Population immunity to pre-Omicron and Omicron SARS-CoV-2 variants in US states and counties through December 1, 2021 Prior infection and vaccination both contribute to population-level SARS-CoV-2 immunity. We used a Bayesian model to synthesize evidence and estimate population immunity to prevalent SARS-CoV-2 variants in the United States over the course of the epidemic until December 1, 2021, and how this changed with the introduction of the Omicron variant. We used daily SARS-CoV-2 infection estimates and vaccination coverage data for each US state and county. We estimated relative rates of vaccination conditional on previous infection status using the Census Bureaus Household Pulse Survey. We used published evidence on natural and vaccine-induced immunity, including waning and immune escape. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%), compared to 24.9% (95%CrI: 18.5%-34.1%) on January 1, 2021. State-level estimates for December 1, 2021, ranged between 76.9% (95%CrI: 67.6%-87.6%, West Virginia) and 94.4% (95%CrI: 91.2%-97.3%, New Mexico). Accounting for waning and immune escape, the effective protection against the Omicron variant on December 1, 2021, was 21.8% (95%CrI: 20.7%-23.4%) nationally and ranged between 14.4% (95%CrI: 13.2%-15.8%, West Virginia), to 26.4% (95%CrI: 25.3%-27.8%, Colorado). Effective protection against severe disease from Omicron was 61.2% (95%CrI: 59.1%-64.0%) nationally and ranged between 53.0% (95%CrI: 47.3%-60.0%, Vermont) and 65.8% (95%CrI: 64.9%-66.7%, Colorado). While over three-quarters of the US population had prior immunological exposure to SARS-CoV-2 via vaccination or infection on December 1, 2021, only a fifth of the population was estimated to have effective protection to infection with the immune-evading Omicron variant.

SignificanceBoth SARS-CoV-2 infection and COVID-19 vaccination contribute to population-level immunity against SARS-CoV-2. This study estimates the immunity and effective protection against future SARS-CoV-2 infection in each US state and county over 2020-2021. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%). Accounting for waning and immune escape, protection against the Omicron variant was 21.8% (95%CrI: 20.7%-23.4%). Protection against infection with the Omicron variant ranged between 14.4% (95%CrI: 13.2%-15.8%%, West Virginia) and 26.4% (95%CrI: 25.3%-27.8%, Colorado) across US states. The introduction of the immune-evading Omicron variant resulted in an effective absolute increase of approximately 30 percentage points in the fraction of the population susceptible to infection.
Estimating the increased transmissibility of the B.1.1.7 strain over previously circulating strains in England using frequencies of GISAID sequences and the distribution of serial intervals The B.1.1.7 strain, also referred to as Alpha variant, is a variant strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Alpha variant is considered to possess higher transmissibility compared to the strains previously circulating in England. This paper proposes a new method to estimate the selective advantage of a mutant strain over another strain using the time course of strain frequencies and the distribution of the serial interval of infections. This method allows the instantaneous reproduction numbers of infections to vary over calendar time. The proposed method also assumes that the selective advantage of a mutant strain over previously circulating strains is constant. Applying the method to SARS-CoV-2 sequence data from England, the instantaneous reproduction number of the B.1.1.7 strain was estimated to be 26.6-45.9% higher than previously circulating strains in England. This result indicates that control measures should be strengthened by 26.6-45.9% when the B.1.1.7 strain is newly introduced to a country where viruses with similar transmissibility to the preexisting strain in England are predominant.
Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases ObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

MethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

ResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

ConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age. Quantifying phenotype and genotype distributions in single muscle fibres from patients carrying the pathogenic mtDNA variant m.3243A>G Cells are thought to tolerate the presence of heteroplasmic pathogenic mitochondrial (mt)DNA variants, up to a threshold proportion with little or no functional consequence, only developing a detectable oxidative phosphorylation (OXPHOS) defect once this threshold is exceeded. We hypothesised that, given the highly variable phenotypic presentation and severity of disease caused by the most common heteroplasmic pathogenic mtDNA variant m.3243A>G, this threshold may vary between patients. To estimate this threshold we examined the relationship between m.3243A>G level and deficiency of respiratory complexes I and IV in hundreds of single skeletal muscle fibres captured by laser microdissection from 17 patients carrying the m.3243A>G variant. We confirmed that tissue homogenate m.3243A>G level is a poor surrogate for the broad and complex distributions of m.3243A>G level in single cells from individual patients. We used unsupervised machine learning to characterise the biochemical status of muscle fibres, based on immunocytochemical measurements and estimate that the m.3243A>G threshold proportion above which myofibres develop a respiratory complex defect is 82.8% (IQR:2.7%). We do not find any significant difference in threshold between individuals, however we demonstrate that the pattern of respiratory complex defect and the distribution of m.3243A>G varies considerably between patients. This observation suggests that the pathogenesis of m.3243A>G is more diverse than previously thought. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. Comparison of in-hospital mortality and clinical outcomes among patients greater than and less than 80 years undergoing TAVR BackgroundTranscatheter aortic valve replacement (TAVR) procedure has been increasingly utilized in the management of aortic stenosis in the elderly. We sought to assess the hospital outcomes and major adverse events of TAVR in patients [&ge;]80 years old compared to those <80 years.

