title: A decision-tree approach to treat platelet hyperactivity and anomalous blood clotting in acute COVID-19 patients

abstract: An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption of normal endothelial function, initiating a state of failing normal clotting physiology. Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin. The end result is hypercoagulation [proven by thromboelastography(R) (TEG(R))] and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules. From the literature it is clear that the role of platelets in severely ill COVID-19 patients has been markedly underestimated or even ignored. We here highlight the value of early management of severe COVID-19 coagulopathy as guided by TEG(R), microclot and platelet mapping. We also argue that the failure of clinical trials, where the efficacy of prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, might be because the significant role of platelet activation was not taken into account during the planning of the trial. We conclude that, because of the overwhelming alteration of clotting, the outcome of any trial evaluating an any single anticoagulant, including thrombolytic, would be negative. Here we suggest the use of the degree of platelet dysfunction and presence of microclots in circulation, together with TEG(R), should be used as a guideline for disease severity. A multi-pronged approach, guided by TEG(R) and platelet mapping, would be required to maintain normal clotting physiology in severe COVID-19 disease.


title: Early management of severe COVID-19 coagulopathy should be guided by TEG, microclot and platelet mapping

category: cardiovascular medicine


title: Better Antimicrobial Resistance Data Analysis & Reporting in Less Time

abstract:
IntroductionThe global challenge of antimicrobial resistances (AMR) requires the rational and responsible use of antimicrobials. Insights and knowledge about the local AMR levels and epidemiology are essential to guide optimal decision-making processes in antimicrobial use. However, dedicated tools for reliable and reproducible AMR data analysis and reporting are often lacking. Previously, we have developed a novel approach to AMR data analysis and reporting using open-source software tools. In this study, we aimed at comparing the effectiveness and efficiency of traditional analysis and reporting versus this new approach for reliable and reproducible AMR data analysis in a clinical setting.

MethodsTen professionals in the field of AMR that routinely work with AMR data were recruited to participate and provided with one years blood culture test results from a tertiary care hospital results including antimicrobial susceptibility test results. Participants were asked to perform a detailed AMR data analysis in a two-step process: first (round 1) using their analysis software of choice and next (round 2) using the previously developed open-source software tools. Accuracy of the results and time spent were compared between the two rounds. Paired students t-tests were used to test for statistical significance. Finally, participants rated the usability of the tools using the systems usability scale.

ResultsThe mean time spent on creating a comprehensive AMR report reduced from 93.7 (SD {+/-}21.6) minutes to 22.4 (SD {+/-}13.7) minutes (p < 0.001). Average task completion per round changed from 56% (SD: {+/-}23%) to 96% (SD: {+/-}5.5%) (p<0.05). The proportion of correct answers in the available results increased from 37.9% in the first round to 97.9% in the second round (p < 0.001). The usability of the new AMR reporting tool was rated with a median of 83.8 (out of 100) on the system usability scale.

ConclusionThis study demonstrated the significant improvement in efficiency and accuracy in standard AMR data analysis and reporting workflows through the use of open-source software tools in a clinical setting. Integrating these tools in clinical settings can democratise the access to fast and reliable insights about local microbial epidemiology and associated AMR levels. Thereby, our approach can support evidence-based decision-making processes in the use of antimicrobials.

category: epidemiology


title: Sex-specific epidemiological and clinical characteristics of Covid-19 patients in the southeast region of Bangladesh

abstract:
BackgroundCOVID-19 has become a global pandemic with a high growth rate of confirmed cases. In Bangladesh, both mortality and affected rates are increasing at an alarming rate.

Therefore, more comprehensive studies of the epidemiological and clinical characteristics of COVID-19 are required to control this pandemic.

PurposeThe present study aimed to compare and analyze the sex-specific epidemiological, clinical characteristics, comorbidities, and other information of confirmed COVID-19 patients from the southeast region in Bangladesh for the first time.

Methods385 lab-confirmed cases were studied out of 2,471 tested samples between 5 June and 10 September 2020. RT-PCR was used for COVID-19 identification and SPSS (version 25) for statistical data analysis.

ResultsWe found that male patients were roughly affected compared to females patients (male 74.30% vs. female 25.7%) with an average age of 34.86 {+/-} 15.442 years, and B (+ve) blood group has been identified as a high-risk factor for COVID-19 infection. Workplace, local market, and bank were signified as sex-specific risk zone (p < 0.001). Pre-existing medical conditions such as diabetes, hypertension, cardiovascular and respiratory diseases were identified among the patients. Less than half of the confirmed COVID-19 cases in the southeast region were asymptomatic (37.73%) and more prevalent among females than males (male vs. female: 36.84% vs. 40.51%, p = 0.001).

ConclusionsThe findings may help health authorities and the government take necessary steps for identification and isolation, treatment, prevention, and control of this global pandemic.


title: A general model for the demographic signatures of the transition from pandemic emergence to endemicity

abstract:
Anticipating the medium- and long-term trajectory of pathogen emergence has acquired new urgency given the ongoing COVID-19 pandemic. For many human pathogens the burden of disease depends on age and prior exposure. Understanding the intersection between human population demography and transmission dynamics is therefore critical. Here, we develop a realistic age-structured (RAS) mathematical model that integrates demography, social mixing and immunity to establish the suite of possible scenarios of future age-incidence and burden of mortality. With respect to COVID-19, we identify a plausible transition in the age-structure of risks once the disease reaches seasonal endemism, whether assuming long-lasting or brief protective immunity, and across a range of assumptions of relative severity of primary versus subsequent reinfections. We train the model using diverse real-world demographies and age-structured social mixing patterns to bound expectations for changing age-incidence and disease burden. The mathematical framework is flexible and can help tailoring mitigation strategies countries worldwide with varying demographies and social mixing patterns.

One Sentence SummaryA shift of COVID-19 risks to younger age-classes in future endemic circulation.


title: Global Monitoring of the Impact of COVID-19 Pandemic through Online Surveys Sampled from the Facebook User Base

abstract:
Simultaneously tracking the global COVID-19 impact across multiple populations is challenging due to regional variation in resources and reporting. Leveraging self-reported survey outcomes via an existing international social media network has the potential to provide reliable and standardized data streams to support monitoring and decision-making world-wide, in real time, and with limited local resources. The University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), in partnership with Facebook, invites daily cross-sectional samples from the social media platforms active users to participate in the survey since launch April 23, 2020. COVID-19 indicators through December 20, 2020, from N=31,142,582 responses representing N=114 countries, weighted for nonresponse and adjusted to basic demographics, were benchmarked with government data. COVID-19-related signals showed similar concordance with reported benchmark case and test positivity. Bonferroni significance and minimal Spearman correlation strength thresholds were met in the majority. Light Gradient Boost machine learning trained on national and pooled global data verified known symptom indicators, and predicted COVID-19 trends similar to other signals. Risk mitigation behavior trends are correlated with, but sometimes lag, risk perception trends. In regions with strained health infrastructure, but active social media users, we show it is possible to define suitable COVID-19 impact trajectories. This syndromic surveillance public health tool is the largest global health survey to date, and, with brief participant engagement, can provide meaningful, timely insights into the COVID-19 pandemic and response in regions under-represented in epidemiological analyses.

Significance StatementThe University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), launched April 23, 2020, is the largest remote global health monitoring system. This study includes about 30 million UMD-CTIS responses over 34 weeks (through December 2020) from N=114 countries with survey-weights to adjust for nonresponse and demographics. Using limited self-reported data, sampled daily from an international cohort of Facebook users, we demonstrate validity and utility for COVID-19 impacts trends, even in regions with scant or delayed government data. We predict COVID-19 cases in the absence of testing, and characterize perceived COVID-19 risk versus risk-lowering measures. The UMD-CTIS has the potential to support existing monitoring systems for the COVID-19 pandemic, as well as other new, as-yet-undefined global health threats.


title: Socio-economic Transition in an Indian Rural Setting and Its Impact on Health: Pune Maternal Nutrition Study

abstract:
BackgroundThere is scant scientific information on socioeconomic transition and its effects on health parameters in India. The prospective data collection in the Pune Maternal Nutrition Study (PMNS) birth cohort provided an opportunity to examine the changes in socio-economic status (SES) and 1) its comparison against state and district indicators, 2) association with body size and cardio-metabolic risk factors.

MethodWe followed up [~]700 families for biomedical information in the PMNS. SES data was collected in the index pregnancy (1993-96) and serially every six years ([~]2001, [~]2007, [~]2013). Comparisons with rural Maharashtra and Pune were made using data from the National Family Health Survey 1999 and 2006 (NFHS II and III).

ResultsThere was an increase in the proportion of those in the high Standard of Living Index (SLI, NFHS) from 64% to 90% between 2001 and 2013. The increase in SES in our study area was faster and greater compared to the state and district. Higher SLI was associated with higher weight, height, body fat percent and total cholesterol concentrations at each followup. However, there were no associations between transition and health parameters.

