title: Health indicators as a measure of individual health status: public perspectives

abstract:
ObjectiveWe examined the perspectives of the general public on 29 health indicators to provide evidence for further prioritizing the indicators, which were obtained from the literature review. Health status is different from disease status, which can refer to different stages of cancer.

DesignThis study uses a cross-sectional design.

SettingAn online survey was administered through Ohio University, ResearchMatch, and Clemson University.

ParticipantsParticipants included the general public who are 18 years or older. A total of 1153 valid responses were included in the analysis.

Primary outcomes measuresParticipants rated the importance of the 29 health indicators. The data were aggregated, cleaned, and analyzed in three ways: (1) to determine the agreement among the three samples on the importance of each indicator (IV = the three samples, DV = individual survey responses); (2) to examine the mean differences between the retained indicators with agreement across the three samples (IV = the identified indicators, DV = individual survey responses); and (3) to rank the groups of indicators after grouping the indicators with no mean differences (IV = the groups of indicators, DV = individual survey responses).

ResultsThe descriptive statistics indicate that the top-five rated indicators are drug or substance abuse, smoking or tobacco use, alcohol abuse, major depression, diet and nutrition. The importance of 13 of the 29 health indicators was agreed upon among the three samples. The 13 indicators were categorized into seven groups. Groups 1-3 were rated as significantly higher than Groups 4-7.

ConclusionsThis study provides a baseline for prioritizing further the 29 health indicators, which can be used by electronic health records or personal health record system developers. Currently, self-rated health status is used predominantly. Our study provides a foundation to track and measure preventive services more accurately and to develop an individual health status index.

Strengths and limitations of this studyO_LIThe work establishes the foundation to measure individual health status more comprehensively and objectively
C_LIO_LIThe work reflects perspectives from three communities with a relatively large sample size
C_LIO_LIThe work provides the foundation to prioritize the 29 health indicators further
C_LIO_LIWith real-world longitudinal data, the public perspective data on individual health status measurement would be verified and validated further
C_LI

category: health informatics


title: EFFECTS OF HIV INFECTION AND FORMER COCAINE DEPENDENCE ON NEUROANATOMICAL MEASURES AND NEUROCOGNITIVE PERFORMANCE

abstract: Evidence from animal research, postmortem analyses, and MRI investigations indicate substantial morphological alteration in brain structure as a function of HIV or cocaine dependence (CD). Although previous research on HIV+ active cocaine users suggests the presence of deleterious morphological effects in excess of either condition alone, a yet unexplored question is whether there is a similar deleterious interaction in HIV+ individuals with CD who are currently abstinent. To this end, the combinatorial effects of HIV and CD history on regional brain volume, cortical thickness, and neurocognitive performance was examined across four groups of participants: healthy controls, HIV-negative individuals with a history of CD, HIV+ individuals with no history of CD, HIV+ individuals with a history of CD. Our analyses revealed no statistical evidence of an interaction between both conditions on brain morphometry and neurocognitive performance. While descriptively, individuals with comorbid HIV and a history of CD exhibited the lowest neurocognitive performance scores, using Principle Component Analysis of neurocognitive testing data, HIV was identified as a primary driver of neurocognitive impairment. Higher caudate volume was evident in CD+ participants relative to CD-participants. Taken together, these data provide evidence of independent effects of HIV and CD history on brain morphometry and neurocognitive performance in cocaine-abstinent individuals.

category: hiv aids


title: Severity of SARS-CoV-2 Infection in Pregnancy in Ontario: A Matched Cohort Analysis

abstract:
BackgroundPregnancy represents a physiological state associated with increased vulnerability to severe outcomes from infectious diseases, both for the pregnant person and developing infant. The SARS-CoV-2 pandemic may have important health consequences for pregnant individuals, who may also be more reluctant than non-pregnant people to accept vaccination. We sought to estimate the degree to which increased severity of SARS-CoV-2 outcomes can be attributed to pregnancy.

MethodsOur study made use of a population-based SARS-CoV-2 case file from Ontario, Canada. Due to both varying propensity to receive vaccination, and changes in dominant circulating viral strains over time, a time-matched cohort study was performed to evaluate the relative risk of severe illness in pregnant women with SARS-CoV-2 compared to other SARS-CoV-2 infected women of childbearing age (10 to 49 years old). Risk of severe SARS-CoV-2 outcomes (hospitalization or intensive care unit (ICU) admission) was evaluated in pregnant women and time-matched non-pregnant controls using multivariable conditional logistic regression.

ResultsCompared to the rest of the population, non-pregnant women of childbearing age had an elevated risk of infection (standardized morbidity ratio (SMR) 1.28), while risk of infection was reduced among pregnant women (SMR 0.43). After adjustment for age, comorbidity, healthcare worker status, vaccination, and infecting viral variant, pregnant women had a markedly elevated risk of hospitalization (adjusted OR 4.96, 95% CI 3.86 to 6.37) and ICU admission (adjusted OR 6.58, 95% CI 3.29 to 13.18). The relative increase in hospitalization risk associated with pregnancy was greater in women without comorbidities than in those with comorbidities (P for heterogeneity 0.004).

InterpretationA time-matched cohort study suggests that while pregnant women may be at a decreased risk of infection relative to the rest of the population, their risk of severe illness is markedly elevated if infection occurs. Given the safety of SARS-CoV-2 vaccines in pregnancy, risk-benefit calculus strongly favours SARS-CoV-2 vaccination in pregnant women.

category: infectious diseases


title: Protective antibodies and T cell responses to Omicron variant three months after the booster dose of BNT162b2 vaccine

abstract: The high number of mutations in the Omicron variant of SARS-CoV-2 cause its immune escape when compared to the earlier variants of concern (VOC). At least three vaccine doses are required for the induction of Omicron neutralizing antibodies and further reducing the risk for hospitalization. However, most of the studies have focused on the immediate response after the booster vaccination while the duration of immune response is less known. We here studied longitudinal serum samples from the vaccinated individuals up to three months after their third dose of the BNT162b2 vaccine for their capacity to produce protective antibodies and T cell responses to Wuhan and Omicron variants. After the second dose, the antibody levels to the unmutated spike protein were significantly decreased at three months, and only 4% of the individuals were able to inhibit Omicron spike interaction compared to 47%, 38%, and 14% of individuals inhibiting wild-type, delta, and beta variants spike protein. Nine months after the second vaccination, the antibody levels were similar to the levels before the first dose and none of the sera inhibited SARS-CoV-2 wild-type or any of the three VOCs. The booster dose remarkably increased antibody levels and their ability to inhibit all variants. Three months after the booster the antibody levels and the inhibition activity were trending lower but still up and not significantly different from their peak values at two weeks after the third dose. Although responsiveness towards mutated spike peptides was lost in less than 20 % of vaccinated individuals, the wild-type spike-specific CD4+ and CD8+ memory T cells were still present at three months after the booster vaccination in the majority of studied individuals. Our data show that two doses of the BNT62b2 vaccine are not sufficient to protect against the Omicron variant, however, the spike-specific antibodies and T cell responses are strongly elicited and well maintained three months after the third vaccination dose.


title: The mutational steps of SARS-CoV-2 to become like Omicron within seven months: the story of immune escape in an immunocompromised patient.

abstract: We studied a unique case of prolonged viral shedding in an immunocompromised patient that generated a series of SARS-CoV-2 immune escape mutations over a period of seven months. During the persisting SARS-CoV-2 infection seventeen non-synonymous mutations were observed, thirteen (13/17; 76.5%) of which occurred in the genomic region coding for spike. Fifteen (15/17; 88.2%) of these mutations have already been described in the context of variants of concern and include the prominent immune escape mutations S:E484K, S:D950N, S:P681H, S:N501Y, S:del(9), N:S235F and S:H655Y. Fifty percent of all mutations acquired by the investigated strain (11/22) are found in similar form in the Omicron variant of concern. The study shows the chronology of the evolution of intra-host mutations, which can be seen as the straight mutational response of the virus to specific antibodies and should therefore be given special attention in the rating of immune escape mutations of SARS-CoV-2.


title: Q3: An ICU Acuity Score for Exploring the Effects of Changing Acuity Throughout the Stay

abstract:
IntroWe develop a straightforward ICU acuity score (Q3) that is calculated every 3 hours throughout the first 10 days of the ICU stay. Q3 uses components of the Oxford Acute Severity of Illness Score (OASIS) and incorporates a new component score for vasopressor use. In well-behaved models of ICU mortality, the marginal effects of Q3 are significant across the first 10 days of the ICU stay. In separate models, Q3 has significant effects on ICU remaining length of stay. The score has implications for work that seeks to explain modifiable mechanisms of changing acuity during the ICU stay.

MethodsFrom the MIMIC-III database, select ICU stays from 5 adult ICUs were partitioned into consecutive 3-hour segments. For each segment, the number of vasopressors administered and all 10 OASIS component scores were computed. Models of ICU mortality were estimated. OASIS component effects were examined, and vasopressor count bins were weighted. Q3 was defined as the sum of 8 retained OASIS components and a new weighted vasopressor score. Models of ICU mortality quadratic in Q3 were estimated for each of the first 10 ICU days and were subjected to segment-level, location-specific tests of discrimination and calibration on newer ICU stays. Marginal effects of Q3 were computed at different levels of Q3 by ICU day, and average marginal effects of Q3 were computed at each location by ICU day. ICU remaining length of stay (LOS) models were also estimated and the effects of Q3 were similarly examined.

