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Background: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia., Methods: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids., Results: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05), although the effect sizes were relatively small (e.g., < 7 mg/dL of TC per standard deviation in epigenetic age acceleration). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjustment for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment., Conclusion: Multiple measures of epigenetic age acceleration are associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or non-linear relationships between age and these lipids, as both TC and LDL-C decrease faster at older ages., (© 2024. The Author(s).)

While time spent practicing inpatient dermatology has decreased since the 1990s, less is known about the current state of inpatient dermatology. We describe the distribution and frequency of inpatient dermatology encounters servicing the United States Medicare population between 2013 and 2019. Cross-sectional analysis of publicly available inpatient Medicare Part B claims data from 2013 to 2019 was conducted. Main outcomes and measures were characteristics and trends of dermatologists performing inpatient encounters. Categorical variables were compared using χ 2 analysis. Trends were analyzed for linearity using Pearson correlation coefficient. 782 physicians met inclusion criteria for inclusion. Dermatologists were more often male (56.5%), possessing allopathic Medical Doctorate (MD) (86.3%), and in metropolitan settings (98.2%). However, proportion of female inpatient dermatologists increased significantly (37.9% to 46.2%). Across rural and metropolitan practices, number of inpatient physicians (2013: 356; 2019: 281) and number of medical centers in which dermatology encounters occurred (2013: 239; 2019: 157) decreased, more significantly in non-residency-associated institutions. Spatial analysis revealed wide regions lacking dermatologists meeting defined criteria. Limitations included the need for ten Medicare inpatient encounters for inclusion, counties without reported data. In conclusion, the number of dermatologists performing > 10 inpatient encounters per year is decreasing, and large variations exist in the number of U.S. inpatient dermatology visits., (© 2024. The Author(s).)

Background and Objectives: Spouses with concordant (i.e., similar) drinking behaviors often report better quality marriages and are married longer compared with those who report discordant drinking behaviors. Less is known regarding whether concordant or discordant patterns have implications for health, as couples grow older. The present study examined whether drinking patterns among older couples are associated with mortality over time., Research Design and Methods: The Health and Retirement Study (HRS) is a nationally representative sample of individuals and their partners (married/cohabiting) over age 50 in the United States, in which participants completed surveys every 2 years. Participants included 4,656 married/cohabiting different-sex couples (9,312 individuals) who completed at least 3 waves of the HRS from 1996 to 2016. Participants reported whether they drank alcohol at all in the last 3 months, and if so, the average amount they drank per week. Mortality data were from 2016., Results: Analyses revealed concordant drinking spouses (both indicated they drank in the last 3 months) survived longer than discordant drinking spouses (1 partner drinks and the other does not) and concordant nondrinking spouses. Analysis of average drinks per week showed a quadratic association with mortality such that light drinking predicted better survival rates among individuals and their partners compared with abstaining and heavy drinking. Further, similar levels of drinking in terms of the amount of drinking were associated with greater survival, particularly among wives., Discussion and Implications: This study moves the field forward by showing that survival varies as a function of one's own and one's partner's drinking., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Studies examining the perceived association of war time and increasing suicide rates in the U.S. military and U.S. civilian populations have proliferated since the beginning of the Global War on Terror (GWOT). However, additional historical analysis is needed to better place the recent surge in active-duty U.S. Army and U.S. civilian suicide rates into context and better inform researchers, healthcare providers, and policy makers. To do so, a cross sectional study that extracted empirical data from U.S. government websites, publications, and journal articles published from 1900 to 2022 was conducted to identify longitudinal trends. From 1900 to 2020, active-duty U.S. Army soldier and U.S. civilian suicide rates appear to fluctuate similarly, but with soldier rates often displaying more dramatic changes. Since 1900, active-duty U.S. Army soldier and similarly aged U.S. civilian male suicide rates have gradually converged, with the differences in rates narrowing over time. War does not historically appear to increase suicide rates in active-duty U.S. Army soldiers or U.S. civilians. More recently, given the apparent convergence of U.S. Army and similarly aged U.S. civilian male annual suicide rates, larger more universal factors than combat may be similarly affecting both populations., Competing Interests: Declaration of Competing Interest The Authors declare no competing financial or non-financial interests. No external nor internal funding was used to support this research or study., (Copyright © 2023. Published by Elsevier B.V.)

This study examined the viability and diversity of fungi harbored in imported wooden handicraft products sold in six retail stores in Florida, United States. Despite being subjected to trade regulations that require various sterilization/fumigation protocols, our study demonstrates high survival and diversity of fungi in wood products originating from at least seven countries on three continents. Among these fungi were nonendemic plant and human pathogens, as well as mycotoxin producers. Several products that are sold for use in food preparation and consumption harbored a novel (to North America) plant and human pathogen, Paecilomyces formosus . In addition, a high number of species isolated were thermophilic and included halophilic species, suggesting adaptability and selection through current wood treatment protocols that utilize heat and/or fumigation with methyl-bromide. This research suggests that current federal guidelines for imports of wooden goods are not sufficient to avoid the transit of potential live pathogens and demonstrates the need to increase safeguards at both points of origin and entry for biosecurity against introduction from invasive fungal species in wood products. Future import regulations should consider living fungi, their tolerance to extreme conditions, and their potential survival in solid substrates. Mitigation efforts may require additional steps such as more stringent fumigation and/or sterilization strategies and limiting use of wood that has not been processed to remove bark and decay. IMPORTANCE This study, the first of its kind, demonstrates the risk of importation of nonendemic foreign fungi on wooden handicrafts into the United States despite the application of sanitation protocols. Previous risk assessments of imported wood products have focused on potential for introduction of invasive arthropods (and their fungal symbionts) or have focused on other classes of wood products (timber, wooden furniture, garden products, etc.). Little to no attention has been paid to wooden handicrafts and the fungal pathogens (of plants and humans) they may carry. Due to the large size and diversity of this market, the risk for introduction of potentially dangerous pathogens is significant as illustrated by the results of this study.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits., (© 2022. The Author(s).)

