Comparing SARS-CoV-2 case rates between pupils, teachers and the general population: results from Germany Given the inconsistent state of research regarding the role of pupils and teachers during the SARS-CoV-2 pandemic in Germany, statewide and nationwide data of infection case rates were analyzed to contribute to the discourse. Infection data from official sources ranging from mid to late 2020 were collected, prepared and analyzed to answer the question if pupils, teachers and general population differed in active case rates or not. The data showed that pupils and teachers case rates didnt exceeded those of the general population. In conclusion, it seems appropriate to appraise school-related measures to mitigate the SARS-CoV-2 pandemic sufficiently. Data-quality is a yet to overcome obstacle to provide good evidence-based recommendations regarding the management around infection cases in schools.
The military as a neglected pathogen transmitter, from the 19th century to COVID-19: A systematic review BackgroundThe risk of outbreaks escalating into pandemics has soared with globalization. Therefore, understanding transmission mechanisms of infectious diseases has become critical to formulating global public health policy. This systematic review assessed evidence in the medical and public health literature for the military as a disease vector.

MethodsWe searched 3 electronic databases without temporal restrictions. Two researchers independently extracted study data using a standardized form. Through team discussions, studies were grouped according to their type of transmission mechanism and direct quotes were extracted to generate themes and sub-themes. A content analysis was later performed and frequency distributions for each theme were generated.

ResultsOf 6477 studies, 210 met our inclusion criteria and provided evidence, spanning over two centuries (1810 - 2020), for the military as a pathogen transmitter, within itself or between it and civilians. Biological mechanisms driving transmission included person-to-person transmission, contaminated food and water, vector-borne, and airborne routes. Contaminated food and/or water were the most common biological transmission route. Social mechanisms facilitating transmission included crowded living spaces, unhygienic conditions, strenuous working, training conditions, absent or inadequate vaccination programs, pressure from military leadership, poor compliance with public health advice, contractor mismanagement, high-risk behaviours, and occupation-specific freedom of movement. Living conditions were the most common social transmission mechanism, with young, low ranking military personnel repeatedly reported as the most affected group. Selected social mechanisms, such as employment-related freedom of movement, were unique to the military as a social institution. While few studies explicitly studied civilian populations, considerably more contained information that implied that civilians were likely impacted by outbreaks described in the military.

ConclusionsThis study identified features of the military that pose a significant threat to global health, especially to civilian health in countries with substantial military presence or underdeveloped health systems. While biological transmission mechanisms are shared by other social groups, selected social transmission mechanisms are unique to the military. As an increasingly interconnected world faces the challenges of COVID-19 and future infectious diseases, the identified features of the military may exacerbate current and similar challenges and impair attempts to implement successful and equitable global public health policies.
A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Declines and pronounced state disparities in prescription opioid distribution in the United States BackgroundThe United States (US) opioid epidemic is a persistent and pervasive public health emergency as it continues to claim the lives of Americans through addiction and overdose. There have been sustained efforts to reverse this iatrogenic crisis over the past decade. This study analyzed the changes in prescription opioid distribution for pain and identified regional differences between 2010 and 2019.

Methods and FindingsOpioid production data was obtained from the DEAs annual production quotas. Total opioid production has decreased 41.5% from 2013 (87.6 morphine mg equivalent metric tons) to 2019 (51.3). Opioid distribution from 2010 to 2019 was collected for ten prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) from the US Drug Enforcement Administrations Automation of Reports and Consolidated Orders System. Regional variance was expressed as the ratio of the 95th to 5th percentiles of opioid distribution per state, corrected for population. The peak year for all ten prescription opioids was identified, individually, as between 2010 and 2013, except for codeine (2015). There was a 51.96% overall decrease in opioid distribution per capita with the largest decrease in Florida (-61.61%) and smallest in Texas (-18.64%). The largest quantities of opioid distribution were observed in Tennessee (520.70 morphine mg equivalent or MME per person) and Delaware (251.45) in 2011 and 2019. The smallest was Nebraska (153.39) in 2011 and Minnesota (90.49) in 2019. The highest to lowest state ratio of total opioid use, corrected for population, was sizable in 2011 (5.25) and 2019 (2.78). Similarly, the mean 95th/5th ratio was relatively stable in from 2011 (4.78 +0.70) and 2019 (5.64+0.98). The 95th/5th ratio in 2019 was greatest for methadone (10.23) and oxymorphone (10.09) and smallest for morphine (2.20) and fentanyl (2.12). Southern states (e.g MS, TN, AL, AK, DE, and NC) had the highest per capita distribution for eight of the ten opioids in 2019. The strength of the correlation between per capita hydrocodone and codeine, and hydromorphone and codeine increased significantly from 2011 to 2019

