title: Evaluating malnutrition management through an intersectional lens: A case study of a community-based child malnutrition program in rural Uganda

abstract:
In Uganda, almost half of children under 5 years old suffer from undernutrition. Undernutrition, a common form of malnutrition in children, encompasses stunting, wasting and underweight. Causes of child undernutrition are complex, suggesting that interventions to tackle malnutrition must be multifaceted. In addition, limited access to healthcare for vulnerable populations restricts the potential of hospital-based strategies. Community-based management of acute malnutrition (CMAM), which includes nutritional counselling, ready-to-use therapeutic foods and the outpatient management of malnutrition by caregivers, is recognised as an effective approach for childrens recovery. However, evaluations of CMAM programs are largely based on biomedical and behavioural health models, failing to incorporate structural factors that influence malnutrition management. The objective of this evaluation was to understand the factors influencing malnutrition management in a CMAM program in rural Uganda, using the socioecological model to assess the multilevel determinants of outpatient malnutrition management. This evaluation used qualitative methods to identify determinants related to caregivers, healthcare and societal structures influencing childrens outpatient care. Data were collected at a community health clinic in 2019 through observations and interviews with caregivers of malnourished children. We observed 14 caregiver-provider encounters and interviewed 15 caregivers to examine factors hindering outpatient malnutrition management. Data were thematically analysed informed by the socioecological model. Findings showed that caregivers had a limited understanding of malnutrition. Counselling offered to caregivers was inconsistent and insufficient. Gender inequality and poverty limited caregivers access to healthcare and their ability to care for their children. Factors at the caregiver- and healthcare-levels interacted with structural factors to shape malnutrition management. Results suggest that CMAM programs would benefit from providing holistic interventions to tackle the structural barriers to childrens care. Using a socioecological approach to program evaluation could help move beyond individual determinants to address the social dynamics shaping malnutrition management in low- and middle-income countries.

WHAT IS KNOWN?O_LICMAM is recognised as a promising strategy to address moderate and severe acute malnutrition in children under five years old in resource-poor settings.
C_LIO_LIEvaluations of CMAM programs largely focus on factors related to caregivers choices, behaviours, and practices to explain why CMAM has inconsistent results.
C_LIO_LILimited attention has been given to the multilevel determinants that influence the outpatient management of malnutrition in CMAM programs.
C_LI

WHAT THIS PAPER ADDS?O_LICaregivers had limited understandings of malnutrition and its underlying mechanisms.
C_LIO_LICounselling provided to caregivers by program personnel was inconsistent and insufficient, often including contradicting information about treatments prescribed to children.
C_LIO_LIStructural factors limited caregivers access to healthcare and their ability to comply with CMAM outpatient protocols.
C_LI

category: public and global health


title: Understanding malnutrition management through a socioecological lens: Evaluation of a community-based child malnutrition program in rural Uganda


title: Iron deficiency in Women of Childbearing Age with Self-reported Oral Iron Gastrointestinal Intolerance and Management with an oral Iron-Whey-Protein Formulation. PRospectivE study of women of Childbearing age with gastrointeStinal Intolerance to Oral Iron (PRECISION), a randomised, prospective, double-blind, double dummy clinical trial.

abstract:
BackgroundIntolerance to oral iron is thought to result in poor adherence and persistence of nutritional deficit amongst women of childbearing age, however few studies have evaluated oral iron intolerance, iron deficiency and anaemia in this setting. Iron-whey protein microspheres (IWP) could help.

MethodsWe documented self-reported oral iron gastrointestinal intolerance, ferritin and haemoglobin levels in a screening study of women of childbearing age. Following a washout period of 16 days, we randomised 59 of these women with iron deficiency, stratified according to the presence of anaemia, to three doses of IWP: (14mg daily, 25mg daily and 50mg daily). We excluded those with established gastrointestinal disease, potential allergy to whey protein and severe anaemia. The primary endpoint was persistence and adherence (>80% based on pill-counts). Secondary endpoints included changes in self-reported oral iron gastrointestinal intolerance, gastro-intestinal symptom rating scale (GSRS), serum iron, serum ferritin, transferrin saturation and haemoglobin levels.

ResultsA total of 128 (62.7%) of the participants had low iron stores (ferritin < 30 {micro}g/L), 65 (31.9%) had moderate to severe iron deficiency (ferritin <12 {micro}g/L) and 33 (16.2%) had iron deficiency anaemia. Amongst 59 women who participated in the prospective study, 48 (81.4%) were classified as adherent/persistent with therapy using IWP compared to 12 (20.3%) taking the prior oral iron p<0.0001. These patients also showed significantly fewer reports of gastrointestinal intolerance with IWP (0.59 {+/-} 0.91) and lower GSRS scores (6.2 {+/-} 7.5) compared to the previous oral iron product (3.98 {+/-} 2.22, and 15.6 {+/-} 9.7 respectively, both P<0.0001). There were no differences in adherence, self-reported adverse GI effects and GSRS between the dose groups during the study. Serum iron levels increased across the whole cohort from 11.3 {+/-} 7.4 mol/L to 20.5{+/-} 11.0 mol/L (P<0.0001), transferrin saturation levels increased from 18.4 {+/-} 13.3 % to 33.6 {+/-} 17.6 % (P<0.0001) and median ferritin levels overall increased from 8.00 [IQR 6.00;13.0] to 15.5 [IQR 9.00;24.2] {micro}g/L at 12 weeks (P=0.0002). Haemoglobin levels increased from 11.36 g/dL (95%CI 10.95 to 11.77) to 12.40 g/dL (95%CI 12.03 to 12.76, P=0.0007) in patients with anaemia and were normalised in most patients taking 50mg IWP daily.

ConclusionsLow iron, iron deficiency and anaemia are common in women of childbearing age with a history of intolerance to oral iron. Patients with low iron (ferritin < 30 {micro}g/L) and moderate to severe iron deficiency (ferritin <12 {micro}g/L) have similar impairment of energy. IWP can improve self-reported oral iron adherence and tolerability as well as iron stores, haemoglobin and tiredness in these women.

category: obstetrics and gynecology


title: COVID-19 vaccination did not improve employee mental health: A prospective study in an early phase of vaccination in Japan

abstract: The effect of the COVID-19 vaccination as an individual-based preventive measure on mental health is largely unclear in the literature. The authors report a preliminary finding on whether vaccination effectively improves mental health among employees in Japan based on a prospective study (E-COCO-J). Of the total sample (N=948), 105 (11.1%) were vaccinated at least once at the follow-up survey (June 2021). There was no significant effect of vaccination on the change of psychological distress at baseline (February 2021) and follow-up (June 2021), after adjusting for gender, age, marital status, education, chronic disease, company size, industry, and occupation (healthcare workers or non-HCWs). Providing continuous mental health care for employees is important in an early vaccination phase.

category: occupational and environmental health


title: Life course circumstances contribute to the acceleration of phenotypic and functional aging in Chinese middle-aged and older adults

abstract: Accelerated aging implies health inequalities in late life and consequently, poses a huge challenge to society. With two well-validated aging measures, this study aimed to evaluate the relative contributions of life course circumstances to variance in these aging measures with policy implications. We assembled data for 6224 middle-aged and older adults ([≥]45 years) who participated in the 2014 life course survey, the 2015 biomarker collection, and the 2015 main survey of the China Health and Retirement Longitudinal Study (CHARLS). Two aging measures, including physiological dysregulation (PD) and frailty index (FI), were calculated. Life course circumstances, i.e., 70 circumstances variables involving childhood and adulthood circumstances, demographics, and behaviors, were categorized into 11 study domains for simplicity. The Shapley value decomposition, hierarchical clustering, and general linear regression models were performed. The Shapley value decomposition revealed that all 11 study domains accounted for about 6.3% and 29.7% of the variance in PD and FI, respectively. We then identified six subpopulations who shared similar patterns in terms of childhood and adulthood circumstances. One subpopulation (i.e., disadvantaged) who reported experiencing more childhood and adulthood adversity consistently exhibited accelerated aging indicated by the two aging measures. We conclude that life course circumstances contribute differently to the acceleration of phenotypic and functional aging in Chinese middle-aged and older adults. Special attention should be given to promoting health for the disadvantaged subpopulation and narrowing their health gap with advantaged counterparts. Our findings highlight the role of life course circumstances in ameliorating health inequalities in late life.

category: geriatric medicine


title: Long-term Stored Platelets Coupled to Thrombospondin-1 Detection for Rapid and Accurate Identification of Pathogenic HIT Antibodies

abstract: Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening disorder characterized by antibodies to Platelet Factor 4 (PF4)-polyanion complexes which cause thrombocytopenia and thrombosis. Currently used technically-simple frontline assays such as the PF4-polyanion enzyme-linked immunosorbent assays (ELISAs) lack specificity, and more accurate functional assays such as the serotonin release assay (SRA) and PF4-dependent P-selectin expression assay (PEA) have long turnaround times due to technical complexity and availability only in the reference laboratory setting. There is a critical need for accurate near-patient functional testing to guide patient management, but a key barrier to attaining this goal is the short-term viability of platelets. Here, we detail a process of platelet cryopreservation that renders them viable for at least one year and show that PF4-treated cryopreserved platelets, when coupled with ELISA-based measurement of thrombospondin-1 release (a platelet -granule protein), detects pathogenic HIT antibodies with high accuracy. Furthermore, testing of a cohort of non-pathogenic HIT antibodies that were strongly reactive in PF4/polyanion ELISA but negative in functional assays demonstrated negative results in the thrombospondin-1 release assay, confirming high specificity of this technique. These findings have the potential to transform the diagnostic testing paradigm in HIT by making in-hospital functional testing available for rapid and accurate diagnosis.

category: hematology


title: Simultaneous detection of SARS-CoV-2 RNA and host antibodies enabled by a multiplexed electrochemical sensor platform

abstract: The current COVID-19 pandemic highlights the continued need for rapid, accurate, and cost-effective point-of-care (POC) diagnostics that can accurately assess an individuals infection and immunity status for SARS-CoV-2. As the virus continues to spread and vaccines become more widely available, detecting viral RNA and serological biomarkers can provide critical insights into the status of infectious, previously infectious, and vaccinated individuals over time. Here, we describe an integrated, low-cost, 3D printed, lab-on-a-chip device that extracts, concentrates, and amplifies viral RNA from unprocessed patient saliva and simultaneously detects RNA and multiple host anti-SARS-CoV-2 antibodies via multiplexed electrochemical (EC) outputs in two hours. The EC sensor platform enables single-molecule CRISPR/Cas-based molecular detection of SARS-CoV-2 viral RNA as well as serological detection of antibodies against the three immunodominant SARS-CoV-2 viral antigens. This study demonstrates that microfluidic EC sensors can enable multiplexed POC diagnostics that perform on par with traditional laboratory-based techniques, enabling cheaper and more widespread monitoring of infection and immunity over time.

category: infectious diseases


title: Lab-on-a-chip multiplexed electrochemical sensor enables simultaneous detection of SARS-CoV-2 RNA and host antibodies


title: A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

abstract:
Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-resistant and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.

One sentence summaryA third booster dose of inactivated vaccine produces a highly sifted humoral immune response via a sustained evolution of antibodies capable of effectively neutralizing SARS-CoV-2 variants of concern.


title: Effectiveness of inactive COVID-19 vaccines against severe illness in B.1.617.2 (Delta) variant-infected patients in Jiangsu, China

abstract: The SARS-CoV-2 B.1.617.2 (Delta) variant has caused a new surge in the number of COVID-19 cases. The effectiveness of vaccines against this variant is not fully understood. Using data from a recent large-scale outbreak of COVID-19 in China, we conducted a real-world study to explore the effect of inactivated vaccine immunization on the course of disease in patients infected with Delta variants. We recruited 476 confirmed cases over the age of 18, of which 42 were severe. After adjusting for age, gender, and comorbidities, patients who received two doses of inactivated vaccine (fully vaccinated) had an 88% reduced risk in progressing to the severe stage (adjusted OR: 0.12, 95% CI: 0.02- 0.45). However, this protective effect was not observed in patients who only received only one dose of the vaccine(adjusted OR: 1.11, 95% CI: 0.51- 2.36). The full immunization offered 100% protection from a severe illness among women. The effect of the vaccine was potentially affected by underlying medical conditions (OR: 0.26, 95% CI: 0.03-1.23). This is the largest real-world study confirming the effectiveness of inactive COVID-19 vaccines against severe illness in Delta variant-infected patients in Jiangsu, China.


title: Personal protective equipment does not sufficiently protect against virus aerosol unless combined with advanced air purification or ventilation techniques

abstract:
BackgroundHealthcare workers (HCWs) are at risk from nosocomial transmission of SARS-CoV-2 from virus laden aerosols. This study aimed to: 1) quantify the degree of protection from virus aerosol provided by different types of mask (surgical, N95, fit-tested N95) and personal protective equipment (PPE); 2) determine if the use of a portable HEPA filter can enhance the effectiveness of PPE; 3) determine the effectiveness of a decontamination shower to remove virus aerosol contamination of a HCW.

MethodsVirus aerosol exposure experiments were conducted using bacteriophage PhiX174 (108copies/mL). A HCW wearing PPE (mask, gloves, gown, faceshield) was exposed to nebulised viruses for 40mins in a sealed clinical room. After exiting, the HCW doffed PPE. Virus exposure was quantified via skin swabs applied to the face and nostrils, forearms, neck, and forehead. Experiments were performed with and without the presence of a portable HEPA filter (set to 470m3/hr).

FindingsSwabs quantified significant virus exposure under the surgical and N95 mask. Only the fit-tested N95 resulted in lower virus counts compared to no mask control (p=0.027). Nasal swabs demonstrated very high virus exposure, which was not mitigated by the surgical or N95 masks, although there was a trend for the fit-tested N95 mask to reduce virus counts (p=0.058). The addition of HEPA filtration substantially reduced virus counts from all swab sites, and to near zero levels when combined with a fit-tested N95 mask, gloves, gown and faces shield. Virus counts were substantially reduced to near zero levels following a shower.

InterpretationThese data demonstrate that quantitatively fit tested N95 masks combined with a HEPA filter can offer protection against high virus aerosol loads at close range and for prolonged periods of time. Skin contamination from virus aerosol can be effectively by removed by showering.

FundingEpworth Hospital Capacity Building Research Grant ID: EH2020-654

category: intensive care and critical care medicine


title: T1DMicro: A Clinical Risk Calculator for Type 1 Diabetes Related Microvascular Complications

abstract:
Development of complications in type-1 diabetes patients can be reduced by modifying risk factors. We used a cross-sectional cohort of 1646 patients diagnosed with type 1 diabetes (T1D) to develop a clinical risk score for diabetic peripheral neuropathy (DPN), autonomic neuropathy (AN), retinopathy (DR), and nephropathy (DN). Of these patients, 199 (12.1%) had DPN, 63 (3.8%) had AN, 244 (14.9%) had DR, and 88 (5.4%) had DN. We selected five variables to include in each of the four microvascular complications risk models: age, age of T1D diagnosis, duration of T1D, and average systolic blood pressure and HbA1C over the last three clinic visits. These variables were selected for their strong evidence of association with diabetic complications in the literature and because they are modifiable risk factors. We found the optimism-corrected R2 and Harrells C statistic were 0.39 and 0.87 for DPN, 0.24 and 0.86 for AN, 0.49 and 0.91 for DR, and 0.22 and 0.83 for DN respectively.

This tool (https://ptran25.shinyapps.io/Diabetic_Peripheral_Neuropathy_Risk) was built to help inform patients of their current risk of microvascular complications and to motivate patients to control their HbA1c and systolic blood pressure in order to reduce their risk of these complications.

category: endocrinology


title: Advanced analysis in epidemiological modeling: Detection of wave

abstract: Some mathematical concepts have been used in the last decades to predict the behavior of spread of infectious diseases. Among them, the reproductive number concept has been used in several published papers for study the stability of the spread. Some conditions were suggested to predict there would be either stability or instability. An analysis was also suggested to determine conditions under which infectious classes will increase or die out. Some authors pointed out limitations of the reproductive number, as they presented its inability to fairly help understand the spread patterns. The concept of strength number and analysis of second derivatives of the mathematical models were suggested as additional tools to help detect waves. In this paper, we aim at applying these additional analyses in a simple model to predict the future.

category: epidemiology


title: A Delay Differential Equation approach to model the COVID-19 pandemic

abstract: SEIR (Susceptible - Exposed - Infected - Recovered) approach is a classic modeling method that has frequently been applied to the study of infectious disease epidemiology. However, in the vast majority of SEIR models and models derived from them transitions from one population group to another are described using the mass-action law which assumes population homogeneity. That causes some methodological limitations or even drawbacks, particularly inability to reproduce observable dynamics of key characteristics of infection such as, for example, the incubation period and progression of the diseases symptoms which require considering different time scales as well as probabilities of different disease trajectories. In this paper, we propose an alternative approach to simulate the epidemic dynamics that is based on a system of differential equations with time delays to precisely reproduce a duration of infectious processes (e.g. incubation period of the virus) and competing processes like transition from infected state to the hospitalization or recovery. The suggested modeling approach is fundamental and can be applied to the study of many infectious disease epidemiology. However, due to the urgency of the COVID-19 pandemic we have developed and calibrated the delay-based model of the epidemic in Germany and France using the BioUML platform. Additionally, the stringency index was used as a generalized characteristic of the non-pharmaceutical government interventions implemented in corresponding countries to contain the virus spread. The numerical analysis of the calibrated model demonstrates that adequate simulation of each new wave of the SARS-CoV-2 virus spread requires dynamic changes in the parameter values during the epidemic like reduction of the population adherence to non-pharmaceutical interventions or enhancement of the infectivity parameter caused by an emergence of novel virus strains with higher contagiousness than original one. Both models may be accessed and simulated at https://gitlab.sirius-web.org/covid-19/dde-epidemiology-model utilizing visual representation as well as Jupyter Notebook.


title: Common and Disorders-Specific Cortical Thickness Alterations in Internalizing, Externalizing and Thought Disorders in the Preadolescents of the ABCD Study

abstract: Overlap of brain changes across mental disorders has reinforced transdiagnostic models. However, the developmental basis for this overlap is unclear as are neural differences among internalizing, externalizing and thought disorders. These issues are critical to inform the theoretical framework for hierarchical transdiagnostic psychiatric taxonomy. We examined cortical thickness (CT) difference between healthy controls (n=4041) and patients with externalizing (n=1182), internalizing (n=1959) and thought (n=347) disorders in preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study using linear mixed models. Genome-wide association analysis and cell type specificity analysis were performed on regional CT across 4,716 unrelated European youth. We found that youth with externalizing or internalizing disorders, but not thought disorders, exhibited significantly thicker cortex than controls. Externalizing and internalizing disorders shared thicker CT in left pars opercularis and caudal middle frontal gyrus related to lower cognitive performance. Somatosensory and primary auditory cortex were uniquely affected in externalizing disorders; primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only group of externalizing disorders demonstrated significant CT increase than controls at 2-year follow-up and decelerated cortical thinning from 10 to 12 years old. At genetic level, genes associated with CT in common and disorders-specific regions were also implicated in related diagnostic families. Microglia were the cell-type associated with CT for both externalizing/internalizing while dopaminergic/glutamatergic/GABAergic cells related only to externalizing-specific regions. These results showed that distinct anatomical trajectories relevant to internalizing/externalizing phenotypes may result from unique genetic and cell-type changes, but these occur in the background of significantly shared morphological variance.

category: psychiatry and clinical psychology


title: Common and Disorders-Specific Cortical Thickness Alterations in Internalizing, Externalizing and Thought Disorders over a 2-year Period in the Preadolescents of the ABCD Study


title: A Cross-sectional Study on Perceived Workplace Health Support and Health-Related Quality of Life

abstract:
ObjectiveMany companies in Japan have been increasingly interested in "health and productivity management (H&PM)." In terms of H&PM, we supposed that companies can enhance their employees perceived workplace health support (PWHS) by providing support for workers lively working and healthy living. This could then improve health-related QOL (HRQOL) by increasing PWHS. This study explored the relationship between PWHS and health-related quality of life (HRQOL).