Objectives: In the United States, approximately 2.2% to 5% of children discharged from the emergency department (ED) return within 72 hours. There is limited literature examining caregivers' reasons for return to the ED, and none among Hispanics and Spanish-speaking caregivers. We sought to examine why caregivers of pediatric patients return to the ED within 72 hours of a prior ED visit, and assess roles of ethnicity and primary language., Methods: A previously validated survey was prospectively administered to caregivers returning to the ED within 72 hours of discharge at a freestanding, tertiary care, children's hospital over a 7-month period. Reasons for return to the ED, previous ED discharge processes, and events since discharge were summarized according to Hispanic ethnicity, and English or Spanish language preference, and compared using the Fisher exact test., Results: Among 499 caregiver surveys analyzed, caregivers returned mostly because of no symptom improvement (57.5%) and worsening condition (35.5%), with no statistically significant differences between Hispanic/non-Hispanic ethnicity, or English/Spanish preference. Most (85.2%) caregivers recalled reasons to return to the ED. Recall of expected duration until symptom improvement was significantly higher among Hispanic (60.4%) versus non-Hispanic (52.1%) (P = 0.003), and for Spanish- (68.9%) versus English-speaking (54.6%) (P = 0.04), caregivers., Conclusions: Most caregivers returned to the ED because their child's condition was not better or had worsened. Ethnicity and language were not associated with variations in reasons for return. Non-Hispanic and English-speaking caregivers were less likely to recall being informed of time to improvement and may require additional intervention., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Health promotion research and practice consistently reveals that people of colour in the USA face multiple structural and systemic health and social inequities as a direct consequence of racism and discrimination. Recent scholarship on equity and men's health has highlighted the importance of gender-specifically concepts relating to masculinities and manhood-to better understand the inequities experienced by men of colour. A sharper focus on the intersection between race, gender and life stage has also emphasized the importance of early intervention when addressing inequities experienced by boys and young men of colour (BYMOC). This has led to an expansion of health promotion interventions targeting BYMOC across the USA over the past decade. Many of these health promotion strategies have attempted to reduce inequities through action on the social determinants of health, particularly those that intersect with education and justice systems. Reflecting on these developments, this commentary aims to discuss the challenges and opportunities faced by the health promotion community when attempting to reduce health and social inequities experienced by BYMOC. In doing so, the solutions we identify include: strengthening the evidence base about effective health promotion interventions; reducing system fragmentation; promoting connectivity through networks, alliances and partnerships; reducing tensions between collaboration and competition; changing the narrative associated with BYMOC; acknowledging both inclusiveness and diversity; addressing racism and intergenerational trauma; and committing to a national boys and men's health policy. We encourage health promotion researchers, practitioners and policy-makers to adopt these solutions for the benefit of BYMOC in the USA., (© The Author(s) 2020. Published by Oxford University Press.)

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention., Results: Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064)., Conclusions: Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.

Objectives: The disruption and contraction of older adults' social networks are among the less discussed consequences of the COVID-19 pandemic. Our objective was to provide an evidence-based commentary on racial/ethnic disparities in social network resources and draw attention to the ways in which disasters differentially affect social networks, with meaningful insight for the ongoing pandemic., Methods: We draw upon prior research on social networks and past natural disasters to identify major areas of network inequality. Attention is given to how pre-pandemic racial/ethnic network disparities are exacerbated during the current crisis, with implications for physical and mental health outcomes., Results: Evidence from the literature shows a robust association between strong social networks and physical and mental health outcomes. During times of crisis, access to social networks for older adults is disrupted, particularly for marginalized groups. We document pre-pandemic disparities in social networks resources and offer insight for examining the impact of COVID-19 on disrupting social networks among older adults., Discussion: Importantly, racial/ethnic disparities in social networks both prior to and as a result of the pandemic intensify existing inequalities and demonstrate the necessity of better understanding social network inequalities for marginalized older adults, particularly in the context of the COVID-19 health crisis., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants., Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity., Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10 -11 ; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10 -9 ; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10 -9 ). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10 -9 , nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10 -9 , CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants., Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry., Competing Interests: Declaration of Competing Interest GRA is employed by Regeneron Pharmaceuticals and he owns stock and stock options for Regeneron Pharmaceuticals. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. BMP reports serving on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Y-DIC, LRY, JCM, BDM, JIR, KDT, JPL, EB, JAS, GRA report grants from NIH during the conduct of the study. Remaining authors have nothing to disclose., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown 1 . The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer 2-4 and coronary heart disease 5 -this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP) 6 . Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Background: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough., Methods: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18-80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610., Findings: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients' geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was -22·0% (-41·8 to 4·6; p=0·097) with 7·5 mg, -22·2% (-42·0 to 4·3; p=0·093) with 20 mg, and -37·0% (95% CI -53·3 to -14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant., Interpretation: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough., Funding: Afferent Pharmaceuticals (acquired by Merck & Co., Inc., Kenilworth, NJ, USA)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival., Materials and Methods: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis., Results: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome., Conclusions: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations., Competing Interests: Edwin K Silverman and Michael H Cho have received grant support from GSK, MHC has received consulting fees from Genentech. Scott T. Weiss and Kathleen C. Barnes received royalties from UpToDate. Patrick T. Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases, and has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics and Novartis. Steven A Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics, Bristol Myers Squibb / Pfizer. Other authors declared no conflicts of interest.