ConclusionsThis study found a decline in total production and distribution for ten prescription opioids during the last half-decade. However, distribution was non-homogeneous at a state level. Analysis of regional differences revealed a three-fold difference in the 95th:5th percentile ratio between states which was unchanged over the past decade. Future research focused on identifying factors contributing to the observed regional variability could prove valuable to understanding, and potentially remediating, the pronounced disparities in prescription opioid use in the US. 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 "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

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

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

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. Impact of HIV Infection on COVID-19 Outcomes Among Hospitalized Adults in the U.S. BackgroundWhether HIV infection is associated with differences in clinical outcomes among people hospitalized with COVID-19 is uncertain.

ObjectiveTo evaluate the impact of HIV infection on COVID-19 outcomes among hospitalized patients.

MethodsUsing the American Heart Associations COVID-19 Cardiovascular Disease registry, we used hierarchical mixed effects models to assess the association of HIV with in-hospital mortality accounting for patient demographics and comorbidities and clustering by hospital. Secondary outcomes included major adverse cardiac events (MACE), severity of illness, and length of stay (LOS).

ResultsThe registry included 21,528 hospitalization records of people with confirmed COVID-19 from 107 hospitals in 2020, including 220 people living with HIV (PLWH). PLWH were younger (56.0+/-13.0 versus 61.3+/-17.9 years old) and more likely to be male (72.3% vs 52.7%), Non-Hispanic Black (51.4% vs 25.4%), on Medicaid (44.5% vs 24.5), and active tobacco users (12.7% versus 6.5%).

Of the study population, 36 PLWH (16.4%) had in-hospital mortality compared with 3,290 (15.4%) without HIV (Risk ratio 1.06, 95%CI 0.79-1.43; risk difference 0.9%, 95%CI -4.2 to 6.1%; p=0.71). After adjustment for age, sex, race, and insurance, HIV was not associated with in-hospital mortality (aOR 1.13; 95%CI 0.77-1.6; p 0.54) even after adding body mass index and comorbidities (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91), severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86), or LOS (aOR 1.03; 95% CI 0.76-1.66, p=0.21).

ConclusionHIV was not associated with adverse outcomes of COVID-19 including in-hospital mortality, MACE, or severity of illness.

Condensed AbstractWe studied 21,528 patients hospitalized with COVID-19 at 107 hospitals in AHAs COVID-19 registry to examine the association between HIV and COVID-19 outcomes. More patients with HIV were younger, male, non-Hispanic Black, on Medicaid and current smokers. HIV was not associated with worse COVID-19 in-hospital mortality (Risk ratio 1.06, 95%CI 0.79-1.43; p=0.71) even after adjustment (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was also not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91) or severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86. Our findings do not support that HIV is a major risk factor for adverse COVID-19 outcomes. Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis; however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 individual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions.

Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care. 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. Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. Sequencing individual genomes with recurrent genomic disorder deletions reveals genes for autosomal recessive traits In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we now suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics. We present novel genomic insights to enhance discovery in the challenging context of autosomal recessive (AR) traits and bi-allelic variation. We demonstrate computationally that new mutation mediated by nonallelic homologous recombination (NAHR), involving recurrent deletions at 30 genomic regions, likely drives recessive disease burden for over 70% of loci within these segmental deletions or at least 2% of loci genome wide. Meta-analyses of literature-reported patients implicate that NAHR-deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2 and OTUD7A. Our data demonstrate that genomic sequencing of personal genomes with NAHR-deletions could dramatically foment allele and gene discovery, enhance clinical molecular diagnosis, and could potentially enable human haploid genetics screens as an approach to disease biology. The tumor suppressor Adenomatous polyposis coli regulates T lymphocyte migration. Insights from familial polyposis patients Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance for anti-tumor immunity is ill defined. APC regulates cytoskeleton organization, cell polarity and migration in various cells types. Here we address whether APC plays a role in T lymphocyte migration, a key step of anti-tumor immune responses.

