelian randomization (MR) utilizes genetic variants as instrumental variables (IVs) to estimate the causal effect of an exposure variable on an outcome of interest even in the presence of unmeasured confounders. However, the popular inverse-variance weighted (IVW) estimator could be biased in the presence of weak IVs, a common challenge in MR studies. In this article, we develop a novel penalized inverse-variance weighted (pIVW) estimator, which adjusts the original IVW estimator to account for the weak IV issue by using a penalization approach to prevent the denominator of the pIVW estimator from being close to zero. Moreover, we adjust the variance estimation of the pIVW estimator to account for the presence of horizontal pleiotropy. We show that the recently proposed debiased IVW (dIVW) estimator is a special case of our proposed pIVW estimator. We further prove that the pIVW estimator has smaller bias and variance than the dIVW estimator under some regularity conditions. We also conduct extensive simulation studies to demonstrate the performance of the proposed pIVW estimator. Furthermore, we apply the pIVW estimator to estimate the causal effects of five obesity-related exposures on three coronavirus disease 2019 (COVID-19) outcomes. Notably, we find that hypertensive disease is associated with an increased risk of hospitalized COVID-19, and peripheral vascular disease and higher body mass index are associated with increased risks of COVID-19 infection, hospitalized COVID-19 and critically ill COVID-19. The R package for the pIVW method is publicly available at https://github.com/siqixu/mr.pivw.


title: A Novel Penalized Inverse-Variance Weighted Estimator for Mendelian Randomization with Applications to COVID-19 Outcomes


title: Contact surveys reveal heterogeneities in age-group contributions to SARS-CoV-2 dynamics in the United States

abstract: SARS-CoV-2 is spread primarily through person-to-person contacts. Quantifying population contact rates is important for understanding the impact of physical distancing policies and for modeling COVID-19, but contact patterns have changed substantially over time due to shifting policies and behaviors. There are surprisingly few empirical estimates of age-structured contact rates in the United States both before and throughout the COVID-19 pandemic that capture these changes. Here, we use data from six waves of the Berkeley Interpersonal Contact Survey (BICS), which collected detailed contact data between March 22, 2020 and February 15, 2021 across six metropolitan designated market areas (DMA) in the United States. Contact rates were low across all six DMAs at the start of the pandemic. We find steady increases in the mean and median number of contacts across these localities over time, as well as a greater proportion of respondents reporting a high number of contacts. We also find that young adults between ages 18 and 34 reported more contacts on average compared to other age groups. The 65 and older age group consistently reported low levels of contact throughout the study period. To understand the impact of these changing contact patterns, we simulate COVID-19 dynamics in each DMA using an age-structured mechanistic model. We compare results from models that use BICS contact rate estimates versus commonly used alternative contact rate sources. We find that simulations parameterized with BICS estimates give insight into time-varying changes in relative incidence by age group that are not captured in the absence of these frequently updated estimates. We also find that simulation results based on BICS estimates closely match observed data on the age distribution of cases, and changes in these distributions over time. Together these findings highlight the role of different age groups in driving and sustaining SARS-CoV-2 transmission in the U.S. We also show the utility of repeated contact surveys in revealing heterogeneities in the epidemiology of COVID-19 across localities in the United States.


title: Immunogenicity of a third scheduled dose of rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis: a phase IV, double-blind, randomised, placebo-controlled clinical trial

abstract:
BackgroundThe oral rotavirus vaccine, Rotarix (GlaxoSmithKline), is licensed for use in infants as two doses in the first six months of life. For infants living in settings with high child-mortality, and also for rural and remote Australian Aboriginal infants, clinical protection conferred by two doses of Rotarix appears to be reduced. We assessed the effect of an additional dose of Rotarix on vaccine immune responses among Aboriginal children who are 6 to < 12 months old.

MethodsORVAC is a two-stage, double-blind, randomised, placebo-controlled trial conducted across regional urban and remote locations of Australias Northern Territory. Aboriginal children 6 to < 12 months old who had received one or two prior doses of Rotarix were randomised 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological endpoint was seroresponse defined as an anti-rotavirus IgA level [≥] 20 AU/mL, approximately one month following Rotarix or placebo. ClinicalTrials.gov (NCT02941107).

FindingsBetween March 2018 and August 2020, 253 infants were enrolled. Of these, 178 infants (70%) had analysable serological results after follow-up; 89 randomised to Rotarix and 89 to placebo. The proportion with a seroresponse was 85% after Rotarix compared to 71% after placebo; the probability of a higher rate of seroresponse in the Rotarix than the placebo arm was 99%. There were no occurrences of intussusception or any serious adverse events attributed to Rotarix or placebo in the 28 days following the additional dose of Rotarix or placebo.

InterpretationAn additional dose of Rotarix among Australian Aboriginal infants 6 to < 12 months old increased the proportion with a vaccine seroresponse. If it can be proven that this translates into better protection against disease, scheduling an additional dose may be a viable strategy for further reducing the global burden of rotavirus disease.

FundingNHMRC (GNT1086952).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSRotavirus vaccine programs have reduced the global burden of gastroenteritis disease among young children, but rotavirus still causes >200,000 child deaths each year. A recent systematic review in the Lancet Global Health found that the effectiveness of oral rotavirus vaccines is variable, from 45 - 58% in settings with high child mortality to 83%-85% in settings with low child mortality. In high child mortality settings there is also evidence of waning effectiveness after 12 months old. Reduced vaccine effectiveness has also been reported among Australian Aboriginal children. Previous trials have failed to demonstrate improved rotavirus vaccine effectiveness with strategies such as withholding breastfeeding, or co-administering vaccines with probiotics or zinc. Pre-licensure studies of Rotarix in Africa did not clearly indicate whether a three-dose Rotarix schedule had benefit over a two-dose schedule, although all vaccine doses were given before infants were six months old when maternal antibodies may impede vaccine responses. Trials in Bangladesh and Mali found that a third Rotarix dose given after 6 months old improved the immune response to vaccine.

Added value of this studyIn the first stage of our novel two-stage randomised clinical trial, we showed that scheduling an additional Rotarix dose for remote Australian Aboriginal infants after 6 months old increased the proportion with evidence of vaccine seroresponse.

Implications of all the available evidenceScheduling an additional dose of Rotarix after 6 months old is feasible, and trials in three settings have now demonstrated that it improves immune responses. Trials should now be conducted in a number of high burden settings to determine whether this strategy results in improved clinical protection against severe gastroenteritis.

category: pediatrics


title: Racial and ethnic inequalities in COVID-19 mortality within carceral settings: An analysis of Texas prisons and jails

abstract: Several analyses have highlighted racial and ethnic disparities related to COVID-19 health outcomes across the United States. Less focus has been placed on more localized contexts, such as carceral settings, where racial and ethnic inequities in COVID-19 health outcomes also exist, but the proximal drivers of inequality are different. In this study, we analyzed mortality rates among incarcerated people in the Texas Department of Criminal Justice (TDCJ) to assess racial and ethnic differences in COVID-19 mortality. We obtained monthly demographic and mortality information of the TDCJ population from April 1, 2019 to March 31, 2021 from TDCJ monthly reports and open record requests filed by the Texas Justice Initiative. We estimated the risk of COVID-19 mortality for the Hispanic and Black population relative to the White population using a Bayesian regression framework, adjusting for sex and age. In the first 12 months of the pandemic, Hispanic and Black all-cause mortality rates were higher than that of the White population, reversing the pattern observed the 12 months prior. Adjusted risk of COVID-19 mortality relative to the White population was 1.96 (CI 1.32-2.93) for the Hispanic population and 1.66 (CI 1.10-2.52) for the Black population. We find that COVID-19 mortality has disproportionately impacted Hispanic and Black individuals within the TDCJ population. As the proximal mechanisms which drive these inequalities are likely different than those which lead to racial inequalities in the non-incarcerated populations, future studies should look to assess and address the specific drivers of COVID-19 related disparities in carceral settings.


title: Racial and ethnic inequalities in COVID-19 mortality within Texas carceral settings


title: Household Density and Influences from Family and Friends Shape Vaccine Intent Among Latino Families in the San Francisco Bay Area

abstract:
BackgroundLatino have had higher case counts, hospitalization rates and deaths during the COVID-19 pandemic nationally and in the state of California. Meanwhile, Latino vaccination rates remain lower than those of non-Hispanic Whites. COVID-19 vaccine nonintent, defined as intent not to vaccinate for COVID-19, among Latino individuals continues to be an issue in the state of California.

