Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes among schoolchildren exposed to scarlet fever: a longitudinal multi-cohort molecular epidemiology contact tracing study. BackgroundDespite recommendations regarding prompt treatment of cases and enhanced hygiene measures, scarlet fever outbreaks increased in England between 2014-2018. We aimed to assess the impact of standard interventions on transmission of Streptococcus pyogenes to classroom contacts, households, and classroom environments.

MethodsWe undertook a prospective, contact tracing study in schools with 2 consecutive scarlet fever cases that were reported to local Health Protection teams in London between March 1st and May 31st in 2018 and 2019. We cultured throat swabs from cases, household contacts, and classroom contacts at four time points. We also cultured hand swabs and cough plates from all cases, and from classroom contacts in 2019. Surface swabs from toys and other fomites in classrooms were cultured in 2018, and settle plates from classrooms were collected in 2019. Any sample with S. pyogenes detected was recorded as positive and underwent emm genotyping and genome sequencing to compare with the outbreak strain.

FindingsSix classes, comprising 12 scarlet fever cases, 17 household contacts, and 278 classroom contacts were recruited from March 1st to May 31st in 2018 and the same period in 2019. Prevalence of the outbreak S. pyogenes strain in throat swabs from asymptomatic classroom contacts was high, increasing from 9.6% (11/115) in week 1, to 26.9% (34/126) in week 2, to 24.1% (26/108) in week 3, then 14.3% (5/35) in week 4. Colonisation with non-outbreak and non-genotyped S. pyogenes strains was 1.7% (2/115); 3.9% (5/126); 5.6% (6/108); and 0/35 in the same weeks. Genome sequencing showed clonality of isolates within each of six classes, confirming recent transmission accounted for high carriage. When transmissibility was tested, children who were asymptomatic carriers of emm4 and emm3.93 had positive cough plates on 1/14 (7.1%) and 7/21 (33.3%) occasions respectively. Only 1/60 surface swabs taken in 3 classrooms yielded the outbreak S. pyogenes strain. In contrast, 2/12 and 6/12 settle plates placed in elevated locations yielded the outbreak S. pyogenes strain in the two classrooms tested.

InterpretationS. pyogenes transmission in schools is intense and may occur prior to, or inspite of reported treatment of cases, underlining a need for rapid case management. Despite guideline adherence, heavy shedding of S. pyogenes by small numbers of classroom contacts may perpetuate outbreaks, and airborne transmission has a plausible role in spread. The findings highlight the need for research to improve understanding and assess effectiveness of interventions to reduce S. pyogenes airborne transmission.
SARS-CoV-2 Transmission and Impacts of Unvaccinated-Only Screening in Populations of Mixed Vaccination Status Community testing programs focused on the unvaccinated population are being enacted in populations with mixed vaccination status to mitigate SARS-CoV-2 spread. Presumably, these policies assume that the unvaccinated are driving transmission, though it is not well understood how viral spread occurs in mixed-status populations. Here, we analyze a model of transmission in which a variable fraction of the population is vaccinated, with unvaccinated individuals proactively screened for infection. By exploring a range of transmission rates, vaccine effectiveness (VE) scenarios, and rates of prior infection, this analysis reveals principles of viral spread in communities of mixed vaccination status, with implications for screening policies. As vaccination rates increase, the proportion of transmission driven by the unvaccinated population decreases, such that most community spread is driven by breakthrough infections once vaccine coverage exceeds 55% (omicron) or 80% (delta), with additional variation dependent on waning or boosted VE. More broadly, the potential impacts of unvaccinated-only screening fall into three distinct parameter regions: (I) "flattening the curve" with little impact on cumulative infections, (II) effectively suppressing transmission, and (III) negligible impact because herd immunity is reached without screening. By evaluating a wide range of scenarios, this work finds broadly that effective mitigation of SARS-CoV-2 transmission by unvaccinated-only screening is highly dependent on vaccination rate, population-level immunity, screening compliance, and vaccine effectiveness against the current variant.
Impacts of Teaching Modality on U.S. COVID-19 Spread in Fall 2020 Semester We study the impact of college reopening in Fall 2020 on county-level COVID-19 cases and deaths using the information of 1,076 U.S. colleges. We match college and county characteristics using several methods and calculate the average treatment effects of three teaching modalities: in-person, online, and hybrid on COVID-19 outcomes up to two months after college reopening. In pairwise comparison, colleges reopened with in-person teaching mode were found to have about 36% point more cases within 15 days of reopening, compared to those reopened online, and the gap widens over time at a decreasing rate. Death rates follow the pattern with a time lag. However, colleges with hybrid mode catch the pattern of in-person mode after some time. We also find that greater endowment and student population, and fewer republican votes in the county are major predictors of choosing remote teaching modes over in-person.