ConclusionOur data suggest a rapid socio-economic transition in the study area which is faster than the state and district.


title: Ethnic disparities in hospitalisation and hospital-outcomes during the second wave of COVID-19 infection in east London

abstract:
ObjectivesTo determine if changes in public behaviours, developments in COVID-19 treatments, improved patient care, and directed policy initiatives have altered outcomes for minority ethnic groups in the second pandemic wave.

DesignProspectively defined observational study using registry data.

SettingFour acute NHS Hospitals in east London.

ParticipantsPatients aged [≥]16 years with an emergency hospital admission with SARS-CoV-2 infection between 1st September 2020 and 17th February 2021.

Main outcome measuresPrimary outcome was 30-day mortality from time of index COVID-19 hospital admission. Secondary endpoints were 90-day mortality and need for ICU admission. Multivariable survival analysis was used to assess associations between ethnicity and mortality accounting for predefined risk factors. Age-standardised rates of hospital admission relative to the local population were compared between ethnic groups.

ResultsOf 5533 patients, the ethnic distribution was White (n=1805, 32.6%), Asian/Asian British (n=1983, 35.8%), Black/Black British (n=634, 11.4%), Mixed/Other (n=433, 7.8%), and unknown (n=678, 12.2%). Excluding 678 patients with missing data, 4855 were included in multivariable analysis. Relative to the White population, Asian and Black populations experienced 4.1 times (3.77-4.39) and 2.1 times (1.88-2.33) higher rates of age-standardised hospital admission. After adjustment for various patient risk factors including age, sex, and socioeconomic deprivation, Asian patients were at significantly higher risk of death within 30 days (HR 1.47 [1.24-1.73]). No association with increased risk of death in hospitalised patients was observed for Black or Mixed/Other ethnicity.

ConclusionsAsian and Black ethnic groups continue to experience poor outcomes following COVID-19. Despite higher-than-expected rates of admission, Black and Asian patients experienced similar or greater risk of death in hospital, implying a higher overall risk of COVID-19 associated death in these communities.

Strengths and limitations of this studyO_LIThis study represents one of the largest descriptors of outcomes in minority ethnic patients with COVID-19 distinguished by the majority ethnically diverse cohort within a catchment area of approximately one million people in the east of London.
C_LIO_LILarge absolute numbers of patients drawn from a single geographic region and treated within the same hospital system minimize many of the geographic biases present within other studies including the impact of variation in transmission risk.
C_LIO_LIOur analyses are strengthened by adherence to a prespecified analysis plan, inclusion of a detailed baseline, comorbidity, and COVID-19 risk factors in multivariable modelling, and sensitivity tests using different measures of comorbidity.
C_LIO_LIHowever as with all observational studies, not all potential contributing risk factors could be assessed, including other measures of baseline health status such as nutritional or lifestyle influences as well as contextual factors such as household composition and occupation.
C_LIO_LIWe were not able to include suspected but not proven COVID-19 cases or community cases not requiring hospital admission or the effect of the differing viral strains in the first and second wave.
C_LI


title: Spatiotemporal dissemination pattern of SARS-CoV-2 B1.1.28-derived lineages introduced into Uruguay across its southeastern border with Brazil.

abstract: During the first nine months of the SARS-CoV-2 pandemic, Uruguay successfully kept it under control, even when our previous studies support a recurrent viral flux across the Uruguayan-Brazilian border that sourced several local outbreaks in Uruguay. However, towards the end of 2020, a remarkable exponential growth was observed and the TETRIS strategy was lost. Here, we aimed to understand the factors that fueled SARS-CoV-2 viral dynamics during the first epidemic wave in the country. We recovered 84 whole viral genomes from patients diagnosed between November, 2020 and February, 2021 in Rocha, a sentinel eastern Uruguayan department bordering Brazil. The lineage B.1.1.28 was the most prevalent in Rocha during November-December 2020, P.2 became the dominant one during January-February 2021, while the first P.1 sequences corresponds to February, 2021. The lineage replacement process agrees with that observed in several Brazilian states, including Rio Grande do Sul (RS). We observed a one to three month delay between the appearance of P.2 and P.1 in RS and their subsequent detection in Rocha. The phylogenetic analysis detected two B.1.1.28 and one P.2 main Uruguayan SARS-CoV-2 clades, introduced from the southern and southeastern Brazilian regions into Rocha between early November and mid December, 2020. One synonymous mutation distinguishes the sequences of the main B.1.1.28 clade in Rocha from those widely distributed in RS. The minor B.1.1.28 cluster, distinguished by several mutations, harbours non-synonymous changes in the Spike protein: Q675H and Q677H, so far not concurrently reported. The convergent appearance of S:Q677H in different viral lineages and its proximity to the S1/S2 cleavage site raise concerns about its functional relevance. The observed S:E484K-VOI P.2 partial replacement of previously circulating lineages in Rocha might have increased transmissibility as suggested by the significant decrease in Ct values. Our study emphasizes the impact of Brazilian SARS-CoV-2 epidemics in Uruguay and the need of reinforcing real-time genomic surveillance on specific Uruguayan border locations, as one of the key elements for achieving long-term COVID-19 epidemic control.


title: Applying Topical Anesthetic on Pediatric Lacerations in the Emergency Department: A Quality Improvement Project

abstract:
BackgroundCaring for pediatric lacerations in the Emergency Department (ED) is typically painful because of irrigation and suturing. To improve this painful experience, we aimed to increase the use of a topical anesthetic, Eutectic Mixture of Local Anesthetics (EMLA) on eligible pediatric lacerations with an attainable, sustainable, and measurable goal of 60%.

Local ProblemThe baseline rate of applying topical anesthetic to eligible lacerations was 23% in our ED. We aimed to increase the use of topical anesthetics on eligible pediatric lacerations to a measurable goal of 60% within 3 months of implementing our intervention.

MethodsWe conducted a prospective, single center, interrupted time series, ED quality improvement project from November 2019 to July 2020. A multidisciplinary team of physicians and nurses performed a cause-and-effect analysis identifying two key drivers: early placement of EMLA and physician buy-in on which we built our Plan, Do, Study, and Act (PDSA) cycles. We collected data on number of eligible patients receiving EMLA, as well as patient and physician feedback via phone calls within 2 days post encounter. Balancing measures included ED length of stay (LOS), patient and physician satisfaction with EMLA, and side effects of EMLA.

ResultsWe needed 3 PDSA cycles to reach our goal of 60% in 3 months, which was also maintained for 5 months. PDSA cycles used educational interventions, direct provider feedback about non-compliance and patient satisfaction results obtained via phone calls. Balancing measures were minimally impacted: 75% good patient satisfaction, No adverse events but an increase in LOS of patients who received EMLA compared to those who did not (1.79 {+/-} 0.66 VS 1.41 {+/-} 0.83 hours, p<0.001). The main reasons for dissatisfaction for physicians were the increased LOS and the preference for procedural sedation or intranasal medications.

ConclusionWith a few simple interventions, our aim of applying EMLA to 60% of eligible pediatric lacerations was attained and maintained.

category: pediatrics


title: Mental Illness Self-Stigma in Young People: A Scoping Review Protocol

abstract:
BackgroundSelf-stigma (the internalisation of negative stereotypes) is known to reduce help-seeking behaviours and treatment adherence in people who have a mental illness, resulting in worsening health outcomes. Moreover, self-stigma diminishes self-esteem and self-efficacy, and leads to higher levels of depression. Half of all lifetime cases of mental illness have manifested by the age of 14, and therefore young people are vulnerable to the negative impact of suffering mental illness self-stigma. While literature in this field has been flourishing in recent years, mental illness self-stigma remains poorly understood in youth. It is important that we seek to understand what is currently known about mental illness self-stigma in young people, and subsequently use this information to guide future research to advance knowledge of this topic. To date, a scoping review which maps the available literature on mental illness self-stigma in young people has yet to be conducted. Here, we outline the protocol for a scoping review on mental illness self-stigma in young people.

MethodsThis protocol outlines the process of conducting a scoping review of primary research concerning mental illness self-stigma in young people. The Joanna Briggs Institute guidance on best practice for conducting a scoping review will utilised throughout. A systematic search of appropriate databases will be conducted which will allow for a two-step screening process and data charting. Inclusion criteria for this review dictates that eligible studies will i) include a population within the age range of 10-35 (or mean age within this range), ii) include the term  self-stigma or  internalised stigma relating to mental health/illness/disorder, iii) be primary research, iv) be published post-2009 (following the seminal study by Moses, 2009) and v) be published in English.

DiscussionThe findings of the scoping review outlined in this protocol will be used to inform future research which aims to explore self-stigmatising attitudes and beliefs of young people experiencing mental illness. This research will result in co-produced, impactful resources for young people on the topic of mental illness self-stigma with the aim of raising awareness and stigma reduction.

category: psychiatry and clinical psychology


title: Utilization, satisfaction and barriers to access of health services for Arabic-speaking refugees resettled in Connecticut, USA after completion of Refugee Medical Assistance (RMA)

abstract:
BackgroundArabic-speaking refugees are the largest group of resettled persons in the United States since 2008, yet little is known about their rates of healthcare access, utilization and satisfaction.