ResultsDaily ICU mortality models using Q3 show no evidence of misspecification (Pearson-Windmeijer p>0.05, Stukel p>0.05), discriminate well in all ICUs over the first 10 days (AUROC [~] 0.72 - 0.85), and are generally well calibrated (Hosemer-Lemeshow p>0.05, Spiegelhalters z p>0.05). A one-unit increase in Q3 from typical levels (Q3=15) affects the odds of ICU mortality by a factor of 1.14 to 1.20, depending on ICU day (p<0.001), and the ICU remaining LOS by 5.8 to 9.6% (p<0.001). On average, a one-unit increase in Q3 increases the probability of ICU mortality by 1 to 2 percentage points depending on location and ICU day, and ICU remaining LOS by 5 to 10 hours depending on location and ICU day.

ConclusionQ3 significantly affects ICU mortality and ICU remaining LOS in different ICUs across the first 10 days of the ICU stay. Depending on location and ICU day, a one-unit increase in Q3 increases the probability of ICU mortality by or 1-2 percentage points and ICU remaining LOS by 5 to 10 hours. Unlike static acuity scores or those updated infrequently, Q3 could be used in explanatory models to help elucidate mechanisms of changing ICU acuity.

category: intensive care and critical care medicine


title: Platelet Dependent Thrombogenicity, Inflammation and Five Year Mortality in Patients with Non-ST Elevation Acute Coronary Syndrome and Type 2 Diabetes Mellitus: An Observational Study

abstract:
Platelet dependent thrombogenicity is higher in type 2 diabetes mellitus (T2DM) but there is no data on association between thrombus and mortality or vascular inflammation.

We studied 80 patients who received guideline based therapy (40 T2DM) after NSTE-ACS. Platelet dependent thrombus was assessed using the validated ex vivo Badimon Chamber and all patients were followed up for five years. Bio-markers of coagulation and inflammation were measured.

There were 17 (21.3%) deaths in total (12 in the T2DM, 71% of all deaths), at 5 years. Of the patients who died, thrombus burden was higher ({micro}2 per mm, Mean {+/-} SD, 12,164 {+/-} 3235 vs 9,751 {+/-} 4333). Serum inflammatory cytokines, P selectin and soluble CD40 ligand were higher in T2DM. Univariate analysis showed thrombus area, diabetic status, age, interleukin 1 and P selectin were independent predictors of mortality. Inflammatory biomarkers were associated with thrombus burden. If these findings can be proven in large scale studies, this will lead on to novel therapeutic strategies especially in the current Covid 19 pandemic which has renewed our interest of this interplay of pathophysiology between thrombus and inflammation.

category: cardiovascular medicine


title: Sociodemographic Differences in Population-Level Immunosenescence in Older Age

abstract:
BackgroundThe COVID-19 pandemic has highlighted the urgent need to understand variation in immunosenescence at the population-level. Thus far, population patterns of immunosenescence are not well described.

MethodsWe characterized measures of immunosenescence from newly released venous blood data from the nationally representative U.S Health and Retirement Study (HRS) of individuals ages 56 years and older.

FindingsMedian values of the CD8+:CD4+, EMRA:Naive CD4+ and EMRA:Naive CD8+ ratios were higher among older participants and were lower in those with additional educational attainment. Generally, minoritized race and ethnic groups had immune markers suggestive of a more aged immune profile: Hispanics had a CD8+:CD4+ median value of 0.37 (95% CI: 0.35, 0.39) compared to 0.30 in Whites (95% CI: 0.29, 0.31). Blacks had the highest median value of the EMRA:Naive CD4+ ratio (0.08; 95% CI: 0.07, 0.09) compared to Whites (0.03; 95% CI: 0.028, 0.033). In regression analyses, race/ethnicity and education were associated with large differences in the immune ratio measures after adjustment for age and sex. For example, each additional level of education was associated with roughly an additional decade of immunological age, and the racial/ethnic differences were associated with two to four decades of additional immunological age.

InterpretationOur study provides novel insights into population variation in immunosenescence. This has implications for both risk of age-related disease and vulnerability to novel pathogens (e.g., SARS-CoV-2).

FundingThis study was partially funded by the U.S. National Institutes of Health, National Institute on Aging R00AG062749. AEA and GAN acknowledge support from the National Institutes of Health, National Institute on Aging R01AG075719. JBD acknowledges support from the Leverhulme Trust (Centre Grant) and the European Research Council grant ERC-2021-CoG-101002587

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlterations in immunity with chronological aging have been consistently demonstrated across human populations. Some of the hallmark changes in adaptive immunity associated with aging, termed immunosenescence, include a decrease in naive T-cells, an increase in terminal effector memory cells, and an inverted CD8:CD4 T cell ratio. Several studies have shown that social and psychosocial exposures can alter aspects of immunity and lead to increased susceptibility to infectious diseases.

Add value of this studyWhile chronological age is known to impact immunosenescence, there are no studies examining whether social and demographic factors independently impact immunosenescence. This is important because immunosenescence has been associated with greater susceptibility to disease and lower immune response to vaccination. Identifying social and demographic variability in immunosenescence could help inform risk and surveillance efforts for preventing disease in older age. To our knowledge, we present one of the first large-scale population-based investigations of the social and demographic patterns of immunosenescence among individuals ages 50 and older living in the US. We found differences in the measures of immunosenescence by age, sex, race/ethnicity, and education, though the magnitude of these differences varied across immune measures and sociodemographic subgroup. Those occupying more disadvantaged societal positions (i.e., minoritized race and ethnic groups and individuals with lower educational attainment) experience greater levels of immunosenescence compared to those in less disadvantaged positions. Of note, the magnitude of effect of sociodemographic factors was larger than chronological age for many of the associations.

Implications for practice or policy and future researchThe COVID-19 pandemic has highlighted the need to better understand variation in adaptive and innate immunity at the population-level. While chronological age has traditionally been thought of as the primary driver of immunological aging, the magnitude of differences we observed by sociodemographic factors suggests an important role for the social environment in the aging human immune system.

category: epidemiology


title: Epidemiology of Respiratory Viruses in Acute Respiratory Illness in Malaysia: Patterns, Seasonality and Age Distribution

abstract:
ObjectivesAcute Respiratory Infections (ARIs) are one of the leading causes of childhood morbidity and mortality worldwide. However, there is limited surveillance data on the epidemiological burden of respiratory pathogens in tropical countries like Malaysia. This study aims to estimate the prevalence of respiratory pathogens causing ARIs among children aged <18 years old in Malaysia and their epidemiological characteristics.

MethodsNasopharyngeal swab specimens received at 12 laboratories located in different states of Malaysia from 2015-2019 were studied. Detection of 18 respiratory pathogens were performed using multiplex PCR.

ResultsData from a total of 23,306 paediatric patients who presented with ARI over a five-year period was studied. Of these, 18538 (79.5%) were tested positive. The most prevalent respiratory pathogens detected in this study were enterovirus/ rhinovirus (6837/ 23000; 29.7%), influenza virus (5176/ 23000; 22.5%) and respiratory syncytial virus (RSV) (3652/ 23000; 15.9%). Throughout the study period, RSV demonstrated the most pronounce seasonality; peak infection occurred during July to September. Whereas the influenza virus was detected year-round in Malaysia. No seasonal variation was noted in other respiratory pathogens. The risk of RSV hospitalisation was found to be significantly higher in children aged less than two years old, whereas hospitalisation rates for the influenza virus peaked at children aged between 3-6 years old.

ConclusionsThis study provides insight into the epidemiology and the seasonality of the causative pathogens of ARI among the paediatric population in Malaysia. Knowledge of seasonal respiratory pathogens epidemiological dynamics will facilitate the identification of a target window for vaccination.


title: Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts

abstract:
BackgroundPrenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the U.S. Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies.

ResultsIn placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI: - 1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value<0.01 (EARLI cord nCpGs=4,068, EARLI placenta nCpGs =3,647, MARBLES cord nCpGs =4,068, MARBLES placenta nCpGs=9,563) were consistently enriched in neuronal developmental pathways.

