title: Continuous Severity Assessment Of Pulmonary Edema On Chest X-ray Using Siamese Convolutional Networks

abstract: For physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation.

category: radiology and imaging


title: PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks


title: High-intensity interval or circuit-based strength training effects on physical and cognitive functioning for community-dwelling older adults: A systematic review protocol.

abstract:
BackgroundHigh-intensity interval or circuit-based strength training utilizes brief intense periods of strengthening exercises interspersed with rest/light activity or performed in a continuous circuit. The physical and cognitive effects of this time-efficient approach in community-dwelling older adults have not been systematically reviewed.

ObjectivesTo determine the effects of high-intensity interval or circuit-based strength training interventions on physical and cognitive functioning for community-dwelling older adults, and the associated adherence, retention, and adverse event rates.

MethodsSix databases will be searched from inception to November 2021; MEDLINE, EMBASE, CINAHL, AgeLine, SPORTDiscus, and Web of Science. To assess physical and/or cognitive functioning effects, randomized and quasi-randomized controlled trials (RCTs and Q-RCTs) of high-intensity interval or circuit-based strengthening interventions in community-dwelling older adults, utilizing any comparator, will be included. The above criteria will be extended to include non-randomized study designs to assess adherence, retention, and adverse events. All screening, data extraction and risk of bias will be assessed by two independent reviewers. Risk of bias will be assessed utilizing the Cochrane RoB 2 tool for randomized and ROBINS-I for non-randomized studies. Qualitative synthesis will be used to present information on adherence, retention, and adverse event rates. Qualitative and/or quantitative synthesis will be used to present physical and cognitive functioning effects depending on which method is deemed appropriate for the various outcomes.

ConclusionThis systematic review will be the first to summarize the physical and/or cognitive effects, adherence, retention, and adverse events reported in high-intensity interval and circuit-based strengthening interventions for community-dwelling older adults.

Systematic review registration numberCRD42021284010

category: rehabilitation medicine and physical therapy


title: MTPpilot: an interactive software for visualization of NGS results in molecular tumor boards

abstract: Comprehensive targeted Next Generation Sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards the detected genomic alterations are often discussed to decide the next treatment options for the cancer patient. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. We developed the Molecular Tumor Profiling pilot (MTPpilot) software to enable an efficient and quick analysis and visualization of complex NGS results, thanks to a combination of automated annotations and interactive tools. The software is tailored for the use at molecular tumor boards to aid clinical decision making. It is freely available as a web-application at https://www.mtppilot.org.

category: oncology


title: DNA Aptamer Gold Nanoparticle Colorimetric Diagnostic Test Kit of Saliva Samples for SARS-CoV-2 Virus Linked to Mobile Phone Application (AptamexTM).

abstract: The development of the use of DNA aptamers for clinical applications to detect human diseases is at the forefront of research. Synthetic DNA aptamers are easy to generate, inexpensive, highly specific and have been postulated to replace antibodies for research and clinical use. Despite the considerable amount of published work on the use of DNA aptamers for research use, to date they have not been exploited for clinical diagnostics. SARS-CoV-2 virus is a pandemic causing a global disruptive event preventing people from travel, work and leisure activities resulting in a major health crisis, hospital overloads and a high death rate. The detection of SARS-CoV-2 virus in communities is therefore very important, especially for returning normality of life. The current gold standard for detection of SARS-CoV-2 virus is RT-PCR, a technique that is relatively expensive and most importantly with a slow turnaround time between sample procurement and result. This paper describes the development of a rapid, accurate, low-cost, facile to use assay for the detection of the SARS-CoV-2 spike protein in saliva. The assay exploits a simple system based on the use of a gold nanoparticle-aptamer complex, that can be easily produced and distributed, facilitating its deployment to the point-of-need, potentially reaching millions of individuals in resource-limited settings. The proposed colorimetric diagnostic test kit uses a SARS-CoV-2 DNA aptamer adsorbed on gold nanoparticles and salt-induced aggregation to detect the presence of SARS-CoV-2 Spike protein in saliva samples indicated by a color change of the gold absorbance spectrum that can be quantified by a spectrophotometer, linked to a mobile phone for data processing and analysis. The assay parameters were optimized and then tested in a field calibration clinical test in Indonesia. At a research level, a limit of detection of ca. 1.25 nM to synthetic spike protein (S1) was observed and a method to test human saliva samples developed. The DNA aptamer was specific to SARS-CoV-2, with minor cross-reactivity observed with MERS and SARS-CoV-1, but negligible cross-reactivity seen with common cold coronaviruses. A calibration clinical test of patients in Indonesia demonstrated a classification resulting in a > 97% sensitivity and a > 97% specificity compared with saliva RT-PCR test for SARS-CoV-2. Furthermore, the data indicates that anatomical location and sample type (swab vs saliva) can affect RT-PCR results. In conclusion, we have developed the use of a robust and reproducible aptamer-gold nanoparticle assay for clinical diagnostic use based on a colorimetric system that is cheap, simple, rapid, sensitive and can be employed for large scale testing of human populations for SARS-CoV-2 virus.

category: respiratory medicine


title: Viruses previously identified in Brazil as belonging to HIV-1 circulating recombinant form (CRF) 72_BF1 represent two closely related CRFs, one of which, designated CRF122_BF1, is also circulating in Spain.

abstract: Circulating recombinant forms (CRFs) are important components of the HIV-1 pandemic. Those derived from recombination between subtype B and subsubtype F1, with 18 reported, most of them of South American origin, are among the most diverse. Here we identify a HIV-1 BF1 recombinant cluster that is expanding in Spain, transmitted mainly via heterosexual contact, which, analyzed in near full-length genomes in 4 viruses, exhibited a coincident BF1 mosaic structure, with 12 breakpoints, that fully coincided with that of two viruses from Brazil (10BR_MG003 and 10BR_MG005), previously classified as CRF72_BF1. The three remaining Brazilian viruses previously identified as CRF72_BF1 (10BR_MG002, 10BR_MG004, and 10BR_MG008), exhibited mosaic structures highly similar, but not identical, to that of the Spanish viruses and to 10BR_MG003 and 10BR_MG005, with discrepant subtypes in two short genome segments, located in pol and gp120env. Based on these results, we propose that the 5 viruses from Brazil previously identified as CRF72_BF1 actually belong to two closely related CRFs, one comprising 10BR_MG002, 10BR_MG004, and 10BR_MG008, which keep their CRF72_BF1 designation, and the other, designated CRF122_BF1, comprising 10BR_MG003, 10BR_MG005 and the viruses of the identified Spanish cluster. Three other BF1 recombinant genomes, 2 from Brazil and 1 from Italy, previously identified as unique recombinant forms, were classified as CRF72_BF1. CRF122_BF1, but not CRF72_BF1, was associated with protease L89M substitution, reported to contribute to antiretroviral drug resistance. Phylodynamic analyses estimate the emergence of CRF122_BF1 in Brazil around 1987. Given their close phylogenetic relationship and similar structures, the grouping of CRF72_BF1 and CRF122_BF1 in a CRF family is proposed.

category: hiv aids


title: SARS-CoV-2 neutralization after mRNA vaccination and variant breakthrough infection

abstract: Vaccination and infection by viral variants are shaping population immunity to SARS-CoV-21 and breakthrough infections of vaccinated or previously infected individuals have become common as variants evade preexisting immunity. Omicron (B.1.1.529) is highly resistant to plasma neutralizing antibodies elicited by infection with prior variants and the 2-dose mRNA vaccination regimens. However, vaccination after infection or a third mRNA vaccine dose elicit high levels of neutralizing antibodies that can also neutralize omicron to a degree2-4. We compared neutralizing antibody titers in 54 individuals that had received 2 or 3 doses of mRNA vaccines and had experienced breakthrough infection with SARS-CoV-2 variants.

category: infectious diseases


title: Long term antibody response to SARS-CoV-2 in children

abstract:
Almost two years into the pandemic and with vaccination of children significantly lagging behind adults, long-term pediatric humoral immune responses to SARS-CoV-2 are understudied. The C19.CHILD Hamburg (COVID-19 Child Health Investigation of Latent Disease) Study is a prospective cohort study designed to identify and follow up children and their household contacts infected in the early 2020 first wave of SARS-CoV-2. We screened 6113 children <18 years by nasopharyngeal swab-PCR in a low-incidence setting after general lockdown, from May 11 to June 30, 2020. 4657 participants underwent antibody testing. Positive tests were followed up by repeated PCR and serological testing of all household contacts over 6 months. In total, the study identified 67 seropositive children (1.44 %), the median time after infection at first presentation was 83 days post-symptom onset (PSO). Follow up of household contacts showed incomplete seroconversion in most families, with higher seroconversion rates in families with adult index cases compared to pediatric index cases (OR: 1.79, P=0.047). Most importantly, children showed sustained seroconversion up to nine months PSO, and serum antibody concentrations persistently surpassed adult levels (ratio serum IgG Spike children vs. adults 90 days PSO: 1.75, P<0.001, 180 days: 1.38, P=0.01, 270 days: 1.54, P=0.001).

In a low-incidence setting, SARS-CoV-2 infection and humoral immune response present distinct patterns in children including higher antibody levels, and lower seroconversion rates in families with pediatric index cases. Children show long-term SARS-CoV-2 antibody responses. These findings are relevant to novel variants with increased disease burden in children, as well as for the planning of age-appropriate vaccination strategies.


title: Relation of incident Type 1 diabetes to recent COVID-19 infection: cohort study using e-health record linkage in Scotland

abstract:
BackgroundStudies using claims databases have reported that SARS-CoV-2 infection >30 days earlier increased the incidence of type 1 diabetes (T1DM). Using exact dates of type 1 diabetes diagnosis from the national register in Scotland linked to virology laboratory data we sought to replicate this finding.

MethodsA cohort of 1849411 individuals aged <35 years without diabetes, including all those in Scotland who subsequently tested positive for SARS-CoV-2, was followed from 1 March 2020 to 22 November 2021. Incident T1DM was identified by linkage to the national registry. Cox regression was used to test the association of time-updated infection with incident T1DM. Trends in incidence of T1DM in the total population from 2015-2021 were estimated in a generalized additive model.

FindingsThere were 365080 in the cohort with at least one detected SARS-CoV-2 infection during follow-up and 1074 who developed T1DM. The rate ratio for incident T1DM associated with first positive test for SARS-CoV-2 (with no previous infection as reference category) was 0.88 (95% CI 0.63 to 1.23) for infection more than 30 days earlier and 2.62 (95% CI 1.81 to 3.79) for infection in the previous 30 days. However negative and positive SARS-CoV-2 tests were more frequent in the days surrounding T1DM presentation. In those aged 0-14 years incidence of T1DM during 2020-2021 was 20% higher than the 7-year average.

InterpretationT1DM incidence in children increased during the pandemic. However the cohort analysis does not support a causal effect of SARS-CoV-2 infection itself on T1DM incidence.

FundingNone

category: epidemiology


title: Grandparental Childcare During the Pandemic and Effects on Mental Health: Evidence From England

abstract:
ObjectivesPolicies aiming at reducing rates of hospitalisation and death from COVID-19 encouraged older people to reduce physical interactions. For grandparents in England, this meant that provision of care for grandchildren was allowed only under very limited circumstances. Evidence also suggests that reduced face-to-face interactions took a toll on mental health during the pandemic. This study aims to investigate whether changes in grandchild care provision during the pandemic impacted grandparents mental health.

MethodsUsing pre-pandemic data from Wave 9 (2018/19) and the second Covid-19 sub-study (November/December 2020) of the English Longitudinal Study of Ageing, we first describe changes in grandparenting since the start of the pandemic to then investigate, using regression models, associations between changes in grandparenting and mental health (depression, quality of life, life satisfaction) during the pandemic, while controlling for pre-pandemic levels of the outcome variables. Results: About 10% of grandparents stopped altogether to look after grandchildren during the pandemic, with 22% reporting an overall decrease in the amount of grandchild care provided and 20% an increase or similar levels. Compared to grandparents who mostly maintained unchanged their grandchild care provision, those who stopped altogether and those who mostly reduced the amount of grandchild care provided were more likely to report poorer mental health, even accounting for pre-pandemic health.

DiscussionWhile measures to limit physical contact and shield older people were necessary to reduce the spread of COVID-19, policymakers should acknowledge potential adverse consequences for mental health among grandparents who experienced changes in their roles as grandchild caregivers.

category: psychiatry and clinical psychology


title: Impact of COVID-19 pandemic and anti-pandemic measures on tuberculosis, viral hepatitis, HIV/AIDS and malaria - a systematic review

abstract: COVID-19 pandemic puts an enormous strain on health care systems worldwide and may have a detrimental effect on prevention, treatment and outcomes of tuberculosis (TB), viral hepatitis, HIV/AIDS and malaria, whose ending is part of the United Nations 2030 Agenda for Sustainable Development. We conducted a systematic review of scientific and grey literature in order to collect wide-ranging evidence with emphasis on quantification of the projected and actual indirect impacts of COVID-19 on the four infectious diseases with a global focus. We followed PRISMA guidelines and the protocol registered for malaria (CRD42021234974). We searched PubMed, Scopus, preView (last search: January 13, 2021) and websites of main (medical) societies and leading NGOs related to each of the four considered infectious diseases. The identified modelling studies warned about under-diagnosis (TB), anti-retroviral therapy interruption/decrease in viral load suppression (HIV), disruptions of insecticide-treated nets (ITN) distribution and access to effective treatment (malaria), and treatment delays and vaccination interruptions (viral hepatitis). The reported disruptions were very heterogeneous both between and within countries. If observed at several points in time, the initial drops (partly dramatic, e.g. TB notifications/cases, or HIV testing volumes decreased up to -80%) were followed by a gradual recovery. However, the often-missing assessment of the changes against the usual pre-pandemic fluctuations hampered the interpretation of less severe ones. Given the recurring waves of the pandemic and the unknown mid- to long-term effects of adaptation and normalisation, the real consequences for the fight against leading infectious diseases will only manifest over the coming years.

category: public and global health


title: Global Force-of-Infection Trends for Human Taenia solium Taeniasis/Cysticercosis

abstract:
Infection by Taenia solium poses a major burden across endemic countries. The World Health Organization (WHO) 2021-2030 Neglected Tropical Diseases roadmap has proposed that 30% of endemic countries achieve intensified T. solium control in hyperendemic areas by 2030. Understanding geographical variation in age-prevalence profiles and force-of-infection (FoI) estimates will inform intervention designs across settings.

Human taeniasis (HTT) and human cysticercosis (HCC) age-prevalence data from 16 studies in Latin America, Africa and Asia were extracted through a systematic review. Catalytic models, incorporating diagnostic performance uncertainty, were fitted to the data using Bayesian methods, to estimate rates of antibody (Ab)-seroconversion, infection acquisition and Ab-seroreversion or infection loss. HCC FoI and Ab-seroreversion rates were also estimated across 23 departments in Colombia from 28,100 individuals.

Across settings, there was extensive variation in all-ages seroprevalence. Evidence for Ab- seroreversion or infection loss was found in most settings for both HTT and HCC and for HCC Ab- seroreversion in Colombia. The average duration until humans became Ab-seropositive/infected decreased as all-age (sero)prevalence increased. There was no clear relationship between the average duration humans remain Ab-seropositive and all-age seroprevalence.

Marked geographical heterogeneity in T. solium transmission rates indicate the need for setting- specific intervention strategies to achieve the WHO goals.


title: Predictive Machine Learning for Personalised Medicine in Major Depressive Disorder

abstract:
Depression is a common psychiatric disorder with substantial recurrence risk. Accurate prediction from easily collected data would aid in diagnosis, treatment and prevention. We used machine learning in the Generation Scotland cohort to predict lifetime risk of depression and, among cases, recurrent depression. Rank aggregation was used to combine results across ten different algorithms and identify highly predictive variables. The model containing all but the cardiometabolic predictors had the highest predictive ability on independent data. Rank aggregation produced a reduced set of predictors without decreasing predictive performance (lifetime: 20 out of 154 predictors and Receiver Operating Characteristic area under the curve (AUC)=0{middle dot}84, recurrent: 10 out of 180 predictors and AUC=0{middle dot}76). Here we develop a pipeline which leads to a small set of highly predictive variables. This information can be easily collected with a smartphone  application to help diagnosis and treatment, while longitudinal tracking may help patients in self-management.

SignificanceDepression is the most common psychiatric disorder and a leading cause of disability worldwide. Patients are often diagnosed and treated by non-specialist clinicians who have limited time available to assess them. We present a novel methodology which allowed us to identify a small set of highly predictive variables for a diagnosis of depression, or recurrent depression in patients. This information can easily be collected using a tablet or smartphone application in the clinic to aid diagnosis.


title: Coronavirus Disease 2019 (COVID-19) Vaccine Boosting in Persons Already Protected by Natural or Vaccine-Induced Immunity

abstract:
BackgroundThe purpose of this study was to evaluate whether boosting healthcare personnel, already reasonably protected by prior infection or vaccination, with a vaccine developed for an earlier variant of COVID-19 protects against the Omicron variant.

MethodsEmployees of Cleveland Clinic who were previously infected with or vaccinated against COVID-19, and were working in Ohio the day the Omicron variant was declared a variant of concern, were included. The cumulative incidence of COVID-19 was examined over two months during an Omicron variant surge. Protection provided by boosting (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression. Analyses were adjusted for time since proximate overt immunologic challenge (POIC) as a time-dependent covariate.

ResultsAmong 39 766 employees, 8037 (20%) previously infected and the remaining previously vaccinated, COVID-19 occurred in 6230 (16%) during the study. Risk of COVID-19 increased with time since POIC. In multivariable analysis, boosting was independently associated with lower risk of COVID-19 among those with vaccine-induced immunity (HR, .43; 95% CI, .41-.46) as well as those with natural immunity (HR, .66; 95% CI, .58-.76). Among those with natural immunity, receiving 2 compared to 1 dose of vaccine was associated with higher risk of COVID-19 (HR, 1.54; 95% CI, 1.21-1.97).

ConclusionsAdministering a COVID-19 vaccine not designed for the Omicron variant, 6 months or more after prior infection or vaccination, protects against Omicron variant infection in both previously infected and previously vaccinated individuals. There is no evidence of an advantage to administering more than 1 dose of vaccine to previously infected persons.

SummaryAmong 39 766 Cleveland Clinic employees already protected by prior infection or vaccination, vaccine boosting after 6 months was associated with significantly lower risk of COVID-19. After COVID-19 infection, there was no advantage to more than one dose of vaccine.


title: Correlation between post-vaccination titres of combined IgG, IgA, and IgM anti-Spike antibodies and protection against breakthrough SARS-CoV-2 infection: a population-based longitudinal study (COVIDENCE UK)

abstract: In this population-based cohort of 7530 adults, combined IgG/A/M anti-Spike titres measured after SARS-CoV-2 vaccination were predictive of protection against breakthrough SARS-CoV-2 infection. Discrimination was significantly improved by adjustment for factors influencing risk of SARS-CoV-2 exposure including household overcrowding, public transport use, and visits to indoor public places.


title: COVID-19 in Japan: insights from the first three months of the epidemic

abstract:
BackgroundUnderstanding the characteristics and natural history of novel pathogens is crucial to inform successful control measures. Japan was one of the first affected countries in the COVID-19 pandemic reporting their first case on 14 January 2020. Interventions including airport screening, contact tracing, and cluster investigations were quickly implemented. Here we present insights from the first 3 months of the epidemic in Japan based on detailed case data.

