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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.

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.

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).

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.

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.

Background Habitual high-intensity endurance exercise is associated with increased atrial fibrillation (AF) risk and impaired cardiac conduction. It is unknown whether these observations extend to prior strength-type sports exposure. The primary aim of this study was to compare AF prevalence in former National Football League (NFL) athletes to population-based controls. The secondary aim was to characterize other conduction system parameters. Methods and Results This cross-sectional study compared former NFL athletes (n=460, age 56±12 years, black 47%) with population-based controls of similar age and racial composition from the cardiovascular cohort Dallas Heart Study-2 (n=925, age 54±9 years, black 53%). AF was present in 28 individuals (n=23 [5%] in the NFL group; n=5 [0.5%] in the control group). After controlling for other cardiovascular risk factors in multivariable regression analysis, former NFL participation remained associated with a 5.7 (95% CI: 2.1-15.9, P

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.

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.

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

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.

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.

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.

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

Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer's disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17-28% per year. No dementia was detected on neurological examinations. On PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS.

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.

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.

Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.

BackgroundProlonged ileus is one of the most common postoperative complications after colorectal surgery. We sought to investigate the predictors of prolonged ileus following elective colon resections procedures.MethodsThe national participant user files of NSQIP databases were utilized to examine the clinical outcomes of patients undergoing elective colon resection during 2012-2013. Multivariate regression analysis was performed to investigate predictors of prolonged ileus. Prolonged ileus was defined as no return of bowel function in 7 days.ResultsWe sampled a total of 27,560 patients who underwent colon resections; of these, 3497 (12.7%) patients had prolonged ileus. Patients with ileocolonic anastomosis (ICA) had a significantly higher rate of prolonged ileus compared to patients with colorectal anastomosis (CRA) (15 vs. 11.5%, AOR 1.25, P < 0.01). Prolonged ileus was significantly associated with intra-abdominal infections (13 vs. 2.8%, AOR 2.56, P < 0.01) and anastomotic leakage (12 vs. 2.4%, AOR 2.50, P < 0.01). Factors such as preoperative sepsis (AOR 1.63, P < 0.01), disseminated cancer (AOR 1.24, P = 0.01), and chronic obstructive pulmonary disease (AOR 1.27, P = 0.02) were associated with an increased risk of prolonged ileus, whereas oral antibiotic bowel preparation (AOR 0.77, P < 0.01) and laparoscopic surgery (AOR 0.51, P < 0.01) are associated with decreased prolonged ileus risk.ConclusionsProlonged ileus is a common condition following colon resection, with an incidence of 12.7%. Among colon surgeries, colectomy with ICA resulted in the highest rate of postoperative prolonged ileus. Prolonged ileus is positively associated with anastomotic leak and intra-abdominal infections; thus, a high index of suspicion must be had in all patients with prolonged postoperative ileus.

The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

BackgroundThere are limited available data comparing open, laparoscopic, and robotic approaches for rectal cancer surgery.ObjectiveWe sought to investigate outcomes of different surgical approaches to abdominoperineal resection in patients with rectal cancer.DesignThe nationwide inpatient sample database was used to examine the clinical data of patients with rectal cancer who underwent elective abdominoperineal resection between 2009 and 2012 in the United States. Multivariate regression analysis was performed to compare outcomes of different surgical approaches.SettingsA retrospective review according to the national inpatient sample database was designed.PatientsWe included patients with rectal cancer who underwent elective abdominoperineal resection between 2009 and 2012.Main outcome measuresOutcomes of different surgical approaches to abdominoperineal resection were investigated.ResultsWe sampled 18,359 patients with rectal cancer who underwent elective abdominoperineal resections. Of these, 69.5% had open surgery, 25.8% had laparoscopic surgery, and 4.7% had robotic surgery. The rate of robotic procedures increased >4-fold, from 2.1% to 8.1%, from 2009 to 2012. The conversion rate in robotic surgery was significantly lower compared with laparoscopic surgery (5.7% vs 13.4%; p < 0.01). After risk adjustment, patients who underwent laparoscopic and robotic approaches had lower morbidity risks compared with those who underwent the open approach (adjusted OR = 0.77 (95% CI, 0.65-0.92), 0.57 (95% CI, 0.40-0.80); p < 0. 01). There were no significant differences in the morbidity rate of patients who underwent laparoscopic or robotic approaches (adjusted OR = 0.79 (95% CI, 0.55-1.14); p = 0.21). However, patients who underwent the robotic approach had significantly higher total hospital charges compared with those who underwent the laparoscopic approach (mean difference, $24,890; p < 0.01).LimitationsWe could not adjust the results with some important factors, such as the tumor stage and BMI.ConclusionsThe use of robotic and laparoscopic approaches to abdominoperineal resection have increased between 2009 and 2012. Both minimally invasive approaches decrease morbidity rates of patients undergoing abdominoperineal resection. The robotic approach has a significantly lower conversion rate compared with the laparoscopic approach. However, it had significantly higher total hospital charges compared with the laparoscopic approach.