MethodsFrom January to December 2019, a household survey was conducted of Arabic-speaking refugees resettled in CT. Data collected included demographics, prevalence of chronic conditions, patterns of health seeking behavior, insurance status and patient satisfaction using the Patient Satisfaction Questionnaire (PSQ-18).

ResultsSixty-five households responded to the survey representing 295 Arabic-speaking refugees - of which 141 (48%) were children. Forty-seven households (72%) reported members with chronic conditions, 62 persons (21%) needed daily medication, 285 (97%) persons were insured. Respondents reported high median patient satisfaction with wide variation.

ConclusionArabic-speaking refugees resettled in CT are young but have similar adult rates of chronic medical conditions as the host community. They majority remained insured after RMA lapsed. They expressed median high satisfaction with health services but with wide variation. Inaccessibility of health services in Arabic and difficulty obtaining medications remain areas in need of improvement.

category: public and global health


title: Adverse childhood experiences and resilience among adult women: a population-based study

abstract: Adverse childhood experiences (ACEs) have consistently been associated with elevated risk of multiple adverse health outcomes, yet their contribution to coping ability and psychiatric resilience in adulthood is unclear. Participants were 19,613 women in the Icelandic Stress- And-Gene-Analysis cohort with complete data on 13 ACEs measured with the ACE-International Questionnaire. Self-reported coping ability was measured with the Connor-Davidson Resilience Scale and psychiatric resilience was operationalized as absence of psychiatric morbidity. Compared to women with 0 ACEs, women with [≥] 5 ACEs had 33% lower prevalence of high coping ability (PR=0.67, 95% CI 0.60,0.74) and 56% lower prevalence of high psychiatric resilience (PR=0.44; 95% CI 0.41,0.48). Specific ACEs including emotional neglect, bullying, sexual abuse and mental illness of household member were consistently associated with reduced adult resilience. We observed only slightly attenuated associations after controlling for adult socioeconomic factors and social support in adulthood, indicating that adult resilience may be largely determined in childhood.


title: Mitigating outbreaks in congregate settings by decreasing the size of the susceptible population

abstract: While many transmission models have been developed for community spread of respiratory pathogens, less attention has been given to modeling the interdependence of disease introduction and spread seen in congregate settings, such as prisons or nursing homes. As demonstrated by the explosive outbreaks of COVID-19 seen in congregate settings, the need for effective outbreak prevention and mitigation strategies for these settings is critical. Here we consider how interventions that decrease the size of the susceptible populations, such as vaccination or depopulation, impact the expected number of infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a branching process, while spread between residents is modeled via a compartmental model. Control is modeled as a proportional decrease in both the number of susceptible residents and the reproduction number. We find that vaccination or depopulation can have a greater than linear effect on anticipated infections. For example, assuming a reproduction number of 3.0 for density-dependent COVID-19 transmission, we find that reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. We highlight the California state prison system as an example for how these findings provide a quantitative framework for implementing infection control in congregate settings. Additional applications of our modeling framework include optimizing the distribution of residents into independent residential units, and comparison of preemptive versus reactive vaccination strategies.


title: A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation.

abstract:
IntroductionImprovement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor-beta 1 (TGF-{beta}1) on kidney transplant survival, since TGF-{beta}1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long-term kidney graft survival.

MethodsWe performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.

ResultsDonor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T-allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.

ConclusionKidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-{beta}1 is beneficial, rather than harmful, for kidney transplant survival.

category: transplantation


title: A Design Thinking Approach to Enhance Interprofessional Education Between Technology and Medicine for Innovative Elder Pain Care.

abstract:
BackgroundDesign thinking (DT) describes three stages in the design thinking cycle: 1) inspiration, which embodies the initial problem or opportunity; 2) ideation, which encompasses the development and refinement of ideas; and 3) implementation, which involves the introduction and application of the derived solution.

MethodThe prospective educational program evaluation July 2020 - December 2020. A 150 min interactive workshop regarding developing innovative elder pain care. Medical students will be grouping into four medical students: 1 technological student. Then they will be assigned to match with a technology student. The interprofessional education design thinking activity consists of three parts; a brief introduction, the brainstorming process to identified pain points by persona and user journey to generate the idea, and the prototype presentation.

ResultsForty sixth-year medical students and twelve technological students participated. 58% of medical students and 95% of technological students perceived DT as very helpful for their careers. However, only 30% of medical students and 60% of technological students were inspired to develop actual prototypes after the course. Nearly all of the students responded they comfortable with this interdisciplinary project-based style. Still, the time of the workshop is too limited, and among those responding with no interest pursue the project gave a reason that they lack time after rotating to other courses.

ConclusionMost medical students and technological students perceived DT as beneficial for their career and displayed satisfy in this co-project style. However, finding matched schedule of two disciplines made long-term interpersonal education challenging.

category: medical education


title: Vaccination and COVID-19 dynamics in hemodialysis patients: a population-based study in France.

abstract:
ImportanceMaintenance hemodialysis (MHD) patients have a high mortality risk after COVID-19 and an altered humoral response to vaccines, but vaccine clinical efficacy remains unknown in this population.

ObjectiveTo estimate the association between vaccination and COVID-19 hospitalization rate in MHD patients

DesignUsing Bayesian multivariable spatiotemporal models, we estimated the expected number of SARS-CoV-2 severe infections (infections with hospital admission) in MHD patients from simultaneous cases in the general population.

SettingFrench population-based retrospective analysis in MHD and non-dialysis patients.

ParticipantsModels were fitted from 3620 hospitalizations of MHD patients and 457,160 hospitalizations in the general population.

ExposureSevere SARS-CoV-2 infections in the general population and vaccine exposure.

Main Outcome and MeasureWeekly incidence of severe infections in MHD patients.

ResultsDuring the first epidemic wave, incidence of severe infections in MHD patients was approximately proportional to incidence in the general population. However, our model overestimated incidence during the second wave, suggesting an effect of prevention measures during the 2nd wave. A second model (based on data up to the end of the 2nd wave) estimated that the risk in MHD patients decreased between waves 1 and 2, with incidence rate ratio (IRR) = 0.70 (95% CI: 0.64, 0.76). Moreover, while this model correctly estimated the reported MHD cases up to the end of the 2nd wave, predictions overestimated the expected number of cases from the beginning of the vaccination campaign. Using vaccination coverages as additional predictors permitted to correctly fit the weekly reported number of cases, with IRR in MHD patients of 0.41 (95% CI: 0.28, 0.58) for vaccine exposure in MHD patients and 0.50 (95% CI: 0.40, 0.61) per 10% increase in vaccination coverage in the same-age general population.

Conclusions and RelevanceOur findings suggest that both individual and herd immunity due to vaccination may yield a protective effect against severe forms of COVID-19 in MHD patients.

QuestionWhether vaccination against SARS-CoV-2 limits hospitalization rates in hemodialysis patients is still unknown.

FindingsBy modeling the dynamics of 3620 hospital admissions for SARS-CoV-2 infections among hemodialysis patients, as a proportion of 457,160 cases reported in the French general population from March 2020 to April 2021, we identified vaccination coverage in both hemodialysis patients and the general population as independently associated with protection of hemodialysis patients against severe infection.

MeaningVaccination against SARS-CoV-2 is associated with reduced hospitalization rate in hemodialysis patients.

category: nephrology


title: Associations between cardiovascular risk factors, stroke severity, and post-stroke cognition: a moderated mediation analysis

abstract:
IntroductionCognitive impairment may affect one third of the stroke survivors. Cardiovascular risk factors have been described to be risk factors for lower cognition after stroke. However, most previous studies only used multivariate regression models to learn the association. The aim of our study was to investigate whether the effect of cardiovascular risk factors on cognition after stroke was mediated by stroke severity, the estimated effect of direct and indirect pathways, and the moderated association.

MethodIn this incident cross-sectional study, 300 stroke patients received cognitive test within seven days after stroke. Cognitive tested was performed by the Chinese version of Mini-Mental State Examination (MMSE). A second stage dual moderated mediation model was used the select moderation variables. Finally, we constructed a structural equation model to test the indirect effects of cardiovascular and demographic factors on cognition stroke severity, the direct effects of predictors on cognition, and the moderated effects of hypertension.

ResultsAge (estimate, -0.114; 95% bias-corrected CI, -0.205, -0.032; P<0.001), female (estimate, -2.196; 95% bias-corrected CI, -4.359, -0.204; P=0.009), lower education (estimate, -0.893; 95% bias-corrected CI, -1.662, --0.160; P<0.001), stroke severity (estimate, -1.531; 95% bias-corrected CI, -3.015, -0.095), hypertension (estimate, -2.242; 95% bias-corrected CI, -4.436, -0.242; P=0.003) and atrial fibrillation (estimate, -4.930; 95% bias-corrected CI, -12.864, -0.126; P=0.048) were directly associated with lower cognitive function after stroke. We found no evidence that cardiovascular risk factors indirectly correlated cognitive function through stroke severity. The combination of hypertension could alleviate the negative effect of atrial fibrillation on cognition (estimate, -3.928; 95% bias-corrected CI, -7.954, 0.029; P=0.009).