ConclusionsTogether, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.


title: Bladder Cancer Prognosis Using Deep Neural Networks and Histopathology Images

abstract: Recent studies indicate bladder cancer is among the top 10 most common cancer in the world [1]. Bladder cancer frequently reoccurs, and prognostic judgments may vary among clinicians. Classification of histopathology slides is essential for accurate prognosis and effective treatment of bladder cancer patients, as a favorable prognosis might help to inform less aggressive treatment plans. Developing automated and accurate histopathology image analysis methods can help pathologists in determining the prognosis of bladder cancer. In this study, we introduced Bladder4Net, a deep learning pipeline to classify whole-slide histopathology images of bladder cancer into two classes: low-risk (combination of PUNLMP and low-grade tumors) and high-risk (combination of high-grade and invasive tumors). This pipeline consists of 4 convolutional neural network (CNN) based classifiers to address the difficulties of identifying PUNLMP and invasive classes. We evaluated our pipeline on 182 independent whole-slide images from the New Hampshire Bladder Cancer Study (NHBCS) [22] [23] [24] collected from 1994 to 2004 and 378 external digitized slides from The Cancer Genome Atlas (TCGA) database [26]. The weighted average F1-score of our approach was 0.91 (95% confidence interval (CI): 0.86-0.94) on the NHBCS dataset and 0.99 (95% CI: 0.97-1.00) on the TCGA dataset. Additionally, we computed Kaplan-Meier survival curves for patients predicted as high-risk versus those predicted as low-risk. For the NHBCS test set, patients predicted as high-risk had worse overall survival than those predicted as low-risk, with a Log-rank P-value of 0.004. If validated through prospective trials, our model could be used in clinical settings to improve patient care.

category: pathology


title: Social capital, urbanization level, and COVID-19 vaccination uptake in the United States: A national level analysis

abstract: Vaccination remains the most promising mitigation strategy for the COVID-19 pandemic. However, existing literature shows significant disparities in vaccination uptake in the United States. Using publicly available national-level data, we aimed to explore if county-level social capital can further explain disparities in vaccination uptake rate adjusting for demographic and social determinants of health (SDOH) variables; and if association between social capital and vaccination uptake may vary by urbanization level. Bivariate analyses and hierarchical multivariable quasi-binomial regression analysis were conducted, then the regression analysis was stratified by urban-rural status. The current study suggests that social capital contributes significantly to the disparities of vaccination uptake in the US. The results of stratification analysis show common predictors of vaccine uptake but also suggest various patterns based on urbanization level regarding the associations of COVID-19 vaccination uptake with SDOH and social capital factors. The study provides a new perspective to address disparities in vaccination uptake through fostering social capital within communities, which may inform tailored public health intervention efforts in enhancing social capital and promoting vaccination uptake.

category: public and global health


title: A new compartment model of COVID-19 transmission: The broken-link model

abstract: We propose a new compartment model of COVID-19 spread, the broken-link model, which includes the effect from unconnected infectious links of the transmission. The traditional SIR-type epidemic models are widely used to analyze the spread status, and the models show the exponential growth of the number of infected people. However, even in the early stage of the spread, it is proven by the actual data that the exponential growth did not occur all over the world. We consider this is caused by the suppression of secondary and higher transmissions of COVID-19. We find that the proposed broken-link model quantitatively describes the mechanism of this suppression and is consistent with the actual data.


title: Executable models of pathways built using single-cell RNA seq data reveal immune signaling dysregulations in people living with HIV and atherosclerosis

abstract:
BackgroundAtherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk of atherosclerosis has been attributed to viral infection, prolonged usage of anti-retroviral therapy, and subsequent chronic inflammation.

MethodsTo investigate dysregulated immune signaling in PLWH with and without AS, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from 8 PLWH, 4 of whom also had atherosclerosis (AS+). To develop executable models of signaling pathways that drive cellular states in HIV-associated atherosclerosis, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. ScBONITA (a) uses single-cell RNA sequencing data to infer Boolean rules for topologically characterized networks, (b) prioritizes genes based on their impact on signaling, (c) performs pathway analysis, and (d) maps sequenced cells to characteristic signaling states. We used scBONITA to identify dysregulated pathways in different cell-types from AS+ PLWH and AS-PLWH. To compare our findings with pathways associated with HIV infection, we used scBONITA to analyze a publicly available dataset of PBMCs from subjects before and after HIV infection. Additionally, the executable Boolean models characterized by scBONITA were used to analyze observed cellular states corresponding to the steady states of signaling pathways

ResultsWe identified an increased subpopulation of CD8+ T cells and a decreased subpopulation of monocytes in AS+ PLWH. Dynamic modeling of signaling pathways and pathway analysis with scBONITA provided a new perspective on the mechanisms of HIV-associated atherosclerosis. Lipid metabolism and cell migration pathways are induced by AS rather than by HIV infection. These pathways included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Further analysis of other cell subpopulations suggests that the highly interconnected PI3K-AKT signaling pathway drives cell migratory state in response to dyslipidemia. scBONITA attractor analysis mapped cells to pathway-specific signaling states that correspond to distinct cellular states.

ConclusionsDynamic network modeling and pathway analysis with scBONITA indicates that dysregulated lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Attractor analysis with scBONITA facilitated pathway-based characterization of cellular states that are not apparent in gene expression analyses.


title: Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

abstract:
BackgroundRandomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit.

MethodsWe searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation.

ResultsEleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 - 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 - 1.44; I2 = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 - 0.69; I2 = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 - 2.56) with no interaction for dosing and clinical setting.

ConclusionIntensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs.

SummaryIn this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding.


title: Impact of the COVID-19 pandemic on breast cancer screening indicators in a Spanish population-based program: a cohort study

abstract:
BackgroundTo assess the effect of the COVID-19 pandemic on performance indicators in the population-based breast cancer screening program of Parc de Salut Mar (PSMAR), Barcelona, Spain.

MethodsWe conducted a before-and-after, quasi-experimental study to evaluate participation, recall, false-positives, cancer detection rate, and cancer characteristics in our screening population from March 2020 to March 2021 compared with the four previous rounds (2012-2019). Using independent logistic regression models, we estimated the adjusted odds ratios (aOR) of each of the performance indicators for the COVID-19 period, controlling by type of screening (prevalent or incident), socioeconomic index, family history of breast cancer, and menopausal status. We analyzed 144,779 observations from 47,571 women.

ResultsDuring the COVID-19 period, the odds of participation were 11% lower in first-time invitees (aOR=0.89[95%CI=0.84-0.96]) and in those who had previously participated regularly and irregularly (aOR=0.65 [95%CI=0.61-0.69] and aOR=0.93 [95%CI=0.85-1.03], respectively). Participation showed a modest increase in women not attending any of the previous rounds (aOR=1.07 [95%CI=0.99-1.17]). The recall rate slightly decreased in both prevalent and incident screening (aOR=0.89 [95%CI=0.78-1.01] and aOR=0.89 [95%CI=0.79-1.00], respectively). No significant differences were observed in false-positives (prevalent - aOR=1.07 [95%CI=0.92-1.24] and incident screening -aOR=0.94 [95%CI=0.82-1.08]), cancer detection rate (aOR=0.91 [95%CI=0.69-1.18]), or cancer stages.

ConclusionsThe COVID-19 pandemic negatively affected screening attendance, especially in previous participants and newcomers. We found no marked differences in recall, false-positives, or cancer detection, indicating the programs resilience. There is a need for further evaluations of interval cancers and potential diagnostic delays.


title: Topical anticholinergic medications for primary hyperhidrosis: A protocol for systematic review and meta-analysis

abstract:
IntroductionPrimary hyperhidrosis (PHH) is a chronic condition characterized by excessive sweating. Several topical anticholinergic agents have been developed, but the evidence for the efficacy and tolerability of changing medication pathways of anticholinergics for PHH is limited.

Methods and analysisPubMed, the Cochrane Library, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials will be searched from inception to March 2022 for studies that may be eligible for inclusion. Randomized controlled trials (RCTs) of PHH treated by topical anticholinergic drugs will be included. The primary outcomes include severity of hyperhidrosis measured quantitatively, the Hyperhidrosis Disease Severity Scale (HDSS) score or the proportion of subjects with a minimum 2-grade improvement from baseline in HDSS, the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) score and Dermatology Life Quality Index (DLQI). The secondary outcomes focused on safety and tolerability. Study selection, data extraction and assessment of risk of bias will be performed by two investigators independently. Data synthesis will be performed with RevMan 5.4 software.

Ethics and disseminationEthical approval will not be needed in this review due to no data are involved in patients information and privacy. The results will be published and diffused in a peer-reviewed journal or relative conferences.

Strengths and limitations of this studyThis systematic review will be the first to evaluate the efficacy and safety of topical anticholinergic agents in the treatment of PHH.

Different inclusion criteria between studies and different skin sites where drugs applied may lead to clinical heterogeneity, which will be explored in the subgroup analysis.

This study will also focus on evaluating systemic and topical safety and tolerability of topical application of anticholinergics.

category: dermatology


title: Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region

abstract: The COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define  Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures "regional herd exposure" and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.


title: Intentions and willingness to engage in risky driving behaviour among high school adolescents: evaluating the bstreetsmart road safety program

abstract:
Objectiveinvestigate the impact of a road-safety program on adolescent willingness to engage in risky behaviour as probationary drivers, adjusted for covariates of interest.

Methodbstreetsmart is a road-safety program delivered to around 25,000 adolescent students annually in New South Wales. Using a smart phone-based app, student and teacher participation incentives, students were surveyed before and after program attendance. Mixed methods linear regression analysed pre-post modified Behaviour of Young Novice Driver (BYNDS_M) scores.

Results2360 and 1260 students completed pre- and post-event surveys respectively. Post-event BYNDS_M scores were around 3 points lower than pre-event scores (-2.99, 95%CI - 3.418 to -2.466), indicating reduced intention to engage in risky driving behaviours. Covariates associated with higher stated intentions of risky driving were exposure to risky driving as a passenger (1.21, 95% CI 0.622-2.011), identifying as non-binary gender (20.8, 95% CI 8.795 to 40.852), adjusting for other predictors.

ConclusionsTrauma-informed, reality-based injury prevention programs are effective in changing short term stated intentions to engage in risky driving, among a pre-independent driving student population. The adolescent novice driver age group is historically challenging to engage, and injury prevention action must be multi-pronged to address the many factors influencing their behaviour.