Using a series of cell biology tools, we demonstrated that T cells from FAP patients carrying APC mutations display adhesion and migration defects. Concomitantly, they presented lower expression of the integrin VLA-4. To further dissect the cellular mechanisms underpinning these defects, we depleted APC in the CEM T cell line. We found that APC is critical not only for VLA-4-dependent adhesion but also for actomyosin and microtubule organization in migrating T cells. Finally, APC-silenced CEM cells preferentially adopt an ameboid-like migration featuring unstructured pseudopodia and blebbing.

These findings underscore a role of APC in T cell migration via modulation of integrin-dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only drive intestinal neoplasms, but also impair T cell migration, potentially leading to inefficient T cell-mediated anti-tumor immunity. Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry Randomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a "virtual trial" by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases. Capturing Global, Predicting Local for ControllingAntimicrobial Resistance: a retrospective multivariable analysis BackgroundAntimicrobial resistance (AMR) is a complex multifactorial outcome of health, socio-economic and geopolitical factors. Therefore, tailored solutions for mitigation strategies could be more effective in dealing with this challenge. Knowledge-synthesis and actionable models learned upon large datasets are critical in order to diffuse the risk of entering into a post-antimicrobial era.

ObjectiveThis work is focused on learning Global determinants of AMR and predicting the susceptibility of antibiotics at the isolate level (Local) for WHO (world health organization) declared critically important pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Staphylococcus aureus.

MethodsIn this study, we used longitudinal data (2004-2017) of AMR having 633820 isolates from 70 Middle and High-income countries. We integrated AMR data with the Global burden of disease (GBD), Governance (WGI), and Finance data sets in order to find the unbiased and actionable determinants of AMR. We chose a Bayesian Decision Network (BDN) approach within the causal modeling framework to quantify determinants of AMR. Finally Integrating Bayesian networks with classical machine learning approaches lead to effective modeling of the level of AMR.

ResultsFrom MAR (Multiple Antibiotic Resistance) scores, we found that developing countries are at higher risk of AMR compared to developed countries, for all the critically important pathogens. Also, Principal Components Analysis(PCA) revealed that governance, finance, and disease burden variables have a strong association with AMR. We further quantified the impact of determinants in a probabilistic way and observed that health system access and government effectiveness are strong actionable factors in reducing AMR, which was in turn confirmed by what-if analysis. Finally, our supervised machine learning models have shown decent performance, with the highest on Staphylococcus aureus. For Staphylococcus aureus, our model predicted susceptibility to Ceftaroline and Oxacillin with the highest AUROC, 0.94(with SE of 0.01%) and 0.89(with SE of 0.002%) respectively. Clinical impact of the rapid molecular detection of RSV and influenza A and B viruses in the emergency department IntroductionUsing respiratory viruses rapid diagnostic tests in the emergency room (ER) could allow a better and faster clinical management. Point-of-care PCR instruments provide now results in less than 30 minutes. The objective of this study was to assess the impact of the use of the cobas(R) Influenza A/B & RSV Assay for use on Roches cobas(R) Liat(R) instrument on the clinical management of ER patients.

MethodsPatients (adults and children) requiring admission or suffering from an underlying condition at risk of respiratory complication were prospectively recruited in the ER of four hospitals in the Brussels region. Physicians intentions regarding admission, isolation, antibiotic and antiviral use were collected before and after performing a cobas(R) Influenza A/B & RSV molecular test. Additionally, a comparison of the analytical performance of this test against antigen rapid tests and viral culture was performed as well as a time-to-result evaluation.

ResultsPCR yielded twice more positive results than antigen rapid diagnostic tests. It allowed a decrease in the overall need for isolation and treatment by limiting the isolation of negative patients and the antibiotic use for positive patients. Meanwhile, antiviral treatments better targeted patients with a positive influenza PCR.