MethodsDuring the COVID-19 pandemic in December 2020, we conducted an Internet-based nationwide health survey of Japanese workers (CORoNaWork study). A database of 27,036 participants was created. The question regarding the intensity of PWHS was measured using a four-point Likert scale. We used a linear mixed model (LMM) to analyze the relationship between the intensity of PWHS and the four domains of CDC HRQOL-4 (self-rated health, number of poor physical health days, number of poor mental-health days, and activity limitation days during the past 30 days).

ResultsIn the sex- and age-adjusted and multivariate models, the intensity of PWHS had a main effect on self-rated health and the three domains of unhealthy days (physical, mental, activity limitation). There was also a trend toward worse HRQOL scores as the PWHS decreased.

ConclusionsThis study aimed to document the relationship between PWHS and HRQOL. We found that the higher the PWHS of Japanese workers, the higher their self-rated health and the lower their unhealthy days. Companies need to assess workers PWHS and HRQOL and promote H&PM. H&PM is also necessary to maintain and promote the health of workers during the COVID-19 pandemic.


title: Immunogenicity and Safety of the inactivated SARS-CoV-2 vaccine (BBIBP-CoV) in patients with malignancy

abstract:
ObjectivePatients with malignancy suffer from a compromised immune system due to either the effects of malignancies or treatments. Cancer patients are at higher risk of different infections particularly SARS-CoV2 and usually produce weaker response to vaccines. The aim of this study was to evaluate the safety and immunogenicity of the inactivated SARS-CoV-2 vaccine (Sinopharm, BBIBP-CorV) in patients with malignancy.

Material and MethodIn total 364 patients with cancer (median age: 54 years old, F/M ratio: 217/147) who received two doses of Sinopharm vaccine were enrolled in this study. Vaccine related side effects was assessed by a questionnaire and the presence of SARS-CoV-2 anti-Spike protein (S) IgG and neutralizing antibody two months following vaccination were measured by immunological methods.

ResultsInjection site pain and fever were the most common local and systemic side effects in vaccine receivers. Two months after the first dose, anti-S IgG and neutralizing antibody were detectable in 77.1% and 80.7% of all participants, respectively with an overall response to either or both measured in 86.9% of patients The rate of seroconversion was lower in older age, those with hematological malignancies and chemotherapy receivers.

ConclusionThe result of study confirmed the safety and short-term efficacy of Sinopharm inactivated vaccine (BBIBP-CorV) in patients with different type of malignancies.

category: oncology


title: Immunogenicity and Safety of the inactivated SARS-CorV-2 vaccine (BBIBP-CoV) in patients with malignancy


title: Using multivariate models to examine the impact of COVID-19 pandemic and gender differences on health and health care

abstract:
ObjectiveTo examine the effect of the COVID-19 pandemic, the effect of sex, and the joint effect of sex and the COVID-19 pandemic in relation to health communication, physical activity, mental health, and behavioral health.

MethodsWe drew data from the National Cancer Institutes 2020 Health Information National Trends Survey (HINTS). We described and compared the characteristics of social determinants of health, physical activity, mental health, alcohol use, patterns of social networking service use, and health information data sharing. Analyses were weighted to provide nationally representative estimates. Multivariate models (multiple linear regression, multiple logistic regression, and multinomial logistic model) were used to assess the sole and joint effect of sex and pandemic. In addition, we applied the Bonferroni correction to adjust p-values to decrease the risks of type I errors when making multiple statistical tests.

ResultsWomen are more likely to use mobile health and health communication technologies. The effect of sex after the COVID-19 pandemic is significant on mental health, and women are more possible to have depression or anxiety disorders. The effect of sex is also significant before and after the pandemic regarding seeking health or medical information. Women have a smaller quantity and intensity of physical activity, which has a negative effect on health.

ConclusionGender differences exist regardless of the COVID-19 pandemic and the pandemic amplifies the differences in some health and health care domains. Intersectional gender analyses are integral to addressing issues that arise and mitigating the exacerbation of inequities. Responses to the pandemic should consider diverse perspectives, including sex and gender.

category: health informatics


title: Classification of Functional Movement Disorders with Resting State fMRI

abstract: Functional movement disorder (FMD) is a type of functional neurological disorder characterized by abnormal movements that patients do not recognize as self-generated. Prior imaging studies show a complex pattern of altered activity, linking regions of the brain involved in emotional responses, motor control, and agency. This study aimed to better characterize these relationships by building a classifier via support vector machine (SVM) to accurately classify 61 FMD patients from 59 healthy controls using features derived from resting state functional MRI (rs-fMRI). First, we selected 66 seed regions based on prior related studies, then calculated the full correlation matrix between them, before performing recursive feature elimination to winnow the feature set to the most predictive features and building the classifier. We identified 29 features of interest that were highly predictive of FMD condition, classifying patients from controls with 80% accuracy. The features selected by the model highlight the importance of the interconnected relationship between areas associated with emotion, reward and sensorimotor integration, potentially mediating relationships between regions associated with motor function, attention and executive function. Exploratory machine learning was able to identify this distinctive, abnormal pattern, suggesting that alterations in functional linkages between these regions may be a consistent feature of the condition in many FMD patients.

category: neurology


title: Heterogeneity of recurrences in rectal cancer: application of population models facilitates personalized medicine

abstract:
Due to heterogeneity in presentation and outcome, patients with metastatic disease cannot be considered a single group. The timing, location and combinations of recurrences determine the feasibility of treatment of the individual patient in an era in which the options for local and systemic treatment have expanded. Studies investigating this complexity are hampered by the lack of both large cohorts and adequate methods.

In a well-defined cohort of rectal cancer patients from a randomized clinical trial, with long standardized follow-up, we applied spatial projection models derived from population ecology to overcome the complexity problem. We describe the recurrence patterns in detail and performed stochastic simulation experiments resulting in 1.5 million evaluable patients. The risk of subsequent recurrences was dependent on the presentation of the first recurrent event and decreased with increasing recurrence-free interval. The risk of local recurrence for the median patient (65.8 years, pT3 adenocarcinoma) was threefold increased after the development of rare metastases. The risk of development of rare metastases was increased after the development of other extrahepatic metastases.

Our cross-disciplinary approach delivers insights allowing for the development of personalized strategies for (local) treatment of recurrent disease, as well as for surveillance strategies that may potentially impact large patient cohorts. In this proofof-principle study we demonstrate the feasibility of spatial projection models for cancer research.


title: Effects of Dipeptidyl Peptidase-4 Inhibitors and Sulfonylureas on Cognitive and Physical Function in Nursing Home Residents

abstract:
AimsDipeptidyl peptidase-4 inhibitors (DPP4Is) may mitigate hypoglycemia-mediated declines in cognitive and physical functioning compared to sulfonylureas (SUs), yet comparative studies are unavailable among older adults, especially nursing home (NH) residents. We evaluated the effects of DPP4Is versus SUs on cognitive and physical functioning among NH residents.

Materials and MethodsThis new-user cohort study included long-stay NH residents aged [≥]65 years from the 2007-2010 national US Minimum Data Set (MDS) clinical assessments and linked Medicare claims. We measured cognitive decline from the validated 6-point MDS Cognitive Performance Scale, functional decline from the validated 28-point MDS Activities of Daily Living scale, and hospitalizations or emergency department visits for altered mental status from Medicare claims. We compared 180-day outcomes in residents who initiated a DPP4I versus SU after propensity score matching using Cox regression models.

ResultsThe cohort (N=1,784) had a mean (SD) age of 80 (8) years and was 73% female. Approximately 46% had no or mild cognitive impairment and 35% had no or mild functional impairment before treatment initiation. Compared to SU users, DPP4I users had statistically similar 180-day rates of cognitive decline (HR=0.61, 95%CI 0.31-1.19), altered mental status events (HR=0.71, 95%CI 0.39-1.27), and functional decline (HR=0.89, 95%CI 0.51-1.56).

ConclusionsRates of cognitive and functional decline were not markedly reduced among DPP4I users compared to SU users, but the point estimates and lower 95% confidence bounds do not rule out the possibility that DPP4Is result in reduced rates. Larger studies with greater statistical power should resolve this remaining uncertainty.


title: Differences in Skilled Nursing Facility Characteristics and Quality Ratings by Long-Term Care Pharmacy Provider

abstract:
ObjectivesLimited data exist on the U.S. long-term care (LTC) pharmacy market and how skilled nursing facilities (SNFs) may differ by LTC pharmacy provider. We estimated the market shares of two major LTC pharmacies (Omnicare and PharMerica) and assessed if SNF characteristics differ by pharmacy.