MethodsFamilies from three Latino longitudinal mother child cohorts previously recruited in the San Francisco Bay Area were surveyed telephonically from February to July 2021 to assess attitudes towards COVID-19 vaccination and prior vaccination, in general, for themselves and their children. Risk for vaccine nonintent was assessed using Mann-Whitney rank sum non-parametric test for continuous predictors and chi-squared tests for categorical ones.

ResultsThree hundred and eighteen families were surveyed from the Telomere at Birth (TAB), Hispanic Eating and Nutrition (HEN) and Latino Eating and Diabetes Cohort (LEAD). Approximately 36% from TAB and 28% from HEN/LEAD indicated COVID-19 vaccine nonintent for themselves and/or their children. Risk factors for vaccine nonintent included lower maternal age (p=0.01), concern about vaccine side effects (p<0.01) and prior history of a household members being infected with COVID-19 (p<0.01) and indexes of household crowding including number of people sharing a bathroom (p=0.048). Vaccine intent was also associated with receiving vaccine input from friends (p=0.03), family (p<0.01) and/or coworkers (p=0.02) compared with those who were not planning on getting COVID-19 vaccination. It is possible that those with non-intent have received limited input from families, friends and/or coworkers.

DiscussionLatino families living in crowded living situations who may not have received any COVID-19 advice family, coworkers or friends are at particular risk for COVID-19 vaccine nonintent. Community based grassroots interventions that focus on trusted individuals with close ties to the community counseling about COVID-19 vaccination could help to boost vaccination rates in this population group.


title: Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus

abstract:
ObjectivesTo evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE).

MethodsSIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020.

ResultsSLE was confirmed in 76 of 232 patients (32.8%) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared to patients without SLE (p<0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were > 99.9 % and 0.1 %, respectively. Using ROC analysis and Delong testing, the area under the curve (AUC) for SIGLEC1 (AUC=0.95) was significantly higher than for ANA (AUC=0.88, p=0.031), C3 (AUC=0.83, p=0.001) and C4 (AUC=0.83, p=0.002) but not for anti-dsDNA antibodies (AUC=0.90, p=0.163).

ConclusionIFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

category: rheumatology


title: Clinician and patient experience of neurology telephone consultations during the COVID-19 pandemic

abstract:
BackgroundTelephone consultations are already employed in specific neurological settings. At Cambridge University Hospitals, the COVID-19 pandemic initially prompted almost all face-to-face appointments to be delivered by telephone, providing a uniquely unselected population to assess.

ObjectivesWe explored patient and clinician experience of telephone consultations; and whether telephone consultations might be preferable for pre-identifiable subgroups of patients after the pandemic.

MethodsClinicians delivering neurological consultations converted to telephone between April-July 2020 were invited to complete a questionnaire following each consult (430 respondents) and the corresponding patients were subsequently surveyed (290 respondents). The questionnaires assessed clinician and patient goal achievement (and the reasons for any dissatisfaction). Clinicians also described consultation duration (in comparison to face-to-face) while patients detailed comparative convenience and preference.

ResultsThe majority of clinicians (335/430, 78%) and patients (227/290, 78%) achieved their consultation goals by telephone, particularly during follow-up consultations (clinicians 272/329, 83%, patients 176/216, 81%) and in some disease subgroups (e.g. seizures/epilepsy (clinicians 114/122 (93%), patients 71/81 (88%)). 95% of telephone consultations were estimated to take the same or less time than an equivalent face-to-face consultation. Most patients found telephone consultations convenient (69%) with 149/211 (71%) indicating they would like telephone or video consultations to play some role in their future follow-up.

ConclusionTelephone consultations appear effective, convenient and popular in prespecified subgroups of neurological outpatients. Further work comparing telephone, video and face-to-face consultations across multiple centres is now needed.


title: Clinical Annotations for Prostate Cancer Research: Defining Data Elements, Creating a Reproducible Analytical Pipeline, and Assessing Data Quality

abstract:
BackgroundRoutine clinical data from clinical charts are indispensable for retrospective and prospective observational studies and clinical trials. Their reproducibility is often not assessed.

ObjectiveTo develop a prostate cancer-specific database with a defined source hierarchy for clinical annotations in conjunction with molecular profiling and to evaluate data reproducibility.