MethodsWe performed a retrospective observational study using the National Inpatient Sample - 2018. We divided TAVR patients into two cohorts based on age being [&ge;]80 years and <80 years old. The primary outcomes were the comparison of in-hospital mortality and major adverse events (MAE) in the cohorts.

ResultsWe identified 63,630 patients who underwent TAVR procedures from January 1 to December 31, 2018. Among them, 35, 115(55%) were [&ge;]80 years and 28,515(45%) were <80 years of age. There was a higher rate of post-procedure in-hospital mortality rate in patients [&ge;]80 years (1.6% vs. 1.1%, aOR=1.56, [CI 1.13 -2.16], p=0.006). They also had higher rates of pacemaker insertion compared to those <80 years old (7.4 vs 6.5%, aOR=1.17 [CI 1-1.35], p=0.03). On subgroup analysis, the rates of MAE were not different between the two cohorts (23.8 vs 23.4, p=0.09) but patients [&ge;]80 years who experienced MAE had higher in-hospital mortality (5.7 vs 4.3%, aOR=1.58 [CI=1.08-2.32], p=0.01) and shorter length of hospital stay (7.2 vs 8.7 days, p=0.03) compared to those <80. Anemia, liver disease, chronic kidney disease and previous stroke were associated with higher odds of in-hospital MAE in both groups.

ConclusionThis study shows that in patients undergoing TAVR, those [&ge;]80 years old had higher in-hospital mortality and higher rates of pacemaker insertion compared to those < 80 years. The rates of MAE were not significantly different between the two groups. Hair loss in females and thromboembolism in males are significantly enriched in post-acute sequelae of COVID (PASC) relative to recent medical history After one year of the COVID-19 pandemic, over 130 million individuals worldwide have been infected with the novel coronavirus, yet the post-acute sequelae of COVID-19 (PASC), also referred to as the  long COVID syndrome, remains mostly uncharacterized. We leveraged machine-augmented curation of the physician notes from electronic health records (EHRs) across the multi-state Mayo Clinic health system to retrospectively contrast the occurrence of symptoms and diseases in COVID-19 patients in the post-COVID period relative to the pre-COVID period (n=6,413). Through comparison of the frequency of 10,039 signs and symptoms before and after diagnosis, we identified an increase in hypertensive chronic kidney disease (OR 47.3, 95% CI 23.9-93.6, p=3.50x10-9), thromboembolism (OR 3.84, 95% CI 3.22-4.57, p=1.18x10-4), and hair loss (OR 2.44, 95% CI 2.15-2.76, p=8.46x10-3) in COVID-19 patients three to six months after diagnosis. The sequelae associated with long COVID were notably different among male vs female patients and patients above vs under 55 years old, with the hair loss enrichment found primarily in females and the thromboembolism enrichment in males. These findings compel targeted investigations into what may be persistent dermatologic, cardiovascular, and coagulopathic phenotypes following SARS-CoV-2 infection. Colorectal Cancer Disparities Across the Continuum of Cancer Care with a Focus on Surgery and Black Patients: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. Pre-COVID-19 pandemic health-related behaviours in children (2018-2020) and association with being tested for SARS-CoV-2 and testing positive for SARS-CoV-2 (2020-2021): a retrospective cohort study using survey data linked with routine health data in Wales, UK ObjectivesExamine if pre-COVID-19 pandemic (prior March 2020) health-related behaviours during primary school are associated with i) being tested for SARS-CoV-2 and ii) testing positive between 1 March 2020 to 31 August 2021.