Adhesions account for 74 per cent of admissions for small bowel obstruction (SBO). There is a lack of data regarding the usage and outcomes of laparoscopy (LS) for SBO. A retrospective review of urgent admissions for SBO using the Nationwide Inpatient Sample 2001 to 2011 was conducted. Among the estimated 3,948,987 SBO admissions, 36.7 per cent underwent operative management and LS was performed in 26.5 per cent with a 22.5 per cent conversion rate. Admissions increased by 3.1 per cent annually, whereas nonoperative management increased by 3.8 per cent annually. Operative management increased by 1.8 per cent annually, whereas LS increased by 8.9 per cent annually and open surgery decreased by 0.6 per cent annually. LS small bowel resection increased by a mean of 25 per cent annually. LS was associated with a 24.4 per cent in-hospital morbidity with intra-abdominal abscess/enteric fistulas (8.3%) and ileus (8.9%) as the most common complications. In-hospital mortality was 0.9 per cent with length of stay of 13 ± 9 days and a hospital charge of $80,080 ± 6,634. The majority of patients were operated on hospital day (HD) 1 (43.0%). Patients who underwent LS on HD >7 had a higher risk-adjusted mortality compared with earlier HD (odds ratio = 2.63; 95% confidence interval: 2.40-2.89; P < 0.01). There has been an increase in admissions for SBO and an increase in LS over the past 11 years. There seems to be an increase in mortality and morbidity with a later HD operation.

Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte with a reduction in the scaffolding protein caveolin-3 (Cav-3), altered Ca(2+) cycling, increased protein kinase C expression, and hyperactivation of calcineurin/nuclear factor of activated T cell (NFAT) signaling. However, the precise role of Cav-3 in the regulation of local Ca(2+) signaling in pathological cardiac hypertrophy is unclear. We used cardiac-specific Cav-3-overexpressing mice and in vivo and in vitro cardiac hypertrophy models to determine the essential requirement for Cav-3 expression in protection against pharmacologically and pressure overload-induced cardiac hypertrophy. Transverse aortic constriction and angiotensin-II (Ang-II) infusion in wild type (WT) mice resulted in cardiac hypertrophy characterized by significant reduction in fractional shortening, ejection fraction, and a reduced expression of Cav-3. In addition, association of PKCα and angiotensin-II receptor, type 1, with Cav-3 was disrupted in the hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated increased expression of T-type Ca(2+) current (ICa, T) in hypertrophic ventricular myocytes. In contrast, the Cav-3-overexpressing mice demonstrated protection from transverse aortic constriction or Ang-II-induced pathological hypertrophy with inhibition of ICa, T and intact Cav-3-associated macromolecular signaling complexes. siRNA-mediated knockdown of Cav-3 in the neonatal cardiomyocytes resulted in enhanced Ang-II stimulation of ICa, T mediated by PKCα, which caused nuclear translocation of NFAT. Overexpression of Cav-3 in neonatal myocytes prevented a PKCα-mediated increase in ICa, T and nuclear translocation of NFAT. In conclusion, we show that stable Cav-3 expression is essential for protecting the signaling mechanisms in pharmacologically and pressure overload-induced cardiac hypertrophy.

BackgroundA small decrease in the serum albumin from the normal level is a common condition in preoperative laboratory tests of colorectal surgery patients; however, there is limited data examining these patients. We sought to identify outcomes of such patients.MethodsThe National Surgical Quality Improvement Program database was used to evaluate all patients who had modest levels of hypoalbuminemia (3 ≤ serum albumin < 3.5 g/dL) before colorectal resection from 2005 to 2012. Multivariate analysis using logistic regression was performed to quantify complications associated with modest hypoalbuminemia.ResultsA total of 108,898 patients undergoing colorectal resection were identified, of which 16,962 (15.6%) had modest levels of preoperative hypoalbuminemia. Postsurgical complications significantly associated (P < .05) with modest hypoalbuminemia were as follows: hospitalization more than 30 days (adjusted odds ratio [AOR], 1.77), deep vein thrombosis (AOR, 1.64), unplanned intubation (AOR, 1.42), ventilator dependency for more than 48 hours (AOR, 1.30), and wound disruption (AOR, 1.22).ConclusionsModest hypoalbuminemia is a common preoperative condition in patients undergoing colorectal resection. Our analysis demonstrates that modest hypoalbuminemia has associations with increased postoperative complications, especially pulmonary complications.