Design, setting, and participantsFor men with prostate cancer and clinical-grade paired tumor-normal sequencing, we performed team-based retrospective data collection from the electronic medical record at a comprehensive cancer center. We developed an open-source R package for data processing. We assessed reproducibility using blinded repeat annotation by a reference medical oncologist.

Outcome measurements and statistical analysisWe evaluated completeness of data elements, reproducibility of team-based annotation compared to the reference, and impact of measurement error on bias in survival analyses.

Results and limitationsData elements on demographics, diagnosis and staging, disease state at the time of procuring a genomically characterized sample, and clinical outcomes were piloted and then abstracted for 2,261 patients (with 2,631 samples). Completeness of data elements was generally high. Comparing to the repeat annotation by a medical oncologist blinded to the database (100 patients/samples), reproducibility of annotations was high to very high; T stage, metastasis date, and presence and date of castration resistance had lower reproducibility. Impact of measurement error on estimates for strong prognostic factors was modest.

ConclusionsWith a prostate cancer-specific data dictionary and quality control measures, manual clinical annotations by a multidisciplinary team can be scalable and reproducible. The data dictionary and the R package for reproducible data processing are freely available to increase data quality in clinical prostate cancer research.

Patient summaryInformation in the medical record is the backbone for clinical research on prostate cancer. The tools provided in this study can increase quality and efficiency of this research.

category: oncology


title: Single EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer

abstract: Tumor cell derived extracellular vesicles (EV) are being explored as circulating biomarkers for cancer detection. Up to now however, clinical results have been mixed for a number of reasons including the predominant use of bulk measurements, the inability to differentiate tumor from host cell derived vesicles, the general absence of uniquely identifying biomarkers and the unknown frequency of stochastically distributed biomarkers into single circulating vesicles. We hypothesized that a single EV analysis (sEVA) technique could potentially improve diagnostic accuracy necessary to detect early cancers but the actual biomarker frequency and practical detection limits are currently unknown. Using pancreatic cancer, we carefully analyzed the composition of putative cancer markers in 11 established and new patient derived models. In parental PDAC cells positive for KRASmut and/or P53mut proteins only [~]40% of EVs were also positive (range: 30-64%). This rate of positivity increased to 57% when additional PDAC biomarkers were considered (MUC1, EGFR, FG-P4OH) in cell lines. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmut and P53mut protein was detectable at much lower levels, generally in < 0.1% of vesicles. With the analytical capabilities of sEVA however, 15 of the 16 patients with stage 1 PDAC expressed low levels of biomarker positive EV. Using a modeling approach, we estimate that the current PDAC detection limit is at [~]0.1 cm3 tumor volume, below clinical imaging capabilities. These findings establish the potential for single-EV analysis for early cancer detection.


title: Survival prediction with Bayesian Networks in more than 6000 non-small cell lung cancer patients

abstract: A model that predicts survival in lung cancer as a function of treatment choices would be valuable for decision support. In this study we built data flow tasks and a data warehouse to collect from clinical databases a large non-small cell lung cancer dataset from MAASTRO (N=1781) and from Princess Margaret Hospital (PMH, N=4591). We learned Bayesian Network (BN) models for survival prediction from the MAASTRO data and evaluated the models in the PMH dataset. The BN model based on stage and radiotherapy dose had a high predictive accuracy (AUC 0.917). The model correctly showed that radical radiotherapy (>60Gy) is beneficial for non-small cell lung cancer patients and that this benefit is disease stage dependent.


title: Intravenous Immunoglobulin (IVIG) in Treating Non-ventilated COVID-19 Patients with Moderate to Severe Hypoxia is Pharmacoeconomically Favorable When Appropriately Targeted

abstract:
BackgroundPrior studies have shown that intravenous immunoglobulin (IVIG) can improve outcomes in patients with COVID-19, but the high costs of IVIG leave questions as to its pharmacoeconomic value.

MethodsThe hospital costs of 2 IVIG vs. non-IVIG COVID-19 patient groups were compared. The first cohort was a case-control analysis of 10 non-ventilated moderately to severely hypoxic COVID-19 patients who received IVIG (Privigen) matched 1:2 with 20 control patients of similar age, body mass index (BMI), degree of hypoxemia, and co-morbidities. The second cohort consisted of patients enrolled in a previously published randomized open-label prospective study of 14 COVID-19 patients receiving standard of care (SOC) versus 13 patients who received SOC plus IVIG (Octagam 10%).

ResultsAmong the first case control population, mean total direct costs including IVIG for the treatment group was $21,982 per IVIG-treated case versus $42,431 per case for matched non-IVIG receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs including IVIG for the treatment group was $28,268 per case versus $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. 24% of the non-IVIG patients had hospital costs exceeded $80,000, as compared to none of the IVIG patient host (p=0.016, Fisher exact test).

ConclusionWhen allocated to the appropriate patient type (moderate to severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More importantly, it may reduce the demand on scare critical care resources during the COVID-19 pandemic.

category: health economics


title: Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in Sardinian multiple sclerosis patients

abstract:
ObjectivesVaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients.

MethodsWe obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine.

ResultsMS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male, sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients.

ConclusionHumoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.


title: Epidemiology, Clinico-Pathological Characteristics, and Comorbidities of SARS-CoV-2 infected Pakistani Patients

abstract: SARS-CoV-2 is a causative agent for COVI-19 disease, initially reported from Wuhan, China. Infected Patients experienced mild to severe symptoms, resulting in several fatalities due to a weak understanding of its pathogenesis, which is the same even to date. This cross-sectional study has been designed on four hundred and fifty-two symptomatic, mild-to-moderate, and severe/critical patients to understand the epidemiology and clinical characteristics of COVID-19 patients with their comorbidities and response to treatment. The mean age of studied patients was (58{+/-}14.42) years, and the overall male to female ratio was 61.7 to 38.2%, respectively. 27.3% of the patients had a history of exposure, 11.9% travel history, while for 60% of patients, the source of infection was unknown. The most prevalent signs and symptoms in ICU patients were dry coughs, myalgias, shortness of breath, gastrointestinal discomfort, and abnormal Chest X-ray (p<0.001), along with the high percentage of hypertension (p=0.007) and COPD (p=0.029) as leading comorbidities. Complete Blood Counts indicators were significantly increased in severe patients, while the Coagulation Profile and D-dimer values were significantly higher in mild-to-moderate (non-ICU) patients (p < 0.001). Serum Creatinine (1.22 umole L-1; p = 0.016) and LDH (619 umol L-1; p < 0.001) indicators were significantly high in non-ICU patients while, raised values of Total Bilirubin (0.91 umol L-1; p = 0.054), CRP (84.68 mg L-1; p = 0.001) and Ferritin (996.81 mg L-1; p < 0.001) were found in ICU patients. Drug Dexamethasone was the leading prescribed and administrated medicine to the COVID-19 patients, followed by Remdesivir, Meropenem, Heparin, and Tocilizumab, respectively. A characteristic pattern of Ground glass opacities (GGO), consolidation, and interlobular septal thickening were prominent in severely infected patients. These findings could be used for future research, control, and prevention of SARS-CoV-2 infected patients.


title: New insights from GWAS on longitudinal and cross-sectional BMI and related phenotypes in admixed children with Native American and European ancestries

abstract: Body-mass index (BMI) is a well-known marker of adiposity across all ages. The genetic architecture of BMI has been thoroughly studied among adults. In contrast, there are a few genome-wide association studies (GWAS) on children. Further, GWAS on children have been performed almost exclusively in Europeans at single ages. We aimed to better understand the genetic architecture of BMI trajectory across ages and how BMI is affected by Native American genetic ancestry. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed Chilean children with mostly European and Mapuche Native American genetic ancestry. We focused on BMI and two traits that occur at the minimum of the childhood BMI growth trajectory, namely, age at adiposity rebound (Age-AR) and BMI at adiposity rebound (BMI-AR). We found several variants in the immune gene HLA-DQB3 that are strongly associated with BMI at ages 1.5-2.5 years old, but not at other ages. We also identified a variant in the sex-determining gene DMRT1 significantly associated with Age-AR (P = 9.8 x 10-9). Further, BMI was significantly higher in Mapuche than in European children at all ages between 5.5 and 16.5 years old, but not before. Finally, Age-AR was significantly lower (P = 0.013) by 1.64 years in the Mapuche children compared with Europeans.