DesignRetrospective cohort study using an online cohort survey (January 2018 to February 2020) linked to routine PCR SARS-CoV-2 test results.

SettingChildren attending primary schools in Wales (2018-2020), UK who were part of the HAPPEN school network.

ParticipantsComplete linked records of eligible participants were obtained for n=7,062 individuals. 39.1% (n=2,764) were tested (age 10.6{+/-}0.9, 48.9% girls) and 8.1% (n=569) tested positive for SARS-CoV-2 (age 10.6{+/-}1.0, 54.5% girls).

Main outcome measuresLogistic regression of health-related behaviours and demographics were used to determine Odds Ratios (OR) of factors associated with i) being tested for SARS-CoV-2 and ii) testing positive for SARS-CoV-2.

ResultsConsuming sugary snacks (1-2 days/week OR=1.24, 95% CI 1.04 - 1.49; 5-6 days/week 1.31, 1.07 - 1.61; reference 0 days) can swim 25m (1.21, 1.06 - 1.39) and age (1.25, 1.16 - 1.35) were associated with an increased likelihood of being tested for SARS-CoV-2. Eating breakfast (1.52, 1.01 - 2.27), weekly physical activity [&ge;] 60 mins (1-2 days 1.69, 1.04 - 2.74; 3-4 days 1.76, 1.10 - 2.82, reference 0 days), out of school club participation (1.06, 1.02 - 1.10), can ride a bike (1.39, 1.00 - 1.93), age (1.16, 1.05 - 1.28) and girls (1.21, 1.00 - 1.46) were associated with an increased likelihood of testing positive for SARS-CoV-2. Living in least deprived quintiles 4 (0.64, 0.46 - 0.90) and 5 (0.64, 0.46 - 0.89) compared to the most deprived quintile was associated with a decreased likelihood.

ConclusionsAssociations may be related to parental health literacy and monitoring behaviours. Physically active behaviours may include co-participation with others, and exposure to SARS-CoV-2. A risk versus benefit approach must be considered given the importance of health-related behaviours for development.

STRENGTHS AND LIMITATIONSO_LIInvestigation of the association of pre-pandemic child health-related behaviour measures with subsequent SARS-CoV-2 testing and infection.
C_LIO_LIReporting of multiple child health behaviours linked at an individual-level to routine records of SARS-CoV-2 testing data through the SAIL Databank.
C_LIO_LIChild-reported health behaviours were measured before the COVID-19 pandemic (1 January 2018 to 28 February 2020) which may not reflect behaviours during COVID-19.
C_LIO_LIHealth behaviours captured through the national-scale HAPPEN survey represent children attending schools that engaged with the HAPPEN Wales primary school network and may not be representative of the whole population of Wales.
C_LIO_LIThe period of study for PCR-testing for and testing positive for SARS-CoV-2 includes a time frame with varying prevalence rates, approaches to testing children (targeted and mass testing) and restrictions which were not measured in this study.
C_LI A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments We construct a spatially-compartmental individual-based model of the spread of Covid-19 in indoor spaces. The model can be used to predict the infection rates in a variety of locations when various non-pharmaceutical interventions (NPIs) are introduced. Tasked by the Welsh Government, we apply the model to secondary schools and Further and Higher Education environments. Specifically, we consider student populations mixing in a classroom and in halls of residence. We focus on assessing the potential efficacy of Lateral Flow Devices (LFDs) when used in broad-based screens for asymptomatic infection or in  test-to-release scenarios in which individuals who have been exposed to infection are released from isolation given a negative result. LFDs are also compared to other NPIs; we find that, although LFD testing can be used to mitigate the spread of Covid-19, it is more effective to invest in personal protective equipment, e.g. masks, and in increasing ventilation quality. In addition, we provide an open-access and user-friendly online applet that simulates the individual-based model, complete with user tutorials to encourage the use of the model to aid educational policy decisions as input infection data evolves (https://bit.ly/CV19_INTER_IBM). Correction of measurement error in a commercial multiple-breath washout device RationaleNitrogen multiple-breath washout (N2MBW) is an established technique to assess functional residual capacity (FRC) and ventilation inhomogeneity in the lung. Accurate measurement of gas concentrations is essential for the appropriate calculation of clinical outcomes.

ObjectivesWe investigated the accuracy of oxygen and carbon dioxide measurements used for the indirect calculation of nitrogen concentration in a commercial MBW device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and its impact on FRC and lung clearance index (LCI).