ConclusionsWe explored the complex relationship between cardiovascular risk factors, stroke severity, and cognitive function after stroke. Using our method, researchers using other dataset could repeat the analysis and achieve a better understanding of the relationship. Future researchers are needed to find whether the moderated associations were casual or modifiable.

category: neurology


title: Derivation of anthropometric-based equations to predict lean body mass composition of cancer patients

abstract:
BackgroundLean body mass (LBM) composition of cancer patients is a predictor of chemotherapy-related adverse events and overall cancer survival. However, clinicians lack validated algorithms that can be applied to measure the LBM of cancer patients to facilitate accurate chemotherapy dosing. Our goal was to develop LBM predictive equations using routinely measured anthropometric measures among cancer patients.

MethodsWe leveraged the 1999-2006 National Health and Nutrition Examination Survey (NHANES) data cycles containing information on self-reported cancer diagnosis, LBM measures based on dual-energy x-ray absorptiometry (DXA) and several anthropometric and demographic factors. We restricted our analysis to participants who had been diagnosed with cancer at the time of surveys. The data was randomly split to 75%:25% to train and test predictive models. Least absolute shrinkage and selection operator (LASSO) models were used to predict LBM based on anthropometric and demographic factors, overall and separately among sex and sex-by-race/ethnic subgroups. LBM measured directly with DXA served as the gold standard for assessing the predictive abilities (correlations [R2] and the Root Mean Square Error [RMSE]) of the derived LBM-algorithms. We further compared the correlations between both DXA-based LBM and predicted LBM and urine creatinine levels, a known biomarker of muscle mass.

ResultsWe identified 1,777 cancer patients with a median age of 71 (interquartile range [IQR]: 60-80) years. The most parsimonious model comprised of height and weight, which accurately predicted LBM overall (R2=0.86, RMSE =2.26). The predictive abilities of these models varied across sex-by-race/ethnic groups. The magnitude of correlations between derived LBM-algorithm and urine creatinine levels were larger compared to those measured between DXA-based LBM and urine creatinine levels (R2=0.30 vs. R2=0.17)

ConclusionsWe successfully developed a simple sex-specific and sex-by-race/ethnicity-specific models to accurately predict the LBM of cancer patients by using only height and weight. The simplicity and high accuracy of these models make them inexpensive alternatives to measuring the LBM of cancer patients. Data on the LBM of cancer patients could help guide optimal chemotherapy dose selection among cancer patients.

category: oncology


title: Prevalence and causes of vision impairment in Norwest Portugal: a capture and recapture study

abstract:
AimThe aim of this study was to estimate the prevalence and causes of vision impairment (VI) in the Norwest of Portugal.

MethodsInformation about people with VI was obtained from different sources in the Norwest of Portugal during a period spanning years 2014-2015. Log-linear models were applied to estimate the number of individuals missing from lists of cases obtained from Primary Care Centres, blind association (ACAPO) and from hospitals (the PCVIP-study). Log-linear models were used to estimate the crude prevalence and the category specific prevalence of VI. Causes of VI were obtained from the PCVIP-study.

ResultsCrude prevalence of VI was 1.97% (95%CI=1.56-2.54), and normalized prevalence was 1% (95%CI=0.78-1.27). The age-specific prevalence was 3.27% (95% CI,=2.36-4.90), older than 64 years, 0.64% (95%CI=0.49-0.88), aged 25-64 years, and 0.07% (95%CI=0.045-0.13), aged less than 25 years. Prevalence amongst females was 1.3x higher than amongst males. The five leading causes of VI were Diabetic Retinopathy, Cataract, Age-related Macular Degeneration, Glaucoma and Disorders of the Globe.

ConclusionThe prevalence of VI in Portugal was within the expected range and in line with other European countries. A significant number of cases of VI might be due to preventable cases and, therefore, a reduction of the prevalence of VI in Portugal seems possible. Women and old people were more likely to have VI and, therefore, these groups require extra attention. Future studies are necessary to characterize temporal changes in prevalence of VI in Portugal.

category: ophthalmology


title: Discovering Monogenic Patients with a Confirmed Molecular Diagnosis in Millions of Clinical Notes with MonoMiner

abstract:
PurposeCohort building is a powerful foundation for improving clinical care, performing research, clinical trial recruitment, and many other applications. We set out to build a cohort of all patients with monogenic conditions who have received a definitive causal gene diagnosis in a 3 million patient hospital system.

MethodsWe define a subset of half (4,461) of OMIM curated diseases for which at least one monogenic causal gene is definitively known. We then introduce MonoMiner, a natural language processing framework to identify molecularly confirmed monogenic patients from free-text clinical notes.

ResultsWe show that ICD-10-CM codes cover only a fraction of known monogenic diseases, and even where available, code-based patient retrieval offers 0.12 precision. Searching by causal gene symbol offers great recall but an even worse 0.09 precision. MonoMiner achieves 7-9 times higher precision (0.82), with 0.88 precision on disease diagnosis alone, tagging 4,259 patients with 560 monogenic diseases and 534 causal genes, at 0.48 recall.

ConclusionMonoMiner enables the discovery of a large, high-precision cohort of monogenic disease patients with an established molecular diagnosis, empowering numerous downstream uses. Because it relies only on clinical notes, MonoMiner is highly portable, and its approach is adaptable to other domains and languages.

category: genetic and genomic medicine


title: On the effectiveness of COVID-19 restrictions and lockdowns: Pan metron ariston

abstract: I examine the dynamics of confirmed case (and death) growth rates conditional on different levels of severity in implemented NPIs, the mobility of citizens and other non restrictive policies. To account for the endogeneity of many of these variables, and the possibility of correlated latent (unobservable) country characteristics, I estimate a four structural model of the evolution of case growth rates, death growth rates, average changes in mobility and the determination of the severity of NPIs. There are strongly decreasing returns to the stringency of NPIs, especially for extreme lockdowns, as no significant improvement in the main outcome measures is found beyond NPIs corresponding to a Stringency Index range of 51-60 for cases and 41-50 for deaths. A non-restrictive policy of extensive and open testing has half of the impact on pandemic dynamics as the optimal NPIs, with none of the associated social and economic costs resulting from the latter. Decreases in mobility were found to increase, rather than decrease case growth rates, consistent with arguments that within-household transmission-resulting from spending more time at residences due to mobility restrictions-may outweigh the benefits of reduced community transmission. Vaccinations led to a fall in case and death growth rates, however the effect size must be re-evaluated when more data becomes available. Governments conditioned policy choice on recent pandemic dynamics, and were found to de-escalate the associated stringency of implemented NPIs more cautiously than in their escalation, i.e., policy mixes exhibited significant hysteresis. Finally, at least 90% of the maximum effectiveness of NPIs can be achieved by policies with an average Stringency index of 31-40, without restricting internal movement or imposing stay at home measures, and only recommending (not enforcing) closures on workplaces and schools, accompanied by public informational campaigns. Consequently, the positive effects on case and death growth rates of voluntary behavioral changes in response to beliefs about the severity of the pandemic, generally trumped those arising from mandatory behavioral restrictions. The exception being more stringent mandatory restrictions on gatherings and international movement, which were found to be effective. The findings suggest that further work should be directed at re-evaluating the effectiveness of NPIs, particularly towards empirically determining the optimal policy mix and associated stringency of individual NPIs.

category: health policy


title: Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada, February to June, 2021

abstract:
BackgroundThe period from February to June 2021 was one during which initial wild-type SARS-CoV-2 strains were supplanted in Ontario, Canada, first by variants of concern (VOC) with the N501Y mutation (Alpha/B1.1.17, Beta/B.1.351 and Gamma/P.1 variants), and then by the Delta/B.1.617 variant. The increased transmissibility of these VOCs has been documented but data for increased virulence is limited. We used Ontarios COVID-19 case data to evaluate the virulence of these VOCs compared to non-VOC SARS-CoV-2 infections, as measured by risk of hospitalization, intensive care unit (ICU) admission, and death.

MethodsWe created a retrospective cohort of people in Ontario testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and June 27, 2021 (n=212,332). We constructed mixed effects logistic regression models with hospitalization, ICU admission, and death as outcome variables. Models were adjusted for age, sex, time, vaccination status, comorbidities, and pregnancy status. Health units were included as random intercepts.

ResultsCompared to non-VOC SARS-CoV-2 strains, the adjusted elevation in risk associated with N501Y-positive variants was 52% (43-62%) for hospitalization; 89% (67-116%) for ICU admission; and 51% (30-74%) for death. Increases with Delta variant were more pronounced: 108% (80-138%) for hospitalization; 234% (164-331%) for ICU admission; and 132% (47-230%) for death.

InterpretationThe progressive increase in transmissibility and virulence of SARS-CoV-2 VOCs will result in a significantly larger, and more deadly, pandemic than would have occurred in the absence of VOC emergence.

category: infectious diseases


title: Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada


title: Critical timing for triggering public health interventions to prevent COVID-19 resurgence: a mathematical modelling study

abstract: To prevent the catastrophic health and economic consequences from COVID-19 epidemics, some nations have aimed for no community transmission outside of quarantine. To achieve this, governments have had to respond rapidly to outbreaks with public health interventions. But the exact characteristics of an outbreak that trigger these measures differ and are poorly defined. We used existing data from epidemics in Australia to establish a practical model to assist stakeholders in making decisions about the optimal timing and extent of interventions. We found that the number of reported cases on the day that interventions commenced strongly predicted the size of the outbreaks. We quantified how effective interventions were at containing outbreaks in relation to the number of cases at the time the interventions commenced. We also found that containing epidemics from novel variants that had higher transmissibility would require more stringent interventions that commenced earlier. In contrast, increasing vaccination coverage would enable more relaxed interventions. Our model highlights the importance of early and decisive action in the early phase of an outbreak if governments aimed for zero community transmission, although new variants and vaccination coverage may change this.


title: SARS-CoV-2 Infections in mRNA Vaccinated Individuals are Biased for Viruses Encoding Spike E484K and Associated with Reduced Infectious Virus Loads that Correlate with Respiratory Antiviral IgG levels.

abstract:
IntroductionCOVID-19 large scale immunization in the US has been associated with infrequent breakthrough positive molecular testing. Whether a positive test is associated with a high viral RNA load, specific viral variant, recovery of infectious virus, or symptomatic infection is largely not known.

MethodsIn this study, we identified 133 SARS-CoV-2 positive patients who had received two doses of either Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccines, the 2nd of which was received between January and April of 2021. The positive samples were collected between January and May of 2021 with a time that extended from 2 to 100 days after the second dose. Samples were sequenced to characterize the whole genome and Spike protein changes and cycle thresholds that reflect viral loads were determined using a single molecular assay. Local SARS-CoV-2 IgG antibodies were examined using ELISA and specimens were grown on cell culture to assess the recovery of infectious virus as compared to a control unvaccinated cohort from a matched time frame.

ResultsOf 133 specimens, 24 failed sequencing and yielded a negative or very low viral load on the repeat PCR. Of 109 specimens that were used for further genome analysis, 68 (62.4%) were from symptomatic infections, 11 (10.1%) were admitted for COVID-19, and 2 (1.8%) required ICU admission with no associated mortality. The predominant virus variant was the alpha (B.1.1.7), however a significant association between lineage B.1.526 and amino acid change S: E484K with positives after vaccination was noted when genomes were compared to a large control cohort from a matched time frame. A significant reduction of the recovery of infectious virus on cell culture as well as delayed time to the first appearance of cytopathic effect was accompanied by an increase in local IgG levels in respiratory samples of vaccinated individuals but upper respiratory tract IgG levels were not different between symptomatic or asymptomatic infections.

ConclusionsVaccination reduces the recovery of infectious virus in breakthrough infections accompanied by an increase in upper respiratory tract local immune responses.

FundingNational Institute of Health (The Johns Hopkins Center of Excellence in Influenza Research and Surveillance, HHSN272201400007C), Johns Hopkins University, Maryland Department of Health, Centers for Disease Control and Prevention.


title: Next-generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire

abstract: Methods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multi-parametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We apply Ig-MS to plasma from subjects with severe & mild COVID-19, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, with compatibility to any recombinant antigen to gauge our immune responses to vaccination, pathogens, or autoimmune disorders.

category: allergy and immunology


title: Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors

abstract:
BackgroundMature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers of high medical need. TCLs have inferior prognosis compared with their B-cell counterparts, which is attributed to poor understanding of their pathogenesis. Based on phenotypic similarities between normal and neoplastic lymphocytes it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T-cells.

Methods and findingsTo address the debated question of the cell of origin in TCLs we analyzed to identify the highly variable complementarity determining regions (CDR3) regions of T-cell receptor (TCR) to trace the clonal history of the T-cells. We have collected previously published whole genome-exome, and -transcriptome sequencing data from 574 TCL patients comprising five nodal lymphomas [anaplastic large cell lymphoma (n=67), peripheral T-cell lymphoma (PTCL, n=55), adult T-cell lymphoma/leukemia (n=135), natural killer T-cell lymphoma (NKCL, n=25), not specified/other (n=30)] and three extranodal, cutaneous T-cell lymphomas [mycosis fungoides (n=122), Sezary syndrome (n=130), and subcutaneous panniculitis-like T-cell lymphoma (n=10)]. TCR clonotypes contained in the tumor cell fraction, representing the clonotypes of malignant cells, were identified by de novo assembly of CDR3 regions of TCR {gamma}, {beta} and . We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern oligoclonality varied. Anaplastic large cell lymphoma was most diverse comprising multiple clonotypes of TCR{gamma}, {beta} and  whereas adult T-cell lymphoma/leukemia and peripheral T-cell lymphomas often showed monoclonality for TCR{gamma} and {beta} but had diverse TCR clonotypes. These patterns of rearrangements were not compatible with the current mature T-cell precursor model and indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus showing biased usage of V and J segments of high combinatorial probability resulting in recurrent, "public" CDR3 sequences shared between unrelated patients and across different clinical TCL entities. Frequencies of malignant clonotypes followed Zipf-Mandelbrot scaling law suggesting that TCLs comprise an interconnected system of expanding tumor clones.

The major limitation of this study is that it is based on the analysis of the TCR clonotypes and does not directly inform about developmental trajectories of cellular clones.

ConclusionsLymphoid precursors are the likely cells of origin for mature T-cell lymphomas. Anaplastic large cell lymphoma seems to be derived from the most immature precursors with germline TCR whereas peripheral T-cell lymphoma and adult T-cell lymphoma/leukemia map to the later stages after TCR{beta} rearrangement stage. Clonotypically diverse initiating cells may seed target tissues being responsible for disease relapses after therapy.

category: dermatology


title: The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish

abstract: Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Though APOE remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance of APOE and differing genetic architecture of the Amish compared to a general European ancestry population.


title: Untargeted saliva metabolomics reveals COVID-19 severity: Saliva Metabolomics for SARS-COV-2 Prognosis

abstract:
BackgroundThe COVID-19 pandemic is likely to represent an ongoing global health issue given the potential for vaccine escape and the low likelihood of eliminating all reservoirs of the disease. Whilst diagnostic testing has progressed at pace, there is an unmet clinical need to develop tests that are prognostic, to triage the high volumes of patients arriving in hospital settings. Recent research has shown that serum metabolomics has potential for prognosis of disease progression. 1 In a hospital setting, collection of saliva samples is more convenient for both staff and patients, and therefore offers an alternative sampling matrix to serum. We demonstrate here for the first time that saliva metabolomics can reveal COVID-19 severity.

Methods88 saliva samples were collected from hospitalised patients with clinical suspicion of COVID-19, alongside clinical metadata. COVID-19 diagnosis was confirmed using RT-PCR testing. COVID severity was classified using clinical descriptors first proposed by SR Knight et al. Metabolites were extracted from saliva samples and analysed using liquid chromatography mass spectrometry.

ResultsIn this work, positive percent agreement of 1.00 between a PLS-DA metabolomics model and the clinical diagnosis of COVID severity was achieved. The negative percent agreement with the clinical severity diagnosis was also 1.00, for overall percent agreement of 1.00.

ConclusionsThis research demonstrates that liquid chromatography-mass spectrometry can identify salivary biomarkers capable of separating high severity COVID-19 patients from low severity COVID-19 patients in a small cohort study.


title: Prevalence and risk factors of short birth interval in Bangladesh: Evidence from the linked data of population and health facility survey

abstract:
BackgroundThe Sustainable Development Goals target significant reductions in maternal and under-five deaths by 2030. The prevalence of these deaths is significantly associated with short birth interval (SBI). Identification of factors associated with SBI is pivotal for intervening with appropriate programmes to reduce these adverse consequences. This study aimed to determine the factors associated with SBI in Bangladesh.

MethodsThe Bangladesh Demographic and Health Survey 2017/18 and Bangladesh Health Facility Data 2017 were linked and analysed. SBI was defined as an interval between consecutive births of 33 months or less, as recommended by the World Health Organization. We used descriptive statistics to summarise respondents characteristics and multilevel Poisson regression to assess the predictors of SBI.

ResultsAround 26% of live births occurred in short intervals, with a further higher prevalence among younger, uneducated, or rural women. The likelihoods of SBI were lower among women aged 20-34 years (PR, 0.14; 95% CI, 0.11-0.17) and [≥] 35 years (PR, 0.03; 95% CI, 0.02-0.05) as compared to the women aged 19 years or less. Women from households with the richest wealth quintile experienced lower odds of SBI (PR, 0.61; 95% CI, 0.45-0.85) compared to those from the poorest wealth quintile. The prevalences of SBI were higher among women for whom the children born from the second most pregnancies died (PR, 5.23; 95% CI, 4.18-6.55), those who were living in Chattogram (PR, 1.52; 95% CI, 1.12-2.07) or Sylhet (PR, 2.83, 95% CI, 2.08-3.86) divisions. Availability of modern contraceptives at the nearest healthcare facilities was 66% protective to the occurrence of SBI (PR, 0.34; 95% CI, 0.22-0.78). Also, the prevalence of SBI increased around 85% (PR, 1.85; 95% CI, 1.33-2.18) for every kilometer increase in the distance of nearby health facilities from womens homes.

ConclusionMore than a quarter of live births in Bangladesh occurred in short intervals. This relatively high prevalence is a challenge for Bangladesh in reducing pregnancy-related adverse consequences, including maternal and child mortality. Policies and programmes are needed to increase awareness of SBI and associated adverse health outcomes and expand access to modern contraceptives.


title: RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

abstract:
PURPOSETargeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport.

METHODSFive HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS).

RESULTSThe early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi-quantitative RAB5A IHC staining correlated significantly positive to PFS.

CONCLUSIONThe present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.


title: Predicting age from hearing test results with machine learning reveals the genetic and environmental factors underlying accelerated auditory aging

abstract: With the aging of the world population, age-related hearing loss (presbycusis) and other hearing disorders such as tinnitus become more prevalent, leading to reduced quality of life and social isolation. Unveiling the genetic and environmental factors leading to age-related auditory disorders could suggest lifestyle and therapeutic interventions to slow auditory aging. In the following, we built the first machine learning-based hearing age predictor by training models to predict chronological age from hearing test results (root mean squared error=7.10{+/-}0.07 years; R-Squared=31.4{+/-}0.8%). We defined hearing age as the prediction outputted by the model on unseen samples, and accelerated auditory aging as the difference between a participants hearing age and age. We then performed a genome wide association study [GWAS] and found that accelerated hearing aging is 14.1{+/-}0.4% GWAS-heritable. Specifically, accelerated auditory aging is associated with 662 single nucleotide polymorphisms in 243 genes (e.g OR2B4P, involved in smell perception). Similarly, it is associated with biomarkers (e.g cognitive tests), clinical phenotypes (e.g chest pain), diseases (e.g depression), environmental (e.g smoking, sleep) and socioeconomic (e.g income, education, social support) variables. The hearing age predictor could be used to evaluate the efficiency of emerging rejuvenation therapies on hearing.

category: health informatics


title: Modeling of leptospirosis outbreaks in relation to hydroclimatic variables in the northeast of Argentina

abstract: The transmission of leptospirosis is conditioned by climatic variables. In northeastern Argentina leptospirosis outbreaks occur mainly in coincidence with periods of abundant precipitation and high hydrometric level. A Susceptible-Infectious-Recovered Epidemiological Model (SIR) is proposed, which incorporates hydroclimatic variables for the three most populated cities in the area (Santa Fe, Parana and Rosario), during the 2009 - 2018 period. Results obtained by solving the proposed SIR model for the 2010 outbreaks are in good agreement with the actual data, capturing the dynamics of the leptospirosis outbreak wave. However, the model does not perform very well when isolated cases appear outside the outbreak periods, probably due to non-climatic factors not explicitly considered in the present version of the model. Nevertheless, the dynamic modeling of infectious diseases considering hydroclimatic variables constitutes a climatic service for the public health system, not yet available in Argentina.


title: Prevalence of SARS-CoV-2 Antibodies from a one-year National Serosurveillance of Kenyan Blood Transfusion Donors

abstract:
In tropical Africa, SARS-CoV-2 epidemiology is poorly described because of lack of access to testing and weak surveillance systems. Since April 2020, we followed SARS-CoV-2 seroprevalence in plasma samples across the Kenya National Blood Transfusion Service. We developed an IgG ELISA against full length spike protein. Validated in locally-observed, PCR-positive COVID-19 cases and in pre-pandemic sera, sensitivity was 92.7% and specificity was 99.0%. Using sera from 9,922 donors, we estimated national seroprevalence of SARS-CoV-2 antibodies at 4.3% in April-June 2020 and 9.1% in August-September 2020. Kenyas second COVID-19 wave peaked in November 2020. Here we estimate national seroprevalence in early 2021.

Between January 3 and March 15, 2021, we collected 3,062 samples from donors aged 16-64 years. Among 3,018 samples that met our study criteria, 1,333 were seropositive (crude seroprevalence 44.2%, 95% CI 42.4-46.0%). After Bayesian test-performance adjustment and population weighting to represent the national population distribution, the national estimate of seroprevalence was 48.5% (95% CI 45.2-52.1%). Seroprevalence varied little by age or sex but was higher in Nairobi (61.8%), the capital city, and lower in two rural regions.

Almost half of Kenyas adult donors had evidence of past SARS-CoV-2 infection by March 2021. Although high, the estimate is corroborated by other population-specific estimates in country. Between March and June, 2% of the population were vaccinated against COVID-19 and the country experienced a third epidemic wave. Natural infection is outpacing vaccine delivery substantially in Africa, and this reality needs to be considered as objectives of the vaccine programme are set.


title: Evaluation of Clinical Job Demands, Job Resources, and a Novel Intervention on Measures of Health Care Worker Stress at a Community Hospital Pre and Post COVID-19

abstract:
ObjectiveTo explore the relationship and identity of Health Care Worker stressors to a measure of perceived burnout and to a novel intervention tool.

Participants and MethodsFrom July 2019 to June 2020, we surveyed Health Care Workers (HCW) pre and post COVID19 in an independent local community hospital for burnout with the Health Care Provider Wellness Assessment tool. Linear regression and means comparison were used to identify overall job demand and resource perception with burnout, unique stressor portraits by provider subtype and mean survey scores between those who did or did not voluntarily complete at least 14 days of a 28 day novel self-help intervention tool.

ResultsRegarding the pre COVID-19 data, of 73 respondents, there was statistically significant (p<.01) correlation between overall job demands (directly) and resources (inversely) with burnout intensity. With respect to the HCW stressor characteristic analyses there was statistical significance (p<.05) between the mean frequency occurrence of the top 5 stressors identified by respondent subtype when compared to the mean occurrence of overall individual responses within the corresponding subtype. Finally, although limited by a low number of respondents, the intervention tool analysis suggested a therapeutic trend toward disruption of the stress-burnout relationship. Regarding the post COVID-19 data, 18 respondents did not show statistically significant characterizable stressor portraits (ie stressors were present but not patternable).

ConclusionUnique stressor portraits were identified by HCW subtype which correlated with more intense burnout self-perception. Additionally, there was a trend toward self-help tool efficacy in mitigating burnout.

category: primary care research


title: RNA sequencing of whole blood defines the signature of high intensity exercise at altitude in elite speed skaters

abstract:
ObjectivesAlthough high altitude training has been increasingly popular in endurance athletes, the molecular and cellular bases of this adaptation remain poorly understood. We aimed to define the underlying physiological changes and screen for potential biomarkers of adaptation using transcriptional profiling of whole blood. More generally, we aimed to evaluate the utility of blood RNA sequencing as a modern and sensitive method of athletes health monitoring.

MethodsSeven elite female speed skaters were profiled before and after 1h intense exercise, on the 18th day of Live High, Train High (LHTH) training programme. Whole blood RNA sequencing (RNA-seq) with globin depletion was used to measure gene expression changes associated with high intensity exercise at high altitude. Eight public microarray datasets were used to identify genes uniquely regulated at high altitude. Gene markers derived from single cell RNA-seq data were used to evaluate the changes of individual cell types in the whole blood.

ResultsUsing individual cell type signatures, we were able to deconvolute the changes of finely defined cell populations from the whole blood RNA-seq. We have detected the increase in neutrophils, platelets, erythrocytes, and CD14 monocytes, and the decrease in natural killers, CD8 T cells, memory CD4 T cells, B cells, and plasmacytoid dendritic cells. The levels of naive CD4 T cells, CD16 monocytes, and myeloid dendritic cells were unchanged. Leveraging the previously published transcriptomic data allowed us to define the expression signature unique to high-altitude adaptation. Among the identified genes we highlight PHOSPHO1, which has a known role in erythropoiesis, and MARC1 with a proposed role in endogenic NO metabolism. Finally, we find that platelets and, to a lesser extent, erythrocytes are the two major cell types that uniquely respond to altitude exercise, while neutrophils represent a more generic marker of intense exercise.

ConclusionsUsing publicly available data from both single-cell RNA-seq atlases and exercise-related blood profiling dramatically increases the value of whole blood RNA-seq for dynamic evaluation of physiological changes in an athletes body. In addition to the measurement of individual gene expression changes, our approach allowed us to estimate changes of blood cell type counts from a small peripheral blood sample, without sorting or other expensive and unfeasible equipment. We also discuss a surprising parallel of hypoxia and increased thrombosis, and hypothesize about the role exercise can play in COVID-19 outcomes.

category: sports medicine


title: Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients

abstract:
Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ RCTs. Having developed combination therapies for Helicobacter pylori, we tested various COVID-19 combinations and describe the most effective. In 24 consecutive COVID-19 subjects with high risk features, hypoxia and untreated moderate-severe symptoms averaging 9 days, we trialed this novel combination comprising ivermectin, doxycycline, zinc, and Vitamins D and C. It was highly effective. All subjects resolved symptoms in 11 days on average, and oxygen saturation improved in 24hrs (87.4% to 93.1%, p=0.001). Hospitalizations and deaths were significantly fewer (p<0.002 or 0.05, respectively) than in background-matched controls from the CDC database. Triple combination therapy is safe and effective even in moderate-severe patients with hypoxia treated in the outpatient setting.

Trial RegistrationN/A, see methods.


title: Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis

abstract:
BackgroundWe aimed to use individual patient data to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in children and young people (CYP) in hospital.

MethodsWe searched Pubmed, European PMC, Medline and Embase for case series and cohort studies that included all CYP admitted to hospital with [≥]30 CYP with SARS-CoV-2 or [≥]5 CYP with PIMS-TS or MIS-C. Eligible studies contained 1) details of age, sex, ethnicity or co-morbidities, and 2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted grouping of co-morbidities were eligible for narrative review. Authors of eligible studies were approached for individual patient data (IPD). We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).

Findings81 studies were included, 57 in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years, infants had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)).

Number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a dose-related fashion. For critical care admission odds ratios were: 1 comorbidity 1.49 (1.45-1.53); 2 comorbidities 2.58 (2.41-2.75); [≥]3 comorbidities 2.97 (2.04-4.32), and for death: 1 comorbidity 2.15 (1.98-2.34); 2 comorbidities 4.63 (4.54-4.74); [≥]3 co-morbidities 4.98 (3.78-6.65). Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities.

InterpretationHospitalised CYP at greatest vulnerability of severe disease or death from SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions.

FundingRH is in receipt of a funded fellowship from Kidney Research UK. JW is in receipt of a Medical Research Council Fellowship.

Putting Research Into ContextO_ST_ABSEvidence before this studyC_ST_ABSThe risk factors for severe disease following SARS-CoV-2 infection in adults has been extensively studied and reported, with good evidence that increasing age, non-white ethnicity, male gender and co-morbidities increase the risk. SARS-CoV-2 infection in children and young people (CYP) infrequently results in hospital admission and very rarely causes severe disease and death, making it difficult to discern the impact of a range of potential risk factors for severe disease in the many small to moderate sized published studies. More recent larger publications have aimed to address this question in specific populations but the global experience has not been described. We searched Pubmed, European PMC, Medline and Embase from the 1st January 2020 to 21st May 2021 for case series and cohort studies that included all CYP admitted to hospital with 30 children with reverse transcriptase-PCR confirmed SARS-CoV-2 or 5 CYP defined as having PIMS-TS or MIS-C. 57 studies met the eligibility criteria for meta-analysis.

Added value of this studyTo our knowledge, this is the first meta-analysis to use individual patient data to compare the odds and risk of critical care admission and death in CYP with COVID-19 and PIMS-TS. We find that the odds of severe disease in hospitalised children is increased in those with multiple co-morbidities, cardiac and neurological co-morbidities and those who are obese. However, the additional risk compared to children without co-morbidity is small.

Implications of all the available evidenceSevere COVID-19 and PIMS-TS, whilst rare, can occur in CYP. We have identified pre-existing risk factors for severe disease after SARS-CoV-2 and recommend that those with co-orbidities which place them in the highest risk groups are prioritised for vaccination.

category: pediatrics


title: The role of the uncinate fasciculus in the risk-architecture of bipolar disorders: A meta-analysis

abstract:
BackgroundBipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, findings in individuals with BD and at familial risk for BD (AR) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD.

MethodsUsing web-based search engines, we identified diffusion tensor imaging studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or AR to healthy volunteers (HV).

ResultsWe included 32 studies (nBD=1186, nHV=2001; nAR=289, nHV=314). Compared to HV, individuals with BD showed lower FA in the right (p<.0001) and left UF (p=.010), and higher RD in the right UF (p=.009). We found no significant differences between AR and HV. In the right but not the left UF, AR individuals showed higher FA than BD (p=.043).

ConclusionComparable UF microstructure between AR and HV and higher FA in the right UF in AR compared to BD suggest that aberrancies in UF microstructure is not an endophenotype for BD. Longitudinal studies are needed to determine when UF abnormalities emerge in the context of BD.

category: psychiatry and clinical psychology


title: Anthropometric measurements as predictors of hypertension in Busia, Vihiga, Trans Nzoia and Siaya counties of Western Kenya

abstract: Emerging data suggest a rise in the incidence rate of hypertension in many countries within Sub-Saharan Africa. This has been attributed to socioeconomic factors that have influenced diet and reduced physical activity further deranging anthropometric measurements. We assessed the predictive power of three anthropometric indicators namely: waist circumference (WC), waist to height ratio (WHtR) and body mass index (BMI) in detecting hypertension. This cross-sectional community survey was conducted in four counties within Western Kenya between October 2018 to April 2019 among 3594 adults. The participants sociodemographic data were collected using an interviewer-administered questionnaire and anthropometric measurements taken. We used the R-software for descriptive and inferential statistical analysis. Pearson chi-square test was used to assess the association between anthropometric measurements and hypertension while logistic regressions estimated the likelihood of hypertension. Youden method was used to identify optimal anthropometric cut-offs for sensitivity, specificity and area under the receiver operating characteristics (ROC) curve computation. The crude prevalence of hypertension was 23.3%, however it rose with advancement in age. Furthermore, obese individuals had a three-fold (AOR=2.64; 95% CI: 2.09, 3.35) increased likelihood of hypertension compared to those with a normal BMI. The optimal WC cut-off was 82.5cm for men and 87cm for women, an optimal WHtR of 0.47 for men and 0.55 for women; while the optimal BMI cut-off was 23.7 kg/m2 and 22.6 kg/m2 for men and women respectively. The sensitivity of WC, WHtR and BMI for men was 0.60, 0.65 and 0.39 respectively and 0.71, 0.65 and 0.78 respectively for women. BMI is the best predictor for hypertension among women but a poor predictor for men; WC had a high hypertension predictive power for both gender while WHtR is the best hypertension predictor for men.

category: cardiovascular medicine


title: COVID-19 Due to Wild-Type SARS-CoV-2 More Prevalent in Adolescents and Youth than in Older Adults Based on 19 US States in Fall 2020 Prior to Vaccine Availability

abstract:
PURPOSEIn a prior study, we examined data from six US states during Summer 2020, and found that prevalence of COVID-19 for adolescents and youth was significantly greater than for older adults (p<.00001) as was a prevalence-related measure: Number of cases observed / Number of cases expected (p<.005). We now extended our study to more states in Fall 2020 to confirm the prevalence relationships we found previously. Vaccines were still not available as of Fall 2020. Presumably, the SARS-CoV-2 strain circulating at the time was the wild-type lineage since no variants were reported in the US until the end of December 2020.

METHODSWe examined data from 19 U.S. states experiencing surges in cases to determine prevalence of COVID-19, and a prevalence-related measure: [Number of cases observed in a given age group] / [Number of cases expected in the age group based on population demographics].

RESULTSIn 16 of the 19 states, we found that: (1) prevalence of COVID-19 for adolescents and youth was significantly greater than for older adults (p-values ranged from p<0.00001 to p = 0.0175; (2) the ratio of cases observed to cases expected was significantly greater in adolescents and youth than in older adults (p-values ranging from p< 0.00001 to p = 0.004).

CONCLUSIONSOur results are consistent with our previous study in Summer 2020. The finding of lower prevalence in older adults cannot be attributed to access to vaccination since our data are from Fall 2020 when vaccinations were not yet available. Our findings with the SARS-CoV-2 wild-type strain are consistent with the findings currently being reported in the UK for the delta variant. In both studies, prevalence in adolescents and youth exceeded that in older adults. The UK findings are more pronounced perhaps because that study transpired following months of vaccinations of older adults whereas ours occurred before vaccinations were available.

category: epidemiology


title: Estimating the prevalence of discrepancies between study registrations and publications: A systematic review and meta-analyses

abstract:
BackgroundProspectively registering study plans in a permanent time-stamped and publicly accessible document is becoming more common across disciplines and aims to improve the trustworthiness of research findings. Selective reporting persists, however, when researchers deviate from their registered plans without disclosure. This systematic review aims to estimate the prevalence of undisclosed discrepancies between prospectively registered study plans and their associated publication. We further aim to identify the research disciplines where these discrepancies have been observed, whether interventions to reduce discrepancies have been conducted, and gaps in the literature.

MethodsOn 15 December 2019, we searched Scopus and Web of Knowledge for articles that included quantitative data about discrepancies between registrations or study protocols and their associated publications. We used random-effects meta-analyses to synthesize the results.

ResultsWe reviewed k = 89 articles, including k = 70 that report on primary outcome discrepancies from n = 6314 studies and, k = 22 that report on secondary outcome discrepancies from n = 1436 studies. Meta-analyses indicate that between 10% to 68% (95% prediction interval) of studies contain at least one primary outcome discrepancy and between 13% to 95% (95% prediction interval) contain at least one secondary outcome discrepancy. Almost all articles assessed clinical literature, and there was considerable heterogeneity, resulting in wide prediction intervals. We identified only one article that attempted to correct discrepancies.

DiscussionMany articles did not include information on whether discrepancies were disclosed, which version of a registration they compared publications to, and whether the registration was prospective. Thus, our estimates represent discrepancies broadly, rather than our target of undisclosed discrepancies between prospectively registered study plans and their associated publications. Discrepancies are common and reduce the trustworthiness of medical research. Interventions to reduce discrepancies could prove valuable.

Registrationosf.io/ktmdg. Protocol amendments are listed in Supplementary Material A.

category: health systems and quality improvement


title: COVID-19 deaths and hospitalizations averted by rapid vaccination rollout in the United States

abstract:
ImportanceRandomized clinical trials have shown that the COVID-19 vaccines currently approved in the US are highly efficacious. However, more evidence is needed to understand the population-level impact of the US vaccination rollout in the face of the changing landscape of COVID-19 pandemic in the US, including variants with higher transmissibility and immune escape.

ObjectiveTo quantify the population-level impact of the US vaccination campaign in averting cases, hospitalizations and deaths from December 12, 2020 to June 28, 2021.

DesignAge-stratified agent-based model which included transmission dynamics of the Alpha, Gamma and Delta variants in addition to the original Wuhan-1 variant.

SettingOur model was calibrated to COVID-19 outbreak and vaccine rollout in the US. Model predictions were made at the country level.

ParticipantsSimulated age-stratified population representing US demographics.

Main Outcomes and MeasuresCases, hospitalizations and deaths averted by vaccination against COVID-19 in the US, compared to the counterfactuals of no vaccination and vaccination administered at half the actual pace.

ResultsThe swift vaccine rollout in the US curbed a potential resurgence of cases in April 2021, which would have been otherwise fuelled by the Alpha variant. Compared to the scenario without vaccines, we estimated that the actual vaccination program averted more than 26 million cases, 1.2 million hospitalizations and saved 279,000 lives. A vaccination campaign with half the actual rollout rate would have led to an additional 460,000 hospitalizations and 121,000 deaths.

Conclusions and RelevanceThe COVID-19 vaccination campaign in the US has had an extraordinary impact on reducing disease burden despite the emergence of highly transmissible variants. These findings highlight that the pace of vaccination was essential for mitigating COVID-19 in the US, and underscore the urgent need to close the vaccine coverage gaps in communities across the country.

Key PointsO_ST_ABSQuestionC_ST_ABSHow effective was the United States (US) vaccination campaign in suppressing COVID-19 burden?

FindingsThe vaccination campaign was highly effective in curbing the COVID-19 outbreak in the US. We estimated that the vaccine rollout saved over 275,000 lives and averted 1.2 million hospitalizations.

MeaningThe swift vaccine rollout in the US averted a remarkable number of cases, hospitalizations and deaths despite the emergence of highly transmissible variants.


title: Twins in Guinea-Bissau have a 'thin-fat' body composition compared to singletons

abstract:
Thrifty phenotype hypothesis proposed that fetal undernutrition increases risk of diabetes in later life. Undernourished low birthweight Indian babies are paradoxically more adipose compared to well-nourished European babies, and are at higher risk of diabetes in later life. Twin pregnancies are an example of in utero growth restrictive environment due to shared maternal nutrition. There are few studies of body composition in twins. We performed secondary analysis of anthropometric body composition of twins and singletons in Guinea-Bissau, an economically deprived African country.

Anthropometric data was available on 7-34 year-old twins (n=209, 97 males) and singletons (n=182, 86 males) in the Guinea-Bissau Twin Registry at the Bandim Health Project. Twins had lower birth weight (2420 vs 3100 g, p<0.001); and at follow-up, lower height (HAZ mean Z-score difference, -0.21, p=0.055), weight (WAZ -0.73, p=0.024) and BMI (BAZ -0.22, p=0.079) compared to singletons but higher adiposity (skinfolds: +0.33 SD, p=0.001). Twins also had higher fasting (+0.38 SD, p<0.001) and 2-hr OGTT glucose concentrations (+0.29 SD, p<0.05). Linear mixed-effect model accounting for intrapair correlations and interactions confirmed that twins were thinner but fatter across the age range. Data on maternal morbidity and prematurity were not available in this cohort.

African populations are known to have a muscular (less adipose) body composition. Demonstration of a thin-fat phenotype in twins in a low socioeconomic African country supports the thesis that it could be a manifestation of early life undernutrition and not exclusive to Indians. This phenotype could increase risk of diabetes and related conditions.


title: Antibody response to SARS-CoV-2 infection and BNT162b2 vaccine in Israel

abstract: Neutralizing antibodies targeting the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) block viral entry to host cells, preventing disease and further spread of the pathogen. The presence of SARS-CoV-2 antibodies in serum is a reliable indicator of infection, used epidemiologically to estimate the prevalence of infection and clinically as a measurement of an antigen-specific immune response. In this study, we analyzed serum Spike protein-specific IgG antibodies from 26,170 samples, including convalescent individuals who had coronavirus disease 2019 (COVID-19) and recipients of the BNT162b2 vaccine. We find distinct serological patterns in COVID-19 convalescent and vaccinated individuals, correlated with age and gender and the presence symptoms.


title: Mortality among Care Home Residents in England during the first and second waves of the COVID-19 pandemic: an analysis of 4.3 million adults over the age of 65

abstract:
BackgroundResidents in care homes have been severely impacted by the COVID-19 pandemic. We describe trends in risk of mortality among care home residents compared to residents in private homes in England.

MethodsOn behalf of NHS England, we used OpenSAFELY-TPP, an analytics platform running across the linked electronic health records of approximately a third of the English population, to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to the Care and Quality Commission.

FindingsWe included 4,329,078 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to non-residents in February 2019 residents (CMF = 10.59, 95%CI = 9.51, 11.81 among women, CMF = 10.82, 95%CI = 9.89, 11.84 among men). This increased to more than 17 times in April 2020 (CMF = 17.52, 95%CI = 16.38, 18.74 among women, CMF = 18.12, 95%CI = 17.17 - 19.12 among men) before returning to pre-pandemic levels in June 2020. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks.

InterpretationThe first COVID-19 wave had a disproportionate impact on care home residents in England compared to older private home residents. A degree of immunity, improved protective measures or changes in the underlying frailty of the populations may explain the lack of an increase in the relative mortality risks during the second wave. The care home population should be prioritised for measures aimed at controlling the spread of COVID-19.

FundingMedical Research Council MR/V015737/1


title: Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app

abstract:
BackgroundMental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (e.g., obesity, comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study.

MethodsWe assessed anxiety and depression symptoms using two validated questionnaires in 413,148 individuals between February and April 2021; 26,998 had tested positive for SARS-CoV-2. We adjusted for physical and mental pre-pandemic comorbidities, BMI, age, and sex.

FindingsOverall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2 positive (30.4%) vs. negative (26.1%) individuals. This association was small compared to the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants ([≤]40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) vs. more distant (>120 days) infection, suggesting a short-term effect.

InterpretationA small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than pre-pandemic.

FundingZoe Limited, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, Medical Research Council UK


title: What do you mean I can't have a doctor? This is Canada! - The myriad of consequences for unattached patients: health outcomes, mistrust, and strategic efforts to self-manage health and gain access to primary care

abstract:
BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need.


title: "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment


title: Loneliness among people with severe mental ill health during the COVID-19 pandemic: results from a linked UK population cohort study

abstract:
PurposePopulation surveys underrepresent people with severe mental ill health. This paper aims to explore perceived social support and loneliness and factor associations during the Covid-19 pandemic in a sample of individuals with severe mental ill health.

Design/methodology/approachWe sampled an already existing cohort of people with severe mental ill health. Researchers contacted participants by phone or by post to invite them to take part in a survey about how the pandemic restrictions had impacted health, Covid-19 experiences, perceived social support, employment and loneliness. Loneliness was measured by the three item UCLA loneliness scale.

FindingsIn the pandemic sub-cohort, 367 adults with a severe mental ill health diagnosis completed a remote survey. 29-34% of participants reported being lonely. Loneliness was associated with being younger in age (adjusted OR = -.98, p = .02), living alone (adjusted OR = 2.04, p = .01), high levels of social and economic deprivation (adjusted OR = 2.49, p = .04), and lower perceived social support (B = -5.86, p < .001). Living alone was associated with lower perceived social support. Being lonely was associated with a self-reported deterioration in mental health during the pandemic (adjusted OR = 3.46, 95%CI 2.03-5.91).

Practical implicationsIntervention strategies to tackle loneliness in the severe mental ill health population are needed. Further research is needed to follow-up the severe mental ill health population after pandemic restrictions are lifted to understand perceived social support and loneliness trends.

OriginalityLoneliness was a substantial problem for the severe mental ill health population before the Covid-19 pandemic but there is limited evidence to understand perceived social support and loneliness trends during the pandemic.