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Herpes viruses are known for infecting epithelial cells and manifesting as vesicles. However, herpes viruses can also infect stromal cells. While established in the ocular setting, cutaneous stromal herpes (deep herpes) is previously unreported and may evade clinical and microscopic detection. We searched for skin biopsies with herpes stromal disease. Clinical information was retrieved via electronic medical records and pathology records system. Hematoxylin and eosin slides, immunohistochemical staining, and polymerase chain reaction detection of viral DNA was performed. We identified 12 specimens from 10 patients with cutaneous stromal herpes simplex virus 1/2 (n=7) or varicella-zoster virus infection (n=5). The most common site involved was the buttocks/perianal region (n=6). Ulceration was a frequent dermatologic finding (n=8). Pyoderma gangrenosum was clinically suspected in 6 specimens (50%). Eight patients (80%) were immunosuppressed. Biopsies frequently demonstrated a dense dermal mixed inflammatory infiltrate with subcutaneous extension and enlarged cells with viral cytopathic changes confirmed by herpes simplex virus 1/2 or varicella-zoster virus immunohistochemistry (n=10) or polymerase chain reaction (n=2). Most specimens (67%) lacked evidence of characteristic epidermal keratinocyte infection. This study presents the first known report of the ability of herpes virus to infect deep stromal cells of the dermis. We raise awareness of cutaneous stromal herpes in patients presenting with atypical clinical lesions, particularly while immunocompromised. Establishing the correct diagnosis is critical for initiating therapy.

Perceived racial discrimination is linked to unhealthy behaviors and stress-related morbidities. A compelling body of research indicates that perceived racial discrimination may contribute to health disparities among African Americans (AAs). The purposes of this study were to describe the study protocol including data collection procedures and study measures and to evaluate the feasibility and acceptability of intensive biobehavioral data collection using ecological momentary assessment (EMA), salivary biomarkers, and accelerometers over 7 days among middle-aged AAs with a goal of understanding the relationships between perceived racial discrimination and biobehavioral responses to stress. Twelve AA men and women participated in the feasibility/acceptability study. They completed surveys, anthropometrics, and received in-person training in EMA and saliva sample collection at baseline. Participants were asked to respond to the random prompt text message-based EMA five times a day, wear an accelerometer daily for 7 days, and to self-collect saliva samples four times a day for 4 consecutive days. The EMA surveys included perceived racial discrimination, affective states, lifestyle behaviors, and social and physical contexts. The mean EMA response rate was 82.8%. All participants collected saliva samples four times a day for 4 consecutive days. About 83% of participants wore the accelerometer on the hip 6 out of 7 days. Despite the perception that the intensive nature of assessments would result in high participant burden, the acceptability of the study procedures was uniformly favorable.

PurposeThe purpose of this study was to explore the perceived facilitators and barriers for obtaining sufficient sleep in young adults with type 1 diabetes (T1D).MethodsA qualitative descriptive approach was used to generate data. In-depth semi-structured interviews with 30 young adults with T1D (66.7% female, mean age = 22.1 years) were conducted. Interviews were transcribed verbatim and coded using NVivo.ResultsYoung adults with T1D reported feeling challenged at bedtime and overnight by the demands of a complex disease management regimen. General and diabetes-specific barriers and facilitators to obtaining sufficient sleep were the overarching themes in the present study. Young adults perceived that electronic device use was a facilitator for relaxation before bed and a barrier to sleep by some participants. Delays in bedtime or disruptions in sleep were common diabetes-specific barriers.ConclusionsWhen designing sleep-promoting interventions for young adults with T1D, researchers should consider diabetes-specific challenges and solutions in addition to those present in the general young adult population.

Background Glucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects. Hypothesis/Objectives Determine the effects of clopidogrel and prednisone on platelet function. Animals Twenty‐four healthy dogs. Methods Double‐blinded, placebo‐controlled randomized trial. Platelet function was evaluated using a platelet function analyzer and impedance aggregometry (days 0, 14, and 28) for dogs treated with placebo, clopidogrel (2‐3 mg/kg/d), prednisone (2 mg/kg/d), or prednisone with clopidogrel PO for 28 days. Results were categorized as nonresponder versus responder (platelet function analyzer), and inadequate, ideal, or excessive response (aggregometry). Results were compared using mixed model, split‐plot repeated measures analysis of variance and generalized estimating equation proportional odds models. P

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc−/−) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc−/− livers. Treatment of G2-Terc−/− mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc−/− mice also decreases longevity, in contrast to lifespan extension in single S6K1−/− female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres., Telomerase deficiency leads to age-related diseases and shortened lifespan, while inhibition of the mTOR pathway delays aging. Here, the authors show that inhibition of mTORC1 signaling shortens the lifespan of telomerase deficient mice.

Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Purpose The purpose of this study was to evaluate the short-term effects of the Type 1 Teamwork program for parents of adolescents with type 1 diabetes mellitus (T1DM) on the primary outcome of psychosocial stress. Methods The study was a randomized wait-list control trial evaluating an eHealth program to reduce parenting stress around T1DM management during adolescence through interactive sessions on the safe transfer of responsibility, positive communication, and stress management. The primary outcome was psychosocial stress (parenting stress specific to child illness and general stress). Secondary outcomes included depressive and anxiety symptoms, parent support for adolescent autonomy, family conflict, and adolescent metabolic control (A1C). Data were collected at baseline, 3 months, and 6 months online. Mixed-model analyses were conducted, using intent-to-treat procedures. Results Parents (n = 162) had a mean age of 45.6 (±5.3) years, were 98% female, 91% white, 91% married/partnered, 51% of high income, and geographically dispersed around the United States. Parents reported that adolescents had a mean A1C of 7.9% (±1.2%) and T1DM duration of 5.08 (±3.62) years. At 6 months, parents in the Type 1 Teamwork group demonstrated less parenting stress compared with the control group. There were no differences between groups on general stress or secondary outcomes. Attrition at 6 months was 32% in the treatment group and 11% in the control group. Conclusions An eHealth program for parents of adolescents with T1DM improves parenting stress in a sample of parents from across the United States.

People with diabetes frequently have elevated diabetes distress. Although mindfulness-based stress reduction (MBSR) therapy has been shown effective in reducing diabetes distress, it has only been delivered by psychologists or a multidisciplinary team with an attrition rate of up to 39%, which limits its dissemination to a broader audience. This study was aimed to pilot evaluate the feasibility of a nurse-led MBSR therapy and explore its potential efficacy amongst people with type 2 diabetes mellitus. A total of 100 participants were randomly allocated either to the intervention group (nurse-led MBSR therapy + regular diabetes education) or the control group (regular diabetes education). Data on diabetes distress, diabetes self-efficacy, and diabetes self-management were collected at baseline, 8 and 12 weeks. Hemoglobin A1c (HbA1c) was collected at baseline and 12 weeks. A generalized estimating equation analysis for repeated measures was used to determine intervention and time effects. As predicted, the nurse-led MBSR therapy had a significant time-by-group interaction effect on diabetes distress total score (95% confidence interval [CI]: 0.58-0.77, p

Objective To describe hospitalizations involving an intensive care unit (ICU) admission among patients aged 65 years and older within New York City (NYC) hospitals during 2000-2014. Design Observational study using an all-payer hospital discharge dataset. Setting The setting was in NYC hospitals. Patients Patients aged 65 years and older admitted to an ICU within a NYC hospital during 2000-2014. Interventions No interventions were carried out. Measurements and main results We calculated the mean annual number of hospitalizations involving an ICU admission. We also examined characteristics of hospitalizations, including the occurrence of in-hospital death and principal diagnosis. There were 5,338,577 hospitalizations of patients aged ≥65 years within NYC hospitals during 2000-2014, of which 765,084 (14.3%) involved an ICU admission. The mean annual number of hospitalizations involving an ICU admission for this age group decreased from 57,938 during 2000-2002 to 45,785 during 2012-2014. The proportion of hospitalizations involving an ICU admission in which in-hospital death occurred decreased from 15.9% during 2000-2002 to 14.5% during 2012-2014. During 2000-2002, 11.6% of hospitalizations involving an ICU admission listed an "infectious" principal diagnosis, increasing to 20.7% during 2012-2014. Listing of a "cardiovascular" principal diagnosis decreased from 46.4% to 33.4% between these time periods. "Infectious" principal diagnoses accounted for 31.0% of all hospitalizations involving an ICU admission in which in-hospital death occurred during the entire study period, while "cardiovascular" principal diagnoses accounted for 21.3%. Conclusions This investigation provides a clearer understanding of ICU utilization among patients aged 65 years and older in NYC. Ongoing monitoring is warranted given projections that the proportion of New Yorkers aged 65 years and older will increase in coming years. In particular, in light of the observed increase of infectious principal diagnoses during the study period, further investigation is needed into the role of infectious disease in causing critical illness in NYC.