MethodsHigh precision calibration gas mixtures and mass spectrometry were used to evaluate sensor output. We assessed the impact of corrected signal processing on FRC and LCI in a dataset of healthy children and children with cystic fibrosis using custom analysis software.

ResultsWe found inadequate correction for the cross sensitivity of the oxygen and carbon dioxide sensors in the Exhalyzer D device. This results in an overestimation of expired nitrogen concentration, and consequently FRC and LCI outcomes. Breath-by-breath correction of this error reduced mean (SD) FRC by 8.9 (2.2)% and LCI by 11.9 (4.0)%. It also resulted in almost complete disappearance of the tissue nitrogen signal at the end of measurements.

ConclusionsInadequate correction for cross sensitivity between the oxygen and carbon dioxide gas sensors of the Exhalyzer D device leads to an overestimation of FRC and LCI. Correction of this error is possible and could be applied by re-analysing the measurements breath-by-breath in an updated software version.

Grants, Gifts, Equipment, DrugsEco Medics AG (Duernten, Switzerland) provided a research version of their commercial software Spiroware 3.2.1 including insight on signal processing algorithms and helped with the acquisition of mass spectrometry measurements. This project was funded by the Swiss National Science Foundation, Grant Nr. 182719 (P. Latzin) and 168173 (K. Ramsey) Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).

DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.

Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.

Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.

FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.

ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes
C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age
C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC
C_LI

What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention
C_LI Machine Learning Approaches for Binary Classification to Discover Liver Diseases using Clinical Data For a medical diagnosis, health professionals use different kinds of pathological ways to make a decision for medical reports in terms of patients medical condition. In the modern era, because of the advantage of computers and technologies, one can collect data and visualize many hidden outcomes from them. Statistical machine learning algorithms based on specific problems can assist one to make decisions. Machine learning data driven algorithms can be used to validate existing methods and help researchers to suggest potential new decisions. In this paper, Multiple Imputation by Chained Equations was applied to deal with missing data, and Principal Component Analysis to reduce the dimensionality. To reveal significant findings, data visualizations were implemented. We presented and compared many binary classifier machine learning algorithms (Artificial Neural Network, Random Forest, Support Vector Machine) which were used to classify blood donors and non-blood donors with hepatitis, fibrosis and cirrhosis diseases. From the data published in UCI-MLR, all mentioned techniques were applied to find one better method to classify blood donors and non-blood donors (hepatitis, fibrosis, and cirrhosis) that can help health professionals in a laboratory to make better decisions. Our proposed ML-method showed a better accuracy score (e.g. 98.23% for SVM). Thus, it improved the quality of classification. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

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org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

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org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

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org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

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org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Emergence and Evolution of Big Data Science in HIV Research: Bibliometric Analysis of Federally Sponsored Studies 2000-2019 BackgroundThe rapid growth of inherently complex and heterogeneous data in HIV/AIDS research underscores the importance of Big Data Science. Recently, there have been increasing uptakes of Big Data techniques in basic, clinical, and public health fields of HIV/AIDS research. However, no studies have systematically elaborated on the evolving applications of Big Data in HIV/AIDS research. We sought to explore the emergence and evolution of Big Data Science in HIV/AIDS-related publications that were funded by the US federal agencies.

MethodsWe identified HIV/AIDS and Big Data related publications that were funded by seven federal agencies from 2000 to 2019 by integrating data from National Institutes of Health (NIH) ExPORTER, MEDLINE, and MeSH. Building on bibliometrics and Natural Language Processing (NLP) methods, we constructed co-occurrence networks using bibliographic metadata (e.g., countries, institutes, MeSH terms, and keywords) of the retrieved publications. We then detected clusters among the networks as well as the temporal dynamics of clusters, followed by expert evaluation and clinical implications.

ResultsWe harnessed nearly 600 thousand publications related to HIV/AIDS, of which 19,528 publications relating to Big Data were included in bibliometric analysis. Results showed that (1) the number of Big Data publications has been increasing since 2000, (2) US institutes have been in close collaborations with China, Canada, and Germany, (3) some institutes (e.g., University of California system, MD Anderson Cancer Center, and Harvard Medical School) are among the most productive institutes and started using Big Data in HIV/AIDS research early, (4) Big Data research was not active in public health disciplines until 2015, (5) research topics such as genomics, HIV comorbidities, population-based studies, Electronic Health Records (EHR), social media, precision medicine, and methodologies such as machine learning, Deep Learning, radiomics, and data mining emerge quickly in recent years.