Importance: Suicide rates among active-duty personnel in the US military have increased substantially since 2004, and numerous studies have attempted to contextualize and better understand this phenomenon. Placing contemporary examinations of suicides among active-duty personnel in the US Army in historical context provides opportunities for joint historical and epidemiological research to inform health care professionals and policy makers., Objectives: To consolidate data on suicide rates among active-duty personnel in the US Army as far back as historical records allow and to identify historical trends to separate them from more acute causal factors., Design, Setting, and Participants: This cross-sectional study included all active-duty service members in the US Army from 1819 to 2017 as identified and detailed in US government publications, studies, and journal articles. Empirical data were extracted from US government publications and journal articles published from 1819 to 2017. Data collection and analysis were completed between July and August of 2019., Exposure: Suicide., Main Outcomes and Measures: Suicide rates per 100 000 individuals., Results: Starting in 1843, the overall trend in annual suicide rates among active-duty service members in the US Army increased, with a peak rate of 118.3 per 100 000 in 1883. From that historical high point, the rate decreased in 3 successive waves, each corresponding to the end of the following wars: the Spanish-American War (1898), World War I (1914-1918), and World War II (1939-1945). The latter had the historically lowest rate of 5 per 100 000 in 1944 to 1945. During the Cold War (approximately 1945-1991), the rate generally stabilized in the low teens to midteens (ie, 10-15 per 100 000). The rate increased again during the Afghanistan and Iraq Wars, increasing to 29.7 per 100 000 in 2012. From 2008 to present, the annual rate has remained within the range of 20.2 to 29.7 per 100 000., Conclusions and Relevance: This study represents the most extensive historical examination of suicides in the US Army to date. By taking a long-term historical approach to suicide among active-duty personnel in the US Army, this study affords future researchers a new analytical tool and an additional perspective from which to better differentiate long-term and historical trends from more short-term and temporary causal factors.

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA)., Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data., Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features., Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed., Competing Interests: Competing interests: VES reports personal fees from Novartis. GD reports personal fees from Novartis. SC reports personal fees from Novartis and grants from AB2 Bio. GS reports personal fees from Novartis. KB reports personal fees from Novartis. RQC is co-PI of an investigator-initiated clinical trial funded by SOBI. RD reports personal fees from Boehringer Ingelheim, other from NowVitals, personal fees and other from Triple Endoscopy, other from Earables, and NowVitals with patents and lung-related device development. AAG reports grants and personal fees from Novartis and grants from NovImmune. SL reports personal fees from Novartis. RS reports personal fees from Novartis, NovImmune and SOBI. SS reports personal fees from Novartis. MLS reports personal fees from Novartis. LRY reports other from Up-To-Date and other from Boehringer Ingelheim, outside the submitted work. EDM reports grants from Novartis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

The cultural characteristics of fungi can provide useful information for studying the biology and ecology of a group of closely related species, but these features are often overlooked in the order Polyporales. Optimal temperature and growth rate data can also be of utility for strain selection of cultivated fungi such as reishi (i.e., laccate Ganoderma species) and potential novel management tactics (e.g., solarization) for butt rot diseases caused by Ganoderma species. Historically, the taxonomy of the laccate (shiny) Ganoderma species has been unresolved and many species have been treated together as G. lucidum. The cultural characteristics of Ganoderma species from the United States are needed to understand the biology of these unique species that have all been lumped under this name. Culture morphology, average growth rate, optimal temperatures, and resiliency to elevated temperature exposure were characterized for isolates of Ganodermataceae taxa from the eastern United States, including Ganoderma curtisii, G. martinicense, G. meredithiae, G. ravenelii, G. sessile, G. tsugae, G. tuberculosum, G. cf. weberianum, G. zonatum, and Tomophagus colossus. We documented differences in linear growth rates and optimal temperatures between taxa. Isolates of G. sessile and T. colossus grew the fastest, and isolates of G. meredithiae, G. ravenelii, and G. tsugae grew the slowest. Isolates of G. sessile, G. martinicense, G. cf. weberianum, and T. colossus constitutively produced chlamydospores on malt extract agar, and these species were the only species to survive long-term exposure (30 or 40 d) to 40 C. We hypothesize that chlamydospores function as survival structures that serve as propagules resilient to adverse temperature conditions, especially heat. Cultural characteristics of G. martinicense, G. ravenelii, G. tuberculosum, and G. cf. weberianum collected from the United States are described for the first time.

Background: The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs., Objective: To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer., Methods: A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness., Results: At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life-year thresholds., Conclusions: PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost-effective options., Disclosures: This study was unfunded. The authors have nothing to disclose.

Ganoderma is a large, diverse and globally-distributed genus in the Basidiomycota that includes species causing a white rot form of wood decay on a variety of tree species. For the past century, many studies of Ganoderma in North America and other regions of the world have used the name G. lucidum sensu lato for any laccate (shiny or varnished) Ganoderma species growing on hardwood trees or substrates. Molecular studies have established that G. lucidum sensu stricto (Curtis) Karst is native to Europe and some parts of China. To determine the species of the laccate Ganoderma that are present in the United States, we studied over 500 collections from recently collected samples and herbarium specimens from hardwoods, conifers, and monocots. A multilocus phylogeny using ITS, tef1α, rpb1 and rpb2 revealed three well-supported clades, similar to previously reported findings. From the U.S. collections, thirteen taxa representing twelve species were identified, including: G. curtisii, G. lucidum sensu stricto, G. martinicense, G. oregonense, G. polychromum, G. ravenelii, G. sessile, G. tsugae, G. tuberculosum, G. cf. weberianum, G. zonatum, and Tomophagus colossus (syn. G. colossus). The species G. meredithiae is synonymized with G. curtisii, and considered a physiological variant that specializes in decay of pines. The designation G. curtisii f.sp. meredithiae forma specialis nov. is proposed. Species such as G. curtisii and G. sessile, once considered as G. lucidum sensu lato, were found to be divergent from one another, and highly divergent from G. lucidum sensu stricto. Morphological characteristics such as context tissue color and features (e.g. melanoid bands), basidiospore shape and size, geographic location, and host preference were found to aid in species identification. Surprisingly, G. lucidum sensu stricto was found in the U.S., but only in geographically restricted areas of northern Utah and California. These collections appear to have resulted from the introduction of this species into the United States possibly from mushroom growers producing G. lucidum outdoors. Overall, this study clarifies the chaotic taxonomy of the laccate Ganoderma in the United States, and will help to remove ambiguities from future studies focusing on the North American species of laccate Ganoderma., Competing Interests: The authors have the following interests: This project was funded in part by the F.A. Bartlett Tree Experts Company. The first author Andrew Loyd is employed by the F.A. Bartlett Tree Experts Company. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: Federally qualified health centers (FQHCs) were designed to provide care in medically underserved areas. Substantial and sustained federal funding has accelerated FQHC growth., Purpose: To examine temporal trends in primary care provider supply and whether FQHCs have been successful in reducing the gap in provider supply in primary care health professional shortage areas (HPSAs)., Methods: Retrospective cohort study design using national county-level data from 2009 to 2013. Primary care providers included physicians, nurse practitioners, and physician assistants., Findings: Partial-county HPSAs had the highest average provider supply and the greatest increase, followed by non-HPSA counties and whole-county HPSAs. The provider gap was larger in whole-county HPSAs compared with partial-county HPSAs. Counties with one or more FQHC sites had a smaller provider gap than those without FQHC sites. An increase of one FQHC site was statistically significantly associated with a reduction in the annual provider gap., Discussion: FQHCs reduced the gap in primary care provider supply in shortage counties and mitigated uneven distribution of the primary care workforce., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The laccate (shiny or varnished) Ganoderma contain fungi that are important wood decay fungi of living trees and decomposers of woody debris. They are also an important group of fungi for their degradative enzymes and bioprocessing potential. Laboratory decay microcosms (LDMs) were used to study the relative decay ability of G anoderma curtisii, Ganoderma meredithiae, Ganoderma sessile, and G anoderma zonatum, which are four commonly encountered Ganoderma species in the U.S., across four wood types (Pinus taeda, Quercus nigra, Q uercus virginiana, and Sabal palmetto). Generally, all Ganoderma species were able to decay all types of wood tested despite not being associated with only certain wood types in nature. G. sessile, on average caused the most decay across all wood types. Among the wood types tested, water oak (Q. nigra) had the most mass loss by all species of Ganoderma. Scanning electron microscopy was used to assess micromorphological decay patterns across all treatments. All Ganoderma species simultaneously decayed wood cells of all wood types demonstrating their ability to attack all cell wall components. However, G. zonatum caused selective delignification in some sclerenchyma fibers of the vascular bundles in palm (S. palmetto) as well as in fibers of water oak. In addition, G. zonatum hyphae penetrated fibers of palm and oak wood causing an unusual decay not often observed in basidiomycetes resulting in cavity formation in secondary walls. Cavities within the secondary walls of fibers gradually expanded and coalesced resulting in degradation of the S2 layer. Differences in colony growth rates were observed when Ganoderma species were grown on medium amended with water soluble sapwood extracts from each wood type. G. meredithiae had enhanced growth on all media amended with sapwood extracts, while G. curtisii, G. sessile and G. zonatum had slower growth on loblolly pine extract amended medium., (Copyright © 2018 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: Plasma concentrations of lipids (i.e., total cholesterol, high-density cholesterol, low-density cholesterol, and triglycerides) are amenable to therapeutic intervention and remain important factors for assessing risk of cardiovascular diseases. Some of the observed variability in serum lipid concentrations has been associated with genetic and epigenetic variants among cohorts with European ancestry (EA). Serum lipid levels have also been associated with genetic variants in multiethnic populations., Methods: The purpose of this study was to determine whether single-nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) differences contribute to lipid variation among African Americans ([AAs], N = 739) in the Genetic Epidemiology Network of Arteriopathy (GENOA) study., Results: Previous meta-analyses identified 161 SNPs that are associated with lipid traits in populations of EA. We evaluated these SNPs and 66 DNAm sites within the genes containing the SNPs in the GENOA cohort using linear mixed-effects modeling. We did not identify any significant associations of SNPs or DNAm with serum lipid levels. These results suggest that the SNPs identified as being significant for lipid levels through the EA genome-wide association studies may not be significant across AA populations., Conclusions: Reductions in morbidity and mortality due to variation in lipids among AAs may be achieved through a better understanding of the genetic and epigenetic factors associated with serum lipid levels for early and appropriate screening. Further large-scale studies specifically within AA and other non-EA populations are warranted.

Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region ( p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region ( p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript and in the decision to publish the results. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of NIH, NHLBI, NIA, NIMHD, or NHGRI. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services.

Objectives: To examine racial differences in the distribution of histological subtypes of renal cell carcinoma (RCC) and associations with established RCC risk factors by subtype., Materials and Methods: Tumours from 1532 consecutive patients with RCC who underwent nephrectomy at Vanderbilt University Medical Center (1998-2012) were classified as clear-cell, papillary, chromophobe and other subtypes. In pairwise comparisons, we used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between race, sex, age, end-stage renal disease (ESRD) and body mass index at diagnosis according to histological subtype., Results: The RCC subtype distribution was significantly different in black people from that in white people (P < 0.001), with a substantially higher proportion of patients with papillary RCC among black people than white people (35.7 vs 13.8%). In multivariate analyses, compared with clear-cell RCC, people with papillary RCC were significantly more likely to be black (OR 4.15; 95% CI 2.64-6.52) and less likely to be female (OR 0.60; 95% CI 0.43-0.83). People with chromophobe RCC were significantly more likely to be female (OR 2.32; 95% CI 1.44-3.74). Both people with papillary RCC (OR 6.26; 95% CI 2.75-14.24) and those with chromophobe RCC (OR 7.07; 95% CI 2.13-23.46) were strongly and significantly more likely to have ESRD, compared with those with clear-cell RCC., Conclusion: We observed marked racial differences in the proportional subtype distribution of RCCs diagnosed at a large tertiary care academic centre. To our knowledge, no previous study has examined racial differences in the distribution of RCC histologies while adjusting for ESRD, which was the factor most strongly associated with papillary and chromophobe RCC compared with clear-cell RCC., (© 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.)

Diabetes is the seventh leading cause of death in the United States and disproportionately affects ethnic minorities. While research examining health disparities is well-established, an historical understanding of how the disparities evolved over time may be warranted. This article examined racial differences in prevalence of diabetes and associated mortality in Blacks and Whites during the US Civil War. Data were extracted from the Medical and Surgical History of the War of Rebellion, 1861-1865, representing segregated White and Black Union Forces who served during the war. Data were collapsed by war theater (Atlantic, Central, Pacific). Results by race show that, from 1861 to 1866, the rates of Whites diagnosed with diabetes ranged overall from 0% to .11% and was distributed throughout the war theaters as: Atlantic 0.3% to .05%; Central 0.3% to .08%, and Pacific 0% to .11%. For Blacks, Atlantic ranged from .02% to .07% and Central .03% to .06%. None were reported for Pacific. Mortality was approximately .01% for both Blacks and Whites. These data suggest no racial differences in diabetes prevalence and mortality existed between Blacks and Whites during this time, implying that disparities may have evolved more recently.

The hormone cortisol is likely to be a key mediator of the stress response that influences multiple physiologic systems that are involved in common chronic disease, including the cardiovascular system, the immune system, and metabolism. In this paper, a candidate gene approach was used to investigate genetic contributions to variability in multiple correlated features of the daily cortisol profile in a sample of European Americans, African Americans, and Hispanic Americans from the Multi-Ethnic Study of Atherosclerosis (MESA). We proposed and applied a new gene-level multiple-phenotype analysis and carried out a meta-analysis to combine the ethnicity specific results. This new analysis, instead of a more routine single marker-single phenotype approach identified a significant association between one gene (ADRB2) and cortisol features (meta-analysis p-value=0.0025), which was not identified by three other commonly used existing analytic strategies: 1. Single marker association tests involving each single cortisol feature separately; 2. Single marker association tests jointly testing for multiple cortisol features; 3. Gene-level association tests separately carried out for each single cortisol feature. The analytic strategies presented consider different hypotheses regarding genotype-phenotype association and imply different costs of multiple testing. The proposed gene-level analysis integrating multiple cortisol features across multiple ethnic groups provides new insights into the gene-cortisol association.

While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey's one-degree-of-freedom model for non-additivity treats the interaction term as a scaled product of row and column main effects. Because of the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency, and the corresponding test could lead to increased power. Unfortunately, Tukey's model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey's and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies-the Normative Aging Study and the Multi-ethnic Study of Atherosclerosis., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose: We determined the extent to which complications as well as number of hospital-free days within 30 and 90 days of surgery predicted health related quality of life 1 year after radical cystectomy., Materials and Methods: We used data from a prospective health related quality of life study using a validated instrument, the Vanderbilt Cystectomy Index-15. Complications were graded by the Clavien system, and hospital length of stay and length of stay during readmissions were used to calculate 30 and 90-day hospital-free days, respectively. We compared the number of hospital-free days among patients with varying levels of complications. Multivariate analysis was performed to determine predictors of Vanderbilt Cystectomy Index-15 score 1 year after surgery adjusting for demographic (age, gender, comorbidities) and clinical variables (stage and diversion type)., Results: A total of 100 patients with complete baseline and 1-year followup health related quality of life data were included in the analysis. Median (IQR) 30 and 90-day hospital-free days were 24 (22-25) and 84 (82-85), respectively. Patients who experienced any complications had significantly fewer 30-day hospital-free days (22 vs 24 days, p <0.01) and 90-day hospital-free days (81 vs 84 days, p <0.01), and patients with higher grade complications had fewer hospital-free days than those with lower grade or no complications (p <0.01). On multivariate analysis female gender and baseline Vanderbilt Cystectomy Index-15 score independently predicted higher 1-year health related quality of life scores., Conclusions: Patients who experience complications after radical cystectomy have fewer 30 and 90-day hospital-free days. However, neither predicts health related quality of life at 1 year. Instead, long-term health related quality of life appears to be driven largely by baseline health related quality of life and gender., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Infective endocarditis is an uncommon manifestation of infection with Histoplasma capsulatum. The diagnosis is frequently missed, and outcomes historically have been poor. We present 14 cases of Histoplasma endocarditis seen in the last decade at medical centers throughout the United States. All patients were men, and 10 of the 14 had an infected prosthetic aortic valve. One patient had an infected left atrial myxoma. Symptoms were present a median of 7 weeks before the diagnosis was established. Blood cultures yielded H. capsulatum in only 6 (43%) patients. Histoplasma antigen was present in urine and/or serum in all but 3 of the patients and provided the first clue to the diagnosis of histoplasmosis for several patients. Antibody testing was positive for H. capsulatum in 6 of 8 patients in whom the test was performed. Eleven patients underwent surgery for valve replacement or myxoma removal. Large, friable vegetations were noted at surgery in most patients, confirming the preoperative transesophageal echocardiography findings. Histopathologic examination of valve tissue and the myxoma revealed granulomatous inflammation and large numbers of organisms in most specimens. Four of the excised valves and the atrial myxoma showed a mixture of both yeast and hyphal forms on histopathology. A lipid formulation of amphotericin B, administered for a median of 29 days, was the initial therapy in 11 of the 14 patients. This was followed by oral itraconazole therapy, in all but 2 patients. The length of itraconazole suppressive therapy ranged from 11 months to lifelong administration. Three patients (21%) died within 3 months of the date of diagnosis. All 3 deaths were in patients who had received either no or minimal (1 day and 1 week) amphotericin B.

Background: Idealism declines in medical students over the course of training, with some studies identifying the beginning of the decline in year 3 of US curricula., Purposes: This study tested the hypothesis that a decline in medical student idealism is detectable in the first two years of medical school., Methods: We sought to identify differences in survey responses between first-year (MS1) and second-year (MS2) medical students at the beginning (T1) and end (T2) of academic year 2010 on three proxies for idealism, including items asking about: (a) motivations for pursuing a medical career; (b) specialty choice; and (c) attitudes toward primary care. Principle component analysis was used to extract linear composite variables (LCVs) from responses to each group of questions; linear regression was then used to test the effect of on each LCV, controlling for race, ethnicity, rural or urban origins, gender, and marital status., Results: MS2s placed more emphasis on status/income concerns (β=0.153, p<0.001), and much less emphasis on idealism as a motivator (β=-0.081, p=0.054), in pursuing a medical career; more likely to consider lifestyle and family considerations (β=0.098, p=0.023), and less likely to consider idealistic motivations (β=-0.066, p=NS); and were more likely to endorse both negative/antagonistic (β=0.122, p=0.004) and negative/sympathetic (β=0.126, p=0.004) attitudes toward primary care., Conclusions: The results are suggestive that idealism decline begins earlier than noted in other studies, implying a need for curricular interventions in the first two years of medical school.

Unlabelled: What's known on the subject? and What does the study add? Some evidence suggests that ABO blood type may be a risk factor for cancer incidence and prognosis. For example, a large study recently discovered an increased incidence of pancreatic cancer in patients with non-O blood type; however, it is not known whether blood group correlates with outcomes in patients with RCC. We found a significant and independent association between ABO blood group and overall survival in patients undergoing surgery for locoregional RCC. Specifically, we identified non-O blood type as a predictor of mortality., Objective: • To determine whether ABO blood group is associated with survival after nephrectomy or partial nephrectomy for renal cell carcinoma (RCC)., Patients and Methods: • We conducted a retrospective cohort study of 900 patients who underwent surgery for locoregional RCC between 1997 and 2008 at a single institution. • Covariates included age, gender, race, American Society of Anesthesiology Physical Status, preoperative anaemia and hypoalbuminemia, tumour characteristics, lymph node status, procedure performed, transfusion status and ABO blood group. • Primary outcomes were overall (OS) and disease-specific survival (DSS). • Univariable survival analyses were performed using the Kaplan-Meier and log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model., Results: • The 3-year OS estimate was 75% (95%CI 70-79%) for O blood group and 68% (95% CI 63-73%) for non-O blood group (P= 0.072). The 3-year DSS was 81% (95% CI 76-85%) for O blood group and 76% (95%CI 71-80%) for non-O blood group (P= 0.053). • In the multivariable analysis for OS, non-O blood type was significantly associated with decreased OS (HR 1.68, 95%CI 1.18-2.39; P= 0.004) but not DSS (HR 1.53, 95%CI 0.97-2.41; P= 0.065)., Conclusion: • These data suggest that ABO blood group is independently associated with OS in patients undergoing surgery for locoregional RCC. ABO blood group has not been previously recognized as a predictor of survival in RCC., (© 2012 BJU INTERNATIONAL.)

Purpose: Treatment of organ confined renal masses with partial nephrectomy has durable oncologic outcomes comparable to radical nephrectomy. Partial nephrectomy is associated with lower risk of chronic kidney disease and in some series with better overall survival. We report a contemporary analysis on national trends of partial nephrectomy use to determine partial nephrectomy use over time, and whether nontumor related factors such as structural attributes of the treating institution or patient characteristics are associated with the underuse of partial nephrectomy., Materials and Methods: We performed an analysis of the NIS (National Inpatient Sample), which contains 20% of all United States inpatient hospitalizations. We included patients who underwent radical or partial nephrectomy for a renal mass between 2002 and 2008. Survey weights were applied to obtain national estimates of nephrectomy use and to evaluate nonclinical predictors of partial nephrectomy., Results: A total of 46,396 patients were included in the study for a weighted sample of 226,493. There was an increase in partial nephrectomy use from 15.3% in 2002 to 24.7% in 2008 (p <0.001). On multivariate analysis hospital attributes (urban teaching status, nephrectomy volume, geographic region) and patient socioeconomic status (higher income ZIP code and private/HMO payer) were independent predictors of partial nephrectomy use., Conclusions: Since 2002 the national use of partial nephrectomy for the management of renal masses has increased. However, the adoption of partial nephrectomy at smaller, rural and nonacademic hospitals lags behind that of larger hospitals, urban/teaching hospitals and higher volume centers. A lower rate of partial nephrectomy use among patients without private insurance and those living in lower income ZIP code areas highlights the underuse of partial nephrectomy as a quality of care concern., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

At the San Diego Zoo (California, USA), 22 cases of megaesophagus were diagnosed in the parma wallaby (Macropus parma); a prevalence of 21.1%. Parma wallabies often have no clinical signs until severe and chronic dilation of the esophagus is present. Clinical signs of advanced disease include weight loss, swelling of the cervical region, regurgitation without reswallowing of ingesta, short flight distance, depression, collapse, dyspnea, and sudden death. Retrospective and prospective studies at the San Diego Zoo and a multi-institutional survey in the United States were used to try to determine the cause of megaesophagus. The retrospective study did not identify an etiology. The prospective study revealed megaesophagus and severely delayed esophageal transit time in eight of eight animals. Myasthenia gravis, lead toxicosis, toxoplasmosis, and thyroid disease were eliminated as possible causes. Of 286 living and dead parma wallabies surveyed at other institutions, three cases of esophageal diverticulum and one case of megaesophagus were reported. The cause of megaesophagus in parma wallabies was not determined.

Objectives: Routine screening for hepatocellular carcinoma (HCC) is recommended in chronic hepatitis B (HBV) patients with cirrhosis and select non-cirrhotic HBV populations including Asian males ages 40 and older and females ages 50 and older. However, many younger HBV patients develop HCC and there have been few studies examining this group. Additionally, studies of HCC in the Asian immigrant population in the United States have been limited. The objective of this study was to determine the associated risk factors for the development of early-onset (males and females under ages 40 and 50, respectively) and late-onset HCC in immigrants with chronic HBV in the United States., Methods: Clinical, demographic, and laboratory data were retrospectively collected on all Asian immigrants with HBV at Bellevue Hospital Center from 2003 to 2009. Patients with HCC were identified within this cohort. Features of early-onset and late-onset HCC cases were compared with age-matched HBV controls without HCC., Results: We identified 168 cases of HCC in Asians with HBV. In all, 74% (124/168) of cases were late-onset, and 26% (44/168) were early-onset. When comparing the 124 late-onset HCC cases with 199 age-matched HBV controls, gender (odds ratio (OR)=4.4; P<0.05) and cirrhosis (OR=9.6; P<0.05) or surrogate labs (i.e., platelets, international normalized ratio, total bilirubin, albumin) were found to be associated with HCC development. When comparing the 44 early-onset HCC cases with 432 age-matched HBV controls, family history of HCC (OR=2.7; P<0.05), and smoking history (OR=3.4; P<0.05) were independently associated risk factors in addition to gender (OR=2.7; P<0.05), and cirrhosis (OR=19.5; P<0.05) or surrogate labs. In all, 54.8% of late-onset HCC cases were cirrhotic and 29.5% of early-onset HCC cases were cirrhotic., Conclusions: HCC occurs in Asian immigrant HBV patients younger than currently recommended screening guidelines. A large majority of these early-onset patients did not have cirrhosis at the time of their HCC diagnosis; therefore, factors other than cirrhosis need to be considered when evaluating HCC risk in young patients. Factors associated with HCC development across all ages include cirrhosis and male gender, while family history and smoking history may identify younger Asian immigrant HBV patients at risk for HCC. Prospective validation, including cost-effectiveness evaluation, is necessary, but our results suggest that younger Asian HBV patients, especially those with a smoking history or family history of HCC, appear to have an increased risk for HCC and should be considered for enrollment in early screening programs regardless of their age.

Purpose: The purpose of this study was to determine the incidence and distribution of catheter-related problems in long-term indwelling urinary catheter users. We also sought to assess appropriateness of catheter use and examine relationships among catheter complications and catheter care practices., Design: This repeated-measures study involved self-reported data collection by recall at intake and by prospective data collection at 2, 4, and 6 months in long-term urinary catheter users., Subjects and Setting: Two sampling arms were used: a home care (HC) agency with 10 individuals and the Internet with 33 people having spinal cord injury., Methods: Home visit and follow-up telephone call interviews were used with the participants from the HC agency. Data were self-administered through SurveyMonkey in the Internet sample, and communication was through e-mail, telephone, and postal mail. Analysis included descriptive statistics and generalized estimating equation techniques to adjust for within-subject variation over time., Results: All study participants had at least 1 catheter-related problem during 8 months, and many had multiple, recurring problems. Catheter-associated urinary tract infection (CAUTI) was reported by 70%, blockage by 74%, leakage by 79%, and accidental dislodgement by 33%. Key tests of associations (generalized estimating equation) predicted that catheter size contributed to CAUTI, with significant covariates of female gender and younger age. The presence of sediment in the urine on the day of the survey predicted catheter blockage., Conclusion: The incidence of all complications was higher than expected. Problems associated with long-term indwelling catheter use may contribute to excess healthcare utilization adversely affecting both users and their families.

Purpose: We analyzed patient characteristics and practice patterns at our institution with time, and identified current patterns and factors contributing to the choice of urinary diversion., Materials and Methods: We reviewed the records of 553 consecutive radical cystectomy and urinary diversions performed from January 2000 to July 2005. Multivariate analysis was done to determine significant differences in diversion choice., Results: We analyzed the records of 539 patients, including 338 with an ileal conduit and 201 with a neobladder. Patients with a neobladder were younger (mean age 62 vs 71 years) and had fewer comorbidities (American Society of Anesthesiologists class greater than 2 in 31% vs 69%) than those with an ileal conduit. Mean age and the percent of American Society of Anesthesiologists class 3 or 4 cases increased during the study. Neobladder represented 47% of urinary diversions in 2000 and 21% in 2005. On multivariate analysis age (p <0.001), gender (p = 0.004), surgery year (p = 0.002), American Society of Anesthesiologists class greater than 2 (p = 0.004), organ confined disease (p = 0.01) and surgeon (p <0.001) independently predicted diversion choice. Patients were dichotomized into young (younger than 65 years) and old (65 years old or older) groups. Overall 59% of younger and 26% of older patients received a neobladder (p <0.001)., Conclusions: There was a significant trend toward the more liberal use of ileal conduit urinary diversion. Patients with female gender, advanced age, significant medical comorbidity or locally advanced disease were less likely to undergo neobladder urinary diversion. This trend is partly explained by surgeon preference combined with an aging, more comorbid patient population. Neobladder continues to be the most commonly performed urinary diversion in patients younger than 65 years.

Purpose: To describe the disease characteristics and visual outcome of pediatric uveitis., Design: Retrospective, longitudinal observation., Participants: Five hundred twenty-seven pediatric uveitis patients from the National Eye Institute, University of Illinois, Chicago, and Oregon Health Sciences University., Methods: Retrospective chart review., Main Outcome Measures: Demographics, uveitis disease characteristics, complications, treatments, and visual outcomes were determined at baseline and at 1-, 3-, 5-, and 10-year time points., Results: The patient population was 54% female; 62.4% white, 12.5% black, 2.7% Asian, 2.1% multiracial, and 14.61% Hispanic. Median age at diagnosis was 9.4 years. The leading diagnoses were idiopathic uveitis (28.8%), juvenile idiopathic arthritis-associated uveitis (20.9%), and pars planitis (17.1%). Insidious onset (58%) and persistent duration (75.3%) were most common. Anterior uveitis was predominant (44.6%). Complications were frequent, and cystoid macular edema (odds ratio [OR] 2.94; P = 0.006) and hypotony (OR, 4.54; P = 0.026) had the most significant visual impact. Ocular surgery was performed in 18.9% of patients. The prevalence of legal blindness was 9.23% at baseline, 6.52% at 1 year, 3.17% at 3 years, 15.15% at 5 years, and 7.69% at 10 years. Posterior uveitis and panuveitis had more severe vision loss. Hispanic ethnicity was associated with a higher prevalence of infectious uveitis and vision loss at baseline., Conclusions: The rate and spectrum of vision threatening complications of pediatric uveitis are significant. Prospective studies using standard outcome measures and including diverse populations are needed to identify children most at risk.

Background: We sought to determine the impact of radical nephrectomy case volume, hospital size, and geographic region on immediate surgical outcomes for patients undergoing radical nephrectomy in academic centers across the country., Methods: The University HealthSystem Consortium (UHC) Clinical Data Base was queried for data corresponding to patients who underwent radical nephrectomy at 1 of 134 academic medical centers nationwide between 2003 and quarter 2 of 2007 (n = 42,988). Radical nephrectomy case volume (1-99, 100-499, and 500 +), total discharges (1-49,999, 50,000-99,999, 100,000 +), and geographic region (5 categories) were determined for each academic center. ANOVA and the Tukey statistic were used. Length of stay, intensive care unit (ICU) rate, complication (comp) rate, and in-hospital mortality were analyzed., Results: Case volume was a significant predictor of length of stay, ICU, and comp. Mean length of stay was 6.88, 5.61, and 4.76 days, respectively, for centers from lowest to highest case volumes (P < .001). ICU rates for the 3 tiers were 30.77, 17.93, and 12.22 (P < .001). Comp rates were 24.50, 19.40, and 15.48 (P < .001). Tukey analysis revealed a ceiling effect: No differences were seen between the 2 higher case volume groups. Stratification by total discharges revealed differences in ICU rates (P = .001) and comp rates (P = .001). Region of the country had no significant impact on any of the outcome variables in this study., Conclusions: Radical nephrectomy case volume emerged as an important variable in predicting 3 of the 4 outcome parameters in this study. Results suggest that a "critical volume" of cases portends improved surgical outcomes., ((c) 2009 American Cancer Society.)

Study Objective: Federal policy changes and tightened state budgets may reduce Medicaid enrollment in many states. In March 2003, the Oregon Health Plan (Oregon's Medicaid expansion program) made substantial changes in its benefit package that resulted in the disenrollment of more than 50,000 beneficiaries. We sought to study the impact of these Oregon Health Plan policy changes on statewide emergency department (ED) use., Methods: In this observational study, hospital billing data on 2,680,954 visits to 26 Oregon EDs were obtained, sampled up to 24 months before and 24 months after the cutbacks. These visits represent approximately 62% of all visits to Oregon's 58 EDs. We ascertained counts of ED visits by payer group before and after the Oregon Health Plan cutback date, plus hospital admissions from the ED as a measure of acuity., Results: After the Oregon Health Plan policy changes, ED visits by the uninsured underwent an abrupt and sustained increase, from 6,682 per month in 2002 to 9,058 per month in 2004. Oregon Health Plan-sponsored and commercially insured visits decreased, resulting in a slight decrease in overall ED visits. Multivariable models adjusting for secular trends and seasonality showed a 20% (95% confidence interval 13% to 28%) increase in uninsured ED visits, whereas the adjusted number of Oregon Health Plan-sponsored visits decreased. The proportion of uninsured ED visits resulting in hospital admission increased (odds ratio 1.50; 95% confidence interval 1.39 to 1.62)., Conclusion: Oregon's Medicaid cutbacks were followed by increases in ED use and hospitalizations by the uninsured. Recent federal legislation facilitating similar Medicaid changes in other states may lead to replication of these events elsewhere.