JEL codesA23, I18, I23. Impact of a Multidisciplinary Nutritional Support Team on Quality Improvement in Home Parenteral Nutrition IntroductionHPN is essential for patients requiring long term nutritional support. This Quality Improvement Project for HPN Patients (QIP-PN) studied the effect of a Physician Nutrition Expert (PNE)- led multidisciplinary nutritional support team (MNST) on HPN care.

ObjectiveTo test the effect of an MNST on adherence to protocols, outcomes and QOL in HPN.

MethodsData review was conducted in phases 1a and 1b, observation in phase 2 and intervention in phase 3. In Phase 3 the MNST made recommendations to treating physicians. All long-term HPN patients were offered study participation. 75 signed consent forms. Treating physician study participation agreements were signed for 42 patients (the study group). A random sample of 30 long-term HPN patients comprised the case-matched control group (control). Data were collected on demographics, treating physicians PNE status, HPN care variables, recommended interventions, quality-of-life assessment, adverse outcomes and hospitalizations. Independent samples t-test was used for continuous data between study group and control group. Paired t-test was used for phase 2 and phase 3 patient data. Comparison between the study and control group utilized a negative binomial regression model. Statistical analysis utilized R (https://www.r-project.org/).

Results34 patients were reviewed retrospectively in phase 1a and 197 prospectively in phase 1b. 40 study patients completed phase 2 and progressed into phase 3, of whom 30 completed [&ge;]60 therapy days. Improvements in weight, BMI and QOL were seen in the study patients during intervention. Recommendations made and accepted by treating physicians differed based on PNE status. Study patients had fewer adverse outcomes and related hospitalizations than case matched controls.

ConclusionMNST recommendations improved clinical, biochemical parameters and patients self-reported overall health. It reduced adverse outcomes, hospitalization and hospital length of stay. MNST input could have a significant impact on the quality and cost of HPN care. A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies. 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 Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology and clinical severity and disease course. A comprehensive genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 862 symptomatic patients with infections caused by Omicron from late November 2021 through December 18, 2021. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with decreased disease severity. Although the number of Omicron patients we studied is relatively small, in the aggregate the data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and provide information about disease character. The Acute Treatment of Migraine with Low-Dose Naltrexone and acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. 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), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses. Observational study of changes in utilization and outcomes in non-invasive ventilation in COVID-19 RationaleThe role of non-invasive ventilation (NIV) in severe COVID-19 remains a matter of debate.

ObjectivesTo determine the utilization and outcome of NIV in COVID-19 in an unbiased cohort.

MethodsObservational study of confirmed COVID-19 cases of claims data of the Local Health Care Funds comparing patients with non-invasive and invasive mechanical ventilation (IMV) between spring versus autumn period 2020.

Measurements and Main ResultsNationwide cohort of 7490 cases (median/IQR age 70/60-79 years, 66% male) 3851 (51%) patients primarily received IMV without NIV, 1614 (22%) patients received NIV without subsequent intubation, and 1247 (17%) patients had NIV failure (NIV-F), defined by subsequent endotracheal intubation. The proportion of patients who received invasive MV decreased from 74% to 39% during the second period. Accordingly, the proportion of patients with NIV exclusively increased from 10% to 28%, and those failing NIV increased from 9% to 21%. Median length of hospital stay decreased from 26 to 22 days, and duration of MV decreased from 11.6 to 7.6 days. The NIV failure rate decreased from 49% to 42%. Overall mortality remained unchanged (51% versus 53%). Mortality was 39% with NIV-only, 52% with IMV and 66% with NIV-F with mortality rates steadily increasing from 58% in early NIV-F (day 1) to 75% in late NIV-F (>4 days).

ConclusionUtilization of NIV rapidly increased during the autumn period, which was associated with a reduced duration of MV, but not with overall mortality. High NIV-F rates are associated with increased mortality, particularly in late NIV-F.

FundingInstitutional support and physical resources were provided by the University Witten/Herdecke and Kliniken der Stadt Koln and the Federal Association of the Local Health Care Funds.

At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSCurrent management of ventilatory support in COVID-19 patients with respiratory failure is heterogeneous. Despite increasing use of non-invasive ventilation (NIV), defining intubation criteria still remains a matter of uncertainty and discussion, especially with regard to the balance between the NIV benefits and the risk of NIV failure. In addition, robust data concerning the influence of the duration and failure of NIV on intubation and mortality rates are still missing, although the time span between initiation of NIV and subsequent intubation in case of respiratory failure progression is suggested to influence patient outcome.

What This Study Adds to the FieldThis is the first large observational study describing differences of ventilatory strategies between the spring and autumn period of the SARS-CoV-2 pandemic in Germany and provides the in-hospital mortality rate of 7,490 patients who received mechanical ventilation. The increased utilization of NIV from 10% (first period) to 29% (second period) was associated with overall reduced durations of mechanical ventilation and length of hospital stay, but overall mortality remained comparably high and reached 51%, 53% respectively. Patients succeeding with NIV had lower mortality rates than those getting intubated without preceding NIV attempts, but those failing NIV had higher mortality rates, respectively, and this became even more predominant in late NIV failure. The present observational study shows the increasing role of NIV in the concert of ICU medicine related to COVID-19, but also clearly addresses its risks in addition to its benefits, both impacting on mortality. Spatial Allocation of Scarce COVID-19 Vaccines The COVID-19 Vaccines Global Access (COVAX) is an initiative led by the World Health Organization (WHO) and other partners that aims for an equitable access of COVID-19 vaccines. Despite a potential heterogeneous disease burden across space, countries receiving allotments of vaccines via COVAX may want to follow WHOs allocation rule and distribute vaccines to their jurisdictions based on the jurisdictions relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this ad hoc allocation rule by comparing it to the rule that minimizes the economic damages and expenditures over time, including a penalty cost representing the social costs of deviating from the ad hoc allocation. Under different levels of vaccine scarcity and different demographic characteristics, we consider scenarios where length of immunity and compliance to travel restrictions vary, and consider the robustness of the rules when assumptions regarding these factors are incorrect. The benefits from deviating are especially high when immunity is permanent, when there is compliance to travel restrictions, when the supply of vaccine is low, and when there is heterogeneity in demographic characteristics. Interestingly, a lack of compliance to travel restrictions pushes the optimal allocations of vaccine towards the ad hoc and improves the relative robustness of the ad hoc rule, as the mixing of the populations reduces the spatial heterogeneity in disease burden.

JEL ClassificationC61, H12, H84, I18, Q54 Neutrophils and triglycerides predict critical illness in COVID-19 and reveal CDK6 inhibitors as potential preventive treatment Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing - the use of an already existing drug for a new indication - could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection. Using data from the UK Biobank, we describe a workflow to find evidence for high neutrophil cell count and high concentrations of blood triglycerides as predictors of the immune overreaction in critical illness due to COVID-19. Based on these findings, we identified the enzyme CDK6 as a potential drug target to prevent in high risk individuals with high neutrophil cell count the immune overreaction in critical illness due to COVID-19. Three existing CDK4/6 inhibitors -- abemaciclib, ribociclib, and palbociclib -- have been approved for the treatment of breast cancer. Clinical evidence for CDK4/6 inhibitors in treating critically ill COVID-19 patients has been reported. Further clinical investigations are ongoing. Using Adversarial Images to Assess the Stability of Deep Learning Models Trained on Diagnostic Images in Oncology PurposeDeep learning (DL) models have rapidly become a popular and cost-effective tool for image classification within oncology. A major limitation of DL models is output instability, as small perturbations in input data can dramatically alter model output. The purpose of the study is to investigate the robustness of DL models in the oncologic image domain through the application of adversarial images: manipulated images with small pixel-level perturbations designed to assess the stability of DL models.

Experimental DesignWe examined the impact of adversarial images on the classification accuracies of DL models trained to classify cancerous lesions across three common oncologic imaging modalities (CT, mammogram, and MRI). The CT model was trained to classify malignant lung nodules using the LIDC dataset. The mammogram model was trained to classify malignant breast lesions using the DDSM dataset. The MRI model was trained to classify brain metastases using an institutional dataset. We also explored the utility of an iterative adversarial training approach to improve the stability of DL models to small pixel-level changes.