ConclusionsWe identified a rapid growth in the cross-disciplinary research of HIV/AIDS and Big Data over the past two decades. Our findings demonstrated patterns and trends of prevailing research topics and Big Data applications in HIV/AIDS research and suggested a number of fast-evolving areas of Big Data Science in HIV/AIDS research including secondary analysis of EHR, machine learning, Deep Learning, predictive analysis, and NLP. The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Insights on Genetic and Environmental Factors in Parkinson's Disease from a regional Swedish Case-Control Cohort BACKGROUNDRisk factors for Parkinsons disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology.

OBJECTIVEWe aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort.

METHODSPD patients (n=929) and matched population-based controls (n=935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores.

RESULTSThe cohort is a representative PD case-control cohort (64% men, mean age at diagnosis=67 years, median Hoehn and Yahr score=2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in the PLPP4 locus (rs12771445).

CONCLUSIONSThis work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors of PD in the Swedish population. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

MethodsWe used monthly counts of all opioid-related emergency department (ED) visits, hospitalizations, and deaths between January 2014 and December 2020 for our outcomes. For each public health unit (PHU) that implemented any OPS/CTS, we created a synthetic control as a weighted combination of unexposed PHU. We estimated the population-level effects of operating any site using controlled interrupted time series with segmented regression and adjusted for time varying confounders (i.e. OPS/CTS capacity, naloxone kits distributed, and persons receiving opioid agonist treatment per 100,000 population). We repeated the analysis using a multiple baseline approach to estimate province-wide effects.

ResultsBetween 2017 and 2020, nine out of 34 PHU implemented at least one OPS/CTS. ED visit (RR=0.96, 95%CI: 0.92 - 0.99) and hospitalization (RR=0.95, 95%CI: 0.92 - 0.98) trends declined faster among treated units. Improvements in local ED visit rate trends were observed for the majority of treated units. Hospitalization rates declined faster for London (RR=0.97, 95%CI: 0.95 - 0.99) and Niagara (RR=0.95, 95%CI: 0.92 - 0.98); while mortality rates declined faster for Hamilton (RR=0.93, 95%CI: 0.90 - 0.96), Niagara (RR=0.97, 95%CI: 0.94 - 0.99) and Guelph (RR=0.94, 95%CI: 0.88 - 1.00).

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. DNR orders in SARS-CoV-2 patients: a retrospective validation study in a Swiss COVID-19 Center BackgroundThe worldwide pandemic situation forced many hospitals to adapt COVID-19 management strategies. In this scenario, the Swiss Academy of Medical Sciences (SAMW/ASSM) organized national guidelines based on expert opinion to identify Do-Not-Resuscitate (DNR) patients, to reduce futile ICU admission and resource misuse. However, the practical impact of this standardized national protocol has not been yet evaluated. In our specialized COVID-19 Center, we investigated characteristics and mortality of DNR patients identified according to national standardized protocol, comparing them to non-DNR patients.

MethodsThis was a pilot retrospective validation study, evaluating consecutive hospital admitted COVID-19 patients. Primary outcome was 30-days survival of DNR patients in comparison to the control group. Secondary outcomes reported quality of treatment of deceased patients, especially of agitation/sedation and dyspnea, using respectively the Richmond Agitation-Sedation Scale - Palliative care (RASS-PAL) for sedation and agitation (+4/-5) and the modified Borg Scale for dyspnea (1-10).

ResultsFrom March 16 to April 1, 2020, 213 consecutive patients were triaged; at 30-days follow-up, 9 patients (22.5%) died in the DNR group, 4 (2.2%) in the control group. The higher mortality rate in the DNR group was further confirmed by Log-Rank Mantel-Cox (23.104, p < 0.0001). In the DNR-group deceased patients, end-of-life support was performed with oxygen (100%), opioids (100%) and sedatives (89%); the mean RASS-PAL improved from 2.2 to -1.8 (p < 0.0001) and the Borg scale improved from 5.7 to 4.7 (p = 0.581).

ConclusionA national standardized protocol identified patients at higher risk of short-term death. Although the legal status of DNRs varies from country to country, the implementation of national standardized protocol could be the way to guarantee a better treatment of COVID-19 patients in a pandemic situation with limited resources.