Background The prevalence of adults with Type 1 diabetes (T1D) is increasing, and their risk of cardiovascular disease is high. Comorbid diabetes distress and depressive symptoms may affect their cardiovascular health. Objectives The purpose of this study was to describe the relationship between diabetes distress and depressive symptoms with cardiovascular health factors. Methods This was a cross-sectional survey of a sample of adults with T1D. Valid and reliable instruments were used to collect the data on sociodemographics, diabetes-related complications, psychological factors, and cardiovascular health factors. Independent-sample t tests, analysis of variance, chi-square analyses, and linear regression were used to compare the cardiovascular health factors among the three levels of diabetes distress scores and the two levels of depressive symptom scores. Results Our sample included 83 adults with a mean age of 45.2 years and a mean duration of T1D of 20 years. The majority scored low in the Diabetes Distress Scale, whereas 18% scored moderate and 18% scored high. Twenty-two percent had increased levels of depressive symptoms. There were significant correlations between diabetes distress and fear of hypoglycemia, depressive symptom scores, hemoglobin A1c, and total cholesterol. Depressive symptom scores were significantly correlated with hemoglobin A1c. Hemoglobin A1c and total cholesterol were significantly higher in those with higher levels of diabetes distress. There were no significant differences in cardiovascular health between those who scored below or above the cut point for depressive symptoms, but there was a finding toward higher mean body mass index, hemoglobin A1c, and a lower weekly step count in those who had elevated depressive symptoms. In the linear regression, only diabetes distress was significantly associated with hemoglobin A1c. Discussion This is a sample with elevated diabetes distress and depressive symptoms, both of which may affect their risk of cardiovascular disease.

BACKGROUND: Korean American immigrants (KAIs) face diverse sociocultural stressors in the acculturation process. While stress is known to cause short sleep, little is known about how acculturative stress affects sleep differently for KAI men and women. The purpose of this cross-sectional study was to examine gender differences in the association between diverse domains of acculturative stress and sleep duration among KAIs. METHODS: Middle-aged KAIs were recruited in community settings and online. KAIs completed validated measures of acculturative stress (homesickness, social isolation, employment barriers, discrimination, civic disengagement, and family problems) and sleep duration. Multiple linear regression analysis was performed and stratified by gender. RESULTS: 343 KAIs participated (mean age = 41±10 years, 47% female, 11% short sleepers [

Background The prevalence of type 2 diabetes (T2D) in Mexico is one of the highest in the world, with high morbidity and mortality, and difficulty meeting glycemic targets. The purpose of this study was to identify the challenges for T2D self-management as perceived by both adults with T2D and health care providers in primary health clinics from Seguro Popular in Mexico City. Methods This was a qualitative descriptive study conducted in three Seguro Popular primary care clinics in Mexico City using convenience sampling. Semi-structured interviews were conducted with participants and data were analyzed using a content analysis approach. Results The sample included 20 adults with T2D [52.5 years old (SD = 9.9), diagnosed with T2D for 12.3 years (SD = 6.3), mean A1C of 9.8% (SD = 2.4), 80% female, 90% with financial insecurity] and 19 providers [primarily female (78.9%), mean age of 41.6 years old (SD = 11.4), 12.3 mean years in practice (SD = 8.50)]. Personal challenges included cultural beliefs, lack of resources, challenges to lifestyle modification, lack of family support/competing demands, and mental health issues. System level challenges included lack of resources, perceived quality of care, and patient engagement barriers. Conclusions Evidence-based diabetes self-management programs need to become more accessible, taking into consideration the social determinants of health and building upon current initiatives to improve early diagnosis and treatment of T2D. Cultural beliefs, personal control, and low health literacy influence diabetes self-management in adults with T2D with limited resources. Mental health and financial challenges of adults with T2D will require multidisciplinary team-based care. Future research on best practices to implement and scale-up evidence-based patient-centered T2D prevention and DSME programs for the poor and underserved is warranted in Mexico and world-wide.

Background Synbiotics decrease antibiotic‐associated gastrointestinal signs (AAGS) in cats, but data supporting synbiotic use to ameliorate AAGS in dogs are lacking. Objectives To determine if administration of synbiotics mitigates AAGS in dogs. Animals Twenty‐two healthy research dogs. Methods Randomized, double‐blinded, placebo‐controlled, 2‐way, 2‐period, crossover study with an 8‐week washout period. Each period included a 1‐week baseline and 3‐week treatment phase. Dogs received enrofloxacin (10 mg/kg PO q24h) and metronidazole (12.5 mg/kg PO q12h), followed 1 hour later by a bacterial/yeast synbiotic combination or placebo. Food intake, vomiting, and fecal score were compared using repeated‐measures crossover analyses, with P 9 weeks after discontinuation, mitigating AAGS in dogs being treated with antibiotics followed by placebo.

(a) To explore the effect of perceived stress on satisfaction with quality of life (QOL) among Chinese adolescents with type 1 diabetes (T1D); and (b) to determine if coping styles and self-efficacy are mediators of the association between perceived stress and satisfaction with QOL.Adolescents with T1D experience ongoing stress related to a complex treatment regimen and live with a condition that differentiates them from their peers. It is important to know how adolescents with T1D cope with the stress and what psychosocial attributes contribute to satisfaction with QOL.Cross-sectional study.Data were collected from a sample of adolescents with T1D (N = 90) who had enrolled in a randomized control trial (baseline data) and a supplemental sample of N = 59 adolescents with T1D was recruited from a diabetes clinic from January 2016 - December 2016.The mean age of the participants was 13.91 years (range 8-20 years), the mean diabetes duration was 4.02 years. Approximately one-quarter of the sample exceeded the criterion score for perceived stress of 26, indicating stress sufficient to have a negative impact on physical and mental health. Adolescents with increased stress reported lower satisfaction with QOL compared with adolescents with less stress. Both externalization coping and self-efficacy were the mediators of the relationship between perceived stress and satisfaction with QOL.Many Chinese adolescents with T1D reported elevated stress levels which was associated with decreased satisfaction with QOL. There is a need for culturally relevant interventions to improve coping by limiting the use of externalized coping styles and strengthening self-efficacy.目的: (a)探讨中国1型糖尿病(T1D)青少年生活质量知觉压力的影响;以及 (b)确定应对方式和自我效能感是否在感知压力和生活质量满意度之间起中介作用。 背景: 患有T1D的青少年经历着与复杂治疗方案相关的持续压力,并且生活在与同龄人不同的环境中。了解患有T1D的青少年是如何应对压力的,以及什么样的社会心理特征有助于提高他们对生活质量的满意度,这些都是很重要的。 设计: 横断面研究. 方法: 数据收集自登记参加随机对照试验的卫生组织(基线数据)的T1D青少年样本(N = 90) 以及从2016年1月至2016年12月,从一家糖尿病诊所招募了59名患有T1D的青少年作为补充样本。 结果: 平均年龄13.91岁(8 ~ 20岁),平均糖尿病病程4.02年。大约四分之一的样本超过了26分的压力感知评分标准,表明压力足以对身心健康产生负面影响。与压力较小的青少年相比,压力较大的青少年对生活质量的满意度较低。具体化应对和自我效能感是感知压力与生活质量满意度之间的中介因素。 结论: 许多患有T1D的中国青少年报告压力水平升高,这与生活质量满意度下降有关。有必要采取与文化相关的干预措施,通过限制外化应对方式的使用和增强自我效能来改善应对方式。.

Objective To evaluate the effects of a positive psychology intervention for adolescents with type 1 diabetes (T1D) on adherence, glycemic control, and quality of life. Methods Adolescents with T1D (n = 120) and their caregivers were randomized to either an Education (EDU) (n = 60) or Positive Affect (PA) intervention (n = 60). Adolescents in the PA group received the intervention reminders (gratitude, self-affirmation, parental affirmation, and small gifts) via text messages or phone calls over 8 weeks. Questionnaires were completed by adolescents and caregivers and clinical data (glucometer and HbA1c) were collected at baseline 3 and 6 months. Data were analyzed using generalized linear modeling. Results After adjusting for covariates, adolescents in the PA group demonstrated significant improvement in quality of life at 3 months, compared to the EDU group, but this was not sustained at 6 months. Similarly, the PA group showed a significant decrease in disengagement coping at 3 months but not at 6 months. There was no significant intervention effect on blood glucose monitoring, but the odds of clinically significantly improvement (checking at least one more time/day) were about twice as high in the PA group as the EDU group. No significant effects were found for glycemic control. Conclusions A positive psychology intervention had initial significant, positive effects on coping and quality of life in adolescents with T1D. A more intensive or longer-lasting intervention may be needed to sustain these effects and to improve adherence and glycemic control.

The prevalence of obesity among African Americans is higher than among other racial/ethnic groups. African American churches hold a central role in promoting health in the community; yet, church-based interventions have had limited impact on obesity. While recent studies have described the influence of social networks on health behaviors, obesity interventions informed by social network analysis have been limited. We conducted a cross-sectional study with 281 African American men and women from three churches in northeast urban cities in the USA. Data were collected on sociodemographic and clinical factors and anthropometrics. Using a social network survey applying a name generator, we computed network level metrics. Exponential random graph models (ERGM) were performed to examine whether each structural property found in the empirical (observed) networks occurred more frequently than expected by chance by comparing the empirical networks to the randomly simulated networks. Overall, church friendship networks were sparse (low density). We also found that while friendship ties were more reciprocated between dyads in church networks, and there were more tendencies for clustering of friendships (significant positive transitive closure) than in random networks, other characteristics such as expansiveness (number of actors with a great number of friends) did not differ from what would be expected by chance in random networks. These data suggest that interventions with African American churches should not assume a unitary network through which a single intervention should be used.

Reduction in antibiotic-associated gastrointestinal signs (AAGS) in people co-administered probiotics is believed to result from shifts in the microbiome and metabolome. Amelioration of AAGS in cats secondary to synbiotic administration has recently been demonstrated. Thus, the aim of this randomized, double-blinded, placebo-controlled trial was to characterize associated changes in the fecal microbiome and metabolome. Sixteen healthy research cats received clindamycin with food, followed 1 h later by either a placebo or synbiotic, daily for 21 days. Fecal samples were collected during baseline, antibiotic administration, and 6 weeks after antibiotic discontinuation. Sequencing of 16S rRNA genes was performed, and mass spectrometry was used to determine fecal metabolomic profiles. Results were compared using mixed-model analyses, with P

Background Subpatent malaria infections, or low-density infections below the detection threshold of microscopy or standard rapid diagnostic testing (RDT), can perpetuate persistent transmission and, therefore, may be a barrier for countries like Namibia that are pursuing malaria elimination. This potential burden in Namibia has not been well characterized. Methods Using a two-stage cluster sampling, cross-sectional design, subjects of all age were enrolled during the end of the 2015 malaria transmission season in Zambezi region, located in northeast Namibia. Malaria RDTs were performed with subsequent gold standard testing by loop-mediated isothermal amplification (LAMP) using dried blood spots. Infection prevalence was measured and the diagnostic accuracy of RDT calculated. Relationships between recent fever, demographics, epidemiological factors, and infection were assessed. Results Prevalence of Plasmodium falciparum malaria infection was low: 0.8% (16/1919) by RDT and 2.2% (43/1919) by LAMP. All but one LAMP-positive infection was RDT-negative. Using LAMP as gold standard, the sensitivity and specificity of RDT were 2.3% and 99.2%, respectively. Compared to LAMP-negative infections, a higher portion LAMP-positive infections were associated with fever (45.2% vs. 30.4%, p = 0.04), though 55% of infections were not associated with fever. Agricultural occupations and cattle herding were significantly associated with LAMP-detectable infection (Adjusted ORs 5.02, 95% CI 1.77–14.23, and 11.82, 95% CI 1.06–131.81, respectively), while gender, travel, bed net use, and indoor residual spray coverage were not. Conclusions This study presents results from the first large-scale malaria cross-sectional survey from Namibia using molecular testing to characterize subpatent infections. Findings suggest that fever history and standard RDTs are not useful to address this burden. Achievement of malaria elimination may require active case detection using more sensitive point-of-care diagnostics or presumptive treatment and targeted to high-risk groups. Electronic supplementary material The online version of this article (10.1186/s12936-018-2626-5) contains supplementary material, which is available to authorized users.

The study aim was to examine the relationship between socioeconomic status and dietary behaviors through psychological and environmental mediators among African Americans with overweight or obesity. We conducted a cross-sectional study in 225 African American men and women. Data were analyzed using structural equation modeling with bootstrapping procedures. In the multiple mediation model, socioeconomic status had a significant indirect effect on dietary behaviors through psychological and environmental factors (β=−.27, p=.01, 95% confidence interval [CI]=−0.59 to −0.10), but it had no significant direct effect on dietary behaviors (β=.06, p=.70, 95% CI=−0.21 to 0.39). Socioeconomic status had significant direct effects on psychological (β=.52, p=.01, 95% CI=0.31 to 0.77) and environmental factors (β=−.40, p=.03, 95% CI=−0.53 to −0.25). Psychological (β=−.31, p=.02, 95% CI=−0.68 to −0.04) and environmental factors (β=.26, p=.01, 95% CI=0.04 to 0.47) also showed significant direct effects on dietary behaviors. Thus, psychological and environmental factors mediated the relationship between socioeconomic status and dietary behaviors in African Americans with overweight or obesity. Interventions that enhance psychological and environmental factors such as self-efficacy, perceived barriers to healthy eating, health perceptions, and physical and social environments may improve dietary behaviors among socioeconomically disadvantaged African Americans.

Background In New York City (NYC), pneumonia is a leading cause of death and most pneumonia deaths occur in hospitals. Whether the pneumonia death rate in NYC reflects reporting artifact or is associated with factors during pneumonia-associated hospitalization (PAH) is unknown. We aimed to identify hospital-level factors associated with higher than expected in-hospital pneumonia death rates among adults in NYC. Methods Data from January 1, 2010–December 31, 2014 were obtained from the New York Statewide Planning and Research Cooperative System and the American Hospital Association Database. In-hospital pneumonia standardized mortality ratio (SMR) was calculated for each hospital as observed PAH death rate divided by expected PAH death rate. To determine hospital-level factors associated with higher in-hospital pneumonia SMR, we fit a hospital-level multivariable negative binomial regression model. Results Of 148,172 PAH among adult NYC residents in 39 hospitals during 2010–2014, 20,820 (14.06%) resulted in in-hospital death. In-hospital pneumonia SMRs varied across NYC hospitals (0.77–1.23) after controlling for patient-level factors. An increase in average daily occupancy and membership in the Council of Teaching Hospitals were associated with increased in-hospital pneumonia SMR. Conclusions Differences in in-hospital pneumonia SMRs between hospitals might reflect differences in disease severity, quality of care, or coding practices. More research is needed to understand the association between average daily occupancy and in-hospital pneumonia SMR. Additional pneumonia-specific training at teaching hospitals can be considered to address higher in-hospital pneumonia SMR in teaching hospitals.

ObjectiveTo examine prevalence and characteristics of newly diagnosed diabetes (NDD) in younger adults hospitalised with acute myocardial infarction (AMI) and investigate whether NDD is associated with health status and clinical outcomes over 12-month post-AMI.MethodsIn individuals (18–55 years) admitted with AMI, without established diabetes, we defined NDD as (1) baseline or 1-month HbA1c≥6.5%; (2) discharge diabetes diagnosis or (3) diabetes medication initiation within 1 month. We compared baseline characteristics of NDD, established diabetes and no diabetes, and their associations with baseline, 1-month and 12-month health status (angina-specific and non-disease specific), mortality and in-hospital complications.ResultsAmong 3501 patients in Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients study, 14.5% met NDD criteria. Among 508 patients with NDD, 35 (6.9%) received discharge diagnosis, 91 (17.9%) received discharge diabetes education and 14 (2.8%) initiated pharmacological treatment within 1 month. NDD was more common in non-White (OR 1.58, 95% CI 1.23 to 2.03), obese (OR 1.72, 95% CI 1.39 to 2.12), financially stressed patients (OR 1.27, 95% CI 1.02 to 1.58). Compared with established diabetes, NDD was independently associated with better disease-specific health status and quality of life (p≤0.04). No significant differences were found in unadjusted in-hospital mortality and complications between NDD and established or no diabetes.ConclusionsNDD was common among adults≤55 years admitted with AMI and was more frequent in non-White, obese, financially stressed individuals. Under 20% of patients with NDD received discharge diagnosis or initiated discharge diabetes education or pharmacological treatment within 1 month post-AMI. NDD was not associated with increased risk of worse short-term health status compared with risk noted for established diabetes.Trial registration numberNCT00597922.

A 13-year-old castrated male Maine coon cat with a 5-year history of atypical mycobacteriosis was euthanized and submitted for necropsy. The cat had been kept in clinical remission since diagnosis using a combination of the antimycobacterial drug clofazimine and additional multimodal antimicrobial therapy. Grossly, tissues were diffusely discolored red-brown to yellow. Histologically, the myocardial interstitum was expanded by numerous, often multinucleated cells, which were distended by uniformly shaped acicular cytoplasmic spaces. These cells were immunopositive for CD18 and immunonegative for desmin, suggesting a histiocytic rather than muscular origin. Macrophages in other tissues contained similar acicular spaces. Ultrastructurally, the spaces were surrounded by 2 lipid membranes, resembling an autophagosome. Based on the clinical history and histologic, immunohistochemical, and ultrastructural data, we diagnosed clofazimine crystal storage. To our knowledge, this is the first report of clofazimine storage in a cat or within myocardial interstitial macrophages.

A Man with Lymphadenopathy and Petechiae A 35-year-old man was admitted to the hospital with lymphadenopathy and thrombocytopenia (platelet count, 0 per microliter). Four months earlier, painless l...

Background Extracorporeal membrane oxygenation (ECMO) is a rescue treatment option for adult patients with severe cardiac dysfunction or respiratory failure. While short-term patient outcomes, such as in-hospital mortality and complications, have been widely described, little is known about the illness or recovery experience from the perspectives of survivors. Subjective reports of health are important indicators of the full, long-term impact of critical illness and treatment with ECMO on survivors’ lives. Objective The objective of this study was to describe the experiences and needs of adults treated with ECMO, from onset of illness symptoms through the process of survivorship. Methods This study was guided by the qualitative method of interpretive description. We conducted in-depth, semistructured interviews with 16 adult survivors of ECMO who were treated at two participating regional ECMO centres in the northeast United States. Additional data were collected from demographic questionnaires, field notes, memos, and medical record review. Development of interview guides and data analysis were informed by the Family Management Style Framework. Qualitative data were analysed using thematic analysis techniques. Results The sample (n = 16) included 75% male participants; ages ranged from 23 to 65 years. Duration from hospital discharge to interviews ranged from 11 to 90 (M = 54; standard deviation = 28) months. Survivors progressed through three stages: Trauma and Vulnerability, Resiliency and Recovery, and Survivorship. Participants described short- and long-term impacts of the ECMO experience: all experienced physical challenges, two-thirds had at least one psychological or cognitive difficulty, and 25% were unable to return to work. All were deeply influenced by their own specific contexts, family support, and interactions with healthcare providers. Conclusions The ECMO experience is traumatic and complex. Recovery requires considerable time, perseverance, and support. Long-term sequelae include impairments in cognitive, mental, emotional, physical, and social health. Survivors could likely benefit from specialised posthospital health services that include integrated, comprehensive follow-up care.

Traumatic spinal cord injury (SCI) is a devastating neurological condition that involves both primary and secondary tissue loss. Various cytotoxic events including hypoxia, hemorrhage and blood lysis, bioenergetic failure, oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation contribute to secondary injury. The HIF prolyl hydroxylase domain (PHD/EGLN) family of proteins are iron-dependent, oxygen-sensing enzymes that regulate the stability of hypoxia inducible factor-1α (HIF-1α) and also mediate oxidative stress caused by free iron liberated from the lysis of blood. PHD inhibition improves outcome after experimental intracerebral hemorrhage (ICH) by reducing activating transcription factor 4 (ATF4)-driven neuronal death. As the ATF4-CHOP (CCAAT-enhancer-binding protein homologous protein) pathway plays a role in the pathogenesis of contusive SCI, we examined the effects of PHD inhibition in a mouse model of moderate T9 contusive SCI in which white matter damage is the primary driver of locomotor dysfunction. Pharmacological inhibition of PHDs using adaptaquin (AQ) moderately lowers acute induction of Atf4 and Chop mRNAs and prevents the acute decline of oligodendrocyte (OL) lineage mRNAs, but does not improve long-term recovery of hindlimb locomotion or increase chronic white matter sparing. Conditional genetic ablation of all three PHD isoenzymes in OLs did not affect Atf4, Chop or OL mRNAs expression levels, locomotor recovery, and white matter sparing after SCI. Hence, PHDs may not be suitable targets to improve outcomes in traumatic CNS pathologies that involve acute white matter injury.

Background Maintaining adherence to antiretroviral therapy (ART) is a significant challenge for human immunodeficiency virus (HIV)-infected racial and ethnic minority adolescents and young adults (youth). Given the consequences of suboptimal ART adherence, there is a pressing need for an expanded understanding of adherence behavior in this cohort. Objectives As part of an exploratory sequential, mixed-methods study, we used qualitative inquiry to explore adherence information, motivation, and behavioral skills among HIV-infected racial and ethnic minority youth. Our secondary aim was to gain an understanding of the contextual factors surrounding adherence behavior. Methods The information-motivation-behavioral skills model (IMB model) was applied to identify the conceptual determinants of adherence behavior in our target population, along with attention to emergent themes. In-depth, individual, semistructured interviews, including open-ended questions with probes, were conducted with a convenience sample of HIV-infected racial and ethnic minority youth (ages 16-29 years), receiving ART and with evidence of virologic failure (i.e., detectable HIV viral load). New participants were interviewed until information redundancy was reached. Qualitative interviews were digitally recorded, transcribed verbatim, and analyzed using Atlas.ti (v8). Directed content analysis was performed to generate categories and broad themes. Coding was initially conceptually driven (IMB model) and shifted to a data-driven approach, allowing for the discovery of key contextual factors that influence adherence behavior in this population. Methodological rigor was ensured by member checks, an audit trail, thick descriptive data, and triangulation of data sources. Results Twenty racial and ethnic minority participants (mean age = 24.3 years, 55.0% male) completed interviews. We found adherence information was understood in relation to HIV biomarkers; adherence motivation and behavioral skills were influenced by stigma and social context. We identified five primary themes regarding ART self-management: (a) emerging adulthood with a chronic illness, (b) stigma and disclosure concerns, (c) support systems and support deficits, (d) mental and behavioral health risks and challenges, and (e) mode of HIV transmission and perceptions of power and control. Discussion Key constructs of the IMB model were applicable to participating HIV-infected youth yet did not fully explain the essence of adherence behavior. As such, we recommend expansion of current adherence models and frameworks to include known contextual factors associated with ART self-management among HIV-infected racial and ethnic minority youth.

Introduction The aim of this study was to develop and validate a simple prognostic scoring system using readily available clinical and pathological variables that could stratify patients according to the risk of death following lung cancer resection. We hypothesized that by using additional pathological variables not accounted for by pathological stage alone coupled with markers of overall fitness a new prognostic tool could be developed. Methods Multivariable logistic regression analysis of pathological and other clinical variables from patients undergoing surgical resection of non-small cell lung cancer (NSCLC) were used to determine factors independently associated with 2-year overall survival and so derive the scoring system. The model was then validated in an external multi-centre dataset. Results Using multivariable logistic regression on a large dataset (n = 1,421) the ‘LNC-PATH’ (Lymphovascular invasion, N-stage, adjuvant Chemotherapy, Performance status, Age, T-stage, Histology) prognostic score was devised and then validated using an external dataset (n = 402). This can be used to risk stratify patients into low, moderate and high-risk groups with a statistically significant difference between the three groups in their survival distributions. 83.8% of patients in the low-risk group survived two years after surgery compared to 55.6% in the moderate-risk group and 26.2% in the high-risk group. The score was shown to perform moderately well with an Area Under the Receiver Operating Characteristic curve (AUROC) value of 0.76 (95% CI: 0.73–0.79) and 0.70 (95% CI: 0.64–0.76) in the derivation and validation cohorts respectively. Discussion The LNC-PATH score predicts 2-year overall survival after surgery for NSCLC. This may allow the development of risk stratified follow-up protocols in survivorship clinics which could be the subject of future prospective studies.

Background Customizing monitor alarm settings to individual patients can reduce alarm fatigue in intensive care units (ICUs), but has not been widely studied. Objectives To understand ICU nurses' approaches to customization of electrocardiographic (ECG) monitor alarms. Methods A convergent mixed methods study was conducted in 3 ICUs in 1 hospital. Data on the type and frequency of ECG alarm customization were collected from patient monitors (n=298). Nurses' customization clinical reasoning was explored through semi-structured interviews (n=27). Results Of the 298 patients, 58.7% had ≥1 alarm(s) customized. Heart rate limits, irregular heart rate, and atrial fibrillation were the most commonly customized alarms. Interviews revealed that customization practices varied widely and were influenced by factors including clinical expertise, lack of customization education, and negative experiences. Conclusion Alarm customization is nuanced and requires adequate support to develop safe and effective practices. The challenges identified can inform development of strategies to improve alarm customization.

Objectives African Americans (AAs) have a higher prevalence of sleep disorders than other racial/ethnic groups. However, little is known about the relationships among individual and neighborhood factors related to sleep quality in AAs. The purposes of this study were to (1) describe beliefs about sleep, sleep hygiene behaviors, and sleep quality among AAs; and (2) examine the relationships among sociodemographic characteristics, neighborhood environment, beliefs about sleep, sleep hygiene behaviors, and sleep quality. Methods We conducted a cross-sectional study of 252 AA men and women in the Greater New Haven, CT, USA community. We assessed their sociodemographic characteristics, neighborhood environment, beliefs about sleep, sleep hygiene, and sleep quality with the following measures, respectively: the Neighborhood Environment Scale, the brief version of Dysfunctional Beliefs and Attitudes about Sleep, the Sleep Hygiene Practice Scale, the Pittsburgh Sleep Quality Index. We performed descriptive statistics, correlations and multiple hierarchical regression. Results About 72% of the participants (mean age: 53.88 ± 14.17 years, 77.8% women) reported experiencing sleep disturbance. People with poor sleep quality were more likely to report poorer neighborhood social environment (social cohesion), poorer overall neighborhood environment, more dysfunctional beliefs toward sleep, and poorer sleep hygiene than those who had good sleep quality. In the final multivariate model that controlled for a number of chronic comorbid conditions, neighborhood environment, beliefs about sleep, and sleep hygiene behaviors were significantly associated with sleep quality. Conclusions Future efforts are needed to improve sleep among AAs by considering both the individual's belief about sleep, sleep hygiene behaviors and neighborhood factors.

AIMS AND OBJECTIVES To describe obesity-risk behaviours (diet, physical activity and sedentary behaviour) and examine the relationships of the obesity-risk behaviours with body mass index (BMI) in school-aged Korean American children. BACKGROUND Korean American children have a risk of becoming overweight or obese and developing obesity-related complications; however, there is limited research about obesity-risk behaviours in Korean American children. DESIGN A cross-sectional study. METHODS Obesity-risk behaviours of children were assessed with well-validated self-report questionnaires (i.e., Elementary-level School-based Nutrition Monitoring Questionnaire) from children and their mothers. Height and weight of children were measured. Data were analysed with bivariate and multivariate analyses using mixed effects models to incorporate the correlation within siblings. RESULTS A total of 170 Korean American children (mean age 10.9 [2.0] years; 52.4% girls; mean BMI 19.3 [3.2]; 28.7% ≥85 percentiles) participated in the study. Only 38.3% of Korean American children met established recommendations of five fruits/vegetables per day; 56.5% met recommendations for more than 3 days per week of vigorous physical activity; and 40.8% met recommendations for

Background Synbiotics often are prescribed to limit antibiotic-associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking. Objective To determine whether synbiotic co-administration mitigates AAGS in healthy research cats treated with clindamycin. Animals 16 healthy research cats. Methods A randomized, double-blinded, placebo-controlled, 2-way, 2-period, crossover study with a 6-week washout was performed. Each study period consisted of a 1-week baseline and a 3-week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant. Results Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F-value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F-value = 31.1, P < 0.01) despite period effects (F-value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F-value = 17.9, P < 0.01). Conclusions and Clinical Importance Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic-associated diarrhea.

Background Ileoscopy is increasingly performed in dogs and cats with gastrointestinal signs, but iatrogenic ileocecocolic (ICC) perforations have not been described. Hypothesis/objectives To characterize endoscopic ICC perforations in dogs and cats. Animals Thirteen dogs and 2 cats. Methods This is a retrospective case series. Signalment, presentation, endoscopic equipment, colonic preparation, endoscopist's experience level, ileal intubation technique, method of diagnosis, perforation location, histopathology, management, and outcome data were collected and reviewed. Results Six ileal, 5 cecal, and 4 colonic perforations were identified between 2012 and 2019. Dogs weighed 2.4-26 kg (median, 10.3 kg) and cats 4.6-5.1 kg (median, 4.9 kg). Endoscopy was performed in dogs presented for vomiting (n = 4), as well as large (n = 5), mixed (n = 4), and small (n = 1) bowel diarrhea. Cats had large bowel diarrhea. Endoscopists included 1 supervised intern, 9 supervised internal medicine residents (2 first year, 6 second year, 1 third year), and 5 internal medicine diplomates. Diagnosis was delayed in 5 dogs, occurring 1-5 days after endoscopy (median, 3 days); dogs were presented again with inappetence (n = 4), lethargy (n = 4), abdominal pain (n = 3), retching (n = 2), and syncope (n = 1). All animals underwent surgical correction. Histopathology did not identify lesions at the perforation site in any animal. Two dogs required a second surgery; 1 died 12 hours after surgery. Survival to discharge was 93%, with 78% surviving ≥8 months. Conclusions and clinical importance Iatrogenic endoscopic ICC perforation is not indicative of underlying disease and is associated with a good prognosis. Delayed diagnosis can occur. Therefore, perforation should be considered in the differential diagnosis for animals with clinical deterioration after endoscopy.

We explored perceptions and experiences of living with type 1 diabetes mellitus (T1DM) among U.S. Latino adolescents (age 12-19 years) with T1DM and parents with limited English proficiency. We used a qualitative descriptive approach with semi-structured interviews of adolescents together with their parents. Interview data were reviewed, coded, and combined into themes about participant experiences with T1DM. Twenty-four adolescents (mean age: 15.4 years) and 23 parents participated. Analysis resulted in three themes: (a) Understanding and adapting to T1DM (i.e., initial fear and misunderstandings of T1DM; adolescents' reflections on living with a chronic health condition); (b) Coming to terms with social and environmental influences on T1DM self-management (i.e., T1DM as disruptive to school and social activities; dealing with stigma and judgments related to diabetes); and, (c) Integrating T1DM self-management expectations with components of Latino cultures (i.e., orientation toward family well-being; parent concerns about cultural preferences that influence food choices, positive influence of spirituality and religiousness; parental views of their current health care in comparison to that available in their place of birth). Adolescents and their parents reported experiences that are universal to adolescents with T1DM in addition to challenges that are unique to Latinos. Efforts aimed at improving T1DM self-management during adolescence with this population need to be tailored to meet the unique social and cultural contexts and delivered in a culturally and linguistically congruent manner.

Despite high rates of cardiometabolic diseases in Korean immigrants (KIs), little is known about cultural and environmental factors contributing to lifestyle behaviors. The purpose of this cross-sectional study was to examine the relationships among acculturation, environment, and lifestyle behaviors (dietary behavior, physical activity, and sedentary behavior) through culturally sensitive psychological mediators, body image discrepancy and acculturative stress in middle-aged KIs.A cross-sectional study was conducted. KIs aged 30-65 years were recruited online and at Korean community centers and churches in the Northeastern US Participants completed validated measures of dietary behavior (the Nutrition Subscale of the Health Promoting Lifestyle Profile (HPLP) II), physical activity (the International Physical Activity Questionnaire (IPAQ) - short form), and sedentary behavior (the Sedentary Behavior Questionnaire). Acculturative stress was measured by the Acculturative Stress Index and body image discrepancy was measured by the Stunkard Figure Rating Scale. Acculturation was defined as a latent variable measured by Korean and American orientation (Vancouver Index of Acculturation), age of immigration to the US, length of residency in the US, and English proficiency. Data were analyzed with structural equation modeling (SEM).The sample included 361 KIs (mean age = 41.77 ±In our study, acculturation and environmental support for physical activity and healthy food simultaneously influenced KIs' lifestyle behaviors. Addressing an unhealthy body image and acculturative stress may be additional strategies for lifestyle intervention programs to prevent cardiometabolic diseases in KIs.

Managing type 1 diabetes can be challenging, especially for youth, so there is a need for effective interventions to help youth live with diabetes.To determine the efficacy of a coping skills training (CST) program for Chinese youth with type 1 diabetes and to explore whether the efficacy of the program was different for school-aged children than for adolescents with type 1 diabetes.A total of 100 youth with type 1 diabetes aged 8 to 20 years were randomly placed in either an intervention group (CST + standard care [SC]) or a control group (SC). Data were collected at baseline, 6-month, and 12-month follow-ups on primary outcomes of perceived stress, coping, and self-efficacy and secondary outcomes of diabetes self-management, quality of life, and glycated hemoglobin A1c (HbA1c). A generalized estimating equation analysis for repeated measures was used to determine the program effects and differential effects by age group.The CST program had no significant effect on primary or secondary outcomes over 12 months. However, there was a significant increase in positive coping (P .001), self-efficacy (P = .017), diabetes problem-solving and goals of diabetes self-management (P = .007, P = .001), and quality of life (P = .016) of school-aged children in the intervention group compared with the control group. There were no significant differences in primary or secondary outcomes between the intervention group and the control group (P .05).The CST program was effective for school-aged children, improving psychosocial and diabetes self-management outcomes. Further research is needed to develop programs that improve outcomes in adolescents with type 1 diabetes.

Background Diabetes mellitus increases the risk of mortality after acute myocardial infarction ( AMI ). However, little is known about the association of diabetes mellitus with post‐ AMI health status outcomes (symptoms, functioning, and quality of life) in younger adults. Methods and Results We investigated the association between diabetes mellitus and health status during the first 12 months after AMI , using data from 3501 adults with AMI (42.6% with diabetes mellitus) aged 18 to 55 years enrolled in the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study. Health status was measured with Seattle Angina Questionnaire ( SAQ ), 12‐item Short‐Form Health Survey, and EuroQol‐Visual Analogue Scale at baseline hospitalization, 1‐month, and 12‐months post‐ AMI . At baseline, patients with diabetes mellitus had significantly worse SAQ ‐angina frequency (81±22 versus 86±19), SAQ ‐physical limitations (77±28 versus 85±23), SAQ ‐quality of life (55±25 versus 57±23), 12‐item Short‐Form Health Survey mental (44±13 versus 46±12)/physical functioning (41±12 versus 46±12), and EuroQol‐Visual Analogue Scale (61±22 versus 66±21) than those without diabetes mellitus. Over time, both groups (with and without diabetes mellitus) improved considerably and the differences in health status scores progressively narrowed (except for 12‐item Short‐Form Health Survey physical functioning). In the linear‐mixed effects models, adjusted for sociodemographics, cardiovascular risk factors, comorbidities, clinical characteristics, psychosocial factors, healthcare use, and AMI treatment, diabetes mellitus was associated with worse health status at baseline but not after discharge, and the association did not vary by sex. Conclusions At baseline, young adults with diabetes mellitus had poorer health status than those without diabetes mellitus. After AMI , however, they experienced significant improvements and diabetes mellitus was not associated with worse angina, SAQ ‐physical limitations, mental functioning, and quality of life, after adjustment for baseline covariates. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00597922.

Type 2 diabetes (T2D) is a complex, lifelong condition that is disproportionately prevalent among minority populations. Haitian immigrants (HIs) living in the US with T2D have unique factors that influence diagnosis, treatment, and self-management. The purpose of this integrative review was to provide a synthesis of the research on T2D in the HI population. In a systematic literature search, 14 studies met the inclusion criteria. Three themes were identified: risk factors for less self-management and/or worse metabolic control; protective factors for better self-management and/or metabolic control; and mixed results. HIs had higher HbA(1c), yet better self-management, different genetic profiles, and lower levels of vitamin D and hemoglobin concentration compared to other ethnic groups. HIs also reported better dietary quality, less healthcare utilization, and higher perceived emotional/psychological stress compared to other ethnic groups. This study has implications for practice for integrating the unique cultural factors when assessing and intervening with HIs.

EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes in phenotypically identical tumors or partner with the same genes in morphologically and behaviorally different neoplasms. Our study set out to examine the EWSR1 fusions identified at our institution over a 3-year period, using various methods, their association with specific entities and possible detection of novel partners and associations. Sixty-three consecutive cases investigated for EWSR1 gene fusions between 2015 and 2018 at our institution were included in this study. Fusions were identified by either break-apart fluorescence in-situ hybridization (FISH), our clinical RNA-based assay for fusion transcript detection or both. Twenty-eight cases were concurrently tested by FISH and NGS, 24 were tested by FISH alone and 11 by NGS alone. Of the 28 cases with dual testing, 24 were positive by both assays for an EWSR1 gene fusion, 3 cases were discordant with a positive FISH assay and a negative NGS assay, and 1 case was discordant with a negative FISH assay but a positive NGS assay. Three novel fusions were identified: a complex rearrangement involving three genes (EWSR1/RBFOX2/ERG) in Ewing sarcoma, a EWSR1/TCF7L2 fusion in a colon adenocarcinoma, and a EWSR1/TFEB fusion in a translocation-associated renal cell carcinoma. Both colonic adenocarcinoma and renal cell carcinoma had not been previously associated with EWSR1 rearrangements to our knowledge. In a subset of cases, detection of a specific partner had an impact on the histological diagnosis and patient management. In our experience, the use of a targeted NGS-based fusion assay is superior to EWSR1 break-apart FISH for the detection of known and novel EWSR1 rearrangements and fusion partners, particularly given the emerging understanding that distinct fusion partners result in different diseases with distinct prognostic and therapeutic implications.

Publisher's version (útgefin grein)., Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis., The authors in this manuscript were working on behalf of BCAC, CCFR, CIMBA, CORECT, GECCO, OCAC, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS, TRICL-ILCCO, ABCTB, APCB, BCFR, CONSIT TEAM, EMBRACE, GC-HBOC, GEMO, HEBON, kConFab/AOCS Mod SQuaD, and SWE-BRCA. The breast cancer genome-wide association analyses: BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSR-SIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, and BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). COLBCCC is supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany. D.T. was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C eceives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf-Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and “Practical Research for Innovative Cancer Control (15ck0106177h0001)” from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014, and 17-44-020498. ICICLE was supported by Breast Cancer Now, CRUK, and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (A.L.F.) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (E.V.O.) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.-T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The KOHBRA study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. L.M.B.C. is supported by the ‘Stichting tegen Kanker’. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839, and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286, and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A.-L. Børresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, and U01 CA179715), and the North Carolina University Cancer Research Fund. The NGOBCS was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation, and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956, and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the National Cancer Institute of the National Institutes of Health (R01 CA89085 and P50 CA125183 and the D43 TW009112 grant), Susan G. Komen (SAC110026), the Dr. Ralph and Marian Falk Medical Research Trust, and the Avon Foundation for Women. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. D.G.E. is supported by the all Manchester NIHR Biomedical research center Manchester (IS-BRC-1215-20007). HUNBOCS, Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745, NKFI_OTKA K-112228. C.I. received support from the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI P30-CA-51008) and the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. K.M. is supported by CRUK C18281/A19169. City of Hope Clinical Cancer Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J Weitzel) from the National Cancer Institute and the office of the Directory, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The colorectal cancer genome-wide association analyses: Colorectal Transdisciplinary Study (CORECT): The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the CORECT Consortium. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong. ColoCare: we thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. CCFR: the Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and financial support from the U.S. National Cancer Institute, without which this important registry would not exist. Galeon: GALEON wishes to thank the Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M Redondo, and the staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigación Sanitaria de Santiago (IDIS), Instituto de Investigación Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. MCCS: this study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH: We acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish low-risk colorectal cancer study: we thank Berith Wejderot and the Swedish low-risk colorectal cancer study group. Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO): we thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK: we are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. HPFS, NHS and PHS: we acknowledge Patrice Soule and Hardeep Ranu of the Dana-Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo, and Lixue Zhu who assisted in programming for NHS and HPFS and Haiyan Zhang who assisted in programming for the PHS. We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. PLCO: we thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services Inc., Ms. Barbara O’Brien and staff, Westat Inc. and Drs. Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions for making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI. PMH: we thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short20List.pdf. CORECT: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; and R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 (Gilliland)), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, and U01 CA164930). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S.G.). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai’i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: A.Z., C.O., M.N., N.C., N.H., and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden–Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC: the work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). SEARCH: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: the study was supported by grants from the Swedish research council; K2015-55 × -22674-01-4, K2008-55 × -20157-03-3, K2006-72 × -20157-01-2 and the Stockholm County Council (ALF project). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K.D.), through grant 101HG007491-01 (to C.I.A.). The Norris Cotton Cancer Center - P30CA023108, The Quantitative Biology Research Institute - P20GM103534, and the Coordinating Center for Screen Detected Lesions - U01CA196386 also supported efforts of C.I.A. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (grant number R01 CA060987). DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: National Institutes of Health (grant number R01 CA048998 to M.L.S). HPFS is supported by National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), NHS by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHSII by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and PHS by the National Institutes of Health (grant number R01 CA042182). MEC: National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783); see Colon CFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. and B.W.Z. are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, 23 and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (grant number R01 CA076366). VITAL: National Institutes of Health (grant number K05-CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The head and neck cancer genome-wide association analyses: The study was supported by NIH/NCI: P50 CA097190, and P30 CA047904, Canadian Cancer Society Research Institute (no. 020214) and Cancer Care Ontario Research Chair to R.H. The Princess Margaret Hospital Head and Neck Cancer Translational Research Program is funded by the Wharton family, Joe’s Team, Gordon Tozer, Bruce Galloway and the Elia family. Geoffrey Liu was supported by the Posluns Family Fund and the Lusi Wong Family Fund at the Princess Margaret Foundation, and the Alan B. Brown Chair in Molecular Genomics. This publication presents data from Head and Neck 5000 (H&N5000). H&N5000 was a component of independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) in H&N5000 serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). National Cancer Institute (R01-CA90731); National Institute of Environmental Health Sciences (P30ES10126). The authors thank all the members of the GENCAPO team/The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). CPS-II recruitment and maintenance is supported with intramural research funding from the American Cancer Society. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1 × 01HG007780-0. The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19-CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission’s 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to S.B., and Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). We thank Leticia Fernandez, Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba and Sergio and Rosalina Koifman, for their efforts with the IARC Latin America study São Paulo center. The IARC Central Europe study was supported by European Commission’s INCO-COPERNICUS Program (IC15- CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The lung cancer genome-wide association analyses: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127, CA148127S1, U19CA203654, and Cancer Prevention Research Institute of Texas RR170048). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multi-ethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The Singapore Chinese Health Study (SCHS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568) (to X.W.), Cancer Prevention & Research Institute of Texas (RP130502) (to X.W.), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The deCODE study of smoking and nicotine dependence was funded in part by a grant from NIDA (R01- DA017932). The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Genetic sharing analysis was funded by NIH grant CA194393. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The work to assemble the FTND GWAS meta-analysis was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant number R01 DA035825 (Principal Investigator [PI]: DBH). The study populations included COGEND (dbGaP phs000092.v1.p1 and phs000404.v1.p1), COPDGene (dbGaP phs000179.v3.p2), deCODE Genetics, EAGLE (dbGaP phs000093.vs.p2), and SAGE. dbGaP phs000092.v1.p1). See Hancock et al. Transl Psychiatry 2015 (PMCID: PMC4930126) for the full listing of funding sources and other acknowledgments. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT)study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. The ovarian cancer genome-wide association analysis: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.), and R01-CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP-86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175) and through a grant from the U.S. National Institutes of Health (R01-CA122443 (E.L.G)). Funding for individual studies: AAS: National Institutes of Health (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; and R01-CA080742); DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, and P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey; If Sara Olson and/or Irene Orlow is a co-author, please add NCI CCSG award (P30-CA008748) to the funding sources; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women’s Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50-CA159981, R01-CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01-ES044005 and Z01-ES049033; SMC: The bbSwedish Research Council-SIMPLER infrastructure; the Swedish Cancer Foundation; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and VårKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01-CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academia Reserve. The prostate cancer genome-wide association analyses: we pay tribute to Brian Henderson, who was a driving force behind the OncoArray project, for his vision and leadership, and who sadly passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. The ELLIPSE/PRACTICAL (http//:practical.icr.ac.uk) prostate cancer consortium and his collaborating partners were supported by multiple funding mechanisms enabling this current work. ELLIPSE/PRACTICAL Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA148537 for ELucidating Loci Involved in Prostate Cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392 (F.R.S.). Funding for the iCOGS infrastructure came from the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, C5047/A21332 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010-70 × -20430-04-3, 2014-2269). The Hannover Prostate Cancer Study was supported by the Lower Saxonian Cancer Society. PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. RAPPER was supported by the NIHR Manchester Biomedical Research Center, Cancer Research UK (C147/A25254, C1094/A18504) and the EU’s 7th Framework Programme Grant/Agreement no 60186. Overall: this research has been conducted using the UK Biobank Resource (application number 16549). NHS is supported by UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969, and R01 CA49449. NHSII is supported by UM1 CA176726 (NHSII cohort infrastructure grant), and R01-CA67262. A.L.K. is supported by R01 MH107649. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

The aims of this study were to: (a) determine if self-efficacy mediates the relationship between perceived stress and diabetes self-management in adolescents with type 1 diabetes (T1D); and (b) explore whether perceived stress moderated the self-efficacy and diabetes self-management relationship.Non-experimental, descriptive correlational design, conducted from January-December 2016.Guided by the Adaptation to Diabetes framework, data on demographic and clinical characteristics, perceived stress, self-efficacy and diabetes self-management were collected. Descriptive analyses and regression analyses were generated by SPSS Version 22. Structural equation modelling was implemented with the MPlus program.There was no direct effect of perceived stress on diabetes self-management; however, self-efficacy mediated the relationship between perceived stress and diabetes self-management. Adolescents who had high self-efficacy and low perceived stress demonstrated better diabetes care activities and diabetes communication than would be predicted from the main effects of self-efficacy and perceived stress alone.Decreasing perceived stress and improving self-efficacy are important strategies to improve diabetes self-management in adolescents with T1D.Adolescents with T1D experience considerable stress with daily self-management demands. This study highlights the mediating role of self-efficacy on perceived stress and diabetes self-management. Assessment of perceived stress and self-efficacy in self-management tasks in adolescents with T1D may help nurses individualize self-management education and support. Incorporating strategies to promote stress management and self-efficacy in diabetes education may also improve diabetes self-management.目的: 本研究的目的是:(a)确定自我效能感是否调节在1型糖尿病(T1D)青少年的感知压力和糖尿病自我管理之间的关系;(b)探讨感知压力是否调节自我效能感和糖尿病自我管理关系。 设计: 2016年1月-12月间实施的非实验性的描述性相关设计。 方法: 在糖尿病适应性框架的指导下,收集了人口学和临床特征、感知压力、自我效能和糖尿病自我管理方面的数据。采用SPSS 22版本进行描述性分析和回归分析。利用MPlus程序进行结构方程建模。 结果: 感知压力对糖尿病自我管理没有直接影响;然而,自我效能感调节了感知压力和糖尿病自我管理之间的关系。具有高自我效能感和低感知压力的青少年表现出更好的糖尿病护理活动和糖尿病沟通能力,这是自我效能感和感知压力的主要影响所不能预测的。 结论: 减少感知压力和提高自我效能感是改善青少年T1D患者糖尿病自我管理的重要策略。 影响: 患有T1D的青少年在日常自我管理需求方面承受着相当大的压力。本研究强调了自我效能感在感知压力和糖尿病自我管理中的中介作用。评估青少年T1D患者的自我管理任务中的感知压力和自我效能感可以帮助护士赋予自我管理教育和支持个性化。在糖尿病教育中采用促进压力管理和自我效能感的策略也可以改善糖尿病自我管理。.

Background Dogs with immune‐mediated disease are often coadministered glucocorticoids and aspirin, but ulcerogenic effects of current protocols are unknown. Objectives To compare gastrointestinal changes among dogs administered aspirin, prednisone, and combination treatment. Animals Twenty‐four healthy research dogs. Methods Double‐blinded, placebo‐controlled randomized trial of dogs administered placebo, aspirin (2 mg/kg q24h), prednisone (2 mg/kg q24h), or combination treatment PO for 28 days. Clinical signs were recorded daily, with laboratory work performed at baseline and day 28. Gastrointestinal mucosal hemorrhages, erosions, and ulcers were numerated for endoscopic studies performed on days 0, 14, and 28; endoscopic mucosal lesion scores were calculated. Results were compared using mixed model repeated‐measures analyses of variance and generalized estimating equation proportional odds models. P < .05 was considered significant. Results Gastric mucosal lesion scores differed by treatment‐by‐time (F[6, 40] = 4.4, P = .002), treatment (F[3, 20] = 7.1, P = .002), and time (F[2, 40] = 18.9, P < .001). Post hoc analysis revealed increased scores in the aspirin (day 14 only), prednisone, and prednisone/aspirin groups during treatment. Ulcers were identified on 14 studies, representing 10 dogs. Dogs receiving prednisone and prednisone/aspirin had 11.1 times (95% CI, 1.7‐73.6) and 31.5 times (95% CI, 3.5‐288.0) higher odds, respectively, of having endoscopic mucosal lesion scores ≥4 than dogs receiving placebo (P ≤ .01). Conclusions and Clinical Importance Gastrointestinal bleeding occurs commonly in dogs administered aspirin, prednisone, or prednisone/aspirin treatment, with higher lesion scores for dogs receiving combination treatment. Even severe lesions are not accompanied by clinical signs.

Aims and objectives To explore clinical reasoning about alarm customisation among nurses in intensive care units. Background Critical care nurses are responsible for detecting and rapidly acting upon changes in patients' clinical condition. Nurses use medical devices including bedside physiologic monitors to assist them in their practice. Customising alarm settings on these devices can help nurses better monitor their patients and reduce the number of clinically irrelevant alarms. As a result, customisation may also help address the problem of alarm fatigue. However, little is known about nurses' clinical reasoning with respect to customising physiologic monitor alarm settings. Design This article is an in-depth report of the qualitative arm of a mixed methods study conducted using an interpretive descriptive methodological approach. Methods Twenty-seven nurses were purposively sampled from three intensive care units in an academic medical centre. Semi-structured interviews were conducted by telephone and were analysed using thematic analysis. Consolidated Criteria for Reporting Qualitative Research (COREQ) reporting guidelines were used. Results Four themes were identified from the interview data: unit alarm culture and context, nurse attributes, motivation to customise and customisation "know-how." A conceptual model demonstrating the relationship of these themes was developed to portray the factors that affect nurses' customisation of alarms. Conclusions In addition to drawing on clinical data, nurses customised physiologic monitor alarms based on their level of clinical expertise and comfort. Nurses were influenced by the alarm culture on their clinical unit and colleagues' and patients' responses to alarms, as well as their own technical understanding of the physiologic monitors. Relevance to clinical practice The results of this study can be used to design strategies to support the application of clinical reasoning to alarm management, which may contribute to more appropriate alarm customisation practices and improvements in safety.