PurposeAlthough diseases of the lower gastrointestinal tract are common in patients with Parkinson's disease, there is a paucity of data regarding postoperative outcomes after colorectal surgery.MethodsThe Nationwide Inpatient Sample database (2007-2011) was utilized to analyze outcomes in patients with Parkinson's disease (PD) undergoing colorectal surgery. Main outcomes were risk-adjusted inpatient morbidity, mortality, hospital charge, and length of hospital stay.ResultsA total of 6490 patients were identified. Utilization of laparoscopic surgery in Parkinson's patients has progressively increased in frequency over the latest 5 years analyzed. The most common diagnoses were colorectal malignancy (39 %) and intestinal obstruction (20 %). Right hemicolectomy (37 %) and sigmoidectomy (30 %) were the most common operations. Laparoscopy was used in 18 % of Parkinson's patients and most commonly in the elective setting. 54.3 % of Parkinson's patients had emergency surgery compared to 38.6 % in non-Parkinson's. Overall morbidity and mortality were significantly lower after laparoscopic surgery compared to open (20 vs. 25 % and 2.1 vs. 6.6 %, respectively). Length of stay was significantly shorter (OR -1.86; p

Across 366 California hospitals, we identified hospital-level characteristics predicting increased hospital-associated Clostridium difficile infection (HA-CDI) rates including more licensed beds, teaching and long-term acute care (LTAC) hospitals, and polymerase chain reaction testing. Adjustment for these characteristics impacted rankings in 24% of teaching hospitals, 13% of community hospitals, and 11% of LTAC hospitals.

BackgroundPatients with rectal prolapse often have significant comorbidities that lead surgeons to select a perineal resection for treatment despite a reported higher recurrence rate over abdominal approaches. There is a lack of data to support this practice in the laparoscopic era. The objective of this study was to evaluate if risk-adjusted morbidity of perineal surgery for rectal prolapse is actually lower than laparoscopic surgery.DesignA retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database as performed for patients undergoing surgical treatment of rectal prolapse between 2005 and 2011. Outcomes were analyzed according to procedure-type: laparoscopic rectopexy (LR), laparoscopic resection/rectopexy (LRR), open rectopexy (OR), open resection/rectopexy (ORR), and perineal resection (PR). A multivariate logistic regression was used to compare risk-adjusted morbidity and mortality between each procedure. Main outcome measures were 30-day morbidity and mortality.ResultsAmong 3,254 cases sampled, a laparoscopic approach was used in 22 %, an open abdominal approach in 30 %, and PR in 48 %. Patients undergoing PR were older (76) and had a higher ASA (3) compared to laparoscopic (58, 2) and open abdominal procedures (58, 2). Risk-adjusted mortality could not be assessed due to a low overall incidence of mortality (0.01 %). Overall morbidity was 9.3 %. ORR was associated with a higher risk-adjusted morbidity compared to PR (OR: 1.89 CI (1.19-2.99), p = 0.03). There were no significant differences in risk-adjusted morbidity found between LR and LRR compared to PR (OR 0.44 CI (0.19-1.03), p = 0.18; OR 1.55 CI (0.86-2.77), p = 0.18). Laparoscopic cases averaged 27 min longer than open cases (p < 0.001).ConclusionLaparoscopic rectal prolapse surgery has comparable morbidity and mortality to perineal surgery. A randomized trial is indicated to validate these findings and to assess recurrence rates and functional outcomes.

BackgroundOur primary objective was to demonstrate the utility and feasibility of the intraoperative assessment of colon and rectal perfusion using fluorescence angiography (FA) during left-sided colectomy and anterior resection. Anastomotic leak (AL) after colorectal resection increases morbidity, mortality, and, in cancer cases, recurrence rates. Inadequate perfusion may contribute to AL. The PINPOINT Endoscopic Fluorescence Imaging System allows for intraoperative assessment of anastomotic perfusion.Study designThis is a prospective, multicenter, open-label, clinical trial that assessed the feasibility and utility of FA for intraoperative perfusion assessment during left-sided colectomy and anterior resection at 11 centers in the United States.ResultsA total of 147 patients were enrolled, of whom 139 were eligible for analysis. Diverticulitis (44%), rectal cancer (25%), and colon cancer (21%) were the most prevalent indications for surgery. The mean level of anastomosis was 10 ± 4 cm from the anal verge. Splenic-flexure mobilization was performed in 81% and high ligation of the inferior mesenteric artery in 61.9% of patients. There was a 99% success rate for FA, and FA changed surgical plans in 11 (8%) patients, with the majority of changes occurring at the time of transection of the proximal margin (7%). Overall morbidity rates were 17%. The anastomotic leak rate was 1.4% (n = 2). There were no anastomotic leaks in the 11 patients who had a change in surgical plan based on intraoperative perfusion assessment with FA.ConclusionsPINPOINT is a safe and feasible tool for intraoperative assessment of tissue perfusion during colorectal resection. There were no anastomotic leaks in patients in whom the anastomosis was revised based on inadequate perfusion with FA.

ObjectivesThere is limited data regarding the effects of preoperative dehydration on postoperative renal function. We sought to identify associations between hydration status before operation and postoperative acute renal failure (ARF) in patients undergoing colorectal resection.MethodsThe NSQIP database was used to examine the data of patients undergoing colorectal resection from 2005 to 2011. We used preoperative blood urea nitrogen (BUN)/creatinine ratio >20 as a marker of relative dehydration. Multivariate analysis using logistic regression was performed to quantify the association of BUN/Cr ratio with ARF.ResultsWe sampled 27,860 patients who underwent colorectal resection. Patients with dehydration had higher risk of ARF compared to patients with BUN/Cr

BackgroundStates have established public reporting of hospital-associated (HA) infections-including those of methicillin-resistant Staphylococcus aureus (MRSA)-but do not account for hospital case mix or postdischarge events.ObjectiveIdentify facility-level characteristics associated with HA-MRSA infection admissions and create adjusted hospital rankings.MethodsA retrospective cohort study of 2009-2010 California acute care hospitals. We defined HA-MRSA admissions as involving MRSA pneumonia or septicemia events arising during hospitalization or within 30 days after discharge. We used mandatory hospitalization and US Census data sets to generate hospital population characteristics by summarizing across admissions. Facility-level factors associated with hospitals' proportions of HA-MRSA infection admissions were identified using generalized linear models. Using state methodology, hospitals were categorized into 3 tiers of HA-MRSA infection prevention performance, using raw and adjusted values.ResultsAmong 323 hospitals, a median of 16 HA-MRSA infections (range, 0-102) per 10,000 admissions was found. Hospitals serving a greater proportion of patients who had serious comorbidities, were from low-education zip codes, and were discharged to locations other than home were associated with higher HA-MRSA infection risk. Total concordance between all raw and adjusted hospital rankings was 0.45 (95% confidence interval, 0.40-0.51). Among 53 community hospitals in the poor-performance category, more than 20% moved into the average-performance category after adjustment. Similarly, among 71 hospitals in the superior-performance category, half moved into the average-performance category after adjustment.ConclusionsWhen adjusting for nonmodifiable facility characteristics and case mix, hospital rankings based on HA-MRSA infections substantially changed. Quality indicators for hospitals require adequate adjustment for patient population characteristics for valid interhospital performance comparisons.

BackgroundIn 2006, the Centers for Medicare and Medicaid Services issued a National Coverage Determination (NCD), which mandates that bariatric procedures be performed only at accredited centers. The aim of this study was to analyze outcomes of Medicare beneficiaries who underwent bariatric surgery before (2001 through 2005) vs after (2006 through 2010) implementation of the NCD.Study designThe Nationwide Inpatient Sample database was used to analyze data on patients who underwent bariatric surgery between 2001 and 2010. Main outcomes measures were demographics, length of stay, risk-adjusted inpatient morbidity and mortality, and cost.ResultsThere were 775,040 patients who underwent bariatric surgery, with 16% of the patients Medicare beneficiaries. There was an overall trend for improved in-hospital mortality during the decade (0.35% in 2001 to 0.10% in 2010). Medicare patients who underwent bariatric surgery had higher rates of comorbidities and a higher rate of in-hospital mortality than non-Medicare patients. After the NCD, there was a significant reduction of the in-hospital mortality (0.56% vs 0.23%; p < 0.01) and serious morbidity (9.92% vs 6.98%; p < 0.01) for Medicare patients and a similar reduction of the in-hospital mortality (0.18% vs 0.08%; p < 0.01) and serious morbidity (6.84% vs 5.08%; p < 0.01) for non-Medicare patients. Compared with patients who underwent stapling bariatric procedures at accredited centers, patients at nonaccredited centers had higher risk-adjusted in-hospital mortality (odds ratio = 3.53; 95% CI, 1.01-6.52) and serious morbidity (odds ratio = 1.18; 95% CI, 1.07-1.30). After the NCD, use of bariatric surgery within Medicare beneficiaries increased by 71%.ConclusionsOutcomes of bariatric surgery in Medicare beneficiaries have improved substantially since the 2006 NCD. Facility accreditation appears to be a contributing factor to the observed improvement in outcomes.