Combining machine learning and mathematical models of disease dynamics to guide development of novel malaria interventions BackgroundSubstantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. This study highlights the role of mathematical models to support intervention development.

MethodsA mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. We demonstrate the power of our approach by application to five malaria interventions in development.

ResultsAiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that the efficacy and duration needs depend on the biological action of the interventions. Interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements.

ConclusionsOur approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions.
Confirmed forecasts for the expansion of the COVID-19 epidemic in the largest Brazilian City ObjectiveA SEIR compartmental model was previously selected to estimate future outcomes to the dynamics of the Covid-19 epidemic breakout in Brazil.

MethodCompartments for individuals vaccinated, and prevalent SARS-Cov-2 variants were not included. A time-dependent incidence weight on the reproductive basic number accounted for Non Pharmaceutical Interventions (NPI). A first series of published data from March 1st to May 8, 2020 was used to adjust all model parameters aiming to forecast one year of evolutionary outbreak. The cohort study was set as a city population-based analysis.

AnalysisThe population-based sample, 25,366 during the study period, was the number of confirmed cases on exposed individuals. The analysis was applied to predict the consequences of holding for posterior NPI releases, and indicates the appearance of a second wave starting last quarter of 2020.

FindingsBy March 1st2021, the number of confirmed cases was predicted to reach 0.47Million (0.24-0.78), and fatalities would account for 21 thousand (12-33), 5 to 95% CRI. A second series of data published from May 9, 2020 to March 1st, 2021 confirms the forecasts previously reported for the evolution of infected people and fatalities.

NoveltyBy March 1st 2021, the number of confirmed cases reached 527,710 (12% bellow predicted average of accumulated cases), and fatalities accounted for 18,769 (10% above the accumulated average of estimated fatalities). After March 1st, new peaks on reported numbers of daily new infected and new fatalities appeared as a combined result to the appearance of the prevalent SARS-CoV-2 P1 variant, and the increased number of vaccinated individuals.
Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression. Colorectal Cancer Disparities Across the Continuum of Cancer Care: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

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

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

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

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

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

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

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

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. 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. Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis：A cohort study BackgroundThe selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization in the range of predicted death risk

MethodsThe multivariable Cox regression model (MVR) was estimated to predict mortality at 5yr. The cut-off values were determined by a two-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality.

Results825 IM-HCC with hepatitis B cirrhosis were included for analysis (TACE, n=622; LR, n=203). The 5-yr overall survival rate of LR patients was higher than the TACE group (52.8% vs. 20.8%; P<0.0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction =0.008). The benefit of LR versus TACE decreased progressively as predicted death risk>0.55 (95%CI: 0.45,0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into four subgroups by the cut-off values (<0.45, 0.45[&ge;] /<0.62, 0.62[&ge;] /<0.7, [&ge;] 0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively.

ConclusionsLR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-yr death risk over 0.7. Detection of COVID-19 and age-dependent dysosmia with paired crushable odorant ampules BackgroundSigns of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis.

Methods and FindingsWe adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent and decreased with aging. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups.

Conclusionsn-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making. 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. A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy. Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant BackgroundThere has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines.

MethodsThe levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples.

ResultsA booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses.

ConclusionsHeterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron. 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. Early Stopping in Experimentation with Real-time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test IntroductionFunctional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically-driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed.

MethodsVoxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR).

ResultsUse of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 minutes on a 12 minute scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters.

ConclusionA systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects. 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. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Association of preference and frequency of teleworking with work functioning impairment: a nationwide cross-sectional study of Japanese full-time employees ObjectiveWe examined whether teleworking preference and frequency were associated with work functioning impairment.

MethodsThis online cross-sectional study was conducted using a self-administered questionnaire among 27,036 full-time Japanese workers. The Work Functioning Impairment Scale was used to measure work functioning impairment, and we performed multilevel logistic regression analysis.

ResultsHigher odds ratios for work functioning impairment were observed among employees who preferred to telework compared with those who preferred working in the workplace. A similar trend was observed among employees who teleworked 4 or more days a week compared with those who almost never teleworked. When teleworking preference and frequency were adjusted, only teleworking preference was associated with work functioning impairment.

ConclusionsA preference for teleworking was associated with work functioning impairment and one factor that increased the teleworking frequency. Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

Materials and MethodsA cross-sectional study was conducted on 179 patients with knee OA aged [&ge;] 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. IADL status was assessed using eight activity items. Participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model. Demographics, motor functions, and pain intensity were also included as confounders.

ResultsOf the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82-0.99, p=0.02) was a significant independent variable among all psychological factors.

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. COVID Outcome Prediction in the Emergency Department (COPE): Development and validation of a model for predicting death and need for intensive care in COVID-19 patients Background and aimCOVID-19 is putting extraordinary pressure on emergency departments (EDs). To support decision making in the ED, we aimed to develop a simple and valid model for predicting mortality and need for intensive care unit (ICU) admission in suspected COVID-19 patients.

MethodsFor model development, we retrospectively collected data of patients who were admitted to 4 large Dutch hospitals with suspected COVID-19 between March and August 2020 (first wave of the pandemic). Based on prior literature we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. Logistic regression analyses with post-hoc uniform shrinkage was used to obtain predicted probabilities of in-hospital death and of the need for ICU admission, both within 28 days after hospital admission. We assessed model performance (Area Under the ROC curve (AUC); calibration plots) with temporal validation in patients who presented between September and December 2020 (second wave). We used multiple imputation to account for missing values.

ResultsThe development data included 5,831 patients, of whom 629 (10.8%) died and 5,070 (86.9%) were discharged within 28 days after admission. ICU admission was fully recorded for 2,633 first wave patients in 2 hospitals, with 214 (8%) ICU admissions within 28 days. A simple model - COVID Outcome Prediction in the Emergency Department (COPE) - with age, respiratory rate, C-reactive protein, lactic dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well-calibrated and showed good discrimination in 3,252 second wave patients (AUC in 4 hospitals: 0.82 [0.78; 0.86]; 0.82 [0.74; 0.90]; 0.79 [0.70; 0.88]; 0.83 [0.79; 0.86]). COPE was also able to identify patients at high risk of needing IC in 706 second wave patients with complete information on ICU admission (AUC: 0.84 [0.78; 0.90]; 0.81 [0.66; 0.95]). The models are implemented in web-based and mobile applications.

ConclusionCOPE is a simple tool that is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

CONTRIBUTION TO THE LITERATUREO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPrediction models have the potential to support decision making about hospital admission of patients presenting to the emergency department with suspected COVID-19
C_LIO_LIMost currently available models that were independently assessed contain a high risk of bias
C_LIO_LIPromising models were developed in different patient selections and included predictors that are not quickly and objective obtainable in emergency departments
C_LI

What this study addsO_LIA simple and objective tool ("COPE") is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19
C_LIO_LICOPE may support ED physicians to identify high-risk patients - i.e. those at high risk of deterioration and/or death - requiring treatment in the ICU, intermediate-risk patients requiring admission to the clinical ward, and low-risk patients who can potentially be sent home
C_LI Effect of RBD mutations in spike glycoprotein of SARS-CoV-2 on neutralizing IgG affinity BackgroundCertain mutant strains of SARS-CoV-2 are known to spread widely among humans, including the receptor binding domain (RBD) mutant, Y453F, from farmed minks, and the RBD mutant, N501Y, a mutation common to three major SARS-CoV-2 subspecies (B.1.1.7, B.1.351, and B.1.1.248).

MethodsWe investigated the characteristics of the RBD mutants, Y453F and N501Y, using three-dimensional structural analysis. We also investigated the effect of Y453F and N501Y on neutralizing antibodies in serum derived from COVID-19-positive patients.

ResultsOur results suggest that SARS-CoV-2 subspecies with the RBD mutations Y453F or N501Y partially escaped detection by 4 neutralizing monoclonal antibodies and 21 neutralizing antibodies in serums derived from COVID-19-positive patients.

ConclusionsInfection with SARS-CoV-2 subspecies that cause serious symptoms in humans may spread globally. 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. 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. 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.) Post-stroke executive function in relation to white matter damage on clinically acquired CT brain imaging ImportanceExecutive function impairments are highly prevalent post-stroke and are a feature of vascular dementia. Computed tomography (CT) neuroimaging is routinely acquired in clinical settings. Therefore, determining the prognostic utility of CT-derived markers for post-stroke cognitive outcomes is of key clinical and academic interest.

ObjectiveTo determine whether post-stroke executive function is associated with stroke-related white matter damage and/or white matter hypoattenuations of presumed vascular origin (WMHs) on routine CT brain scans.

DesignRetrospective cross-sectional analysis of data collected within the Oxford Cognitive Screening (OCS) programme (2016-2020).

SettingPatients were recruited at Oxford University Hospitals acute stroke unit. Follow-up cognitive assessment was conducted six-months post-stroke at patients homes.

ParticipantsOCS programme recruited a consecutive patient sample with a confirmed diagnosis of stroke, who were minimum 18 years old, able to remain alert for 20 minutes, and able to provide informed consent. This study included all patients who completed six-month follow-up assessment with the Oxford Cognitive Screen-Plus (OCS-Plus) and had a usable acute CT scan with a visible stroke lesion.

Main Outcome and MeasuresAssociation between post-stroke executive function and both stroke-specific white matter damage and WMHs on routine CT. Executive function was evaluated using the OCS-Plus Rule Finding task. Stroke lesions were manually delineated on CT, and stroke-related white matter damage was quantified then dichotomised using the HCP-842 atlas. WMHs were visually rated using the Age-Related White Matter Changes scale and dichotomised as present or absent.

ResultsAmong 87 stroke patients (mean/SD age = 73.60/11.75; 41 female; 61 ischaemic stroke), multivariable linear regression analyses demonstrated that poorer executive function six-months post-stroke was associated with both stroke damage to the medial lemniscus (B= - 8.86, p< .001, 95% CI [-13.29 -4.43]) and the presence of WMHs (B= -5.42, p= .005, 95% CI [-9.12 -1.72]), after adjusting for covariates including age and education.

Conclusions and RelevancePoorer post-stroke executive functioning was associated with both localised patterns of stroke-specific white matter damage and white matter degeneration. Our results confirm the necessary role of white matter integrity for executive functioning post-stroke and highlight the prognostic utility of CT-derived neuroimaging markers for long-term post-stroke cognitive outcomes. 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. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

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

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

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

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

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

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

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients Hereditary cancer risk syndromes are caused by germline variants. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all regions of the country with Next-generation sequencing (NGS) panels. Most were women with personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%) distributed among 32 genes. Most were on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP, respectively), MUTYH (42 monoallelic patients, 13.1%), PALB2 (25, 7.8%), Lynch syndrome genes (17, 5.3%), and TP53 (17, 5.3%). Transheterozygosity prevalence in our sample was 0.89% (15/1682). BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We evaluated the performance of the genetic testing criteria by NCCN and Brazilian National Health Agency (ANS). We observed false negative rates of 17.3% and 44.2%, meaning that both failed to detect a substantial part of P/LP positive patients. Our results add knowledge on the Brazilian spectrum of cancer risk germline variants, demonstrate that large multigene panels have high rates of positivity, and indicate that Brazilian testing guidelines should be improved.