MethodsWe conducted descriptive analyses based on information systematically extracted from individual case reports from 13 January to 31 March 2020 including patient demographics, date of report and symptom onset, symptom progression, travel history, and contact type. We analysed symptom progression and estimated the time-varying reproduction number, Rt, correcting for epidemic growth using an established Bayesian framework. Key delays and the age-specific probability of transmission were estimated using data on exposures and transmission pairs.

ResultsThe corrected fitted mean onset-to-reporting delay after the peak was 4 days (standard deviation: {+/-}2 days). Early transmission was driven primarily by returning travellers with Rt peaking at 2.4 (95%CrI:1.6, 3.3) nationally. In the final week of the trusted period, Rt accounting for importations diverged from overall Rt at 1.1 (95% CrI: 1.0, 1.2) compared to 1.5 (95% CrI: 1.3, 1.6) respectively. Household (39.0%) and workplace (11.6%) exposures were the most frequently reported potential source of infection. The estimated probability of transmission was assortative by age. Across all age groups, cases most frequently onset with cough, fever, and fatigue. There were no reported cases of patients <20 years old developing pneumonia or severe respiratory symptoms.

ConclusionsInformation collected in the early phases of an outbreak are important in characterising any novel pathogen. Timely recognition of key symptoms and high-risk settings for transmission can help to inform response strategies. The data analysed here were the result of robust and timely investigations and demonstrate the improvements to epidemic control as a result of such surveillance.


title: Does the Heart Fall Asleep? - Diurnal Variations of Heart Rate Variability in Patients with Disorders of Consciousness

abstract: The current study investigated heart rate (HR) and heart rate variability (HRV) across day and night in patients with disorders of consciousness (DOC). We recorded 24-h ECG in 26 patients with DOC (i.e., unresponsive wakefulness syndrome [UWS; n=16] and (exit) minimally conscious state [(E)MCS; n=10]). To examine diurnal variations, HR and HRV indices in the time, frequency, and entropy domains were computed for periods of clear day- (forenoon: 8am-2pm; afternoon: 2pm-8pm) and nighttime (11pm-5am). Results indicate that patients interbeat intervals (IBIs) were larger during the night than during the day indicating HR slowing. Additionally, higher HRV entropy was associated with higher EEG entropy during the night. Patients in UWS showed larger IBIs compared to patients in (E)MCS, and patients with non-traumatic brain injury showed lower ECG entropy than patients with traumatic brain injury. Thus, cardiac activity varies with a diurnal pattern in patients with DOC and can differentiate between patients diagnoses and etiologies. Moreover, also the interaction of heart and brain appears to follow a diurnal rhythm. Thus, HR and HRV seem to mirror the integrity of brain functioning and consequently might serve as supplementary measures for improving the validity of assessments in patients with DOC.

category: neurology


title: Food intake patterns, social determinants and emotions during COVID-19 confinement: an online survey among adults in Panama.

abstract:
Background to the studyThe COVID-19 pandemic was accompanied by varying movement restriction measures across populations worldwide. These restrictions altered daily activities at all levels, including food access and intake, as well as psychological feelings during lockdown. The main objective of the present study was to evaluate health, and nutrition behaviors during confinement during the first wave of the COVID-19 pandemic in Panama.

MethodologyWe conducted a cross-sectional study using an online survey for data collection; a total of 1,561 surveys were validated.

ResultsThe majority of respondents were women (74.2%) between 18 and 49 years old. Among the respondents, 83.3% indicated a university education level, and 49.9% reported a monthly family income equal to or less than 1,000 USD. In addition, more than 50% self-reported overweight or obesity. Responses were analyzed using k-means algorithms to identify food intake patterns; we found three patterns: a healthy food intake pattern, a non-healthy food intake pattern and a mixed food intake pattern. The respondents with healthy food intake and non-healthy food intake patterns reported better socioeconomic conditions. Individuals classified as having mixed food intake patterns had lower incomes, less education and higher unemployment rates. Regarding emotions, we found that women experienced more negative emotions, such as fear, worry and anxiety, during the lockdown period.

Prncipal conclusionsTaken together, these results suggest that the mobility restriction measures imposed during the COVID-19 pandemic affected food intake patterns by exacerbating existing inequalities. We believe that directing resources towards strategies with the greatest positive impacts on public health remains key, especially in critical situations such as the COVID-19 pandemic.

category: nutrition


title: Neonatal and Maternal Outcome of COVID-19 positive women in Sri Lanka: Secondary Analysis using National COVID-19 Positive Pregnant Women Surveillance

abstract:
ObjectivesThis study aims to describe the population level data on neonatal and maternal outcomes of COVID-19 positive pregnant women of Sri Lanka by secondary analysis using National COVID-19 Positive Pregnant Women Surveillance.

DesignSecondary analysis of surveillance data from the National COVID-19 positive pregnant women surveillance, Sri Lanka. Data of all pregnant women whose maternal and neonatal outcomes were reported in National Surveillance from 1st March 2020 to 31st October 2021 were included in the study. Associated factors for maternal and neonatal outcomes, namely POA at delivery, mode of delivery, birthweight, immediate place of newborn care, congenital abnormalities, and condition of neonate at completion of one month were calculated using univariate and multivariate Odds ratios.

ResultsMaternal COVID-19 infection reported preterm birth rate of 11.9%, LSCS rate of 54.5%, low birthweight rate16.5% and 8.3% of the newborns requiring intensive care. Neonatal mortality rate was 9 per 1000 live births. Pre-pregnancy overweight and obesity increased the risk of preterm delivery compared to pregnant women with normal BMI by 46.7% (AOR=1.467, CI=1.111-1.938, P=0.007). In contrast, the risk of preterm delivery reduced by 82.4% (AOR=0.176, CI=0.097-0.317, p<0.001) and presence of any type of congenital abnormalities in newborns by 72.4% among the COVID-19 positive women who required only inward treatment in comparison to women with severe COVID-19 infection requiring intensive care (AOR=0.276, CI=0.112-0.683, p=0.005).

ConclusionIncreased severity of maternal COVID-19 infection and pre-pregnancy overweight/ obesity were associated with many adverse pregnancy and neonatal outcomes. Therefore, close observation and aggressive management of COVID-19 among the pregnant women should be considered to reduce the risk of progressing to severe illness.

category: obstetrics and gynecology


title: Socio-economic deprivation and cancer incidence in England: Quantifying the role of smoking

abstract:
BackgroundMore deprived populations typically experience higher cancer incidence rates and smoking prevalence compared to less deprived populations. We calculated the proportion of cancer cases attributable to smoking by socio-economic deprivation in England and estimated the impact smoking has on the deprivation gap for cancer incidence.

MethodsData for cancer incidence (2013-2017), smoking prevalence (2003-2007) and population estimates (2013-2017) were split by sex, age-group and deprivation quintile. Relative risk estimates from meta-analyses were used to estimate the population attributable fraction (PAF) for 15 cancer types associated with smoking. The deprivation gap was calculated using age-specific incidence rates by deprivation quintile.

ResultsSmoking-related cancer PAFs in England are 2.2 times larger in the most deprived quintile compared to the least deprived quintile (from 9.7% to 21.1%). If everyone had the same smoking prevalence as the least deprived quintile, 20% of the deprivation gap in cancer incidence could have been prevented. If nobody smoked, 61% of the deprivation gap could have been prevented.

ConclusionsThe majority of the deprivation gap in cancer incidence could have been prevented in England between 2013-2017 if nobody had smoked. Policy makers should ensure that tobacco control policies reduce overall smoking prevalence by tackling smoking inequalities.


title: Polygenic coronary artery disease association with brain atrophy in the cognitively impaired

abstract: The role cardiac function plays in the predilection for, and progression of, Alzheimers disease (AD), is complex and unclear. While a number of low-frequency genetic variants of large effect-size have been shown to underlie both cardiovascular disease and dementia, recent studies have highlighted the importance of common genetic variants of small-effect size, which, in aggregate, are embodied by a polygenic risk score (PRS). In this study we aim to investigate the effect of polygenic risk for coronary artery disease (CAD) on brain atrophy in AD using whole brain volume (WBV) and put our findings in context with the polygenic risk for AD and presumed small vessel disease as quantified by white matter hyperintensities (WMH). We used 730 subjects from the ADNI database to investigate PRS effects (beyond APOE) on whole brain volumes, total and regional WMH and amyloid beta across diagnostic groups. In a subset of these subjects (N=602) we utilise longitudinal changes in whole brain volume over a maximum of 24 months using the boundary shift integral approach. Linear regression and linear mixed effects models were used to investigate the effect of WMH at baseline as well as AD-PRS and CAD-PRS on whole brain atrophy and whole brain atrophy acceleration, respectively. All genetic associations were examined under oligogenic (p=1e-5) and the more variant-inclusive polygenic (p=0.5) scenarios. Our results suggest no evidence for a link between PRS score and markers of AD pathology at baseline (when stratified by diagnostic group). However, both AD-PRS and CAD-PRS were associated with longitudinal decline in WBV (AD PRS t=3.3, PFDR=0.007 over 24 months in healthy controls) and surprisingly, under certain conditions WBV atrophy is statistically more correlated with cardiac PRS than AD PRS (CAD PRS t=2.1, PFDR=0.04 over 24 months in the MCI group). Further, in our regional analysis of WMH, AD PRS beyond APOE is predictive of white matter volume in the occipital lobe in AD subjects in the polygenic regime. Finally, the rate of change of brain volume (or atrophy acceleration) may be sensitive to AD polygenic risk beyond APOE in healthy individuals (t=2, p=0.04). For subjects with mild cognitive impairment (MCI), beyond APOE, a more inclusive polygenic risk score including more variants, shows CAD PRS to be more predictive of WBV atrophy, than an oligogenic approach including fewer larger effect size variants.

category: genetic and genomic medicine


title: Half the picture: Word frequencies reveal racial differences in clinical documentation, but not their causes

abstract: Clinical notes are the best record of a providers perceptions of their patients, but their use in studying racial bias in clinical documentation has typically been limited to manual evaluation of small datasets. We investigated the use of computational methods to scale these insights to large, heterogeneous clinical text data. We found significant differences in negative emotional tone and language implying social dominance in clinical notes between Black and White patients, but identified multiple contributing factors in addition to potential provider bias, including mis-categorization of some healthcare vocabulary as emotion-related. We further found that notes for Black patients were significantly less likely to mention opioids than for White patients, potentially reflecting both inequitable access to medication and provider bias. Our analysis showed that computational tools have significant potential for studying racial bias in large clinical corpora, and identified key challenges to providing a nuanced analysis of bias in clinical documentation.

category: health informatics


title: Evaluation of the specificity and accuracy of SARS-CoV-2 rapid antigen self-tests compared to RT-PCR from 1015 asymptomatic volunteers

abstract:
ObjectiveEvaluation of the specificity and accuracy of four CE-approved SARS-CoV-2 antigen rapid self-tests (AG-ST) Anbio, Clungene, Hotgene and Mexacare.

Method1015 asymptomatic volunteers were screened for SARS-CoV-2 by means of an oropharyngeal swab taken by qualified personnel and subsequent RT-PCR testing. Each participant additionally performed nasal self-swabs for two of the four rapid antigen tests at the same day according to the manufacturers instructions. Study participants transmitted a photo and own interpretation of their test results to the study center. The results of the two self-tests provided by the participants were correlated with the results of the SARS-CoV-2 RT-PCR and independently assessed and evaluated by the study center.

ResultsNone of the volunteers tested positive upon RT-PCR, whereas 13 AG-ST showed a false positive test result (0.7 %). The highest false positivity rate was found for the Clungene test (2.1 % compared to 0.2 % for the other tests), while the highest test failure rate (invalid) was found for the Mexacare test (3.7%). The Anbio and Hotgene tests produced the fewest false positive results when evaluated by the participants and also showed the best agreement among themselves.

ConclusionSARS-CoV-2 Antigen rapid self-tests with higher false positive test rates, such as the Clungene test, or with high rates of invalid test results, such as the Mexacare test, are less suitable for screening purposes of asymptomatic study participants especially in low-prevalence settings. False positive or inadequate test results increase the burden on certified test laboratories due to verification PCR tests and cause a substantial economic loss due to unnecessary quarantine measurements and cause psychological stress in the affected study participants. In addition to earlier defined requirements for sensitivity for SARS-CoV-2 detection, a lower acceptance boundary for the false positivity rate of < 0.3% should be demanded.

category: health systems and quality improvement


title: Clinico epidemiological profile of Omicron variant of SARS CoV2 in Rajasthan

abstract:
BackgroundOmicron a new variant of SARS COV2 was first detected in November 2021. This was believed to be highly transmissible and evade immunity as a result urgent need was felt to screen all positive, identify Omicron cases and isolate them to prevent spread of infection and study their clinico-epidemiological profile.

MethodologyAll positive cases detected in state of Rajasthan during November to January beginning were selected for next generation sequencing. Processing was done as per protocol on Ion Torrent S5 system for 1210 samples and bioinformatics analysis was done.

ResultsAmong the 1210 samples tested 762(62.9%) were Delta/Delta like and other lineages, 291(24%) were Omicron and 157(12.9%) were invalid or repeat samples. Within a month the proportion of Delta and other variants was reversed, from zero omicron became 81% and delta and other variants 19%, initially all omicron cases were international travelers and their contacts but soon community transmission was seen. Majority of omicron patients were asymptomatic (56.7%) or had mild disease (33%), 9.2% had moderate symptoms and 2(0.7%) had severe disease requiring hospitalization, of which one (0.3%) died and rest (99.7%) recovered. History of vaccination was seen in 81.1%, of previous infection in 43.2%. Among the Omicron cases BA.1 (62.8%) was the predominant lineage followed by BA.2(23.7%) and B.1.529 (13.4%), however rising trends were seen initially for BA.1 and later for BA.2 also.

ConclusionIn very short time Omicron has spread in community and has taken over the preexisting Delta/Delta like and other lineages, it evades immunity, but the good part is most of the cases were asymptomatic or had mild disease and mortality rate was very low.


title: Changing dynamics of COVID-19 deaths during the SARS-CoV2 B.1.617.2 (Delta variant) outbreak in England and Wales: Reduced COVID-19 deaths among the Care Home residents.

abstract:
ObjectivesCare Homes faced crisis during the SARS-CoV2 pandemic with increased mortality and various corrective interventions were undertaken. The impact of current SARS-CoV2 B.1.617.2 (Delta variant) outbreak on COVID-19 deaths in Care Homes is not completely known.

DesignObservational study

Setting and ParticipantsWe included nationwide data of deaths from all causes and COVID-19 in England and Wales during March 7, 2020-November 26, 2021.

MethodsImpact of COVID-19 deaths in Care Homes, Hospital and Homes relative to total deaths from all causes was investigated.

ResultsDuring March 7-August 28,2020; 15,414 (29.8%) of the 51,740 COVID-19 deaths occurred in Care Homes. During August 29, 2020-May 28, 2021, there were significant decrease in COVID-19 deaths in Care Homes ([19.2%]; RR 0.64; 95%CI 0.63-0.65;p<0.0001], which significantly declined further ([8.9%]; RR 0.46; 95%CI 0.43-0.48;p<0.0001) during May 29-November 26, 2021. During the March 7-August 28, 2020; 20.0% (15,514/76,906) of all Care Home deaths were caused by COVID-19, which significantly declined to 18.5% (RR 0.92; 95%CI 0.90-0.93; p<0.0001) during August 29, 2020-May 28, 2021 and declined further to 2.5% (RR 0.13; 95% CI 0.12-0.14;p<0.0001) during May 29-November 26, 2021. Increased percentages of COVID-19 deaths occurred in Hospitals ([72.3%]; RR 1.14; 95% CI 1.1-1.15;p<0.0001) and Homes ([6.3%]; RR 1.33; 95% CI 1.27-1.40; p<0.0001) during August 29, 2020-May 28, 2021 and further increases in the Hospitals ([80.8%]; RR 1.11; 95% CI 1.10-1.12; p<0.0001) and Homes ([8.8%]; RR 1.39; 95% CI 1.31-1.47; p<0.0001) during May 29-November 26, 2021.

Conclusions and ImplicationsThere was a significantly lower number of COVID-19 deaths occurred in Care Homes and a significantly lower number of Care Homes deaths caused by COVID-19 during the Delta variant surge in England and Wales than the prior surges. Care Home residents are at highest risk for mortality, continuous monitoring and research on COVID-19 preventive interventions are essential.


title: Evaluating the effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control teams: the COG-UK hospital-onset COVID-19 infection study

abstract:
IntroductionViral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings.

MethodsWe conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data-collection period, followed by intervention periods comprising 8 weeks of  rapid (<48h) and 4 weeks of  longer-turnaround (5-10 day) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital onset COVID-19 infections (HOCIs; detected [≥]48h from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on incidence of probable/definite hospital-acquired infections (HAIs) was evaluated.

ResultsA total of 2170 HOCI cases were recorded from October 2020-April 2021, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (IRR 1.60, 95%CI 0.85-3.01; P=0.14) or rapid (0.85, 0.48-1.50; P=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8% and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2% and 11.6% of cases where the report was returned. In a per-protocol sensitivity analysis there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days.

ConclusionWhile we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days.


title: Persistence, prevalence, and polymorphism of sequelae after COVID-19 in young adults

abstract:
BackgroundCOVID-19 sequelae are poorly defined with an ambiguous pathophysiology. Persistent sequelae could have global, public health and societal ramifications. We aimed to describe sequelae presenting more than six months after COVID-19 in non-hospitalized young adults.

MethodsA prospective, longitudinal cohort study followed-up on young Swiss Armed Forces (SAF) personnel. The comprehensive test battery was administered during a single full day of testing at the University of Zurich. It quantified the impact of SARS-CoV-2 infection on cardiovascular, pulmonary, neurological, renal, ophthalmological, male reproductive, psychological, and general health in addition to laboratory parameters.

ResultsWe included 501 participants (5.6% females) with a median age of 21 years (range 19-29). Cases of previous COVID -19 (>6 months (mean 10 months) since diagnosis, n=177) were compared with never infected controls (n=248). We also included more recent COVID-19 cases ([≤]6 months, n=19) and asymptomatically infected individuals (n=49). We found a significant trend towards metabolic disorders, higher Body Mass Index (BMI) (p=0.03), lower aerobic threshold (p=0.007), higher blood cholesterol (p<0.001) and low-density lipoprotein LDL levels (p<0.001) in participants> 6 months post Covid-19 when compared to controls. There were no significant differences in psychosocial questionnaire scores, ophthalmological outcomes, sperm quality or motility between controls and those infected more than 6 months previously with SARS-CoV-2.

ConclusionsYoung, previously healthy, individuals largely recover from mild infection and the multi-system impact of the infection is less that seen in older or hospitalized patients. These results may be extrapolated to health-care workers and other young workforce adults. However, the constellation of higher body mass index, dyslipidemia and lower physical endurance 6 months post COVID-19 is suggestive of a higher risk of developing metabolic disorders and possible cardiovascular complications. These findings will guide investigation and follow-up management.


title: Underdispersion in the reported Covid-19 case and death numbers may suggest data manipulations

abstract: We suggest a statistical test for underdispersion in the reported Covid-19 case and death numbers, compared to the variance expected under the Poisson distribution. Screening all countries in the World Health Organization (WHO) dataset for evidence of underdispersion yields 21 country with statistically significant underdispersion. Most of the countries in this list are known, based on the excess mortality data, to strongly undercount Covid deaths. We argue that Poisson underdispersion provides a simple and useful test to detect reporting anomalies and highlight unreliable data.


title: Language Matters - Representations of the term heart failure in English discourse: a large-scale linguistic study

abstract:
AimsHeart failure (HF) has a lower public profile compared to other serious health conditions, notably cancer. This discourse analysis study investigates the extent to which HF is discussed in general contemporary English, UK parliamentary debates, and the ways in which HF is framed in discussions, when compared to two other serious health conditions, cancer and dementia.

MethodsThe Oxford English Corpus of 21st century English-language texts (2 billion words) and the UK Hansard Reports of parliamentary debates from 1945 to early 2021 were used to investigate the relative frequencies, contexts of use of the terms  heart failure,  cancer and  dementia.

ResultsIn the Oxford English Corpus, the term  heart failure occurs 4.26 times per million words (pmw),  dementia occurs 3.68 times pmw and  cancer occurs 81.96 times pmw. Cancer is talked about 19 times more often than HF and 22 times more often than dementia. These are disproportionately high in relation to actual incidence: annual cancer incidence is 1.8 times that of the other conditions; annual cancer mortality is twice that caused by coronary heart disease (including heart failure) or dementia.

 Heart failure is used much less than  cancer in UK parliamentary debates(House of Commons and House of Lords) between 1945 and early 2021, and less than  dementia from 1990 onwards. Moreover, HF is even mentioned much less than potholes in UK roads and pavements. In 2018, for example,  pothole/s were mentioned over 10 times pmw, 37 times more often than  heart failure, mentioned 0.28 times pmw. Discussions of HF are comparatively technical and formulaic, lacking the survivor narratives that occur in discussions of cancer.

ConclusionsHF is under-discussed in contemporary English compared to cancer and dementia. HF is also under-discussed in UK parliamentary debates, even compared to the less-obviously life threatening topic of potholes in roads and pavements.

What is already known on this topicHeart failure is a serious health condition with significant morbidity and mortality, which is comparable to other serious health conditions such as cancer.

What this study addsOur study has shown that heart failure is less frequently discussed in contemporary English as well as in UK parliamentary debates in comparison to other serious health conditions such as cancer and dementia, despite comparably significant adverse outcomes and also that discussions regarding people with heart failure are less empowering in comparison to discussions regarding cancer.

How this study might affect research, practice or policy?Results of this study should motivate all stakeholders involved in heart failure to redouble their efforts to spread awareness regarding the seriousness of the condition in general discourse as well as to engage parliamentarians better and thereby exert influence upon commissioners to significantly improve investment in prevention, early diagnosis and better management of heart failure.

category: cardiovascular medicine


title: Persistence of SARS-CoV-2 immunity, Omicron's footprints, and projections of epidemic resurgences in South African population cohorts.

abstract:
Understanding the build-up of immunity with successive SARS-CoV-2 variants and the epidemiological conditions that favor rapidly expanding epidemics will facilitate future pandemic control. High-resolution infection and serology data from longitudinal household cohorts in South Africa reveal high cumulative infection rates and durable cross-protective immunity conferred by prior infection in the pre-Omicron era. Building on the cohorts history of past exposures to different SARS-CoV-2 variants and vaccination, we use mathematical models to explore the fitness advantage of the Omicron variant and its epidemic trajectory. Modelling suggests the Omicron wave infected a large fraction of the population, leaving a complex landscape of population immunity primed and boosted with antigenically distinct variants. Future SARS-CoV-2 resurgences are likely under a range of scenarios of viral characteristics, population contacts, and residual cross-protection.

One Sentence SummaryClosely monitored population in South Africa reveal high cumulative infection rates and durable protection by prior infection against pre-Omicron variants. Modelling indicates that a large fraction of the population has been infected with Omicron; yet epidemic resurgences are plausible under a wide range of epidemiologic scenarios.


title: Syndromic surveillance for severe acute respiratory infections (SARI) enables valid estimation of COVID-19 hospitalization incidence and reveals underreporting of hospitalizations during pandemic peaks of three COVID-19 waves in Germany, 2020-2021

abstract:
ObjectiveWith the emergence of coronavirus disease 2019 (COVID-19) countries had to establish COVID-19 surveillance by adapting existing systems, such as the mandatory notification system and syndromic surveillance systems. We estimated COVID-19 hospitalization and ICU burden from existing severe acute respiratory infections (SARI) surveillance and compared it to COVID-19 notification data.

MethodsUsing data from the ICD-10 based hospital sentinel, we estimated SARI incidence and validated our estimations retrospectively using full population data. We estimated age-specific incidences for COVID-19 hospitalization and ICU for the first three COVID-19 waves in Germany, based on information of SARI cases (COVID-SARI). We compared these estimations to hospitalization and ICU burden of COVID-19 from notification data and described potential underreporting of hospitalizations in notification data.

FindingsThe estimation of SARI incidence from sentinel data corresponded very well to full population data. The estimated COVID-SARI incidence matched the notified COVID-19 hospitalization incidence in the first wave, but was much higher during the second and the third wave. The proportion of unknown hospitalization status among notified COVID-19 cases was much higher in the later waves compared to the first wave. For all waves, the ICU incidence estimated from COVID-SARI was considerably higher than the results from notification data.

ConclusionThe use of SARI sentinel data adds valid and important information for assessing COVID-19 hospitalization and ICU burden, especially in times with high case numbers where notification data may be more incomplete.


title: Excess COVID-19 associated deaths among the unvaccinated population >= 18 years old in the US, May 30 through December 4, 2021

abstract: Vaccines against SARS-CoV-2 were authorized at the end of 2020 and are effective in preventing deaths; however, many persons remain unvaccinated. Using weekly publicly available CDC data of COVID-19-associated death rates by age and vaccination status from 26 US jurisdictions, we estimated the number of excess deaths that might have been averted by vaccination among unvaccinated persons [≥] 18 years old from May 30 to December 4, 2021. We subtracted the death rate in the vaccinated from rates in the unvaccinated to estimate the death rate each week that could be attributable to non-vaccination and multiplied this rate difference by the number of people in the unvaccinated group for each age group and each week, to estimate the excess mortality among the unvaccinated. Then, we extrapolated the number of deaths due to non-vaccination in the 26 jurisdictions to the whole US population using 2020 census estimates. In the 26 participating jurisdictions there were an estimated 83,400 excess deaths among the unvaccinated from May 30 to December 4, 2021. The largest number of excess deaths occurred in those 65-79 years old (n=28,900; 34.7% of total), followed by those 50-64 years old (n=25,900; 31.1%). Extrapolated to the US population we estimated approximately 135,000 excess deaths during the study period in persons [≥]18 years old. Our estimates are an underestimate of all excess deaths that have occurred since vaccine became available because our analysis period was limited to May 30 to December 4, 2021, and many excess deaths occurred before and after this period. In summary, we used retrospective data to estimate the substantial number of COVID-19-associated deaths among the unvaccinated illustrating the importance of vaccination to prevent further unnecessary mortality during this pandemic.


title: Excess COVID-19-associated deaths among the unvaccinated population >= 18 years old in the United States, May 30 through December 4, 2021


title: Development and validation of radiomics nomograms for preoperative prediction of characteristics in non-small cell lung cancer and circulating tumor cells

abstract:
PurposeTo develop and validate three radiomics nomograms for preoperative prediction of pathological and progression diagnosis in non-small cell lung cancer (NSCLC) as well as circulating tumor cells (CTCs).

Patients and methodsA total of 224 and 134 patients diagnosed with NSCLC were respectively gathered in 2018 and 2019 in this study. There were totally 1,197 radiomics features that were extracted and quantified from the images produced by computed tomography (CT). Then we selected the radiomics features with predictive value by LASSO and combined them into radiomics signature. Logistic regression models were built using radiomics signature as the only predictor, which were then converted to nomograms for individualized predictions. Finally, the performance of the nomograms was assessed on both two cohorts.

ResultsAs for discrimination, the AUC of pathological diagnosis nomogram and progression diagnosis nomogram in NSCLC were both higher than 90% in the training cohort and higher than 80% in the validation cohort. The performance of the CTC-diagnosis nomogram was somehow unexpected where the AUC were range from 60% to 70% in both two cohorts. As for calibration, nonsignificant statistics (p>0.05) yielded by Hosmer-Lemeshow tests suggested no departure between model prediction and perfect fit. Additionally, decision curve analyses demonstrated the clinically usefulness of the nomograms.

ConclusionWe developed radiomics-based nomograms for pathological, progression and CTC diagnosis prediction in NSCLC, respectively. Nomograms for pathological and progression diagnosis were demonstrated well performed to facilitate the preoperative individualized prediction, while the nomogram for CTC-diagnosis prediction needed improvement.


title: Nerve excitability as a biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.

abstract:
ObjectiveTo determine which nerve excitability outcome measures are potential biomarkers for ALS via systematic review and meta-analysis.

MethodsPotential studies were identified from the following databases: MEDLINE, PubMed Central, CINAHL Plus, EMBASE, HealthSTAR, Scopus, and Web of Science up to March 2020. Only studies performed in human participants and assessing median motor axons were included. Forest Plot analyses using a random-effects model to determine pooled effect (Z-score), heterogeneity (I2) and Cohens d were used to identify potential biomarkers.

ResultsFrom 2866 studies, 26 (patients=942, controls=719) were used in the systematic review and 23 in the meta-analysis. Seven axonal excitability indices met the three criteria for: significant Z-score, heterogeneity I2<40% and Cohens d >0.2 (in descending rank order): TEd 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing, and subexcitability. A sensitivity analysis restricted to patients with  early ALS indicated that four indices are potential early biomarkers of ALS (Z ranging from 2.99 to 2.16, in descending rank order): TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC.

ConclusionSeven excitability indices differentiate ALS patients from healthy controls, four of which may serve as early biomarkers for ALS. The candidate biomarkers may be used to monitor disease progression, predict survivability, and measure treatment response in clinical trials. High quality diagnostic test accuracy studies are warranted to firmly establish the utility of these indices in individuals suspected of an ALS diagnosis.


title: Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

abstract:
ImportanceAn evidence-based appraisal of the COVID-19 vaccination policies among people with multiple sclerosis (pwMS) with respect to disease-modifying therapies (DMT) is important for our understandings and their further management.

ObjectiveTo synthesize the available evidence concerning the effect of DMTs on COVID-19 vaccination immunogenicity and effectiveness.

Data SourcesWe searched MEDLINE, Scopus, Web of Science, MedRxiv, and Google Scholar from January 2021 until January 2022.

Study SelectionThe exclusion criteria included: not a primary investigation; retracted/withdrawn; no eligible participants - people with no history/evidence of previous COVID-19 and corticosteroid administration within two months of vaccination; no eligible exposures - all nine DMT classes; and no eligible comparators - DMT-unexposed at the time of vaccination.

Data Extraction and SynthesisEntries were assessed independently by two reviewers for eligibility and quality. Dichotomized data was extracted by two reviewers in accordance with Cochrane guidelines, and were pooled using either Peto fixed-effects or Inverse-variance random-effects methods.

Main Outcomes and MeasuresMain outcomes were i) B-cell response, measured by seroconversion odds ratio (OR); ii) T-cell response, measured by interferon-gamma release response OR, and CD4+/CD8+ activation-induced marker+ OR. Further outcomes including immunity waning speed and breakthrough COVID-19 incidence/severity were synthesized narratively.

ResultsData from 28 studies (5,025 pwMS and 1,635 healthy participants) after COVID-19 vaccination suggests mildly-lower B-cell responses in teriflunomide- and alemtuzumab-treated, extensively-lower B-cell responses in sphingosine-1-phosphate receptor modulator (S1PRM)- and anti-CD20 (aCD20)-treated, and lower T-cell responses in interferon-, S1PRM-, alemtuzumab- and cladribine-treated pwMS. Every ten-week increase in aCD20-to-vaccine period is associated with a 1.94-time (95%CI: 1.57, 2.41, P<0.00001) increase in odds of seroconversion. B-cell-depleting therapies seem to accelerate post-vaccination humoral waning, and booster immunogenicity is predictable with the same factors affecting the priming vaccination. Furthermore, comparatively-increased breakthrough COVID-19 incidence and severity is being observed only among S1PRM- and anti-CD20-treated pwMS - i.e., among the pwMS with extensively-blunted B-cell response, despite adequate T-cell responses in the aCD20-treated. To date, pwMS on only-T-cell-blunting DMTs have not shown increased susceptibility to breakthrough COVID-19.

Conclusion and RelevanceThe implemented vaccination strategy to date has been effective for pwMS on all DMTs other than S1PRM and aCD20. As B-cell immunity seems to be a more important predictor of vaccine effectiveness than T-cell immunity, optimization of humoral immunogenicity and ensuring its durability among pwMS on DMTs are the necessities of an effective COVID-19 vaccination policy.


title: Healthcare utilization and expenditure among people with type 2 diabetes and/or hypertension in Cambodia: results from a cross-sectional survey

abstract:
ObjectiveTo assess utilization of public and private healthcare, related healthcare expenditure, and associated factors for people with type 2 diabetes (T2D) and/or hypertension (HTN) and for people without those conditions in Cambodia.

MethodsA cross-sectional household survey.

SettingsFive operational districts in Cambodia.

ParticipantsData was from 2,360 participants aged [≥] 40 years who had used healthcare services at least once in the three months preceding the survey.

Primary and secondary outcomeThe main variables of interest were the number of healthcare visits and healthcare expenditure in the last three months.

ResultsThe majority of healthcare visits took place in the private sector. Only 22.0% of healthcare visits took place in public healthcare facilities: 21.7% in people with HTN, 37.2% in people with T2D, 34.7% in people with T2D plus HTN, and 18.9% in people without the two conditions (P-value<0.01). In people with T2D and/or HTN, increased public healthcare use was significantly associated with Health Equity Fund (HEF) membership and living in operational districts with community-based care. Furthermore, significant healthcare expenditure reduction was associated with HEF membership and using public healthcare facilities in these populations.

ConclusionOverall public healthcare utilization was relatively low; however, it was higher in people with chronic conditions. HEF membership and community-based care contributed to higher public healthcare utilization among people with chronic conditions. Using public healthcare services regardless of HEF status reduced healthcare expenditure, but the reduction in spending was more noticeable in people with HEF membership. To increase public healthcare utilization among people with T2D and/or HTN, the public healthcare system should further improve care quality, expand social health protection, and expand community-based care for this population. However, these may require more time and resources. One potential strategy in the short run is to partner the private sector with the public sector.

STRENGTHS AND LIMITATIONS OF THIS STUDY{blacksquare} Our study is among the few to examine healthcare utilization and expenditure among people with two major chronic conditions type 2 diabetes (T2D) and/or hypertension (HTN) in Cambodia, in comparison with the people without the two conditions.
{blacksquare}The findings in this study provides could inform decision-makers about strategies for T2D and HTN management in Cambodia and similar settings.
{blacksquare}Our study is not representative for the national level as most of the study sites we selected were rural or semi-rural.
{blacksquare}We only calculated the healthcare expenditure for those who used the service in the three months preceding the study, which cannot be generalized to the target population in the study (people aged 40 years or older).


title: Comparing Sexual Network Mean Active Degree Measurement Metrics among Men who have Sex with Men

abstract:
BackgroundMean active degree is an important proxy measure of network connectivity in HIV/STI epidemiology. The performance of different degree estimands are not known for men who have sex with men (MSM) in the United States, especially within the context of fixed choice designs in behavioral surveys.

MethodsWe compared estimates of mean active degree based on reported ongoing main and casual partnerships (current method) against dates of first and last sex (retrospective method) in ARTnet, a cross-sectional survey of U.S. MSM with partnership reporting limited to the 5 most recent partners. We used linear regression to understand the impact of this data truncation on differences between the current and retrospective methods.

ResultsRetrospective estimates declined as the offset was shifted backwards in time. Among participants with more than 5 total past-year partners compared to those with 5 or fewer partners, the average change in main degree between 12- and 0-month offsets was -0.05 (95% CI: -0.08, -0.03) after adjusting for demographics. The adjusted average change in casual degree was -0.40 (95% CI: -0.45, -0.35).

ConclusionsThe retrospective method underestimates mean degree in surveys that limit partner reporting, especially for offsets further from the survey date and for casual partnerships.


title: Adequacy of serial self-performed SARS-CoV-2 rapid antigen-detection testing for longitudinal mass screening in the workplace

abstract:
ImportanceLongitudinal mass testing using rapid antigen detection tests (RADT) for serial screening of asymptomatic persons has been proposed for preventing SARS-CoV-2 community transmission. The feasibility of this strategy relies on implementation of accurate self-performed RADT testing where people live, work, or attend school.

ObjectiveTo quantify the adequacy of serial self-performed SARS-CoV-2 RADT testing in the workplace, in terms of the frequency of correct execution of procedural steps and accurate interpretation of the range of possible RADT results. We compared results using the instructions provided by the manufacturer to those with modified instructions that were informed by the most frequent or most critical errors we observed.

DesignRepeated cross-sectional, diagnostic accuracy study performed prospectively in the field.

SettingBusinesses in Montreal, Quebec, Canada, with at least 2 active cases of SARS-CoV-2 infection.

ParticipantsUntrained, asymptomatic persons in their workplace, not meeting Public Health quarantine criteria.

ExposuresA Modified Quick Reference Guide compared to the original manufacturers instructions.

Main Outcome(s) and Measure(s)The difference in the proportions of correctly performed procedural steps, and the difference in proportions of correctly interpreted RADT proficiency panel results. The secondary outcome, among subjects with two self-testing visits, compared the second to the first self-test visit using the same measures.

ResultsOverall, 1892 tests were performed among 647 subjects. For self-test visit 1, significantly better accuracy in test interpretation was observed using the Modified Quick Reference Guide for weak positive (55.6% vs. 12.3%; 43.3 percentage point improvement, 95% confidence interval [CI] 33.0%-53.8%), positive (89.6% vs. 51.5%; 38.1% difference, 95%CI 28.5%-47.5%), strong positive (95.6% vs. 84.0%; 11.6% improvement, 95%CI 6.8%-16.3%) and invalid (87.3% vs. 77.3%; 10.0% improvement, 95%CI 3.8%-16.3%) tests. Use of the modified guide was associated with smaller, statistically significant, improvements on self-test visit 2. For procedural steps identified as critical for the validity of test results, adherence to procedural testing steps did not differ meaningfully according to instructions provided or reader experience.

Conclusions and RelevanceLongitudinal mass RADT testing for SARS-CoV-2 can be accurately self-performed in an intended-use setting; this work provides evidence for how to optimise performance.

Key PointsO_ST_ABSQuestioC_ST_ABSDo untrained users correctly perform and interpret the results of SARS-CoV-2 rapid antigen detection tests (RADT) in the workplace, and how can their performance be optimised?

FindingsIn this prospective field evaluation of self-performed SARS-CoV-2 RADT in an intended-use setting, we found that the accuracy of RADT interpretation was poor when the manufacturers instructions were used. A Modified Quick Reference Guide yielded significantly better user performance.

MeaningLongitudinal mass RADT testing for SARS-CoV-2 can be accurately self-performed in an intended-use setting; this work provides evidence for how to optimise performance.


title: Empirical evidence of transmission over a school-household network for SARS-CoV-2; exploration of transmission pairs stratified by primary and secondary school.

abstract:
BackgroundChildren play a key role in the transmission of many infectious diseases. They have many of their close social encounters at home or at school. We hypothesized that most of the transmission of respiratory infections among children occur in these two settings and that transmission patterns can be predicted by a bipartite network of schools and households.

Aim and methodsTo confirm transmission over a school-household network, SARS-CoV-2 transmission pairs in children aged 4-17 years were analyzed by study year and primary/secondary school. Cases with symptom onset between the 1st of March 2021 and the 4th of April 2021 identified by source and contact-tracing in the Netherlands were included. In this period, primary schools were open and secondary school students attended class at least once per week. Within pairs, spatial distance between the postcodes was calculated as the Euclidean distance.

ResultsA total of 4,059 transmission pairs were identified; 51.9% between primary schoolers; 19.6% between primary and secondary schoolers; 28.5% between secondary schoolers. Most (68.5%) of the transmission for children in the same study year occurred at school. In contrast, most of the transmission of children from different study years (64.3%) and most primary-secondary transmission (81.7%) occurred at home. The average spatial distance between infections was 1.2km (median 0.4) for primary school pairs, 1.6km (median 0) for primary-secondary school pairs and 4.1km (median 1.2) for secondary school pairs.

ConclusionThe results provide evidence of transmission on a bipartite school-household network. Schools play an important role in transmission within study years, and households play an important role in transmission between study years and between primary and secondary schools. Spatial distance between infections in a transmission pair reflects the smaller school catchment area of primary schools versus secondary schools. Many of these observed patterns likely hold for other respiratory pathogens.


title: The UCLA ATLAS Community Health Initiative: promoting precision health research in a diverse biobank

abstract: The UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system, with the goal of creating a genomic database to accelerate precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHR). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with a de-identified EHR extract. This database enables the study of numerous clinically-related phenotypes within the same medical system. Here we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome-wide and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.


title: Unpacking COVID-19 and Conspiracy Theories in the UK Black Community

abstract:
ObjectivesConspiracy theories are associated with significant COVID-19 health consequences including lower engagement with protective behaviours. This study uses sensemaking theory, a process of constructing meanings through interpersonal exchanges that enable people to interpret their world to explain the theoretical process underlying the development of conspiratorial beliefs around COVID-19 within Black African and Caribbean communities in the UK.

DesignQualitative, in-depth interviews were used.

MethodsTwenty-eight members of the communities were recruited; semi-structured interviews were analysed using grounded theory.

ResultsOur findings provide an explanation of how an environment of crisis combined with current and historical mistrust, perceived injustice and inequality provided a context in which alternative conspiracy narratives could thrive. The nature of these conspiratorial beliefs made more sense to many of our respondents than institutional sources (such as the UK Government). Critically, these alternative beliefs helped respondents shape their decision-making, leading to non-engagement with COVID protective behaviours.

ConclusionsWe conclude that the uncertainty of the pandemic, combined with historical and contemporary perceived injustice and mistrust, and a lack of specific identity-aligned messaging, created a perfect environment for conspiratorial sense-making to thrive. This alternative sensemaking was inconsistent with the health-protection messaging espoused by Government. To ensure all groups in society are protected, and for health promotion messages to take purchase, the experiences of different target audiences must be taken into account, with sensemaking anchored in lived experience.


title: Genetic scores explain variation in birthweight that is not captured by easily measured clinical and anthropometric variables

abstract:
BackgroundHuman birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables.

MethodsWe analysed 549 European-ancestry parent-offspring trios. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models.

ResultsMaternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 =0.233 vs Adj-R2=0.210, p<0.001). Fetal genetic score improved variance explained (Adj-R2=0.264 vs 0.248, p<0.001) when added to maternal characteristics and parental heights.

ConclusionsGenetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.

Key messagesO_LIKnown contributors to variation in birthweight include (i) factors associated with the maternal intrauterine environment (e.g. maternal glycaemia or smoking), and (ii) parental heights, which capture some of the genetic contribution to fetal growth. However, the added contribution of genetic scores composed of common birthweight-associated variants has not been assessed.
C_LIO_LIWe showed, using 549 parent-offspring trios, that maternal and fetal genetic scores explained additional variation in sex-and gestational age-adjusted birthweight, when added to maternal variables that are easily obtained in a clinical setting (age, weight, smoking, parity and 28-week fasting glucose).
C_LIO_LIParental heights explained variance in birthweight independently of routinely measured maternal clinical variables, but the maternal and fetal (or paternal) genetic scores made additional, independent contributions to birthweight variance.
C_LIO_LIThe genetic score contribution was modest, but it was comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.
C_LIO_LISince this work was limited to a UK sample of European ancestry, it will, however, be important to test the relative contributions of genetics and other factors to birthweight variation in diverse populations.
C_LI


title: Quantifying political influence on COVID-19 fatality in Brazil

abstract: The COVID-19 pandemic was severely aggravated in Brazil due to its politicization by the countrys central government. However, the impact of diffuse political forces on the fatality of an epidemic is commonly hard to quantify. Here we introduce a method to measure this effect in the Brazilian case, based on the inhomogeneous distribution throughout the national territory of political support to the central government. The correlation between fatality rate and political support grows as the governments misinformation campaign is developed, leading to the dominance of such political factor for the pandemic impact in Brazil in 2021. Once this dominance is established, this correlation allows for an estimation of the total number of deaths due to political influence as 350 {+/-} 70 thousands up to the end of 2021.


title: On the in vivo kinetics of gene delivery vectors

abstract:
Gene therapy is the most promising strategy for treating a number of diseases at their most fundamental, genetic level, and it has a wide range of promising clinical and emerging preclinical uses in both the clinic and the laboratory. Gene therapy systems are composed of three fundamental components, with the delivery platform being responsible for the protection and successful delivery of the incorporated therapeutic nucleic acid sequences. A successful delivery platform is critical in the achievement of a therapeutic outcome, and an effective delivery platform is essential in achieving this. A variety of different gene delivery platforms - vectors - are evaluated in this dissertation in terms of their nature, mechanism of action, potential applications, and safety. Of particular importance is the evaluation of their post-delivery pharmacokinetic and adverse drug-metabolite profiles. The different types of vectors, including viral, non-viral, and alternative vectors, are discussed separately in each chapter, while important issues related to the incorporation of these vectors into clinical practice are discussed as well, including the topics of vector development and manufacturing, as well as the current regulatory landscape and efforts to improve it, and finally their prospects for the immediate future.

ContextGene delivery vectors consist of a broad spectrum of natural or synthetically produced vehicles that represent one out of the three essential aspects of each gene delivery system, without which the successful and effective (in terms of the clinical translation) delivery of therapeutic nucleic acids to a diseased mal- or sub-functioning cell would be impossible.

ObjectiveThe presentation and evaluation of the in vivo pharmacokinetic behavior of different viral and non viral gene delivery vectors including a wide review of their mechanism of action, possible safety concerns as well as the promise each holds for future applications.

Data SourcesA systematic literature search was conducted using the electronic databases PubMed, Google Scholar and Science Direct while also utilizing the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The keywords included in the research effort were the following: viral vectors, adeno-associated viral vectors, non viral vectors, oncolytic vectors, novel gene delivery vectors, pharmacokinetics of viral vectors, retroviral vectors, recombinant adeno-associated viral vectors, toxicity of gene delivery vectors, Vitravene, Oncorene, Approved gene delivery vectors.

Study SelectionCase studies and review articles published in scientifically accepted, high impact factor journals focused on gene delivery vectors and published in English between the years 1999 to 2021 in order to include the most significant findings in terms of both well established data through the years as well as the most recent breakthroughs in terms of preclinical and clinical application.

Data ExtractionEssential information were retrieved regarding the various types, behavior, mechanisms of action, safety and in vivo pharmacokinetic behavior of the most prominent viral and non viral gene delivery vectors.

ResultsOf a total of 186 records a total of 36 full text articles were reviewed covering a total of 92 case studies and review articles on the topic of the pharmacokinetic behavior of gene delivery vectors including promising future considerations for their clinical use.

LimitationsThe outcome of this review article was limited by findings that were shared between different articles published in a variety of literary platforms as well as from papers that lacked sufficient details in order to be included.

ConclusionThis scoping review has examined what is currently known and recently discovered regarding the wholesome of the aspects of utilizing specific gene delivery vehicles for a variety of different therapeutic purposes. Their nature, characteristics, as well as their individual action once inserted into the organism and/or in a variety of different in vivo experiments was examined and the implication of their use regarding their shortcomings and possible dangers, as well as their therapeutic advantages and probable future applications were weighted.

category: pharmacology and therapeutics


title: A methodology for selection and quality control of the radiological computer vision deployment at the megalopolis scale

abstract:
In recent years, there has been tremendous interest in the use of artificial intelligence (AI) in radiology in order to automate the interpretation. However, uncontrolled and widespread use of AI solutions may have negative consequences. Therefore, before implementing such technologies in healthcare, thorough training of personnel, adaptation of information systems, and standardized datasets for an external validation are required. All this necessitates a formation of a unique unified methodology. The best practices of AI introduction in diagnostic radiology are still subject to debate and require new results of a scientific-practical research with the assessment of implementation conditions.

This work discusses expected issues and potential solutions for the introduction of computer vision-based technologies for automatic analysis of radiological examinations with an emphasis on the real-life experience gained during simultaneous AI implementation into practice of more than a hundred state radiology departments in 2020-2021 in Moscow, Russia (an experiment). The experiment used end-user software testing approaches, quality assurance of AI-based radiological solutions, and accuracy assessment of the AI-empowered diagnostic tools on local data. The methods were adapted and optimized to ensure a successful real-life radiological AI deployment on the extraordinary large scale. The experiment involved in total around thousand diagnostic devices and thousand radiologists. AI deployment was associated with additional options in a routine radiologists workflow: triage; additional series formed by AI with indication of pathological findings and their classification; report template prepared by AI in accordance with the target clinical task, user feedback on AI performance.

A multi-stage methodology for implementing AI into radiological practice that was developed and advanced during the experiment is described in this report.

EssentialsO_LIA methodology for the AI deployment for non-academic radiological sites excluded more than half of the offered AI solutions that do not fulfill the diagnostic and functional requirements
C_LIO_LIQuality control of AI should be supported by not only data scientists, IT specialists or engineers, but also by radiologists at all stages of selection and testing.
C_LIO_LIRadiologists need to understand the capabilities, limitations of AI by getting an additional training.
C_LI

category: radiology and imaging


title: Risk of severe COVID-19 in patients with inflammatory rheumatic diseases treated with immunosuppressive therapy in Scotland

abstract:
ObjectivesTo investigate the association of severe COVID-19 in those with inflammatory rheumatic diseases (IRD) treated with immunosuppressive drugs.

MethodsA list of 4633 patients on biologics and targeted synthetic (ts) DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland.

ResultsBy 22 November 2021 433 of the 4633 patients treated with biologics and tsDMARDs had been diagnosed with COVID-19, of whom 58 had been hospitalised. With all those in the population not on DMARDs as reference category, the rate ratio for hospitalised COVID-19 associated with DMARD treatment was 2.14 (95% CI 2.02 to 2.26) in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38 to 2.91) in those on TNF inhibitors as the only biologic agent, and 3.83 (95% CI 2.65 to 5.56) in those on other biologic agents. Among those on csDMARDs, rate ratios for hospitalised COVID-19 were lowest at 1.66 (95% CI 1.51 to 1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4 to 6.7) in those on glucocorticoids at average dose >10 mg/day prednisolone equivalent.

ConclusionThe risk of hospitalised COVID-19 is elevated in IRD patients treated with immunosuppressive drugs. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk, JAK inhibitors and B-cell depleting agents a higher risk and prednisolone the highest risk. A larger study is needed to estimate reliably the risks associated with each class of biologic agent.

Key messagesO_LIRisk of hospitalised COVID-19 is about twofold higher in IRD patients treated with immunosuppressive therapies - csDMARDS or biologics - than in the general population.
C_LIO_LIRisk is lowest in those treated with methotrexate, hydroxychoroquine and TNF inhibitors. Of the other biologic drugs, treatment with B cell depleters and JAK inhibitors is associated with higher risk but the numbers are too small for risk associated with each drug class to be estimated reliably.
C_LIO_LIThe risk of severe COVID-19 with glucocorticoids at a dose greater than 10 mg/day prednisolone equivalent is higher than that of any other drug class studied.
C_LI

category: rheumatology


title: FOLIC ACID AND METHOTREXATE USE AND THEIR ASSOCIATION WITH COVID-19 DIAGNOSIS AND MORTALITY: AN ANALYSIS FROM THE UK BIOBANK

abstract:
ImportanceFolate metabolism is implicated in SARS-CoV-2 infectivity. Medication affecting folate metabolism may influence the risk of COVID-19 diagnosis and outcomes.

Objectiveto determine if methotrexate (an antifolate) or folic acid prescription were associated with differential risk, for COVID-19 diagnosis or mortality.

Design, Setting, and ParticipantsCase-control analysis of COVID-19 from the population-based UK Biobank (UKBB) cohort. Updated medical information was retrieved on the 13th December 2021. Data from 380,380 UKBB participants with general practice prescription data for 2019 to 2021 were used. Criteria for COVID-19 diagnosis were 1) a positive SARS-CoV-2 test or 2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria 26,003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, BMI, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.

ExposuresPrescription of folic acid and/or methotrexate.

Main outcomes and measuresThe outcomes of COVID-19 diagnosis and COVID-19 related mortality were analyzed by multivariable logistic regression. The odds ratios from different exposures were compared.

ResultsCompared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 [1.42 ; 1.61]). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (P[≥]0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 [2.15 ; 3.24]) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19 related death (1.07 [0.57 ; 1.98]).

Conclusions and RelevanceWe report increased risk for COVID-19 diagnosis and COVID-19-related death for people prescribed folic acid supplementation. Prescription and use of supplemental folic acid may confer increased risk of infection with SARS-CoV-2 and increased risk of death resulting from COVID-19. Our results indicate that methotrexate attenuates an increased risk for COVID-19 diagnosis and death conferred by folic acid.

Key PointsO_ST_ABSQuestionC_ST_ABSDoes folate supplementation and/or methotrexate use affect the risk COVID-19 diagnosis and COVID-19 associated mortality?

FindingsIn this epidemiological analysis from the UK Biobank, folic acid supplementation was associated with a 1.5-fold increased risk of COVID-19 diagnosis and a 2.6-fold increased risk of COVID-19 associated mortality. Methotrexate use might attenuate an increased risk for COVID-19 diagnosis and death conferred by folic acid.

MeaningFolic acid supplementation appears to be associated with increased risk for COVID-19 diagnosis and associated mortality while methotrexate use attenuated this risk


title: A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer

abstract:
ImportanceIdentifying patients at higher risk of chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet need given its high incidence, persistence, and detrimental effect on quality of life.

ObjectiveTo determine if expression of p16, a biomarker of aging and cellular senescence, predicts CIPN.

DesignProspective observational cohort study including one hundred fifty-two participants enrolled between January 2014 and August 2018 and followed during the course of adjuvant chemotherapy. Expression of p16 was measured prior to and at the end of chemotherapy. Side effects, including peripheral neuropathy, were assessed prior to each chemotherapy cycle.

SettingA multi-center study including four major academic hospitals and five community oncology clinics.

ParticipantsWomen with newly diagnosed with stage I to III breast cancer to receive chemotherapy including a taxane.

Main Outcomes and MeasureDevelopment of grade 2+ (moderate or worse) CIPN during the course of chemotherapy. CIPN symptoms were graded by participants oncology clinician using the NCI-CTCAE v5 system. Expression of p16 mRNA was measured by qPCR in T-lymphocytes isolated from fresh peripheral blood.

ResultsA multivariate model including taxane regimen type and p16Age Gap, a measure of discordance between chronological age and p16 expression, identified risk factors for CIPN. Participants with higher chronological age but lower p16 expression prior to chemotherapy (molecularly young) were at the highest risk. Incidence of CIPN positively correlated with chemotherapy-induced increase in p16 expression, with the largest increase seen in participants with the lowest p16 expression prior to treatment.

Conclusions and RelevanceThis is the first report using a biomarker of senescence in a model to identify patients at risk for taxane-induced CIPN. Studies to confirm and validate our findings are ongoing. When validated, a p16Age Gap-based model can be used to guide chemotherapy selection in patients with early breast cancer and identify patients at high risk who may be candidates for preventive trials.

Key PointsO_ST_ABSQuestionC_ST_ABSIs cellular senescence an independent risk factor for chemotherapy-induced peripheral neuropathy?

FindingsIn a prospective observational cohort study of women with early-stage breast cancer undergoing treatment with taxane chemotherapy, a regression model containing a measure of cellular senescence and taxane type was a statistically significant predictor of grade 2+ CIPN incidence.

MeaningCellular senescence is an independent risk factor for CIPN that, if validated, could guide treatment selection and identify high-risk patients for preventive strategies.

category: oncology


title: POST-ACUTE SEQUELAE AND ADAPTIVE IMMUNE RESPONSES IN PEOPLE LIVING WITH HIV RECOVERING FROM SARS-COV-2 INFECTION

abstract:
BackgroundLimited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH).

MethodsWe measured SARS-CoV-2 specific humoral and cellular immune responses in people with and without HIV recovering from COVID-19 (n=39 and n=43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing symptomatic post-acute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T cell responses, as well as differences in the prevalence of PASC.

ResultsAmong PWH, we found broadly similar SARS-CoV-2-specific antibody and T cell immune responses as compared with a well-matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2 specific memory CD8+ T cells (p=0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2 specific CD4+ T cells (p=0.007). Higher CD4/CD8 ratio was associated with lower PD-1 expression on SARS-CoV-2 specific CD8+ T cells (0.34-fold effect, p=0.02). HIV status was strongly associated with PASC (odds ratio 4.01, p=0.008), and the proportion of PD-1+ CD4+ T cells and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms.

ConclusionsWe identified potentially important differences in SARS-CoV-2-specific CD4+ and CD8+ T cells that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.