What is already known on this topicRoad traffic injuries are the leading cause of death for adolescents in most developed countries globally. Injury prevention action must be multi-pronged to address the many factors influencing their behaviour

What this study addsThe bstreetsmart injury prevention intervention which incorporates trauma informed, CBT influence and reality-based road safety information to around 25,000 students annually, showed significant short-term impact on the stated willingness of the study population to engage in risky driving behaviour when obtaining their probationary licence. Adolescents are strongly influenced by examples of risky road behaviours among their closest adult drivers.

How this study might affect research, practice, or policyInterventions such as bstreetsmart hold a positive place in the multi-pronged approach needed to address the difficult issue of novice drivers.


title: Changing dynamics of SARS-CoV2 B.1.617.2 (Delta variant) outbreak in the United Kingdom: Shifting of SARS-CoV2 infections from younger to elderly populations with increasing hospitalizations and mortality among elderly.

abstract:
BackgroundTo assess the comprehensive dynamics of outcomes during the SARS-CoV2 B.1.617.2 (Delta variant) compared to the Alpha variant outbreak in the United Kingdom.

MethodsIn this observational study of the cases reported by Public Health England for confirmed (sequencing and genotyping), SARS-CoV2 cases Delta variant (n=592,692) and Alpha variant (n=150,934) were used. Outcomes were analyzed by age groups and compared with all reported weekly cases in the UK.

ResultsThe Delta variant surge is associated with a significantly lower case fatality rate (0.43% vs 1.07; RR 0.39; 95% CI 0.37-0.42; P<0.0001); lower odds of hospitalization (2.1% vs 3.0%; RR 0.70; 95% CI 0.68-0.73; P<0.0001) than the Alpha variant. During the Delta variant surge there were significant increased cases (11.3% to 21.1%, RR 1.87; 95% CI 1.84-1.89; P<0.0001), hospitalizations (40.2% to 56.5%; RR 1.40, 95% CI 1.3-1.46; P<0.0001) among confirmed Delta variant cases in the [≥]50 years age group during the August 3-September 12, 2021 period compared to earlier reported cases. There was also a significant increase in total weekly COVID-19 deaths noted among [≥]70 years old age group (71.4% to 75.1%; RR 1.05; 95% CI 1.01-1.08; P=0.0028) during August 6-October 8, 2021 compared to June 4-July 30, 2021 period.

ConclusionsThe Delta variant surge is associated with significantly lower mortality and hospitalizations than the Alpha variant. As the Delta variant surge progressed, [≥]50 years old had a significant increased percentage of cases, hospitalizations and a significant increased COVID-19 deaths occurred among [≥]70 years old age group.


title: Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis

abstract: This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV; or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N=5,245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2 patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2 patients (RR 0.21, 95%CI 0.09-0.46; RR 0.24, 95%CI 0.11-0.48); no improvement was observed among HFO2 patients. Improved early and late recovery was observed among LFO2 patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2 and LFO2 patients.


title: GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19.

abstract: Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.


title: Culture and identification of a Deltamicron SARS-CoV-2 in a three cases cluster in southern France

abstract: Multiple SARS-CoV-2 variants have successively, or concommitantly spread worldwide since summer 2020. A few co-infections with different variants were reported and genetic recombinations, common among coronaviruses, were reported or suspected based on co-detection of signature mutations of different variants in a given genome. Here we report three infections in southern France with a Delta 21J/AY.4-Omicron 21K/BA.1 "Deltamicron" recombinant. The hybrid genome harbors signature mutations of the two lineages, supported by a mean sequencing depth of 1,163-1,421 reads and mean nucleotide diversity of 0.1-0.6%. It is composed of the near full-length spike gene (from codons 156-179) of an Omicron 21K/BA.1 variant in a Delta 21J/AY.4 lineage backbone. Importantly, we cultured an isolate of this recombinant and sequenced its genome. It was observed by scanning electron microscopy. As it is misidentified with current variant screening qPCR, we designed and implemented for routine diagnosis a specific duplex qPCR. Finally, structural analysis of the recombinant spike suggested its hybrid content could optimize viral binding to the host cell membrane. These findings prompt further studies of the virological, epidemiological, and clinical features of this recombinant.


title: The relative impact of vaccination momentum on COVID-19 rates of death in the USA in 2020/2021. The forgotten role of population wellness.

abstract:
It is widely accepted that individual underlying health conditions contribute to morbidity and mortality associated with COVID-19; and by inference population wellness will also contribute to COVID-19 outcomes. In addition, over the last two years the predominant pharmaceutical public health response to COVID-19 has been vaccination momentum (i.e. mass and rapid inoculation campaigns).

This paper aims to compare vaccination momentum throughout 2021 and measures of population wellness to estimate the relative impact of each on deaths attributed to COVID-19 across the 50 States of America, plus Washington DC, during 2020 (i.e. the pre-vaccination period) and 2021 (i.e. the vaccination period).

Our analysis shows that: (a) COVID-19 rates of death in 2020 are more important, and statistically more significant, at predicting rates of death in 2021 than vaccination momentum during 2021; (b) vaccination momentum does not predict the magnitude of change in COVID-19 rates of death between 2020 and 2021; and (c) for several underlying heath and risk factors vaccination momentum is significantly less important than population wellness at predicting COVID-19 rates of death.

Of particular interest are our observations that exercise and fruit consumption are 10.1 times more significant at predicting COVID-19 deaths than vaccination momentum, obesity (BMI 30+) is 9.6 times more significant at predicting COVID-19 deaths than vaccination momentum, heart attacks are 4.37 times more significant at predicting COVID-19 deaths than vaccination momentum and smoking is 3.2 times more significant at predicting COVID-19 deaths than vaccination momentum.

If medical and health regulators are to deliver a quantum decrease in COVID-19 deaths they must move beyond the overwhelming focus on COVID-19 vaccination. They must have the courage to urge governments and private organisations to mandate greater exercise, weight loss, less junk food, and better nutrition. And a concerted effort at reducing chronic adverse health conditions.


title: Improving the diagnosis of endometrial hyperplasia using computerized analysis and immunohistochemical biomarkers

abstract:
Endometrial hyperplasia (EH) is a precursor lesion to endometrial carcinoma (EC). Risks for EC include genetic, hormonal and metabolic factors most notably those associated with obesity: rates are rising and there is concern that cases in pre-menopausal women may remain undetected. Making an accurate distinction between benign and pre-malignant disease is both a challenge for the pathologist and important to the gynaecologist who wants to deliver the most appropriate care to meet the needs of the patient. Premalignant change may be recognised by histological changes of endometrial hyperplasia (which may occur with or without atypia) and endometrial intraepithelial neoplasia (EIN).

In this study we created a tissue resource of EH samples diagnosed between 2004 and 2009 (n=125) and used this to address key questions: 1. Are the EIN/WHO2014 diagnostic criteria able to consistently identify premalignant endometrium? 2. Can computer aided image analysis inform identification of EIN? 3. Can we improve diagnosis by incorporating analysis of protein expression using immunohistochemistry.

Our findings confirmed the inclusion of EIN in diagnostic criteria resulted in a better agreement between expert pathologists compared with the previous WHO94 criteria used for the original diagnosis of our sample set. A computer model based on assessment of stromal:epithelial ratio appeared most accurate in classification of areas of tissue without EIN. From an extensive panel of putative endometrial protein tissue biomarkers a score based on assessment of HAND2, PTEN and PAX2 was able to identify four clusters one of which appeared to be more likely to be benign.

In summary, our study has highlighted new opportunities to improve diagnosis of pre-malignant disease in endometrium and provide a platform for further research on this important topic.

HighlightsO_LIBlinded re-analysis of n=125 samples previously classified as endometrial hyperplasia found improved intra-observer agreement (67%) using EIN/WHO2014 compared with standard WHO1994 criteria (52%)
C_LIO_LIComputerised analysis of endometrial hyperplasia tissue architecture showed promise as a tool to assist pathologists in diagnosis of difficult to classify cases
C_LIO_LIA diagnosis of endometrial intraepithelial neoplasia (EIN) using the WHO2014 criteria more accurately predicted risk of endometrial cancer than WHO1994 system.
C_LIO_LIEIN samples exhibited altered expression of ARID1A (negative glands) and HAND2 (reduced or absent from stroma)
C_LIO_LIUnsupervised hierarchical cluster analysis based on immunostaining for PTEN, PAX2 and HAND2 identified 4 subtypes one of which segregated with benign disease.
C_LIO_LIThese results provide a framework for improved classification of pre-malignant lesions in endometrium that may inform personalized care pathways
C_LI

category: obstetrics and gynecology


title: Population-based whole-genome sequencing with constrained gene analysis identifies predisposing germline variants in children with central nervous system tumors

abstract:
BackgroundThe underlying cause of central nervous system (CNS) tumors in children is largely unknown. In this nationwide, prospective population-based study we investigate rare germline variants across known and putative CPS genes and genes exhibiting evolutionary intolerance of inactivating alterations in children with CNS tumors.

MethodsOne hundred and twenty-eight children with CNS tumors underwent whole-genome sequencing of germline DNA. Single nucleotide and structural variants in 315 cancer related genes and 2,986 highly evolutionarily constrained genes were assessed. A systematic pedigree analysis covering 3,543 close relatives was performed.

ResultsThirteen patients harbored rare pathogenic variants in nine known CPS genes. The likelihood of carrying pathogenic variants in CPS genes was higher for patients with medulloblastoma than children with other tumors (OR 5.9, CI 1.6-21.2). Metasynchronous CNS tumors were observed exclusively in children harboring pathogenic CPS gene variants (n=2, p=0.01).

In general, known pCPS genes were shown to be significantly more constrained than both genes associated with risk of adult-onset malignancies (p=5e-4) and all other genes (p=5e-17). Forty-seven patients carried 66 loss-of-functions variants in 60 constrained genes, including eight variants in six known pCPS genes. A deletion in the extremely constrained EHMT1 gene, formerly somatically linked with sonic hedgehog medulloblastoma, was found in a patient with this tumor.

Conclusions{bsim}10% of pediatric CNS tumors can be attributed to rare variants in known CPS genes. Analysis of evolutionarily constrained genes may increase our understanding of pediatric cancer susceptibility.

3 key pointsO_LI{bsim}10% of children with CNS tumors carry a pathogenic variant in a known cancer predisposition gene
C_LIO_LIKnown pediatric-onset cancer predisposition genes show high evolutionary constraint
C_LIO_LILoss-of-function variants in evolutionarily constrained genes may explain additional risk
C_LI

Importance of this studyAlthough CNS tumors constitute the most common form of solid neoplasms in childhood, our understanding of their underlying causes remains sparse. Predisposition studies often suffer from selection bias, lack of family and clinical data or from being limited to SNVs in established cancer predisposition genes. We report the findings of a prospective, population-based investigation of genetic predisposition to pediatric CNS tumors. Our findings illustrate that 10% of children with CNS tumors harbor a damaging alteration in a known cancer gene, of which the majority (9/13) are loss-of-function alterations. Moreover, we illustrate how recently developed knowledge on evolutionarily loss-of-function intolerant genes may be used to investigate additional pediatric cancer risk and present EHMT1 as a putative novel predisposition gene for SHH medulloblastoma. Previously undescribed links between variants in known cancer predisposition genes and specific brain tumors are presented and the importance of assessing both SV and SNV is illustrated.

category: genetic and genomic medicine


title: Nurses' experience of using video consultation in a digital care setting and its impact on their workflow and communication

abstract: Sweden as many other countries uses video consultation to increase patients access to primary healthcare services particularly during the COVID-19 pandemic. Working in digital care settings and using new technologies, in this case video consultations, require learning new skills and adoption to new workflow. The aim of this study is to explore nurses experience of using video consultation in a digital care setting and its impact on their workflow and communication. Fifteen semi-structured interviews were carried out with registered nurses recruited from a private digital healthcare provider. Interviews were recorded, transcribed, and analysed using an abductive approach. Nurses workflow was modeled, and several categories and subcategories were identified: nurses workflow (efficiency, flexibility, and information accessibility); communication (interaction with patients and interprofessional communication); user experience (change and development of the platform, challenges, and combining digital and physical care). Even though providing online care has its limitations, the nurses were positive towards using video consultations.


title: Usefulness of real-time RT-PCR to understand the kinetics of SARS-CoV-2 in blood: a prospective study.

abstract:
BackgroundSARS-CoV-2 viral load and kinetics assessed in serial blood samples from hospitalised COVID-19 patients by RT-PCR are poorly understood.

MethodsWe conducted an observational, prospective case series study in hospitalised COVID-19 patients. Clinical outcome data (Intensive Care Unit admission and mortality) were collected from all patients until discharge. Viremia was determined longitudinally during hospitalisation, in plasma and serum samples using two commercial and standardised RT-PCR techniques approved for use in diagnosis of SARS-CoV-2. Viral load (copies/mL and log10) was determined with quantitative TaqPathCOVID-19 test.

ResultsSARS-CoV-2 viremia was studied in 57 hospitalised COVID-19 patients. Persistent viremia (PV) was defined as two or more quantifiable viral loads detected in blood samples (plasma/serum) during hospitalisation. PV was detected in 16 (28%) patients. All of them, except for one who rapidly progressed to death, cleared viremia during hospitalisation. Poor clinical outcome occurred in 62.5% of patients with PV, while none of the negative patients or those with sporadic viremia presented this outcome (p<0.0001). Viral load was significantly higher in patients with PV than in those with Sporadic Viremia (p<0.05). Patients presented PV for a short period of time: median time from admission was 5 days (Range=2-12) and 4.5 days (Range=2-8) for plasma and serum samples, respectively. Similar results were obtained with all RT-PCR assays for both types of samples.

ConclusionsDetection of persistent SARS-CoV-2 viremia, by real time RT-PCR, expressed as viral load over time, could allow identifying hospitalised COVID-19 patients at risk of poor clinical outcome.

HighlightsO_LICommercial RT-PCR techniques could be used to monitor SARS-CoV-2 viremia kinetics.
C_LIO_LISARS-CoV-2 persistent viremia is related with poor outcome in COVID-19 patient.
C_LIO_LISARS-Cov-2 viremia kinetics could be used as a biomarker of poor prognosis.
C_LIO_LIPlasma samples are the best choice for analysis of SARS-CoV-2 viremia kinetics.
C_LI


title: High frequency and persistence of Anti-DSG2 antibodies in post COVID-19 serum samples

abstract:
BackgroundThere is growing recognition that COVID-19 does cause cardiac sequelae. The underlying mechanisms involved are still poorly understood to date. Viral infections, including COVID-19, have been hypothesized to contribute to autoimmunity, by exposing previously hidden cryptic epitopes on damaged cells to an activated immune system Given the high incidence of cardiac involvement seen in COVID-19, our aim was to determine the frequency of anti-DSG2 antibodies in a population of post COVID-19 patients.

Methods and Results300 convalescent serum samples were obtained from a group of post COVID-19 infected patients from October 2020 to February 2021. 154 samples were drawn 6 months post-COVID-19 infection and 146 samples were drawn 9 months post COVID infection. 17 samples were obtained from the same patient at the 6- and 9-month mark. An electrochemiluminescent-based immunoassay utilizing the extracellular domain of DSG2 for antibody capture was used. The mean signal intensity of anti-DSG2 antibodies in the post COVID-19 samples was significantly higher than that of a healthy control population (19+/-83.2 vs. 2.1+/-6.8, P value <0.001). Of note, 29.3% of the post COVID-19 infection samples demonstrated a signal higher than the 90th percentile of the control population and 8.7% were higher than the median found in ARVC patients. The signal intensity between the 6-month and 9-month samples did not differ significantly.

ConclusionsWe report for the first time that recovered COVID-19 patients demonstrate significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, comparable to that of a diagnosed ARVC group.


title: Regional variation in cardiovascular genes enables a tractable genome editing strategy

abstract: Recent rise in the number and therapeutic potential of genome engineering technologies has generated excitement in cardiovascular genetics. One significant barrier to their implementation is costly and time consuming reagent development for novel unique variants. Prior data have illuminated the potential for regional clustering of disease-causing genetic variants in known and potential novel functional protein domains. We hypothesized that most cardiovascular disease-relevant genes in ClinVar would display regional variant clustering, and that multiple variants within a regional hotspot could be targeted with limited prime editing reagents. We collated 2,471 high confidence pathogenic or likely pathogenic (P/LP) missense and truncating variants from 111 cardiovascular disease genes. We then defined a regional clustering index (RCI), the percent of P/LP variants in a given gene located within a pre-specified window around each variant. At a window size commensurate with maximally reported prime editing extension length, 78bp, we found that missense variants displayed a higher mean RCI than truncating variants. We next identified genes particularly attractive for pathogenic hotspot-targeted prime editing with at least 20 P/LP variants and observed that the mean RCI in missense variants remained higher than for truncating variants and for rare variants observed in the same genes in gnomAD (Mean{+/-}SD RCI78bp: P/LP ClinVar Missense=5.2{+/-}5.9%; P/LP ClinVar Truncating=2.1{+/-}3.2%, gnomAD Missense=2{+/-}3.2%, gnomAD Truncating=1.1{+/-}2.4%. p<2.2e-16; ANOVA with post hoc Bonferroni correction). Further, we tested the feasibility of prime editing for multiple variants in a single hotspot in KCNH2, a gene with a high mean missense variant RCI. Sixty variants were induced in this hotspot in HEK293 cells with CRISPR-X. Correction of these variants was attempted with prime editing using two overlapping prime editing guide RNA extensions. The mean prime editing efficiency across CRISPR-X-enriched variants within this hotspot was 57{+/-}27%, including 3 P/LP variants. These data underscore the utility of pathogenic variant hotspots in the diagnosis and treatment of inherited cardiovascular disease.


title: Detecting eczema areas in digital images: an impossible task?

abstract:
Assessing the severity of atopic dermatitis (AD, or eczema) traditionally relies on a face-to-face assessment by healthcare professionals, and may suffer from inter- and intra-rater variability. With the expanding role of telemedicine, several machine learning algorithms have been proposed to automatically assess AD severity from digital images. Those algorithms usually detect and then delineate ("segment") AD lesions before assessing lesional severity, and are trained using the data of AD areas detected by healthcare professionals. To evaluate the reliability of such data, we estimated the inter-rater reliability of AD segmentation in digital images.

Four dermatologists independently segmented AD lesions in 80 digital images collected in a published clinical trial. We estimated the inter-rater reliability of the AD segmentation using the intra-class correlation coefficients (ICCs) at the pixel-level and the area-levels for different resolutions of the images. The average ICC was 0.45 (SE = 0.04) corresponding to a "poor" agreement between raters, while the degree of agreement for AD segmentation varied from image to image.

The AD segmentation in digital images is highly rater-dependent even between dermatologists. Such limitations need to be taken into consideration when the AD segmentation data are used to train machine learning algorithms that assess eczema severity.


title: Predictability and Stability Testing to Assess Clinical Decision Instrument Performance for Children After Blunt Torso Trauma

abstract:
ObjectiveThe Pediatric Emergency Care Applied Research Network (PECARN) has developed a clinical-decision instrument (CDI) to identify children at very low risk of intra-abdominal injury. However, the CDI has not been externally validated. We sought to vet the PECARN CDI with the Predictability Computability Stability (PCS) data science framework, potentially increasing its chance of a successful external validation.

Materials & MethodsWe performed a secondary analysis of two prospectively collected datasets: PECARN (12,044 children from 20 emergency departments) and an independent external validation dataset from the Pediatric Surgical Research Collaborative (PedSRC; 2,188 children from 14 emergency departments). We used PCS to reanalyze the original PECARN CDI along with new interpretable PCS CDIs we developed using the PECARN dataset. External validation was then measured on the PedSRC dataset.

ResultsThree predictor variables (abdominal wall trauma, Glasgow Coma Scale Score <14, and abdominal tenderness) were found to be stable. Using only these variables, we developed a PCS CDI which had a lower sensitivity than the original PECARN CDI on internal PECARN validation but performed the same on external PedSRC validation (sensitivity 96.8% and specificity 44%).

ConclusionThe PCS data science framework vetted the PECARN CDI and its constituent predictor variables prior to external validation. In this case, the PECARN CDI with 7 predictors, and our PCS-based CDI with 3 stable predictors, had identical performance on independent external validation. This suggests that both CDIs will generalize well to new populations, offering a potential strategy to increase the chance of a successful (costly) prospective validation.

category: emergency medicine


title: The association between major trauma centre care and outcomes of adult patients injured by low falls in England and Wales.

abstract:
BackgroundDisability and death due to low falls is increasing worldwide and disproportionately affects older adults. Current trauma systems were not designed to suit the needs of these patients. This study assessed the effectiveness of major trauma centre care in adult patients injured by low falls.

MethodsData were obtained from the Trauma Audit and Research Network on adult patients injured by falls from <2 metres between 2017-2019 in England and Wales. 30-day survival, length of hospital stay and discharge destination were compared between major trauma centres (MTCs) and trauma units or local emergency hospitals (TU/LEHs).

Results127,334 patients were included of whom 27.6% attended an MTC. The median age was 79.4 years (IQR 64.5-87.2 years), and 74.2% of patients were aged >65 years. MTC care was not associated with improved 30-day survival (adjusted odds ratio [AOR] 0.91, 95% CI 0.87-0.96). Transferred patients had a significant impact upon the results. After excluding transferred patients, the AOR for survival in MTCs was 1.056 (95% CI 1.001-1.113).

ConclusionTU/LEH care is at least as effective as MTC care due to the facility for secondary transfer from TU/LEHs to MTCs. In patients who are not transferred, MTCs are associated with greater odds of 30-day survival in the whole cohort and in the most severely injured patients. Future research must determine the optimum means of identifying patients in need of higher-level care; the components of care which improve patient outcomes; and develop patient-focused outcomes which reflect the characteristics and priorities of contemporary trauma patients.

KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LICurrent trauma systems were not designed to manage rising numbers of elderly patients injured by low falls.
C_LIO_LIPrevious evidence for the role of major trauma centre (MTC) care in such patients yielded conflicting results.
C_LI

What this study addsO_LIThis study demonstrates that non-trauma centre care is no worse than MTC care, as long as the possibility of transfer exists.
C_LIO_LITherefore MTCs do have a role in the management of elderly adults injured by low falls, particularly the severely injured.
C_LI

How this study might affect research, policy or practiceO_LIResearch must identify those patients who need transfer, the most effective components of care, and patient-centric outcomes.
C_LI


title: Metabolic changes induced by pharmacological castration of young, healthy men: a study of the plasma metabolome

abstract: Testosterone is a hormone that plays a key role in carbohydrate, fat, and protein metabolism. Testosterone deficiency is associated with multiple comorbidities, e.g., metabolic syndrome and type 2 diabetes. Despite its importance in many metabolic pathways, the mechanisms by which it controls metabolism are not fully understood. The present study investigated the short-term metabolic changes of pharmacologically induced castration and testosterone supplementation in healthy young males. Thirty subjects were submitted to testosterone depletion (TD) followed by testosterone supplementation (TS). Plasma samples were collected three times corresponding to basal, low, and restored testosterone levels. An untargeted metabolomics study was performed by liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to monitor the metabolic changes induced by the altered hormone levels. Our results demonstrated that TD is associated with major metabolic changes partially restored by TS. Carnitine and amino acid metabolism were the metabolic pathways most impacted by variations in testosterone. Furthermore, our results also indicate that LH and FSH might strongly alter the plasma levels of indoles and lipids, especially glycerophospholipids and sphingolipids. Our results demonstrate major metabolic changes induced by low testosterone that may be important for understanding the mechanisms behind the association of testosterone deficiency and its comorbidities.

category: endocrinology


title: Risk of myocarditis and pericarditis following COVID-19 vaccination in England and Wales

abstract: We describe our analyses of data from over 49.7 million people in England, representing near-complete coverage of the relevant population, to assess the risk of myocarditis and pericarditis following BNT162b2 and ChAdOx1 COVID-19 vaccination. A self-controlled case series (SCCS) design has previously reported increased risk of myocarditis after first ChAdOx1, BNT162b2, and mRNA-1273 dose and after second doses of mRNA COVID-19 vaccines in England. Here, we use a cohort design to estimate hazard ratios for hospitalised or fatal myocarditis/pericarditis after first and second doses of BNT162b2 and ChAdOx1 vaccinations. SCCS and cohort designs are subject to different assumptions and biases and therefore provide the opportunity for triangulation of evidence. In contrast to the findings from the SCCS approach previously reported for England, we found evidence for lower incidence of hospitalised or fatal myocarditis/pericarditis after first ChAdOx1 and BNT162b2 vaccination, as well as little evidence to suggest higher incidence of these events after second dose of either vaccination.


title: Post COVID-19 Condition in South Africa: 3-month follow-up after hospitalisation with SARS-CoV-2

abstract:
BackgroundPost COVID-19 Condition (PCC) as defined by WHO refers to a wide range of new, returning, or ongoing health problems experienced by COVID-19 survivors, and represents a rapidly emerging public health priority. We aimed to establish how this developing condition has impacted patients in South Africa and which population groups are at risk.

MethodsIn this prospective cohort study, participants [≥]18 years who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection during the second and third wave between December 2020 and August 2021 underwent telephonic follow-up assessment up at one-month and three-months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life and occupational status. Multivariable logistic regression models were used to determine factors associated with PCC.

FindingsIn total, 1,873 of 2,413 (78%) enrolled hospitalised COVID-19 participants were followed up at three-months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51.3%) were women. At three-months follow-up, 1,249 (66.7%) participants reported one or more persistent COVID-related symptom(s), compared to 1,978/2,413 (82.1%) at one-month post-hospital discharge. The most common symptoms reported were fatigue (50.3%), shortness of breath (23.4%), confusion or lack of concentration (17.5%), headaches (13.8%) and problems seeing/blurred vision (10.1%). On multivariable analysis, factors associated with new or persistent symptoms following acute COVID-19 were age [≥]65 years [adjusted odds ratio (aOR) 1.62; 95%confidence interval (CI) 1.00-2.61]; female sex (aOR 2.00; 95% CI 1.51-2.65); mixed ethnicity (aOR 2.15; 95% CI 1.26-3.66) compared to black ethnicity; requiring supplemental oxygen during admission (aOR 1.44; 95% CI 1.06-1.97); ICU admission (aOR 1.87; 95% CI 1.36-2.57); pre-existing obesity (aOR 1.44; 95% CI 1.09-1.91); and the presence of [≥]4 acute symptoms (aOR 1.94; 95% CI 1.19-3.15) compared to no symptoms at onset.

InterpretationThe majority of COVID-19 survivors in this cohort of previously hospitalised participants reported persistent symptoms at three-months from hospital discharge, as well as a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health care workers, in identifying, assessing and caring for patients affected by PCC, establishment of multidisciplinary national health services, and provision of information and support to people who suffer from PCC.


title: "Pandemic of the unvaccinated"? At midlife, white people are less vaccinated but still at less risk of Covid-19 mortality in Minnesota

abstract: Recent research underscores the exceptionally young age distribution of Covid-19 deaths in the United States compared with international peers. We show that the high level of Covid mortality at midlife ages (45-64) is deeply intertwined with continuing racial inequality in Covid-19 mortality, which persists even in contexts in which non-white populations might seem to have a survival advantage. We use data from Minnesota, which allows vaccination and mortality rates to be observed with greater age and temporal precision than national data. At midlife ages in Minnesota, Black, Hispanic, and Asian populations were all more highly vaccinated than white populations during the states substantial and sustained Delta surge. Yet white mortality rates were lower than those of all other racial groups. These mortality disparities were extreme; during the Delta period, non-white Covid-19 mortality at ages 55-64 was greater than white mortality at 10 years older. This discrepancy between vaccination and mortality patterning by race suggests that, if the current period is a "pandemic of the unvaccinated," it also remains a "pandemic of the disadvantaged" in ways that can decouple from vaccination rates. This result implies an urgent need to center health equity in the development of Covid-19 policy measures.


title: Tract-based white matter hyperintensity patterns in patients with Systemic Lupus Erythematosus using an unsupervised machine learning approach.

abstract: Currently, little is known about the spatial distribution of white matter hyperintensities (WMH) in the brain of patients with Systemic Lupus erythematosus (SLE). Previous lesion markers, such as number and volume, ignore the strategic location of WMH. The goal of this work was to develop a fully-automated method to identify predominant patterns of WMH across WM tracts based on cluster analysis. A total of 221 SLE patients with and without neuropsychiatric symptoms from two different sites were included in this study. WMH segmentations and lesion locations were acquired automatically. Cluster analysis was performed on the WMH distribution in 20 WM tracts. Our pipeline identified five distinct clusters with predominant involvement of the forceps major, forceps minor, as well as right and left anterior thalamic radiations and the right inferior fronto-occipital fasciculus. The patterns of the affected WM tracts were consistent over the SLE subtypes and sites. Our approach revealed distinct and robust tract-based WMH patterns within SLE patients. This method could provide a basis, to link the location of WMH with clinical symptoms. Furthermore, it could be used for other diseases characterized by presence of WMH to investigate both the clinical relevance of WMH and underlying pathomechanism in the brain.

category: radiology and imaging


title: A qualitative examination of the factors affecting the adoption of injury focused wearable technologies in recreational runners

abstract:
PurposeUnderstanding users perceived usefulness and ease of use of technologies will influence their adoption and sustained use. The objectives of this study were to determine the metrics deemed important by runners for monitoring running-related injury (RRI) risk, and identify the barriers and facilitators to their use of injury focused wearable technologies.

MethodsA qualitative focus group study was undertaken. Nine semi-structured focus groups with male (n=13) and female (n=14) recreational runners took place. Focus groups were audio and video recorded, and transcribed verbatim. Transcripts were thematically analysed. A critical friend approach was taken to data coding, and multiple methods of trustworthiness were executed.

ResultsExcessive loading and inadequate recovery were deemed the most important risk factors to monitor for RRI risk. Other important factors included training activities, injury status and history, and running technique. The location and attachment method of a wearable device and the design of a smartphone application were identified as important barriers and facilitators, with receiving useful injury-related feedback identified as a further facilitator.

ConclusionsOvertraining, training-related and individual- related risk factors are essential metrics that need to be monitored for RRI risk. RRI apps should include the metrics deemed important by runners, once there is supporting evidence- based research. The difficulty and/or ease of use of a device, and receiving useful feedback will influence the adoption of injury focused running technologies. There is a clear willingness from recreational runners to adopt injury focused wearable technologies whilst running.

category: sports medicine


title: Exploring potential causal genes for uterine leiomyomas: A summary data-based Mendelian randomization and FUMA analysis

abstract:
ObjectiveTo explore potential causal genetic variants and genes underlying the pathogenesis of uterine leiomyomas (ULs).

MethodsWe conducted the summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to examine genetic variants and genes that are potentially involved in the pathogenies of ULs.

Both analyses used summarized data of a recent genome-wide association study (GWAS) on ULs, which has a total sample size of 244,324 (20,406 cases and 223,918 controls). For the SMR analysis, we performed separate analysis using CAGE and GTEx eQTL data.

ResultsUsing the CAGE eQTL data, our SMR analysis identified 13 probes tagging 10 unique genes that were pleiotropically/potentially causally associated with ULs, with the top three probes being ILMN_1675156 (tagging CDC42, PSMR=8.03x10-9), ILMN_1705330 (tagging CDC42, PSMR=1.02x10-7) and ILMN_2343048 (tagging ABCB9, PSMR=9.37x10-7). Using GTEx eQTL data, our SMR analysis did not identify any significant genes after correction for multiple testing. FUMA analysis identified 106 independent SNPs, 24 genomic loci and 137 genes that are potentially involved in the pathogenesis of ULs, seven of which were also identified by the SMR analysis.

ConclusionsWe identified many genetic variants, genes, and genomic loci that are potentially involved in the pathogenesis of ULs. More studies are needed to explore the exact underlying mechanisms in the etiology of ULs.


title: SETBP1 variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder

abstract: Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few individual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders.


title: Mining for Health: A Comparison of Word Embedding Methods for Analysis of EHRs Data

abstract: Electronic health records (EHRs), routinely collected as part of healthcare delivery, offer great promise for advancing precision health. At the same time, they present significant analytical challenges. In EHRs, data for individual patients are collected at irregular time intervals and with varying frequencies; they include both structured and unstructured data. Advanced statistical and machine learning methods have been developed to tackle these challenges, for example, for predicting diagnoses earlier and more accurately. One powerful tool for extracting useful information from EHRs data is word embedding algorithms, which represent words as vectors of real numbers that capture the words semantic and syntactic similarities. Learning embeddings can be viewed as automated feature engineering, producing features that can be used for predictive modeling of medical events. Methods such as Word2Vec, BERT, FastText, ELMo, and GloVe have been developed for word embedding, but there has been little work on re-purposing these algorithms for the analysis of structured medical data. Our work seeks to fill this important gap. We extended word embedding methods to embed (structured) medical codes from a patients entire medical history, and used the resultant embeddings to build prediction models for diseases. We assessed the performance of multiple embedding methods in terms of predictive accuracy and computation time using the Medical Information Mart for Intensive Care (MIMIC) database. We found that using Word2Vec, Fast-Text, and GloVe algorithms yield comparable models, while more recent contextual embeddings provide marginal further improvement. Our results provide insights and guidance to practitioners regarding the use of word embedding methods for the analysis of EHR data.


title: VinDr-PCXR: An open, large-scale chest radiograph dataset for interpretation of thoracic diseases in children

abstract: Computer-aided diagnosis systems in adult chest radiography (CXR) have recently achieved great success thanks to the availability of large-scale, annotated datasets and the advent of high-performance supervised learning algorithms. However, the development of diagnostic models for detecting and diagnosing pediatric diseases in CXR scans is undertaken due to the lack of high-quality physician-annotated datasets. To overcome this challenge, we introduce and release VinDr-PCXR, a new pediatric CXR dataset of 9,125 studies retrospectively collected from a major pediatric hospital in Vietnam between 2020 and 2021. Each scan was manually annotated by a pediatric radiologist who has more than ten years of experience. The dataset was labeled for the presence of 36 critical findings and 15 diseases. In particular, each abnormal finding was identified via a rectangle bounding box on the image. To the best of our knowledge, this is the first and largest pediatric CXR dataset containing lesion-level annotations and image-level labels for the detection of multiple findings and diseases. For algorithm development, the dataset was divided into a training set of 7,728 and a test set of 1,397. To encourage new advances in pediatric CXR interpretation using data-driven approaches, we provide a detailed description of the VinDr-PCXR data sample and make the dataset publicly available on https://physionet.org/.


title: A scoping systematic review of implementation frameworks to effectively transition interventions into clinical practice in oncology, nuclear medicine and radiology

abstract:
BackgroundClinical research studies have made significant strides globally requiring clear processes to transition research interventions into clinical practice. Theoretically, implementation of novel interventions require clear methods as part of a fit-for-purpose (FFP) framework comprising of effective adaptation processes in conjunction with practice policies. Implementation science (IS) based operational research (OR) is vital in global health as it addresses the  know-how-do gap using a real-world setting to achieve best practices to sustain healthcare. Despite this, limited OR is available to evaluate and validate implementation frameworks for complex clinical specialties such as oncology, diagnostic radiology (DR), nuclear medicine (NM) and interventional radiology (IR). This is the first study to systematically review implementation frameworks including its validity and applicability in healthcare.

MethodWe searched 17 databases including PubMed, Medline/OvidSP, Science Direct, PROSPERO, PRISMA, PubMed Health, Embase, EBSCOhost, SciELO, TRIP, ProQuest, Academic search complete, Ageline, Cochrane, Web-of-Science and BIOSIS using a comprehensive search strategy and MeSH indexing to review publications from January 1st 1980 to 31st March 2019 in English. We selected 20 publications as per the inclusion/exclusion criteria developed under a review protocol registered with PROSPERO (CRDG42019124020).

FindingsThere were no publications indicating a validated framework or a specific system used to implement evidence based interventions (EBIs) within oncology, IR, NM and DR although there were generalized implementation processes, adaptation models and policies. Furthermore, validation studies were not conducted against these frameworks to review their applicability and viability in healthcare especially in the UK.

InterpretationIt is evident there is a research implementation gap in healthcare and further research is required to establish a fit for purpose framework to cover multiple  blind spots using a real-world (RW) setting. Current evidence also suggests, alignment of academic theories to healthcare including its applicability to various clinical specialties is needed.

category: health systems and quality improvement


title: Three separate spike antigen exposures by COVID-19 vaccination or SARS-CoV-2 infection elicit strong humoral immune responses in healthcare workers

abstract: As part of our ongoing prospective seroprevalence study, we assessed the SARS-CoV-2 infection and COVID-19 vaccination-induced immunity of 697 hospital workers at the University Medical Center Hamburg-Eppendorf between January 17 and 31, 2022. The overall prevalence of anti-NC-SARS-CoV-2 antibodies indicating prior infection was 9.8% (n=68) and thus lower than the seroprevalence in the general population in Hamburg. At the current study visit, 99.3% (n=692) had received at least one vaccine dose and 93.1% (n=649) had received at least three vaccine doses. All vaccinated individuals had detectable anti-S1-RBD-SARS-CoV-2 antibodies (median AU/ml [IQR]: 13891 [8505 - 23543]), indicating strong protection against severe COVID-19. In addition, we show that individuals who received three COVID-19 vaccine doses (median AU/ml [IQR]: 13856 [8635 - 22705]), and those who resolved a prior SARS-CoV-2 infection and received two COVID-19 vaccine doses (median AU/ml [IQR] 13409 [6934 - 25000]) exhibited the strongest humoral immune responses. The low prevalence of anti-NC-SARS-CoV-2 antibodies indicates persistent effectiveness of established infection control interventions in preventing nosocomial SARS-CoV-2 transmission with the delta and omicron viral variants as predominant strains. Our study further indicates that three exposures to the viral spike protein by either SARS-CoV-2 infection or COVID-19 vaccination are necessary to elicit particularly strong humoral immune responses, which supports current vaccination recommendations.


title: Nanopore sequencing for Mycobacterium tuberculosis drug susceptibility testing and outbreak investigation

abstract:
BackgroundMycobacterium tuberculosis whole-genome sequencing (WGS) using Illumina technology has been widely adopted for genotypic drug susceptibility testing (DST) and outbreak investigation. Oxford Nanopore Technologies is reported to have higher error rates but has not been thoroughly evaluated for these applications.

MethodsWe analyse 151 isolates from Madagascar, South Africa and England with phenotypic DST and matched Illumina and Nanopore data. Using PacBio assemblies, we select Nanopore filters for BCFtools (software) detection of single nucleotide polymorphisms (SNPs). We compare transmission clusters identified by Nanopore and the United Kingdom Health Security Agency Illumina pipeline (COMPASS). We compare Illumina and Nanopore WGS-based DST predictions using Mykrobe (software).

FindingsNanopore/BCFtools identifies SNPs with median precision/recall of 99{middle dot}5/90{middle dot}2% compared with 99{middle dot}6/91{middle dot}9% for Illumina/COMPASS. Using a threshold of 12 SNPs for putative transmission clusters, Illumina identifies 98 isolates as unrelated and 53 as belonging to 19 distinct clusters (size range 2-7). Nanopore reproduces this distribution with addition of 5 singleton isolates to distinct clusters and merging of two cluster pairs. Illumina-based clusters are also replicated using a 5 SNP threshold. Clustering accuracy is maintained using mixed Illumina/Nanopore datasets. Genotyping resistance variants is highly concordant, with 0(4) discordant SNPs (indels) across 151 isolates genotyped at >3000 (60,000) SNPs (indels).

InterpretationIllumina and Nanopore sequence data provide comparable cluster-identification and DST results.

FundingAcademy for Medical Sciences (SGL018\110), Oxford Wellcome Institutional Strategic Support Fund (ISSF TT17 4). Swiss South Africa Joint Research Award (Swiss national science Foundation and South African national research foundation).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTwo key types of information can be obtained from laboratory testing of M. tuberculosis isolates to help directly guide public health interventions: drug susceptibility testing (DST) to guide therapy, and bacterial typing to enrich understanding of the epidemiology and guide interventions to mitigate transmission.

DST is typically performed by the "gold standard" culture-based phenotyping method or nucleic acid amplification assays targeting specific resistance-conferring mutations. Studies over the last 7 years have shown that prediction of susceptibility profile using Illumina-technology genome sequence data is possible, and can be automated. In a key publication, the CRyPTIC consortium and UK 100,000 Genomes project evaluated the method on over 10,000 genomes including prospectively sampled isolates and showed that for first-line tuberculosis (TB) drugs (isoniazid, rifampicin, ethambutol, pyrazinamide) a pan-susceptibility profile is accurate enough to be used clinically. The genetic basis of resistance remains imperfectly understood for second-line TB drugs, in particular for new and repurposed drugs (bedaquiline, clofazimine, delamanid, linezolid). Prior work in the field of genotypic DST was heavily based on Illumina technology, which provides short (70-300 base pair) sequence reads of very high quality. Many different softwares (e.g. TBProfiler, Mykrobe, MTBseq, kvarq) have been designed for sequence analysis and genotypic DST. However, the increasingly used Nanopore sequencing platforms yield very different data with much longer sequence reads (frequently over 1kb) and higher error rates including systematic biases. To date, very limited evaluation of Nanopore-based drug susceptibility prediction has been performed using the only two compatible tools (Mykrobe (n=5 independent samples), TBProfiler (n=3 independent samples)).

Molecular typing of M. tuberculosis allows lineage identification and detection of putative transmission clusters. In the last decade, multiple M. tuberculosis molecular epidemiology studies have shown how genomic information can complement traditional epidemiology in identifying person-to-person transmission clusters with a high level of resolution. Typically, the number of single nucleotide polymorphism (SNP) disagreements between genomes, or SNP distance, is calculated and single-linkage clustering is performed for genomes falling within retrospectively established transmission thresholds of either 5 or 12 SNPs. Just as with DST, these thresholds were established with Illumina sequencing data. The increased error rate in Nanopore sequencing is believed to lead to inflated SNP distances if standard genome analysis tools are used. Prior to this study it was unknown what impact on isolate-clustering this would incur.

Added value of this studyFull-scale adoption of genomic sequencing in tuberculosis reference laboratories has so far taken place in a limited number of settings - England, the Netherlands, and New York State - all using Illumina-based sequencing data. Building on current evidence, specific WHO technical guidance and diversification and democratisation of technology, sequencing is expected to be increasingly used in tuberculosis control globally. For the first time, our study offers 4 key deliverables intended to inform adoption of Nanopore technology as an alternative, or a complement, to Illumina. First: a systematic head-to-head comparison of Nanopore and Illumina data for M. tuberculosis drug susceptibility profiling and isolate clustering, including quantitative metrics for cluster precision and recall. Second: an assessment of the impact of mixed Illumina and Nanopore data on clustering which represents an increasingly common challenge. Third: an open-source software pipeline allowing research and reference laboratories to replicate our analytical approach. Fourth: a publicly available curated test set of 151 isolates, including matched Illumina and Nanopore sequence data, and (for a subset of seven isolates) high-quality PacBio assemblies, for method development and validation.

Implications of all the available evidenceCatalogues of drug resistance conferring mutations will keep improving, especially for new and repurposed drugs. Our data confirms that Illumina and Nanopore sequencing technologies can be used to identify those mutations equally accurately in M. tuberculosis. Bacterial molecular typing is constantly shown to support the understanding of disease transmission and tuberculosis control in new settings. The bioinformatics tools and filters we have developed, assessed, and made publicly available allow the use of Nanopore or mixed-technology data to appropriately cluster genetically related isolates. We provide a measure of the expected level of over-clustering associated with Nanopore technology. This study confirms that Illumina and Nanopore sequence data provide comparable DST results and isolate cluster-identification.


title: Risk Factor Stratification for Postoperative Delirium: A Retrospective Database Study

abstract:
BackgroundPostoperative Delirium (POD) is a disturbing reality for patients and their families. Absence of easy-to-use and accurate risk scores prompted us to retrospectively extract data from the electronic health records (EHR) to identify clinical factors associated with POD. We seek to create a multivariate nomogram to predict the risk of POD based upon the most significant clinical factors.

MethodsThe EHR of patients >18 years of age undergoing surgery and had POD assessment were reviewed. Patient characteristics and study variables were summarized between delirium groups. We constructed univariate logistic regression models for POD using each study variable to estimate odds ratios (OR) and constructed a multivariable logistic regression model with stepwise variable selection. In order to create a clinically useful/implementable tool we created a nomogram to predict risk of delirium.

ResultsOverall, we found a rate of POD of 3.7% across our study population. The Model achieved an AUC of the ROC curve of 0.83 (95% CI 0.82-0.84). We found that age, increased ASA score (ASA 3-4 OR 2.81, CI1.49-5.28, p<0.001), depression (OR 1.28, CI1.12-1.47, p<0.001), postoperative benzodiazepine use (OR 3.52, CI3.06-4.06, p<0.001) and urgent cases (Urgent OR 3.51, CI2.92-4.21, p<0.001; Emergent OR 3.99, CI3.21-4.96, p<0.001; Critically Emergent OR 5.30, CI3.53-7.96, p<0.001) were associated with POD.

ConclusionsWe were able to distinguish the contribution of individual risk factors to the development of POD. We created a clinically useful easy-to-use tool that has the potential to accurately identify those at high-risk of delirium, a first step to prevent POD.

category: anesthesia