ResultsOncologic images showed instability with small pixel-level changes. A pixel-level of perturbation of .004 resulted in a majority of oncologic images to be misclassified by their respective DL models (CT 25.64%, mammogram 23.93%, MRI 6.36%). Adversarial training mitigated improved the stability and robustness of DL models trained on oncologic images compared to naive models [(CT 67.72% vs 26.92%), mammogram (63.39% vs 27.68%), MRI (87.20% vs 24.32%)].

ConclusionsDL models naively trained on oncologic images exhibited dramatic instability to small pixel-level changes resulting in substantial decreases in accuracy. Adversarial training techniques improved the stability and robustness of DL models to such pixel-level changes. Prior to clinical implementation, adversarial training should be considered to proposed DL models to improve overall performance and safety. 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. iBKH: The integrative Biomedical Knowledge Hub The rapidly increasing biomedical knowledge, derived from biological experiments or gained from clinical practice, has become the important treasure in the biomedical research. The emerging knowledge graphs (KGs) provide an efficient and effective way to organize and retrieval the huge and increasing volume of biomedical knowledge. A biomedical KG (BKG) typically stores and represents knowledge by constructing a semantic network describing entities and the relationships between them. Previous efforts have been conducted to construct and curate BKGs by comprehensively integrating various biomedical data resources. Though the resulting BKGs have made a significant progress in this filed in advancing biological and medical research, there remain a big gap to a perfect one that is comprehensive and fine-grained enough. To this end, in the present study, we collected and integrated data from diverse well-curated biomedical knowledge bases and BKGs to curate a more comprehensive one, named the integrative Biomedical Knowledge Hub (iBKH). To enhance the usage in accelerating biomedical research, we deployed iBKH using the famous graph database, Neo4j. This is a continuing effort and we are adding in more and more contents in iBKH to support the various complex needs in biomedical data analysis. Please contact us if you have better ideas and suggestions. 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.) 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. 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). 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. 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. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. 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. Prime hAd5 Spike plus Nucleocapsid Vaccination Induces Ten-Fold Increases in Mean T-Cell Responses in Phase 1 Subjects that are Sustained Against Spike Variants In response to the need for a safe, efficacious vaccine that elicits vigorous T cell as well as humoral protection against SARS-CoV-2 infection, we have developed a dual-antigen COVID-19 vaccine comprising both the viral spike (S) protein modified to increase cell-surface expression (S-Fusion) and nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to enhance MHC class I and II presentation and T-cell responses. The antigens are delivered using a human adenovirus serotype 5 (hAd5) platform with E1, E2b, and E3 regions deleted that has been shown previously in cancer vaccine studies to be safe and effective in the presence of pre-existing hAd5 immunity. The findings reported here are focused on human T-cell responses due to the likelihood that such responses will sustain efficacy against emerging variants, a hypothesis supported by our in silico prediction of T-cell epitope HLA binding for both the first-wave SARS-CoV-2  A strain and the B.1.351 strain K417N, E484K, and N501Y spike and T201I N variants. We demonstrate the hAd5 S-Fusion + N-ETSD vaccine antigens expressed by previously SARS-CoV-2-infected patient dendritic cells elicit Th1 dominant activation of autologous patient T cells, indicating the vaccine antigens have the potential to elicit immune responses in previously infected patients. For participants in our open-label Phase 1b study of the vaccine (NCT04591717; https://clinicaltrials.gov/ct2/show/NCT04591717), the magnitude of Th-1 dominant S- and N-specific T-cell responses after a single prime subcutaneous injection were comparable to T-cell responses from previously infected patients. Furthermore, vaccinated participant T-cell responses to S were similar for A strain S and a series of spike variant peptides, including S variants in the B.1.1.7 and B.1.351 strains. The findings that this dual-antigen vaccine elicits SARS-CoV-2-relevant T-cell responses and that such cell-mediated protection is likely to be sustained against emerging variants supports the testing of this vaccine as a universal booster that would enhance and broaden existing immune protection conferred by currently approved S-based vaccines. The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

DesignParticipants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individuals real-ear or prescribed gain. The second segment was presented with a {+/-}0-12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was "better", "worse" or "no different" from the first.

Study SampleTwenty-nine adults, all with hearing-aid experience.

ResultsThe minimum gain adjustments needed to elicit "better" or "worse" judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable.

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation.