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AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 childrens hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

BACKGROUND AND OBJECTIVE: Pediatric firearm injuries increased during the coronavirus disease 2019 pandemic, but recent trends in firearm injury emergency department (ED) visits are not well described. We aimed to assess how pediatric firearm injury ED visits during the pandemic differed from expected prepandemic trends. METHODS: We retrospectively studied firearm injury ED visits by children

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA in children with headaches based on clinically sensible and reliable variables. METHODS AND ANALYSIS: Prospective cohort study of 28 000 children with headaches presenting to any of 18 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). We include children aged 2-17 years with a chief complaint of headache. We exclude children with a clear non-intracranial alternative diagnosis, fever, neuroimaging within previous year, neurological or developmental condition such that patient history or physical examination may be unreliable, Glasgow Coma Scale score

BackgroundWomen with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC.MethodsWe performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves.ResultsOf the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage.ConclusionThis multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

BackgroundDown syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS.ObjectiveDoes lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS?MethodsResting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years).ResultsLower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity.ConclusionReduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

BackgroundPhysical activity and macronutrient intake, important contributors to energy balance, may be independently associated with female urinary incontinence (UI).MethodsWe evaluated the association of baseline self-reported physical activity and macronutrient intake, via food frequency questionnaire, with incident UI subtypes after 3 years among 19 741 postmenopausal women in the Women's Health Initiative Observational Study. Odds ratios (ORs) for incident urgency, stress, and mixed UI were calculated using multivariable logistic regression.ResultsWomen who reported total physical activity (metabolic equivalent task [MET]-hours/week) ≥30 versus .05 for all).ConclusionsAmong postmenopausal women, higher physical activity was associated with lower risk of incident urgency and mixed UI, but not stress UI, independent of baseline weight and weight change. Higher protein intake was associated with increased risk of urgency UI, but no associations were observed between other macronutrient and UI subtypes.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.

Emerging evidence indicates that the predictability of signals early in life may influence the developing brain. This study examines links between a novel indicator of maternal mood dysregulation, mood entropy, and child neurodevelopmental outcomes. Associations between prenatal maternal mood entropy and child neurodevelopment were assessed in 2 longitudinal cohorts. Maternal mood was measured several times over pregnancy beginning as early as 15 weeks gestation. Shannons mood entropy was applied to distributions of mothers responses on mood questionnaires. Child cognitive and language development were evaluated at 2 and 6-9 years of age. Higher prenatal maternal mood entropy was associated with lower cognitive development scores at 2 years of age and lower expressive language scores at 6-9 years of age. These associations persisted after adjusting for maternal pre and postnatal mood levels and for other relevant sociodemographic factors. Our findings identify maternal mood entropy as a novel predictor of child neurodevelopment. Characterizing components of maternal mood in addition to level of severity or valence may further our understanding of specific processes by which maternal mood shapes child development. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BackgroundDifferences in risk and protective factors (e.g., victimization, abuse, social support) have been used to explain elevated rates of suicidal ideation and suicide attempts in sexual minority youth (SMY) relative to heterosexual peers. However, little is known regarding how risk and protective factors may explain suicide risk differences among subgroups of SMY. The aims of this study were to 1) examine differences in prevalence and severity for suicide risk and protective factors among SMY, and 2) explore whether risk and protective factors are differentially associated with suicidal ideation and suicide attempts for SMY subgroups.MethodsParticipants were 6,423 adolescents (ages 12-17) recruited from 14 Emergency Departments across the United States who completed an assessment of suicide risk and protective factors. SMY were 20% of the sample (n = 1,275) and categorized as bisexual (8%), gay/lesbian (2%), mostly straight (5%), or other sexual minority (5%).ResultsBisexual youth had elevated rates of suicidal ideation and attempts, more risk factors (e.g., bullying victimization, depression), and fewer protective factors (e.g., parent-family connectedness, positive affect) relative to mostly straight and other sexual minority youth. Bisexual and gay/lesbian youth only differed in parent-family connectedness (lower among bisexual youth). Depression and parent-family connectedness had weaker associations with suicidal ideation for bisexual youth.LimitationsEmergency departments were not nationally representative. Study design was cross-sectional, preventing causal inferences.ConclusionsInterventions seeking to mitigate risk factors and promote protective factors are greatly needed for SMY and may benefit from tailoring to address unique stressors for sexual minority subgroups.

To determine the effectiveness of a school-based curriculum, Eliminating the Stigma of Differences (ESD), in improving attitudinal and/or behavioral contexts regarding mental illness in schools and increasing the likelihood that youth seek treatment for mental health problems when needed. We conducted a cluster randomized trial in sixth-grade classes from 14 schools in 2011 and 2012 with follow-up at 6-month intervals through 24 months (2012-2015). Using a fully crossed 2 × 2 × 2 factorial design, we compared ESD to a no-intervention control and to 2 comparator interventions: (1) contact with 2 young adults with a history of mental illness and (2) exposure to antistigma printed materials. We implemented interventions in classrooms in an ethnically and socioeconomically diverse school district. There were 416 youth who participated in the follow-up, and 312 (75%) of these participated for the full 2 years. Outcome measures were knowledge and positive attitudes, social distance from peers with mental illness, and mental health treatment seeking. Youth assigned to ESD reported greater knowledge and positive attitudes and reduced social distance (Cohen's d = 0.35 and 0.16, respectively) than youth in the comparator interventions and no-intervention groups across the 2-year follow-up. Youth with high levels of mental health symptoms were more likely (odds ratio = 3.51; confidence interval = 1.08-11.31) to seek treatment during follow-up if assigned to ESD than if they were assigned to comparator interventions or no intervention. ESD shows potential for improving the social climate related to mental illnesses in schools and increasing treatment seeking when needed. ESD and interventions like it show promise as part of a public mental health response to youth with mental health needs in schools.

BACKGROUNDPrehospital plasma improves survival in severely injured patients transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage.METHODSWe sampled blood from 405 trauma patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites. We assayed samples for 21 inflammatory mediators and 7 markers associated with endothelial function and damage. We performed hierarchical clustering analysis (HCA) of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for differences across study and to assess any association with prehospital plasma resuscitation.RESULTSHCA distinguished two patient clusters with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of the most seriously injured patients, prehospital plasma was associated with an increase in adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission, and a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E 24 hours later.CONCLUSIONPrehospital plasma may ameliorate immune dysfunction and the endotheliopathy of trauma. These effects of plasma may contribute to improved survival in injured patients.TRIAL REGISTRATIONNCT01818427.FUNDINGDepartment of Defense; National Institutes of Health, U.S. Army.

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.InterpretationChildren, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.FundingNational Institute of Neurological Disorders and Stroke, National Institutes of Health.

OBJECTIVE:The aim of this study is to examine the effect of postoperative chemotherapy on survival in patients with stage II or III rectal adenocarcinoma who undergo neoadjuvant chemoradiation (CRT) and surgical resection. METHODS:A retrospective review of the National Cancer Database (NCDB) from 2006 to 2013 was performed. Cases were analyzed based on pathologic complete response (pCR) status and use of adjuvant therapy. The Kaplan-Meier method was used to estimate overall survival probabilities. RESULTS:23,045 cases were identified, of which 5832 (25.31%) achieved pCR. In the pCR group, 1513 (25.9%) received adjuvant chemotherapy, and in the non-pCR group, 5966 (34.7%) received adjuvant therapy. In the pCR group, five-year survival probability was 87% (95% CI 84%-89%) with adjuvant therapy and 81% (95% CI 79%-82%) without adjuvant therapy. In the non-pCR group, five-year survival probability was 78% (95% CI 76%-79%) with adjuvant therapy and 70% (95% CI 69%-71%) without adjuvant therapy. In the non-pCR and node-negative subgroup (ypN-), five-year survival probability was 86% (95% CI 84%-88%) with adjuvant therapy and 76% (95% CI 74%-77%) without adjuvant therapy. In the non-pCR and node-positive subgroup (ypN+), five-year survival probability was 67% (95% CI 65%-70%) with adjuvant therapy and 60% (95% CI 58%-63%) without adjuvant therapy. CONCLUSIONS:Adjuvant chemotherapy in stage II or III rectal adenocarcinoma is associated with increased five-year survival probability regardless of pCR status. We observed similar survival outcomes among non-pCR ypN- treated with adjuvant chemotherapy compared with patients achieving pCR treated with adjuvant chemotherapy.

The purpose of this study was to include youth, parents, researchers, and clinicians in the identification of feasible and acceptable strategies for teen suicide screening in the pediatric emergency department (ED). Concept mapping methodology was used to elicit stakeholder responses. Regarding the most important result of suicide screening for teens in the pediatric ED, suicide prevention and education for parents, friends, and community members was rated easiest to implement, while short- and long-term follow-up and treatment was rated most important. In terms of successful suicide screening for teens in the pediatric ED, provision of resources and information was rated most feasible, and a safe, friendly, private screening environment was rated most important. The concept maps can be used to align suicide risk screening with the priorities and recommendations of pediatric ED stakeholders.

BackgroundThe incidence of adolescent suicide is rising in the United States, yet we have limited information regarding short-term prediction of suicide attempts. Our aim was to identify predictors of suicide attempts within 3-months of an emergency department (ED) visit.MethodsAdolescents, ages 12-17, seeking health care at 13 pediatric EDs (Pediatric Emergency Care Applied Research Network) and one Indian Health Service Hospital in the United States were consecutively recruited. Among 10,664 approached patients, 6,448 (60%) were enrolled and completed a suicide risk survey. A subset of participants (n = 2,897) was assigned to a 3-month telephone follow-up, and 2,104 participants completed this follow-up (73% retention). Our primary outcome was a suicide attempt between the ED visit and 3-month follow-up.ResultsOne hundred four adolescents (4.9%) made a suicide attempt between enrollment and 3-month follow-up. A large number of baseline predictors of suicide attempt were identified in bivariate analyses. The final multivariable model for the full sample included the presence of suicidal ideation during the past week, lifetime severity of suicidal ideation, lifetime history of suicidal behavior, and school connectedness. For the subgroup of adolescents who did not report recent suicidal ideation at baseline, the final model included only lifetime severity of suicidal ideation and social connectedness. Among males, the final model included only lifetime severity of suicidal ideation and past week suicidal ideation. For females, the final model included past week suicidal ideation, lifetime severity of suicidal ideation, number of past-year nonsuicidal self-injury (NSSI) incidents, and social connectedness.ConclusionsResults indicate that the key risk factors for adolescent suicide attempts differ for subgroups of adolescents defined by sex and whether or not they report recent suicidal thoughts. Results also point to the importance of school and social connectedness as protective factors against suicide attempts.

KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large data sets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and these findings were validated in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (hazard ratio, 3.74; 95% CI, 1.43-22.97; P = 0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. In addition, KHSRP promoted a proangiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes, such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.

IntroductionInflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.MethodsWe collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.ResultsForty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT.ConclusionsIn this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

ObjectivesTo determine the test-retest reliability, concurrent, convergent, and discriminant validity of a recently devised screen (the Newton screen) for alcohol and cannabis use/misuse, and its predictive validity at follow-up.Study designAdolescents, 12-17 years old (n = 4898), treated in 1 of 16 participating pediatric emergency departments across the US were enrolled in a study as part of a larger study within the Pediatric Emergency Care Applied Research Network. Concurrent and predictive validity (at 1, 2, and 3 years of follow-up) were assessed in a random subsample with a structured Diagnostic and Statistical Manual of Mental Disorders-based interview. Convergent validity was assessed with the Alcohol Use Disorders Identification, a widely used alcohol screening measure.ResultsThe sensitivity of the Newton screen for alcohol use disorder at baseline was 78.3% with a specificity of 93.0%. The cannabis use question had a baseline sensitivity of 93.1% and specificity of 93.5% for cannabis use disorder. Predictive validity analyses at 1, 2, and 3 years revealed high specificity but low sensitivity for alcohol and high specificity and moderate sensitivity for cannabis.ConclusionsThe Newton screening instrument may be an appropriate brief screening tool for use in the busy clinical environment. Specificity was high for both alcohol and cannabis, but sensitivity was higher for cannabis than alcohol. Like other brief screens, more detailed follow-up questions may be necessary to definitively assess substance misuse risk and the need for referral to treatment.

A behavioral lifestyle intervention with partial meal replacement reduced excess gestational weight gain in ethnically diverse women with overweight/obesity, but the effects on micronutrient intake remained unknown. A secondary analysis of a randomized, controlled trial tested whether the intervention improved micronutrient intake relative to usual care. Pregnant women (n = 211; 30.5 years of age, body mass index, BMI, of 32.0 kg/m2) were enrolled and randomized within site and ethnicity (40% were Hispanic) into intervention (n = 102) or usual care (n = 109) groups. Two 24 h dietary recalls were conducted on random days at study entry and late pregnancy (35⁻36 weeks gestation). Nutrient adequacy was defined using the Estimated Average Requirement cut-point method. At study entry and including prenatal vitamins, ≥90% of participants reported inadequate intake of vitamins D and E and iron; 40⁻50% reported inadequate intake of calcium, protein, vitamins A, C, B6, folate, magnesium, and zinc. From study entry to late pregnancy, the behavioral intervention with partial meal replacement increased the overall intake of vitamins A, E, and D and copper and reduced the odds of inadequate intake of calcium (odds ratio (OR) = 0.37 (0.18, 0.76)), vitamins A (OR = 0.39 (0.21, 0.72)) and E (OR = 0.17 (0.06, 0.48)), and magnesium (OR = 0.36 (0.20, 0.65)). A behavioral intervention with partial meal replacement during pregnancy improved the intake of several micronutrients in Hispanic and non-Hispanic women with overweight/obesity.

BackgroundThe pediatric emergency department (PED) represents an opportune time for alcohol and drug screening. The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recommends a two-question alcohol screen for adolescents as a predictor of alcohol and drug misuse.ObjectiveA multi-site PED study was conducted to determine the association between the NIAAA two-question alcohol screen and adolescent cannabis use disorders (CUD), cigarette smoking, and lifetime use of other drugs.MethodsParticipants included 12-17-year olds (n = 4834) treated in one of 16 participating PEDs. An assessment battery, including the NIAAA two-question screen and other measures of alcohol, tobacco and drug use, was self-administered on a tablet computer.ResultsA diagnosis of CUD, lifetime tobacco use or lifetime drug use was predicted by any self-reported alcohol use in the past year, which indicates a classification of moderate risk for middle school ages and low risk for high school ages on the NIAAA two-question screen. Drinking was most strongly predictive of a CUD, somewhat weaker for lifetime tobacco use, and weakest for lifetime drug use. This same pattern held for high school and middle school students and was stronger for high school students over middle school students for all three categories. This association was also found across gender, ethnicity and race. The association was strongest for CUD for high school students, sensitivity 81.7% (95% CI, 77.0, 86.5) and specificity 70.4% (95% CI, 68.6, 72.1). Conclusions/Importance: A single question about past year alcohol use can provide valuable information about other substance use, particularly marijuana.

ObjectiveGenome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.MethodsGenotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.ResultsAt chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question screen is a valid adolescent alcohol screening tool. No studies have examined if this tool predicts future alcohol problems. We conducted a study at 16 pediatric emergency departments to determine the tool's predictive validity for alcohol misuse and alcohol use disorders (AUDs). Participants (N = 4834) completed a baseline assessment battery. A subsample of participants completed the battery at 1, 2, and 3 years follow up. Of the 2209 participants assigned to follow-up, 1611 (73%) completed a 1-year follow-up, 1591 (72%) completed a 2-year follow-up, and 1377 (62%) completed a 3-year follow-up. The differences in AUDs between baseline NIAAA screen nondrinkers and lower-risk drinkers were statistically significant at 1 year (P = .0002), 2 years (P

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

BackgroundThe traditional sequence of trauma care: Airway, Breathing, Circulation (ABC) has been practiced for many years. It became the standard of care despite the lack of scientific evidence. We hypothesized that patients in hypovolemic shock would have comparable outcomes with initiation of bleeding treatment (transfusion) prior to intubation (CAB), compared to those patients treated with the traditional ABC sequence.MethodsThis study was sponsored by the American Association for the Surgery of Trauma multicenter trials committee. We performed a retrospective analysis of all patients that presented to trauma centers with presumptive hypovolemic shock indicated by pre-hospital or emergency department hypotension and need for intubation from January 1, 2014 to July 1, 2016. Data collected included demographics, timing of intubation, vital signs before and after intubation, timing of the blood transfusion initiation related to intubation, and outcomes.ResultsFrom 440 patients that met inclusion criteria, 245 (55.7%) received intravenous blood product resuscitation first (CAB), and 195 (44.3%) were intubated before any resuscitation was started (ABC). There was no difference in ISS, mechanism, or comorbidities. Those intubated prior to receiving transfusion had a lower GCS than those with transfusion initiation prior to intubation (ABC: 4, CAB:9, p = 0.005). Although mortality was high in both groups, there was no statistically significant difference (CAB 47% and ABC 50%). In multivariate analysis, initial SBP and initial GCS were the only independent predictors of death.ConclusionThe current study highlights that many trauma centers are already initiating circulation first prior to intubation when treating hypovolemic shock (CAB), even in patients with a low GCS. This practice was not associated with an increased mortality. Further prospective investigation is warranted.Trial registrationIRB approval number: HM20006627. Retrospective trial not registered.

RationaleParents are one of several key gatekeepers to mental health (MH) services for adolescents with MH problems. Parental MH stigma is a significant barrier to treatment, yet little is known about how stigma may bias parental recognition of mental illness in youth.ObjectiveThis study examines how stigma influences a critical and early stage of the help-seeking process-the recognition of MH problems in preadolescents by their parents.MethodParents from a school-based anti-stigma intervention study were analyzed. Logistic regressions examined the association of stigma with parental recognition of MH problems in their preadolescent child (10-12 years old) and that of two preadolescent vignette characters described as having bipolar disorder and social anxiety disorder.ResultsThe more parents desired their preadolescent child to avoid interaction with individuals with a mental illness-that is, to be more socially distant-the less likely these parents believed their child had a MH problem, controlling for parent-reported MH symptoms and other covariates. This pattern was prominent among parents who reported high symptoms in their child. Social distance had no bearing on whether parents recognized the vignette characters as having a problem. Avoidance of individuals with a mental illness and knowledge/positive MH attitudes were not associated with problem recognition.ConclusionStigmatizing attitudes of parents may be detrimental when trying to understand the psychopathology of their own preadolescent children but not preadolescents outside their family. Stigma may present itself as a barrier to problem recognition because it may impose a significant personal cost on the family, thereby affecting the help-seeking process earlier than considered by previous work.

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

ObjectiveThe primary endpoints of this study were long-term weight loss, morbidity, and changes in comorbidities and quality of life.BackgroundBariatric surgery is an effective option for the treatment of severe obesity and its related comorbidities. However, few studies have reported on the long-term outcome (>5 yrs) of bariatric surgery.MethodsBetween 2002 and 2007, 250 patients with a body mass index (BMI) of 35 to 60 kg/m were randomly assigned to undergo laparoscopic gastric bypass or laparoscopic gastric banding. After exclusions, 111 patients underwent gastric bypass and 86 patients underwent gastric banding. Factors predictive of improved weight loss were analyzed using multiple logistic regressions.ResultsAt baseline, the mean age was 43 ± 10 years and the mean BMI was 46.5 ± 5.6 kg/m. At 10-year follow-up, the mean total body weight loss for the entire cohort was -37.5 ± 19.4 kg, -42.4 ± 19.6 kg for gastric bypass versus -27.4 ± 14.5 kg for gastric banding. Late reoperation was significantly higher after gastric banding compared with the gastric bypass group (31.4% vs. 8.1%, respectively, P < 0.01). For the entire cohort, improvement or remission of diabetes occurred in 68%; 61% for hypertension; and 57% for dyslipidemia. The long-term mortality for the entire cohort was 1.0% at a mean follow-up of 9.5 ± 0.4 years. Factors predictive of improved weight loss included the type of operation (ie, gastric bypass), female sex, and the absence of diabetes at baseline. At long-term follow-up, quality of life continues to be improved from baseline for both the groups.ConclusionsBariatric surgery is an effective treatment for severe obesity with durable 10-year weight loss and improvement in comorbidities and quality of life. Compared with gastric banding, gastric bypass was associated with better long-term weight loss, lower rate of late reoperation, and improved remission of comorbidities.

BackgroundThis study quantifies the dynamics of maternal mood focusing on unpredictability, and to assess if greater unpredictability of prenatal maternal mood predicts child temperament and internalizing symptoms through early adolescence.MethodsThe association between prenatal mood predictability and child internalizing symptoms were assessed in two longitudinal cohorts (N's = 227 and 180). Maternal mood was assessed repeatedly during pregnancy as early as 15 weeks' gestation. Predictability of maternal mood was calculated by applying Shannon's entropy to the distribution of responses on mood questionnaires. Maternal reports of child negative affectivity (a predictor of later internalizing) were collected at 6, 12, 24 months and 7 years of age. Child self-reports of anxiety symptoms were collected at 10 years and reports of depression symptoms at 13 years.ResultsFetal exposure to more elevated maternal mood entropy predicted higher levels of child negative affectivity at 12 months (r = .36; p < 01), 24 months (r = .31; p < 01) and 7 years (r = .32; p < 01) of age. In addition, children exposed to higher prenatal maternal mood entropy, reported higher levels of anxiety symptoms at 10 years (r = .24; p < 01) and elevated depressive symptoms at 13 years (r = .29; p < .01). These associations persisted after adjusting for maternal pre and postnatal mood valence (e.g. depression levels) and for other relevant demographic characteristics.ConclusionsOur findings provide strong support for the notion that patterns of maternal mood influence the developing brain. More specifically, they suggest that prenatal maternal mood predictability may be a critical predictor of developmental mental health trajectories and should be considered when assessing early life influences on lifespan mental health.

Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies.Methods: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression.Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58-0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65-1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001).Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype.Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. ©2017 AACR.

People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD) with age. Typically, by age 40 years, most people with DS have sufficient neuropathology for an AD diagnosis. Interestingly, atherosclerosis and hypertension are atypical in DS with age, suggesting the lack of these vascular risk factors may be associated with reduced cerebrovascular pathology. However, because the extra copy of APP leads to increased beta-amyloid peptide (Aβ) accumulation in DS, we hypothesized that there would be more extensive and widespread cerebral amyloid angiopathy (CAA) with age in DS relative to sporadic AD. To test this hypothesis CAA, atherosclerosis and arteriolosclerosis were used as measures of cerebrovascular pathology and compared in post mortem tissue from individuals with DS (n = 32), sporadic AD (n = 80) and controls (n = 37). CAA was observed with significantly higher frequencies in brains of individuals with DS compared to sporadic AD and controls. Atherosclerosis and arteriolosclerosis were rare in the cases with DS. CAA in DS may be a target for future interventional clinical trials.

BackgroundThe effectiveness of thoracic epidural analgesia (EA) vs conventional IV analgesia (IA) after minimally invasive surgery is still unproven. We designed a randomized controlled trial comparing EA with IA after minimally invasive colorectal surgery.Study designA total of 87 patients who underwent minimally invasive colorectal procedures at a single institution between 2011 and 2014 were enrolled. Eight patients were excluded and 38 were randomized to EA and 41 to IA. Pain was assessed with the Visual Analogue Scale and quality of life with the Overall Benefit of Analgesia Score daily until discharge.ResultsMean age was 57 ± 14 years, 43% of patients were female, and mean BMI was 28.6 ± 6 kg/m2. The 2 groups were similar in demographic characteristics and distribution of diagnoses and procedures. Epidural analgesia had a higher incidence of hypotensive systolic blood pressure ( 0.05). Epidural and IA had equivalent mean lengths of stay (4 ± 3 days vs 4 ± 3 days), daily Visual Analogue Scale scores (2.4 ± 2.0 vs 3.0 ± 2.0), and Overall Benefit of Analgesia Scores (3.2 ± 2.0 vs 3.2 ± 2.0), and similar time to start oral diet (2.8 ± 2 days vs 2.2 ± 1 days). Epidural analgesia patients used a higher total dose of narcotics (147.5 ± 192.0 mg vs 98.1 ± 112.0 mg; p > 0.05). Epidural and IV analgesia had equivalent total hospital charges ($144,991 ± $67,636 vs $141,339 ± $75,579; p > 0.05).ConclusionsThis study indicates that EA has no added clinical benefit in patients undergoing minimally invasive colorectal surgery. A trend toward higher total narcotics use and complications with EA was demonstrated.

BackgroundThere is no published data regarding the relationship between hospital volume and outcomes in patients undergoing laparoscopic diaphragmatic hernia repair. We hypothesize that hospitals performing high case volume have improved outcomes compared to low-volume hospitals.Materials and methodsWe reviewed the National Inpatient Sample (NIS) database between 2008 and 2012 for adults with the diagnosis of diaphragmatic hernia who underwent elective laparoscopic repair of diaphragmatic Hernia and/or Nissen fundoplication. Pediatric, emergent, and open cases were excluded. Main outcome measures included logistic regression analysis of factors predictive of in-hospital mortality and outcomes according to annual hospital case volume.ResultsA total of 31,228 laparoscopic diaphragmatic hernia operations were analyzed. The overall in-hospital mortality was 0.14%. Risk factors for higher in-hospital mortality included renal failure (AOR: 6.26; 95% CI: 2.48-15.78; p 60 years (AOR: 5.06; 95% CI: 2.38-10.76; p

OBJECTIVE:The aim of this study was to determine the psychometric properties of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question alcohol screen within 16 Pediatric Emergency Care Applied Research Network pediatric emergency departments. This article describes the study methodology, sample characteristics, and baseline outcomes of the NIAAA 2-question screen. METHODS:Participants included 12- to 17-year-olds treated in one of the participating pediatric emergency departments across the United States. After enrollment, a criterion assessment battery including the NIAAA 2-question screen and other measures of alcohol, drug use, and risk behavior was self-administered by participants on a tablet computer. Two subsamples were derived from the sample. The first subsample was readministered the NIAAA 2-question screen 1 week after their initial visit to assess test-retest reliability. The second subsample is being reassessed at 12 and 24 months to examine predictive validity of the NIAAA 2-question screen. RESULTS:There were 4834 participants enrolled into the study who completed baseline assessments. Participants were equally distributed across sex and age. Forty-six percent of the participants identified as white, and 26% identified as black. Approximately one quarter identified as Hispanic. Using the NIAAA 2-question screen algorithm, approximately 8% were classified as low risk, 12% were classified as moderate risk, and 4% were classified as highest risk. Alcohol use was less likely to be reported by black participants, non-Hispanic participants, and those younger than 16 years. DISCUSSION:This study successfully recruited a large, demographically diverse sample to establish rates of the NIAAA screen risk categories across age, sex, ethnicity, and race within pediatric emergency departments.

BackgroundThe management algorithm for appendiceal adenocarcinoma is not well defined. This study sought to determine whether tumor size or depth of invasion better correlates with the presence of lymph node metastases in appendiceal adenocarcinoma, and to compare these rates with colon adenocarcinoma.Study designA retrospective review of the National Cancer Database was performed to identify patients with appendiceal or colonic adenocarcinoma from 2004 to 2013 who underwent surgical resection. Cases were categorized by tumor size and by T stage. Rates of lymph node metastases were examined as a function of size and T stage.ResultsA total of 3,402 appendiceal and 314,864 colonic cases were identified. For appendiceal adenocarcinoma, larger tumor size was associated with higher T stage: Pearson correlation of 0.41 (95% CI 0.408 to 0.414; p < 0.001). Lymph node metastases were present in 19.1%, 27.8%, 39.6%, 39.4%, 42.4% and 39.1% for tumor sizes 1 to 2 cm, >2 to 3 cm, >3 to 4 cm, >4 to 5 cm, and >5 cm, respectively. Lymph node metastases were present in 0%, 11.2%, 12.3%, 35.5%, and 40.0% for in situ, T1, T2, T3, and T4 tumors, respectively. There was no difference in the rates of lymph node metastases between appendiceal and colonic adenocarcinoma for tumor sizes 3 cm and for T2, T3, and T4 tumors (p < 0.01).ConclusionsIn appendiceal adenocarcinoma, the rate of lymph node metastases is substantial, even for small tumors. Tumor size should play no role in the decision of whether to perform a hemicolectomy. Appendectomy alone does not produce an adequate lymph node sample. Right hemicolectomy should be performed for all appendiceal adenocarcinomas.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

ObjectiveSchool-based interventions for preadolescents provide the opportunity, in a ubiquitous institutional setting, to attack stigmatizing attitudes before they are firmly entrenched, and thus they may reduce mental illness stigma in the overall population. This study evaluated the effectiveness of classroom-based interventions in reducing stigma and increasing understanding of mental illness and positive attitudes toward treatment seeking among sixth-grade students.MethodsIn an ethnically and racially diverse sample (N=721), 40% of participants were Latino, 26% were white, and 24% were African American; the mean age was 11.5. In a fully crossed design, classrooms from a school district in Texas were randomly assigned to receive all three, two, one, or none of the following interventions: a PowerPoint- and discussion-based curriculum, contact with two college students who described their experiences with mental illness, and exposure to antistigma printed materials. Standard and vignette-based quantitative measures of mental health knowledge and attitudes, social distance, and help-seeking attitudes were assessed pre- and postintervention.ResultsPrinted materials had no significant effects on outcomes and were grouped with the control condition for analysis. For eight of 13 outcomes, the curriculum-only group reported significantly more positive outcomes than the control group; the largest between-group differences were for stigma awareness and action, recognition of mental illness in the vignettes, and positive orientation to treatment. The contact-alone group reported significantly more positive outcomes on three vignette-based measures.ConclusionsResults were most promising for a classroom-based curriculum that can be relatively easily disseminated to and delivered by teachers, offering the potential for broad application in the population.

BackgroundMotor peripheral nerve injury is a rare but serious event after colorectal surgery, and a nationwide study of this complication is lacking.ObjectiveThe purpose of this study was to report the incidence, trends, and risk factors of motor peripheral nerve injury during colorectal surgery.DesignThe National Surgical Quality Improvement Program database was surveyed for motor peripheral nerve injury complicating colorectal procedures. Risk factors for this complication were identified using logistic regression analysis.SettingsThe study used a national database.PatientsPatients undergoing colorectal resection between 2005 and 2013 were included.Main outcome measuresThe incidence, trends, and risk factors for motor peripheral nerve injury complicating colorectal procedures were measured.ResultsWe identified 186,936 colorectal cases, of which 50,470 (27%) were performed laparoscopically. Motor peripheral nerve injury occurred in 122 patients (0.065%). Injury rates declined over the study period, from 0.025% in 2006 to

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P

BackgroundIn vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.MethodsWe employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).ResultsThe odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).ConclusionsGenetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

BackgroundThe use of laparoscopy for right hemicolectomy has gained popularity allowing the option of a totally laparoscopic intracorporeal anastomosis (IA) for intestinal reconstruction. This technique may alleviate some of the technical limitations that a surgeon faces with a laparoscopic-assisted extracorporeal anastomosis (EA).MethodsA retrospective chart review of 195 consecutive patients who underwent laparoscopic right hemicolectomy by four colorectal surgeons at three institutions from March 2005 to June 2014 was performed. Multivariate regression analysis was used to compare postoperative and oncologic outcomes.ResultsA total of 195 patients underwent laparoscopic right hemicolectomy over the study period, with 86 (44 %) patients receiving IA and 109 (56 %) patients receiving an EA. The most common indication for surgery in both groups was cancer: 56 (65 %) of IA cases and 57 (52 %) of EA cases. IA had a significantly higher rate of minor complications but no difference in serious complications compared to EA. Conversion to open resection was higher in EA. Using multivariate analysis to compare IA versus EA, there was no significant difference in length of stay, return of bowel function, risk of anastomotic leak, risk of intraabdominal abscess or risk of wound complications. Amongst cancer resections, there was no significant difference in the median number of lymph nodes harvested (18 LNs in IA group vs. 19 LNs in EA group, P > 0.05). There was also no significant difference in overall survival and disease-free survival at 5.7 years between the two groups.ConclusionsIA in laparoscopic right hemicolectomy is associated with similar postoperative and oncologic outcomes compared to EA. IA may possess advantages in terms of conversion and flexibility of specimen extraction, but this is counterbalanced by a higher incidence of minor complications. These findings suggest that IA represents a valid technique in the arsenal of the experienced colorectal surgeon without compromising outcomes.

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P  P≥5.0 ×10 -  7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 -  5; PSKAT-o = 9.23 × 10 -  4) and KRT13 (PAML = 1.67 × 10 -  4; PSKAT-o = 1.07 × 10 -  5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

BackgroundColorectal cancer (CRC) incidence is rising among patients under age 50. As such, we set out to determine the proportion of CRC-related hospital admissions and distribution of colon cancer by stage in different age groups.MethodsThe NIS database for 2002-2012 was used to investigate trends of colorectal cancer resection by age, and the ACS NSQIP database for 2012-2013 was used to investigate contemporary stage at diagnosis for colon cancer in different age groups.ResultsA total of 1,198,421 patients were admitted to a hospital with a diagnosis of CRC and captured by the NIS database. Although the number of hospitalized CRC patients decreased from 2002 to 2012, the observed decrease was predominant in patients older than 65 years (P

Objective(1) To develop an automated algorithm to predict a patient's response (ie, if the patient agrees or declines) before he/she is approached for a clinical trial invitation; (2) to assess the algorithm performance and the predictors on real-world patient recruitment data for a diverse set of clinical trials in a pediatric emergency department; and (3) to identify directions for future studies in predicting patients' participation response.Materials and methodsWe collected 3345 patients' response to trial invitations on 18 clinical trials at one center that were actively enrolling patients between January 1, 2010 and December 31, 2012. In parallel, we retrospectively extracted demographic, socioeconomic, and clinical predictors from multiple sources to represent the patients' profiles. Leveraging machine learning methodology, the automated algorithms predicted participation response for individual patients and identified influential features associated with their decision-making. The performance was validated on the collection of actual patient response, where precision, recall, F-measure, and area under the ROC curve were assessed.ResultsCompared to the random response predictor that simulated the current practice, the machine learning algorithms achieved significantly better performance (Precision/Recall/F-measure/area under the ROC curve: 70.82%/92.02%/80.04%/72.78% on 10-fold cross validation and 71.52%/92.68%/80.74%/75.74% on the test set). By analyzing the significant features output by the algorithms, the study confirmed several literature findings and identified challenges that could be mitigated to optimize recruitment.ConclusionBy exploiting predictive variables from multiple sources, we demonstrated that machine learning algorithms have great potential in improving the effectiveness of the recruitment process by automatically predicting patients' participation response to trial invitations.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.