DesignCross-sectional.

Setting and ParticipantsSeventy-five Rhode Island (RI) SNFs that provided post-acute care (PAC) services in 2019.

MethodsSNF location, structure, staffing measures, and quality ratings were ascertained from publicly available data sources. The LTC pharmacy used by each SNF was compiled by case managers at a RI health system.

ResultsAmong 75 SNFs, 32 (43%) were served by Omnicare and 36 (48%) by PharMerica. LASSO logistic regression and random forest models identified 5 key predictors of SNFs selecting PharMerica over Omnicare: number of skilled beds, total number of beds, nursing hours per resident per day, five-star health inspection rating, and average number of residents per day. In a multivariable regression model including 4 predictors (total number of beds excluded due to collinearity), SNFs had a 6% higher prevalence of using Omnicare over PharMerica for every additional 10 skilled beds (Prevalence Ratio 1.06, 95% CI 1.02-1.10).

Conclusions and ImplicationsOmnicare and PharMerica comprised over 90% of the SNF PAC market in RI, with Omnicare covering larger facilities. Understanding if these companies serve a similar proportion of SNFs in other U.S. states is necessary to advance future research initiatives and examine how collaborations between SNFs and LTC pharmacy chains may improve medication management in SNFs.

Brief SummaryTwo pharmacies may comprise over 90% of the skilled nursing facility post-acute care market. This market concentration may represent a prime opportunity to efficiently improve medication management.

category: health systems and quality improvement


title: Taking a participatory research approach within workplace health promotion research to improve physical activity levels in office-based workers: a scoping review protocol

abstract:
IntroductionPhysical activity (PA) workplace health promotion (WHP) interventions have traditionally utilised a top-down research approach at an individual level where participants are considered as passive subjects. Whereas participatory research involves the participants and relevant stakeholders within the research process utilising a bottom-up approach which focuses on the health priorities of the participants and allows the integration of the researchers expertise and the end-users lived experiences, which has been shown to aid in the acceptability and relevance of the research.

This protocol describes a scoping review which will explore, identify and map participatory research techniques and their impact when utilised in office based WHP interventions designed to improve PA levels and/or decrease sitting time. Providing an overview of key characteristics of WHP interventions which took a participatory research approach.

Methods and analysisThis scoping review will follow the guidelines and framework from the PRISMA-ScR. Articles will be retrieved via five databases: Web of Science, PubMED, Scopus, Google Scholar and OpenGrey. A search strategy was piloted, and relevant review articles search strategies were explored, to identify appropriate key words and MeSH terms. Two independent reviewers will screen retrieved articles based on our inclusion and exclusion criteria by title and abstract first, followed by the full text. Any discrepancies will be discussed until a consensus is reached. Data will be extracted, charted and summarised via a narrative synthesis and qualitative analyses.

Ethics and disseminationEthical approval was not required or obtained for this scoping review. The completed scoping review findings will be disseminated in a peer-reviewed journal which has a research scope that encompasses participatory research and health promotion. The findings will be presented at appropriate academic conferences and to project partners to inform the design of a WHP intervention.

Strengths and limitations of this studyO_LIThe proposed scoping review will explore and map the current participatory research techniques and approaches taken when completing an office-based workplace health promotion intervention designed to increase physical activity.
C_LIO_LIThe scoping review by nature and the search strategy proposed will allow for a wide breadth of literature to be explored.
C_LIO_LIThere is no critical appraisal or quality assessment of the included studies which is typical of a systematic review but not of a scoping review or the aim of this review article.
C_LIO_LIThis scoping review has a narrow focus on physical activity and may limit/exclude articles aiming to improve psychological wellbeing or work performance.
C_LI


title: National Population-Level Disparities in COVID-19 Mortality Across the Intersection of Race/Ethnicity and Sex in the United States

abstract: Males and certain racial/ethnic minority groups have borne a disproportionate burden of COVID-19 mortality in the United States, and substantial scientific research has sought to quantify and characterize population-level disparities in COVID-19 mortality outcomes by sex and across categories of race/ethnicity. However, there has not yet been a national population-level study to quantify disparities in COVID-19 mortality outcomes across the intersection of these demographic dimensions. Here, we analyze a publicly available dataset from the National Center for Health Statistics comprising COVID-19 death counts stratified by race/ethnicity, sex, and age for the year 2020, calculating mortality rates for each race/ethnicity-sex-age stratum and age-adjusted mortality rates for each race/ethnicity-sex stratum, quantifying disparities in terms of mortality rate ratios and rate differences. Our results reveal persistently higher COVID-19 age-adjusted mortality rates for males compared to females within every racial/ethnic group, with notable variation in the magnitudes of the sex disparity by race/ethnicity. However, non-Hispanic Black, Hispanic, and non-Hispanic American Indian or Alaska Native females have higher age-adjusted mortality rates than non-Hispanic White and non-Hispanic Asian/Pacific Islander males. Moreover, persistent racial/ethnic disparities are observed among both males and females, with higher COVID-19 age-adjusted mortality rates observed for non-Hispanic Blacks, Hispanics, and non-Hispanic American Indian or Alaska Natives relative to non-Hispanic Whites.


title: How Informative were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov

abstract:
BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

category: medical ethics


title: How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov


title: Large-scale proteome analysis of CSF implicates altered glucose metabolism in Alzheimer's disease

abstract: A major hallmark of Alzheimers disease (AD) is the aggregation of misfolded proteins ({beta}-amyloid (A) and hyperphosphorylated tau (T)) in the brain. As these proteins can be monitored by cerebrospinal fluid (CSF) measures, the AD proteome in CSF has been of particular interest. Here, we conducted a proteome-wide assessment of the CSF in an AD cohort among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), identifying a diverse set of proteins in the CSF enriched for extracellular and immune system processes. We then interrogated the proteome using the amyloid, tau, and neurodegeneration (ATN) framework of AD and a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. After multiple testing correction, we identified a total of 61 proteins significantly associated with AT group (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25) across all measures except for interleukin-6, which had no significantly associated proteins. Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks: one related to amyloid and tau measures, one to CSF neurogranin, and one to the remaining CSF biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were replicated as strongly associated with AD (P = 1.07 x 10-19 and P = 7.43 x 10-14, respectively) in an independent CSF proteomics cohort (n = 717 participants). Comparative performance of the CSF proteome in predicting AT categorization was high (mean AUC range 0.891-0.924 with number of protein predictors ranging from 37-97) relative to other omic predictors from the genome, CSF metabolome, and demographics from the same cohort of individuals. Collectively, these results emphasize the importance of the CSF proteome relative to other omics and implicate glucose metabolic dysregulation as amyloid and tau pathology emerges in AD.


title: The association between SARS-CoV-2 infection and neuronal damage: A population-based nested case-control study

abstract:
ObjectiveTo assess whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with changes in plasma levels of neurofilament light chain (NfL), an extremely sensitive marker of neuroaxonal damage, in community-dwelling individuals.

SettingThis study was embedded within the Rhineland Study, an ongoing community-based cohort study in Bonn, Germany

DesignCross-sectional nested case-control study.

ParticipantsParticipants were selected based on results from a previously conducted seroprevalence survey within the framework of the Rhineland Study. Cases were defined as those individuals who had had two positive confirmatory test results, including a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (N=21). As controls, a random sample of individuals with a negative ELISA test result (Controls I, N=1117), and those with a borderline or positive ELISA test result who failed confirmatory testing (Controls II, N=68), were selected.

Outcome measuresPlasma levels of NfL at the time of measurement, as well as change in plasma NfL levels compared to previously measured pre-pandemic levels

ResultsAfter adjustment for age, sex and batch effects, serologically confirmed SARS-CoV-2 infection was neither associated with cross-sectional NfL levels, nor with the magnitude of change from pre-pandemic levels, compared to either of the two control groups. Similarly, after adjustment for age, sex and batch effects, self-reported neurological symptoms - including altered sense of smell or taste, headache, myalgia and fever - were not associated with changes in NfL levels in participants with a serologically confirmed SARS-CoV-2 infection (all p [≥] 0.56).

ConclusionsOur findings indicate that mild-to-moderate coronavirus disease-19 is unlikely to be associated with a clinically relevant degree of neuroaxonal damage, even in those cases associated with neurological symptoms.


title: Artificial Intelligence in Dry Eye Disease

abstract: Dry eye disease (DED) has a prevalence of between 5 and 50%, depending on the diagnostic criteria used and population under study. However, it remains one of the most underdiagnosed and undertreated conditions in ophthalmology. Many tests used in the diagnosis of DED rely on an experienced observer for image interpretation, which may be considered subjective and result in variation in diagnosis. Since artificial intelligence (AI) systems are capable of advanced problem solving, use of such techniques could lead to more objective diagnosis. Although the term  AI is commonly used, recent success in its applications to medicine is mainly due to advancements in the sub-field of machine learning, which has been used to automatically classify images and predict medical outcomes. Powerful machine learning techniques have been harnessed to understand nuances in patient data and medical images, aiming for consistent diagnosis and stratification of disease severity. This is the first literature review on the use of AI in DED. We provide a brief introduction to AI, report its current use in DED research and its potential for application in the clinic. Our review found that AI has been employed in a wide range of DED clinical tests and research applications, primarily for interpretation of interferometry, slit-lamp and meibography images. While initial results are promising, much work is still needed on model development, clinical testing and standardisation.

category: ophthalmology


title: Validation of HER2 status in whole genome sequencing data of breast cancers with AI-driven, ploidy-corrected approach

abstract:
The HER2 protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, prediction, and prognostics. The availability of HER2-inhibitors in routine clinical practice directly translates into the diagnostic need for precise and robust marker identification.

At the brink of the genomic era, multigene next-generation sequencing methodologies slowly take over the field of single-biomarker molecular and cytogenetic tests. However, copy number alterations such as amplification of the HER2-coding ERBB2 gene, are certainly harder to validate as an NGS biomarker than simple SNV mutations. They are characterized by several compound genomic factors i.a. structural heterogeneity, dependence on chromosome count and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of NGS panels to robustly and accurately determine HER2 status in clinical setup. Based on the large dataset of 877 breast cancer patients genomes with curated clinical data and a machine learning approach for optimization of an unbiased diagnostic classifier, we provide a reliable algorithm of HER2 status assessment.

category: genetic and genomic medicine


title: Impact of Stratified Interventions in University Reopenings

abstract: More than 4,000 colleges and universities in the U.S. are scheduled to start a new semester in August or September, 2021. Many colleges require Covid-19 vaccination, as well as some combination of face coverings or diagnostic testing, while others do not (in some cases due to governance structure). Large state universities may especially have limitations and are not requiring vaccination, testing, or indoor face coverings, nor offering hybrid classes (to promote physical distancing). Group living quarters or classrooms with densely packed students are among the riskiest settings for infectious disease spread.


title: Comparative quantitative analysis of SARS-CoV-2 Spike neutralizing antibody titers following  two anti COVID-19 vaccines in India

abstract: In COVID 19 Pandemic,first line of defence is effective vaccination program.Because of multiple platforms available for vaccine production we tested relative immunogenicity of two vaccines available in India, Covaxin(R) and Covishield(R) We performed quantitative analysis of neutralizing antibodies to SARS Cov2 spike (receptor binding domain) protein, from sera of 53 subjects who completed vaccines schedules.There was significantly higher immunogenic response with Covishield(R) as compared to Covaxin(R) and are independent of age. Studies on a large scale with long term follow up are needed to further advance the knowledge in this domain.


title: The comparability of Anti-Spike SARS-CoV-2 antibody tests is time-dependent: a prospective observational study

abstract:
ObjectivesVarious commercial anti-Spike SARS-CoV-2 antibody tests are used for studies and in clinical settings after vaccination. An international standard for SARS-CoV-2 antibodies has been established to achieve comparability of such tests, allowing conversions to BAU/ml. This study aimed to investigate the comparability of antibody tests regarding the timing of blood collection after vaccination.

MethodsFor this prospective observational study, antibody levels of 50 participants with homologous AZD1222 vaccination were evaluated at 3 and 11 weeks after the first dose and 3 weeks after the second dose using two commercial anti-Spike binding antibody assays (Roche and Abbott) and a surrogate neutralization assay.

ResultsThe correlation between Roche and Abbott changed significantly depending on the time point studied. Although 3 weeks after the first dose, Abbott provided values three times higher than Roche, 11 weeks after the first dose, the values for Roche were twice as high as for Abbott, and 3 weeks after the second dose even 5-6 times higher.

ConclusionsThe comparability of quantitative anti-Spike SARS-CoV-2 antibody tests is highly dependent on the timing of blood collection after vaccination. Therefore, standardization of the timing of blood collection might be necessary for the comparability of different quantitative SARS-COV-2 antibody assays.

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title: No difference in risk of hospitalisation between reported cases of the SARS-CoV-2 Delta variant and Alpha variant in Norway

abstract:
ObjectivesTo estimate the risk of hospitalisation among reported cases of the Delta-variant of SARS-CoV-2 compared to the Alpha variant in Norway. We also estimated the risk of hospitalisation by vaccination status.

MethodsWe conducted a cohort study on laboratory-confirmed cases of SARS-CoV-2 in Norway, diagnosed between 3 May and 15 August 2021. We calculated adjusted risk ratios (aRR) with 95% confidence intervals (CIs) using multivariable binomial regression, accounting for variant, vaccination status, demographic characteristics, week of sampling and underlying comorbidities.

ResultsWe included 7,977 cases of Delta and 12,078 cases of Alpha. Overall, 347 (1.7%) cases were hospitalised. The aRR of hospitalisation for Delta compared to Alpha was 0.97 (95%CI 0.76-1.23). Partially vaccinated cases had a 72% reduced risk of hospitalisation (95%CI 59%-82%), and fully vaccinated cases had a 76% reduced risk (95%CI 61%-85%), compared to unvaccinated cases.

ConclusionsWe found no difference in the risk of hospitalisation for Delta cases compared to Alpha cases in Norway. Further research from a wide variety of settings is needed to better understand the association between the Delta variant and severe disease. Our results support the notion that partially and fully vaccinated persons are highly protected against hospitalisation with COVID-19.

HighlightsO_LIThe SARS-CoV-2 Delta variant has dominated in Norway since July 2021
C_LIO_LIThere was no difference in the risk of hospitalisation for Delta cases compared to Alpha
C_LIO_LIPartially and fully vaccinated cases had >70% decreased risk of hospitalisation
C_LI


title: MITIGATING THE 4th WAVE OF THE COVID-19 PANDEMIC IN ONTARIO

abstract:
BackgroundThe goal of this study was to project the number of COVID-19 cases and demand for acute hospital resources for Fall of 2021 in a representative mid-sized community in southwestern Ontario. We sought to evaluate whether current levels of vaccine coverage and contact reduction could mitigate a potential 4th wave fueled by the Delta variant, or whether the reinstitution of more intense public health measures will be required.

MethodsWe developed an age-stratified dynamic transmission model of COVID-19 in a mid-sized city (population 500,000) currently experiencing a relatively low, but increasing, infection rate in Step 3 of Ontarios Wave 3 recovery. We parameterized the model using the medical literature, grey literature, and government reports. We estimated the current level of contact reduction by model calibration to cases and hospitalizations. We projected the number of infections, number of hospitalizations, and the time to re-instate high intensity public health measures over the fall of 2021 under different levels of vaccine coverage and contact reduction.

ResultsMaintaining contact reductions at the current level, estimated to be a 17% reduction compared to pre-pandemic contact levels, results in COVID-related admissions exceeding 20% of pre-pandemic critical care capacity by late October, leading to cancellation of elective surgeries and other non-COVID health services. At high levels of vaccination and relatively high levels of mask wearing, a moderate additional effort to reduce contacts (30% reduction compared to pre-pandemic contact levels), is necessary to avoid re-instating intensive public health measures. Compared to prior waves, the age distribution of both cases and hospitalizations shifts younger and the estimated number of pediatric critical care hospitalizations may substantially exceed 20% of capacity.

DiscussionHigh rates of vaccination coverage in people over the age of 12 and mask wearing in public settings will not be sufficient to prevent an overwhelming resurgence of COVID-19 in the Fall of 2021. Our analysis indicates that immediate moderate public health measures can prevent the necessity for more intense and disruptive measures later.


title: Expected Rates of Select Adverse Events following Immunization for COVID-19 Vaccine Safety Monitoring

abstract:
BackgroundKnowledge of expected rates of potential adverse events of special interest (AESI) that may occur coincidentally following COVID-19 vaccination is essential for vaccine safety surveillance and assessment. We calculated the expected rates of 21 potential AESI following COVID-19 vaccination among vaccinated persons within 1 day, 7 days, and 42 days of vaccination.

MethodsWe used meta-analytic methods to estimate background rates of 21 medical conditions considered potential AESI and calculated expected rates of each potential AESI within 1 day, 7 days, and 42 days of vaccination.

ResultsBackground rates of three commonly monitored AESI, Guillain-Barre syndrome (GBS), myopericarditis, and all-cause deaths were 2.0 GBS cases/100,000 person-years, 1.3 myopericarditis cases/100,000 person-years, and 863.8 all-cause deaths/100,000 person-years, respectively. Based on these background rates, if 10,000,000 persons are vaccinated, we would expect 0.5, 3.7, and 22.5 GBS cases; 0.3, 2.4, and 14.3 myopericarditis cases; and 236.5, 1655.5, and 9932.8 all-cause deaths to occur in coincident temporal association (i.e., as a result of background incidence) within 1 day, 7 days, and 42 days of vaccination, respectively.

ConclusionKnowledge of expected rates of potential AESI can help contextualize adverse health events associated temporally with immunization, aid in safety signal detection, guide COVID-19 vaccine public health communication, and inform benefit-risk assessments of COVID-19 vaccines.


title: Monitoring populations at increased risk for SARS-CoV-2 infection in the community

abstract:
BackgroundThe COVID-19 pandemic is rapidly evolving, with emerging variants and fluctuating control policies. Real-time population screening and identification of groups in whom positivity is highest could help monitor spread and inform public health messaging and strategy.

MethodsTo develop a real-time screening process, we included results from nose and throat swabs and questionnaires taken 19 July 2020-17 July 2021 in the UKs national COVID-19 Infection Survey. Fortnightly, associations between SARS-CoV-2 positivity and 60 demographic and behavioural characteristics were estimated using logistic regression models adjusted for potential confounders, considering multiple testing, collinearity, and reverse causality.

FindingsOf 4,091,537 RT-PCR results from 482,677 individuals, 29,903 (0{middle dot}73%) were positive. As positivity rose September-November 2020, rates were independently higher in younger ages, and those living in Northern England, major urban conurbations, more deprived areas, and larger households. Rates were also higher in those returning from abroad, and working in healthcare or outside of home. When positivity peaked December 2020-January 2021 (Alpha), high positivity shifted to southern geographical regions. With national vaccine roll-out from December 2020, positivity reduced in vaccinated individuals. Associations attenuated as rates decreased between February-May 2021. Rising positivity rates in June-July 2021 (Delta) were independently higher in younger, male, and unvaccinated groups. Few factors were consistently associated with positivity. 25/45 (56%) confirmed associations would have been detected later using 28-day rather than 14-day periods.

InterpretationPopulation-level demographic and behavioural surveillance can be a valuable tool in identifying the varying characteristics driving current SARS-CoV-2 positivity, allowing monitoring to inform public health policy.

FundingDepartment of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.


title: Clinical validity of single-gene non-invasive prenatal testing for sickle cell disease and beta thalassemia

abstract:
BackgroundSickle cell disease (SCD) and beta thalassemia ({beta}-thalassemia) are among the most common and severe genetically inherited disorders in the world. Although the maternal carrier status of these beta hemoglobinopathies is screened as a part of routine prenatal care in the US, the paternal carrier status is usually unavailable. Under this current screening paradigm, identification of the majority of SCD and beta thalassemia cases could therefore be delayed until newborn screening results are available. An effective reflex, non-invasive prenatal test (NIPT) that uses only maternal blood would permit prenatal detection of sickle cell disease and beta thalassemia by screening for these disorders without the need for paternal DNA. This screening would enable patients and healthcare providers to make informed decisions about diagnostic testing, and it could expand gene therapy treatment options by requesting cord blood banking at delivery. We have previously developed a single-gene NIPT platform (UNITY) for SCD and beta thalassemia with extensive analytic validation and initial clinical validation in our prior studies.

ObjectivesThe objective of this study is to further assess the clinical validity of single-gene NIPT for SCD and beta thalassemia in a larger pregnancy population.

Study DesignPregnant women who screened positive for at least one allele of a beta hemoglobinopathy were enrolled at two academic medical centers for this retrospective cohort study. Single-gene NIPT for SCD and beta thalassemia was performed in blinded fashion on maternal blood samples to determine the fetal genotype and disease status. Single-gene NIPT findings were compared with either newborn screen results or genotyping of umbilical cord blood.

ResultsSingle-gene NIPT detection of fetuses that are affected versus unaffected with SCD and beta thalassemia was 100% concordant with newborn screening follow-up data, even in challenging samples that contained a low fetal fraction (<5%) or at earlier gestational ages. Additionally, we obtained 98.5% concordance with newborn genotypes, including differentiating healthy fetal sickle cell carriers from homozygous healthy fetuses. The sensitivity of detecting fetal carrier status of beta hemoglobinopathies was 100% (90.8% to 100% CI), and the specificity was 96.4% (81.7% to 99.9 % CI).

ConclusionsSingle-gene NIPT is a highly accurate screen for prenatal detection of SCD and beta thalassemia. The results further suggest that the maternal carrier screen with reflex single-gene NIPT workflow can significantly improve the detection rates of at-risk pregnancies from <50% to >98%.

AJOG at a GlanceA. Why was this study conducted?Effective non-invasive prenatal testing (NIPT) is needed to permit safe in utero diagnosis of sickle cell disease (SCD) and beta thalassemia ({beta}-thalassemia), and permit collection and banking of cord blood for future cell therapy. We have previously developed a single-gene NIPT method for SCD and {beta}-thalassemia, with extensive analytic validation and initial clinical validation in our prior studies.

B. What are the key findings?Our single-gene NIPT detection of SCD and {beta}-thalassemia disease was 100% concordant with newborn screening follow-up data in 79 pregnancies at risk for beta hemoglobinopathies. Furthermore, a more stringent requirement, the detection of exact fetal genotype, was concordant in 67 out of 68 (98.5%) of pregnancies.

C. What does this study add to what is already known?Our results validated that single-gene NIPT is an accurate and significantly improved screen for prenatal detection of SCD and {beta}-thalassemia compared to current carrier screen workflow.


title: Efficacy versus abundancy: which vaccination schemes can better prohibit deaths and active infections?

abstract:
In this paper, we introduce a general novel compartmental model accounting for the effects of vaccine efficacy, deployment rates and timing of initiation of deployment. It consists of compartments corresponding to susceptible, vaccinated susceptible, infectious, vaccinated infectious, active, and dead populations with various vaccine efficacies and vaccination deployment rates.

We simulate different scenarios and initial conditions, and we find that the abundance and higher rate of deployment of low efficacy vaccines would lower the cumulative number of deaths in comparison to slower deployment of high efficacy vaccines. However, the latter can lower the number of active cases and achieve faster and higher herd immunity. We also forecast that, at the same daily deployment rate, the earlier introduction of vaccination schemes with lower efficacy would also lower the number of deaths with respect to a delayed introduction of high efficacy vaccines, which can however, still achieve lower numbers of infections and better herd immunity.


title: Elevation of Neurodegenerative Serum Biomarkers among Hospitalized COVID-19 Patients

abstract:
INTRODUCTIONOlder adults hospitalized with COVID-19 are susceptible to neurological complications, particularly encephalopathy, which may reflect age-related neurodegenerative processes.

METHODSSerum total tau, ptau-181, GFAP, NFL, UCHL1, and amyloid-beta(A{beta}-40,42) were measured in hospitalized COVID-19 patients without a history of dementia, and compared among patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions using multivariable Cox proportional hazards regression analyses.

RESULTSAmong 251 patients, admission serum ptau-181 and UCHL1 were significantly elevated in patients with encephalopathy (both P<0.05) and total tau, GFAP, and NFL were significantly lower in those discharged home(all P<0.05). These markers correlated significantly with severity of COVID illness. NFL, GFAP and UCH-L1 were significantly higher in hospitalized COVID patients than in non-COVID controls with mild cognitive impairment or Alzheimers disease(AD).

DISCUSSIONAge-related neurodegenerative biomarkers were elevated to levels observed in AD and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.


title: Insights from complex trait fine-mapping across diverse populations

abstract: Despite the great success of genome-wide association studies (GWAS) in identifying genetic loci significantly associated with diseases, the vast majority of causal variants underlying disease-associated loci have not been identified1-3. To create an atlas of causal variants, we performed and integrated fine-mapping across 148 complex traits in three large-scale biobanks (BioBank Japan4,5, FinnGen6, and UK Biobank7,8; total n = 811,261), resulting in 4,518 variant-trait pairs with high posterior probability (> 0.9) of causality. Of these, we found 285 high-confidence variant-trait pairs replicated across multiple populations, and we characterized multiple contributors to the surprising lack of overlap among fine-mapping results from different biobanks. By studying the bottlenecked Finnish and Japanese populations, we identified 21 and 26 putative causal coding variants with extreme allele frequency enrichment (> 10-fold) in these two populations, respectively. Aggregating data across populations enabled identification of 1,492 unique fine-mapped coding variants and 176 genes in which multiple independent coding variants influence the same trait (i.e., with an allelic series of coding variants). Our results demonstrate that fine-mapping in diverse populations enables novel insights into the biology of complex traits by pinpointing high-confidence causal variants for further characterization.


title: Ideology, policy decision-making and environmental impact in the face of the Coronavirus pandemic in the US

abstract: Covid-19 pandemic was a challenge for the health systems of many countries. It altered peoples way of life and shocked the world economy. In the United States, political ideology has clashed with the fight against the pandemic. President Trumps denial prevailed despite the warnings from the WHO and scientists who alerted of the seriousness of the situation. Despite this, some state governments did not remain passive in the absence of federal government measures, and passed laws restricting mobility (lockdowns). Consequently, the political polarity was accentuated. On the one hand, the defenders of more severe public health measures and, on the other, the advocates of individual rights and freedom above any other consideration. In this study, we analyze whether political partisanship and the political ideology has influenced the way Covid-19 was handled at the outbreak. Specifically, we analyze by using a Diff-in-Diff model, whether the ideology of each state, measure at three levels, affected the decrease in the NO2 levels observed after the pandemic outbreak in the US. We distinguish three alternative post-Covid periods and results show that the State ideology has a robust negative impact on the NO2 levels. There is an important difference between Democratic and Republican states, not just in the scope and following-up of the mobility and activity restrictions, but also in the speed they implemented them.

category: health policy


title: The treatment of scaphoid non-unions with partial and total scaphoid in titanium custom-made 3D-printed prostheses and reconstruction of scapholunate interosseous ligament: a preliminary study

abstract: The treatment of sequelae of scaphoid fractures is still one of the unsolved problems of hand surgery. Between January 2019 and July 2020 in the Hand Surgery Department of San Paolos Hospital in Savona (Italy) 9 partial scaphoid in titanium custom-made 3D-printed prosthesis have performed in 9 patients (all men) with an average age of 27.5 years (minimum 18-maximum 37 years). The aim of the study is to evaluate over time the clinical-functional and radiographic results of the wrists treated with partial and total scaphoid titanium custom-made 3D-printed prostheses and reconstruction of SLIL.

category: orthopedics


title: Multiplex Immunohistochemical Phenotyping of T Cells in Primary Prostate Cancer

abstract: Most prostate cancers are "immune cold" and poorly responsive to immune checkpoint inhibitors. However, the mechanisms responsible for the lack of a robust anti-tumor adaptive immune response in the prostate are poorly understood, which hinders the development of novel immunotherapeutic approaches. In addition, most inflammatory infiltrates in the prostate are centered around benign glands and stroma, which can confound the molecular characterization of the anti-tumor immune response. We analytically validated a chromogenic-based multiplex IHC approach and performed whole slide digital image analysis to quantify T cell subsets from the tumor microenvironment (TME) of primary prostatic adenocarcinomas. We trained a classifier to quantify the densities of eight T cell phenotypes separately in the tumor epithelial and stromal subcompartments. As an initial application, we tested the hypothesis that PTEN loss leads to an altered anti-tumor immune response by comparing matched regions of tumors within the same individual with and without PTEN loss. Our main findings in carcinomas (benign removed) include the following: i) CD4+ T cells are present at higher density than CD8+ T cells; ii) All T cell subsets are present at higher densities in the stromal compartment compared to the epithelial tumor compartment; iii) most CD4+ and CD8+ T cells are PD1+; iv) cancer foci with PTEN loss harbored increased numbers of T cells compared to regions without PTEN loss, in both stromal and epithelial compartments; v) the increases in T cells in PTEN loss regions were associated with ERG gene fusion status. This modular approach can apply to any IHC-validated antibody combination, sets the groundwork for more detailed spatial analyses, can help preserve small tissue samples, and can complement single cell and spatial genomic approaches.

category: pathology


title: Descriptive epidemiology of COVID-19 deaths during the first wave of pandemic in India - a single center experience

abstract:
BackgroundWith the looming threat of recurrent waves of COVID-19 in the presence of mutated strains, its of paramount importance to understand the demographic and clinical attributes of COVID-19 related mortalities in each pandemic waves. This could help policy makers, public health experts, and clinicians to better plan preventive and management strategies to curb COVID-19 related mortality.

MethodThis was a hospital record based, retrospective cross-sectional descriptive study, at a tertiary care hospital in Rishikesh, India. The study included all deceased patients between March 2020 and January 2021 (first wave) who tested positive for SARS-CoV-2 by RT-PCR and were hospitalized. The study was done to describe demography, clinical presentation, laboratory parameters, treatment given and associated complications of all COVID-19 deaths.

ResultOut of 424 mortalities, 298 (70.38%) were males and 126 (29.62%) were females. Mean age of patients was 55.85 {+/-} 16.24 years, out of which 19.5 percent were less than 45 years old, 33.6 percent were 45 to 60 years old and 41.8% were more than 60 years old. Comorbidity in the form of type 2 diabetes mellitus was present in 41.4% [95% CI (41.4-51.1)], hypertension in 39.8% [95% CI (35.1-44.6)], and coronary artery disease in 15.2% [95% CI (11.8-18.8)]. At the time of presentation, shortness of breath was present in 73.6% [95% CI (69.1 -77.7)], fever in 64.92% [95% CI (60.1-69.4)], and cough in 46.1%, [95% CI (41.1-50.8)]. Deranged laboratory parameters were lymphopenia in 90.2% [95% CI (86.8-92.7)], transaminitis in 59.7% [95% CI (54.8-64.3)], and hypercreatinemia in 37.7% [95% CI (33.1-42.5)]. Complications manifested were acute respiratory distress syndrome in 78.3% [95% CI (74-82.1)] and shock in 54.7% [95% CI (49.8-59.5)]. Median time duration between onset of symptom and hospital admission was 5 days (IQR = 3 - 5 days) and median length of hospital stay was 9 days (IQR = 4 - 14 days).

ConclusionDuring first pandemic wave, COVID-19 related mortality was 2.37 times higher among males, 2.14 times in age group >60 than <45 years. Most common associated comorbidities (>40%) were type 2 diabetes mellitus and hypertension. Most common associated symptoms (>60%) were shortness of breath and fever. Lymphopenia was seen in >90% cases while liver involvement in 60% and kidney in 38% cases. Median hospital stay was doubled the pre-hospital illness.


title: Analysis of the Dynamics, Outcome, and Prerequisites of the first German SARS-CoV-2 Superspreading Event

abstract:
BackgroundThe beginning of the COVID-19 pandemic was shaped by superspreading events including large-scale outbreaks. In Germany the first SARS-CoV-2 outbreak was a superspreading event in a rural area during indoor carnival festivities in February 2020.

Methods51 days after the event all known participants were asked to give blood samples, pharyngeal swabs and answer a self-administered questionnaire. Metric room coordinates for all tables, seats, and ventilation-points were assessed.

FindingsWe analyzed infection rates among all 411 participants, and the risk of infection in relation to various factors including age, alcohol consumption, and ventilation system. Overall, 46% (n=186/404) of the participants had been infected. We demonstrate that the spatial distribution of infected participants was associated with proximity to the ventilation system (represented as inverse distance, with Odds Ratio OR 1.39, 95% KI [0.86; 2.25]). Interestingly, the risk of infection was highly associated with age, whereby children (OR: 0.33 [0.267; 0.414]) and young adults (age 18-25) had a lower risk of infection than older participants resulting in an average infection risk increase of 28% per 10 years age difference. Behavioral differences also impacted the risk of infection including time spent outside (OR: 0.55 [0.33; 0.91]) or smoking (OR: 0.32 [0.124; 0.81]).

InterpretationOur findings underline the importance of proper indoor ventilation for events in the future. The lower susceptibility for children and young adults indicates their limited involvement in superspreading events.

FundingThe government of North Rhine-Westphalia (Germany) supported the study with 65,000 Euro.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe scientific literature was searched for the term "superspreading event AND Covid-19 OR Sars Cov 2" and identified published papers from China, South Korea, Europe, and North America. Most researchers analyzed superspreading events within a health care setting e.g. in hospitals or nursing homes, or described the general impact of superspreading events on the global pandemic. Only a few metanalyses of transmission clusters analyzed party occasions (e.g. a nightclub in Berlin, Germany) as superspreading events. These reports describe less than 100 infections and are very limited due to missing data or reporting biases. Therefore, the ability to draw scientific conclusions is also limited. Additionally, to our knowledge, there are no studies, which investigated individual behavior, the location, and role of children during a superspreading event. The research for the study started April 2020 and was concluded in June 2021.

Added value of this studyOur report analyzes the first COVID-19 superspreading event in Germany in detail, which was not only a unique setting but also included children and adults in the same room. We demonstrate that nearly half of the participants were infected with SARS-CoV-2 and that the proximity of the seating to the ventilation system was an important risk factor for infection. The data showed that low physical distance including singing and duration of attendance at this event increased the risk of infection, while regular smoking and spending the break of the event outside lowered the risk of infection. This underlines the benefit of airing to lower the amount of both droplets and aerosols. Furthermore, we found lower infection in children than adults despite being in the same room suggesting differences in infectability in children. Indeed, we observed that an additional 10 years of age is on average associated with 28% increased risk of infection.

Implications of all the available evidenceTaken together, the results demonstrate the importance of the ventilation system during superspreading events. In particular children and young adults had a lower risk of infection during the event indicating that they have a limited role during this pandemic. Overall, our data demonstrate in detail age-dependent infectability as well as highlights to understand transmission dynamics in order to improve comprehensive public health preparedness measures.


title: Development of a machine-learning model to assess terminal ileum Endoscopic healing in pediatric Crohn's disease from Magnetic Resonance Enterography data

abstract:
Background and AimsEndoscopic healing (EH), is a major treatment goal for Crohns disease (CD). However, terminal ileum (TI) intubation failure is common, especially in children. We evaluated the added-value of machine-learning models in imputing a TI Simple Endoscopic Score for CD (SES-CD) from Magnetic Resonance Enterography (MRE) data of pediatric CD patients.

MethodsThis is a sub-study of the prospective ImageKids study. We developed machine-learning and baseline linear-regression models to predict TI SES-CD score from the Magnetic Resonance Index of Activity (MaRIA) and the Pediatric Inflammatory Crohns MRE Index (PICMI) variables. We assessed TI SES-CD predictions accuracy for intubated patients with a stratified 2-fold validation experimental setup, repeated 50 times. We determined clinical impact by imputing TI SES-CD in patients with ileal intubation failure during ileocolonscopy.

ResultsA total of 223 children were included (mean age 14.1{+/-}2.5 years), of whom 132 had all relevant variables (107 with TI intubation and 25 with TI intubation failure). The combination of a machine-learning model with the PICMI variables achieved the lowest SES-CD prediction error compared to a baseline MaRIA-based linear regression model for the intubated patients (N=107, 11.7 (10.5-12.5) vs. 12.1 (11.4-12.9), p<0.05). The PICMI-based models suggested a higher rate of patients with TI disease among the non-intubated patients compared to a baseline MaRIA-based linear regression model (N=25, up to 25/25 (100%) vs. 23/25 (92%)).

ConclusionsMachine-learning models with clinically-relevant variables as input are more accurate than linear-regression models in predicting TI SES-CD and EH when using the same MRE-based variables.

category: gastroenterology


title: Covid spirals: a phase diagram representation of COVID-19 effective reproduction number Rt

abstract: In this paper, we propose a phase diagram representation of COVID-19 effective reproduction number Rt. Specifically, we express Rt as a function of the estimated infected individuals. This function plots a particular clockwise spiral that allows to easily compare the evolution of the number of new infected individuals at different dates and, possibly, provide some hints on the future progression of the infection.


title: Secondary transmission of SARS-CoV-2 in educational settings in Northern Italy from September 2020 to April 2021: a population-based study

abstract:
BackgroundWe aimed to quantify the risk of transmission of SARS-CoV-2 in the school setting by type of school, characteristics of the index case and calendar period in the Reggio Emilia province (RE), Italy. The secondary aim was to estimate the promptness of contact tracing.

MethodsA population-based analysis of surveillance data of all COVID-19 cases occurring in RE, Italy, from September 1, 2020, to April 4th, 2021, for which a school contact and/or exposure was suspected. Indicator of the delay in contact tracing was computed as the time elapsed since positivity of the index case and the date on which the swab for classmates was scheduled (or most were scheduled).

ResultsOverall, 30,184 and 13,608 contacts among classmates and teachers/staff, respectively, were identified and received recommendation for testing; 43,214 (98.7%) performed the test. Secondary transmission occurred in about 40% of the investigated classes, and the overall secondary case attack rate was 4%, slightly higher when the index case was a teacher, but with almost no differences by type of school and stable during the study period. Promptness of contact tracing increased during the study period, reducing the time from index case identification and testing of contacts from 7 to 3 days, as well the ability to identify possible source of infection in the index case.

ConclusionsDespite the spread of the Alpha variant during the study period in RE, the secondary case attack rate remained stable from school reopening in September 2020 until the beginning of April 2021.


title: Long COVID: Assessment of Neuropsychiatric Symptoms in Children and Adolescents - A Clinical Data Analysis

abstract:
COVID-19 infections in adults often result in medical, neuropsychiatric, and unspecific symptoms, called Long COVID, and the premorbid functional status cannot be achieved. Regarding the course in children and adolescents, however, reliable data are not yet available.

Objective380 children and adolescents/young adults aged between 6 and 21 years, being treated for various psychiatric diseases in an outpatient clinical service, were examined for COVID-19 infections and Long COVID symptoms following a structured protocol.

ResultsThree patients had COVID-19; one patient had symptoms of Long COVID in his medical history, but they could not be objectivized in an in-depth neuropsychiatric and neuropsychological assessment.

ConclusionsLong COVID seems to occur rarely in children and adolescents. Objectivizing the symptoms is a difficult task that requires various diagnostic considerations.


title: COVID-19 Vaccine Efficacy in a Diverse Urban Healthcare Worker Population

abstract:
ObjectiveTo investigate COVID-19 vaccine efficacy (VE) among healthcare workers (HCWs) in an ethnically diverse community healthcare system, during its initial immunization campaign.

MethodsHCWs of the system were retrospectively included from the beginning of a COVID-19 vaccination program (December 16, 2020) until March 31, 2021. Those with a prior COVID-19 infection before December 15 were excluded. The Occupational Health department of the system ran a COVID-19 screening and testing referral program for workers, consistently throughout the study period. A master database had been established and updated comprising of the demographics, COVID-19 PCR assays, and vaccinations of each HCW. Andersen-Gill extension of the Cox models were built to estimate the VE of fully/partially vaccinated person-days at risk.

ResultsAmong the 4317 eligible HCWs, 3249 (75%) received any vaccination during the study period. Vaccinated HCWs were older, less likely to be Black/African American, Hispanic/Latino or identify as two or more races, and more likely to be medical providers. After adjusting for age, sex, race, and the statewide background incidence at the time of vaccination, we observed a VE of 80.2% (95% CI: 57.5-90.8%) for [greater double equals]14 days after the first dose of Pfizer/Moderna, and 95.5% (95% CI: 88.2-98.3%) among those fully vaccinated (i.e. [greater double equals]14 days after the second dose of Pfizer/Moderna or the single dose of J&J/Janssen).

ConclusionCOVID-19 vaccine effectiveness in the real world is promising, and these data in concert with culturally appropriate may decrease vaccine hesitancy.

category: public and global health


title: How does migratory status affect non-communicable disease risk in a global context? A systematic review.

abstract: Challenges pertaining to the study of migrant health have been reported in medical and sociological literature. A literature review was thus conducted to gauge what research currently holds about the risk of non-communicable disease within migrant populations globally. The search strategy is outlined; CASP checklists were used to critically appraise articles, and the relevant data was synthesised and analysed. The research identifies several overarching quantitative themes regarding risk patterns. Recommendations are made.


title: Functional respiratory capacity in the elderly after COVID-19 -- a pilot study

abstract:
BackgroundThe pandemic spread of SARS-CoV-2 has led to an unprecedented outbreak of viral pneumonia. Despite the current focus of worldwide research being the characterization of post-COVID-19 sequelae, the level of functional impact that this disease causes in the elderly who have presented moderate, severe or critical manifestations is still unknown.

ObjectiveTo identify the main consequences/sequelae on functional respiratory capacity in the elderly after CoViD-19.

MethodologyA cross-sectional study was carried out in the community. Functional aerobic capacity (2min step test), dyspnea perception (modified Medical Research Council Dyspnea Questionnaire), respiratory and peripheral muscle strength (maximum inspiratory and expiratory pressure, grip strength) and the Frailty Index (Clinical Fragility Scale) were assessed in 25 community-dwelling individuals aged [≥]65 years, who have had a diagnosis of CoViD-19 for up to 6 months, and in an equal number of elderly people with the same characteristics without a known diagnosis of CoViD-19.

ResultsThe elderly with a diagnosis of CoViD-19 up to 6 months presented a decrease in the values of maximum inspiratory pressure (p=0.001) and maximum expiratory pressure (p=0.015), in aerobic capacity (p<0.001) with significant presence of desaturation on exertion (p<0.001), and increased values of dyspnea perception (p=0.001) and Frailty Index (p=0.026).

ConclusionSignificant changes were found in the functional respiratory capacity of elderly patients diagnosed with CoViD-19 for up to 6 months, when compared with elderly individuals without a known diagnosis of CoViD-19. It is not possible to extrapolate the results obtained to the Portuguese population, however these results may be an important indicator in the characterization of sequelae in the elderly after infection by SARS-CoV-2.

category: rehabilitation medicine and physical therapy


title: Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage II Colon Cancer (DYNAMIC Trial): Statistical Analysis Plan

abstract:
BackgroundDetection of circulating tumour DNA (ctDNA) after curative intent treatment reflects the presence of minimal residual disease and predicts for recurrence. DYNAMIC trial is a randomised phase II investigating the clinical utility of ctDNA-guided adjuvant treatment strategy compared with the standard of care (non-ctDNA based) approach in patients with stage II colon cancer. The primary trial endpoint is recurrence-free survival estimated from Kaplan Meier Method at 2 years. Secondary endpoints include proportion of patients treated with adjuvant chemotherapy, time-to-recurrence, overall survival, ctDNA clearance rate (investigational arm) and quality-adjusted life-years.

ObjectiveTo outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis.

MethodsThe SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data.

Trial RegistrationANZ Clinical Trials Registry, ACTRN12615000381583. Registered on 27th April 2015.


title: Epigenome and phenome study reveals circulating markers pertinent to brain health

abstract: Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circulating proteome in relation to brain health. We perform epigenome-wide studies of 4,235 plasma proteins (n=778), identifying 2,895 CpG-protein associations (protein quantitative trait methylation loci; pQTMs) after stringent correction for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTL) and common lifestyle effects, extending current knowledge by analysing a further 3,286 protein measurements with 2,854 novel pQTMs. We then perform a phenome-wide study of each protein in relation to neurological traits in 1,065 individuals, identifying 644 proteins related to cognitive, brain imaging phenotypes or APOE status. By integrating our pQTM dataset with our phenome association study, we uncovered 88 epigenetic associations for protein markers of neurological traits, 83 of which were previously unreported. These data are pertinent to understanding heterogeneity in brain health.


title: Significant Sparse Polygenic Risk Scores across 428 traits in UK Biobank

abstract:
We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearmans {rho} = 0.61, p = 2.2 x 10-59 for quantitative traits, {rho} = 0.21, p = 9.6 x 10-4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).

Author summaryPolygenic risk scores (PRSs), an approach to estimate genetic predisposition on disease liability by aggregating the effects across multiple genetic variants, has attracted increasing research interest. While there have been improvements in the predictive performance of PRS for some traits, the applicability of PRS models across a wide range of human traits has not been clear. Here, applying penalized regression using Batch Screening Iterative Lasso (BASIL) algorithm to more than 269,000 individuals of white British ancestry in UK Biobank, we systematically characterize PRS models across more than 1,500 traits. We report 813 traits with PRS models of statistically significant predictive performance. While the statistical significance does not necessarily directly translate into clinical relevance, we investigate the properties of the 813 significant PRS models and report a significant correlation between predictive performance and estimated SNP-based heritability. We find that the number of genetic variants selected in our sparse PRS model is significantly correlated with the incremental predictive performance in both quantitative and binary traits. Our transferability assessment of PRS models in UK Biobank revealed that the sparse PRS models trained on individuals of European ancestry had a lower predictive performance for individuals of African and Asian ancestry groups.


title: Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank


title: Genome-wide by environment interaction study of stressful life events and hospital-treated depression in the iPSYCH2012 sample

abstract: Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. We conducted a genome-wide environment interaction study in 18,532 depression cases from hospital-based settings and 20,184 population-representative non-cases from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability and child maltreatment were identified from population-based registers and operationalized as a time-varying count variable (0-4+). Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. The analyses yielded three novel, genome-wide significant (P < 5 x 10-8) loci located in the ATP-binding cassette transporter C 1 (ABCC1) gene, in the A-kinase anchor protein 6 (AKAP6) gene, and near the Major facilitator superfamily domain 1 (MFSD1) gene, as well as 50 loci of suggestive significance. These top 3 hits did not replicate in a case-control sample of depression drawn from the UK Biobank. These results suggest that there may be individual genetic variants that confer risk for or protection against clinical depression only in the presence of stressful life events; however, replication in a sample with similar design and ascertainment methods is needed before any firm conclusions can be drawn. Future gene-by-stress research in depression should focus on establishing even larger collaborative genome-wide environment interaction studies to attain sufficient power.