ConclusionThe use of a rapid influenza and RSV molecular test improves the clinical management of patients admitted to the ER by providing a fast and reliable result. Their additional cost compared to antigen tests should be balanced with the benefit of their analytical performance, leading to efficient reductions in the need of isolation and antibiotic use. Benchmarking saliency methods for chest X-ray interpretation Saliency methods, which "explain" deep neural networks by producing heat maps that highlight the areas of the medical image that influence model prediction, are often presented to clinicians as an aid in diagnostic decision-making. Although many saliency methods have been proposed for medical imaging interpretation, rigorous investigation of the accuracy and reliability of these strategies is necessary before they are integrated into the clinical setting. In this work, we quantitatively evaluate three saliency methods (Grad-CAM, Grad-CAM++, and Integrated Gradients) across multiple neural network architectures using two evaluation metrics. We establish the first human benchmark for chest X-ray interpretation in a multilabel classification set up, and examine under what clinical conditions saliency maps might be more prone to failure in localizing important pathologies compared to a human expert benchmark. We find that (i) while Grad-CAM generally localized pathologies better than the two other saliency methods, all three performed significantly worse compared with the human benchmark; (ii) the gap in localization performance between Grad-CAM and the human benchmark was largest for pathologies that had multiple instances, were smaller in size, and had shapes that were more complex; (iii) model confidence was positively correlated with Grad-CAM localization performance. Our work demonstrates that several important limitations of saliency methods must be addressed before we can rely on them for deep learning explainability in medical imaging. Treatment interruption is a risk factor for sickness presenteeism: a large-scale cross-sectional study during the COVID-19 pandemic ObjectivesThis study examined the relationship between interruption to routine medical care during the coronavirus disease 2019 pandemic and sickness presenteeism among workers in Japan.

MethodsA cross-sectional study using data obtained from an internet monitor questionnaire was conducted. Interruption to medical care was defined based on the response "I have not been able to go to the hospital or receive treatment as scheduled." The fraction of sickness presenteeism days in the past 30 days was employed as the primary outcome. A fractional logit model was used for analysis to treat bounded data.

ResultsOf the 27,036 participants, 17,526 (65%) were workers who did not require routine medical care, 8,451 (31%) were using medical care as scheduled, and 1,059 (4%) experienced interrupted medical care. The adjusted odds ratio (aOR) of sickness presenteeism was significantly higher among workers who experienced interrupted medical care (3.44; 95% confidence interval [CI]: 3.04-3.89) than those who did not require routine medical care. In terms of symptoms, the highest aOR was observed among workers with mental health symptoms (aOR: 5.59, 95%CI: 5.04-6.20).

ConclusionsThis study suggests the importance of continuing necessary treatment during a pandemic to prevent presenteeism. Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 "India" variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. 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. 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. Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries BackgroundThrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries.

MethodsElectronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner.

FindingsA total of 25,432,658 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 30.9 (28.6 to 33.3) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event.

InterpretationAlthough rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

FundingThis study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3). Post-viral parenchymal lung disease following COVID-19 and viral pneumonitis hospitalisation: A systematic review and meta-analysis BackgroundApproximately half of COVID-19 survivors present persisting breathlessness, which may include development of pulmonary fibrosis.

Research QuestionWhat is the prevalence of long-term radiological and functional pulmonary sequelae of parenchymal lung disease following hospitalisation with COVID-19 and other viral pneumonia?

Study design and methodsWe performed systematic review and random effects meta-analysis of studies in adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV, or Influenza pneumonia and followed within 12 months from discharge. Searches were run on MEDLINE and Embase, updated 29 July 2021. Primary outcomes were proportion of 1) radiologic sequelae at CT scans; 2) restrictive impairment; 3) impaired gas transfer. Heterogeneity was explored in meta-regression.

ResultsNinety-five studies were included for qualitative synthesis, of which 70 were suitable for meta-analysis, including 60 studies of SARS-CoV-2 with a median follow up of 3 months. In SARS-CoV-2 the overall estimated proportion of inflammatory changes during follow up was 0.50 (95%CI 0.41 to 0.58, I2=94.6%), whilst fibrotic changes were estimated at 0.29 (95%CI 0.22 to 0.37, I2=94.1%). Inflammatory changes reduced compared with CTs performed during hospitalisation (-0.47; 95%CI -0.56 to -0.37), whereas no significant resolution was observed in fibrotic changes (-0.09; 95%CI -0.25 to 0.07). Impaired gas transfer was estimated at 0.38 (95%CI 0.32 to 0.44, I2=92.1%), which was greater than estimated restrictive impairment (0.17; 95%CI 0.13 to 0.23, I2=92.5%). High heterogeneity means that estimates should be interpreted with caution. Confidence in the estimates was deemed low due to the heterogeneity and because studies were largely observational without controls.

InterpretationA substantial proportion of radiological and functional sequelae consistent with parenchymal lung disease are observed following COVID-19 and other viral pneumonitis. Estimates of prevalence are limited by differences in case mix and initial severity. This highlights the importance of extended radiological and functional follow-up post hospitalisation.

PROSPERO registrationCRD42020183139 (April 2020) 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. The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury.