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Diagnostic sample collection, including venipuncture, is critical to diagnosing and treating cattle. Clinical skills models permit learners to practice a skill and improve their competency before performing the skill on a live animal; however, relatively few bovine models exist. This study aimed to develop and validate a bovine coccygeal venipuncture model and rubric for teaching and assessing veterinary students using a validation framework consisting of content evidence, internal structure evidence, and relationship with other variables evidence. Veterinary students ( n = 38) and experienced veterinarians ( n = 12) performed venipuncture on the model while being video recorded. Recordings were scored blindly using a six-item rubric and a global rating score. Time to perform the task and total number of needle sticks were recorded. Veterinarians reported that the model was suitably realistic for students to learn to perform the task ( content evidence ). Rubric scores had acceptable reliability ( a = .783, internal structure evidence ). Veterinarians received higher rubric scores and used fewer needle sticks to complete the task ( p = .033 and .047, relationship with other variables evidence-level of training ). Students' survey responses were very positive. The evidence collected in this study supported validation of the model and rubric. The use of validated models and rubrics allows educators to teach and assess skills reliably, and the model allowed students to practice the skill repetitively, reducing the use of live animals. Additional studies would be necessary to evaluate the model for use in teaching veterinary technicians, extension agents, and livestock producers to perform this task.

Objective. Artificial intelligence (AI) based treatment planning tools are being implemented in clinic. However, human interactions with such AI tools are rarely analyzed. This study aims to comprehend human planner's interaction with the AI planning tool and incorporate the analysis to improve the existing AI tool. Approach. An in-house AI tool for whole breast radiation therapy planning was deployed in our institution since 2019, among which 522 patients were included in this study. The AI tool automatically generates fluence maps of the tangential beams to create an AI plan . Human planner makes fluence edits deemed necessary and after attending physician approval for treatment, it is recorded as final plan . Manual modification value maps were collected, which is the difference between the AI-plan and the final plan . Subsequently, a human-AI interaction (HAI) model using full scale connected U-Net was trained to learn such interactions and perform plan enhancements. The trained HAI model automatically modifies the AI plan to generate AI-modified plans ( AI-m plan ), simulating human editing. Its performance was evaluated against original AI-plan and final plan. Main results. AI-m plan showed statistically significant improvement in hotspot control over the AI plan , with an average of 25.2cc volume reduction in breast V105% ( p = 0.011) and 0.805% decrease in Dmax ( p < .001). It also maintained the same planning target volume (PTV) coverage as the final plan , demonstrating the model has captured the clinic focus of improving PTV hot spots without degrading coverage. Significance. The proposed HAI model has demonstrated capability of further enhancing the AI plan via modeling human-AI tool interactions. This study shows analysis of human interaction with the AI planning tool is a significant step to improve the AI tool., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Objectives: The primary objective of this multisite study, High-Alert Medication Stratification Tool-Revised (HAMST-R) phase II, was to assess the content validity of HAMST-R. Secondary outcomes included interrater reliability and ease of use., Methods: HAMST-R was designed as an objective tool to evaluate high-alert medications (HAMs) at a single site during HAMST-R Phase I. Medication safety experts from 7 health systems across the United States volunteered to participate in this phase II study. Participants completed a demographic survey, oversaw evaluation of 47 HAMs and 35 non-HAMs using HAMST-R, and submitted scores for each medication evaluated. In addition, participants rated each question of HAMST-R on its relevance to assess a medication's safety risk, measured as scale-content validity index. Positive and negative predictive values were evaluated in a post hoc analysis. Interrater reliability was evaluated using the Kendall coefficient of concordance (K), and ease of use was assessed using a mixed-methods approach., Results: Scale-content validity index was 0.80, indicating that the tool was valid. Positive predictive value was 90.5% (95% confidence interval, 87.2%-93.0%), and negative predictive value was 98.2% (95% confidence interval, 95.4%-99.3%). A score of 4 or more differentiated between HAMs and non-HAMs, confirming phase I findings. K was 0.56, indicating moderate agreement. Participants confirmed that the tool was easy to use and plan to incorporate the tool into HAM policies and procedures, formulary review, and safety strategy implementation., Conclusions: HAMST-R is a valid, objective, and easy to use method that institutions may implement to evaluate a medication's potential safety risk., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Patients undergoing outpatient radiotherapy (RT) or chemoradiation (CRT) frequently require acute care (emergency department evaluation or hospitalization). Machine learning (ML) may guide interventions to reduce this risk. There are limited prospective studies investigating the clinical impact of ML in health care. The objective of this study was to determine whether ML can identify high-risk patients and direct mandatory twice-weekly clinical evaluation to reduce acute care visits during treatment., Patients and Methods: During this single-institution randomized quality improvement study (ClinicalTrials.gov identifier: NCT04277650), 963 outpatient adult courses of RT and CRT started from January 7 to June 30, 2019, were evaluated by an ML algorithm. Among these, 311 courses identified by ML as high risk (> 10% risk of acute care during treatment) were randomized to standard once-weekly clinical evaluation (n = 157) or mandatory twice-weekly evaluation (n = 154). Both arms allowed additional evaluations on the basis of clinician discretion. The primary end point was the rate of acute care visits during RT. Model performance was evaluated using receiver operating characteristic area under the curve (AUC) and decile calibration plots., Results: Twice-weekly evaluation reduced rates of acute care during treatment from 22.3% to 12.3% (difference, -10.0%; 95% CI, -18.3 to -1.6; relative risk, 0.556; 95% CI, 0.332 to 0.924; P = .02). Low-risk patients had a 2.7% acute care rate. Model discrimination was good in high- and low-risk patients undergoing standard once-weekly evaluation (AUC, 0.851)., Conclusion: In this prospective randomized study, ML accurately triaged patients undergoing RT and CRT, directing clinical management with reduced acute care rates versus standard of care. This prospective study demonstrates the potential benefit of ML in health care and offers opportunities to enhance care quality and reduce health care costs.

Purpose: This review aims to explore intravenous opioid pain protocols and their dose-time intervals in managing acute postoperative pain in adults in the postanesthesia care unit (PACU)., Design: A scoping review using a systematic search strategy., Methods: Sixteen articles were identified from MEDLINE, CINAHL, PubMed, Embase, and Cochrane specific to the aims., Findings: The literature demonstrated several variations on dose-time intervals used for opioid pain protocol administration globally. Furthermore, opioid analgesic pain protocols in the PACU appear to be effective in postoperative pain management. However, the literature did not identify optimal time intervals related to dose administration within these protocols., Conclusions: Literature gaps were identified regarding the significance of dose-time intervals when using opioid analgesic pain protocols in the PACU., (Copyright © 2019 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Objective: Evaluate trends in place of death for patients with head and neck cancers (HNC) in the U.S. from 1999 to 2017 based on the CDC WONDER (Wide-ranging Online Data for Epidemiologic Research) database., Materials/methods: Using patient-level data from 2015 and aggregate data from 1999 to 2017, multivariable logistic regression analyses (MLR) were performed to evaluate for disparities in place of death., Results: We obtained aggregate data for 101,963 people who died of HNC between 1999 and 2017 (25.9% oral cavity, 24.6% oropharynx/pharynx, 0.4% nasopharynx, and 49.1% larynx/hypopharynx). Most were Caucasian (92.7%) and male (87.0%). Deaths at home or hospice increased over the study period (R 2  = 0.96, p < 0.05) from 29.2% in 1999 to 61.2% in 2017. On MLR of patient-level data from 2015, those who were single (ref), ages 85+ (OR 0.78; 95% CI: 0.68, 0.90), African American (OR 0.73; 95% CI: 0.65, 0.82), or Asian/Pacific Islanders (OR 0.66; 95% CI: 0.54, 0.81) were less likely to die at home or hospice. On MLR of the aggregate data (1999-2017), those who were female (OR 0.87; 95% CI: 0.83, 0.91) or ages 75-84 (OR 0.79; 95% CI: 0.76, 0.82) were also less likely to die at home or hospice. In both analyses, those who died from larynx/hypopharynx cancers were less likely to die at home or hospice., Conclusions: HNC-related deaths at home or hospice increased between 1999 and 2017. Those who were single, female, African American, Asian/Pacific Islander, older (ages 75+), or those with larynx/hypopharynx cancers were less likely to die at home or hospice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Lung cancer screening (LCS) is currently advocated in a subset of current or former smokers with a thirty pack-year smoking history or higher. Studies report that few patients meeting the criteria for screening are undergoing LCS. We conducted a survey to assess if barriers to LCS (race, ethnicity, and socioeconomic status) affect the perceptions about LCS that could influence screening uptake. We did not detect different perceptions based on race, ethnicity, or socioeconomic status; however, our survey found that fewer barriers and more benefits to LCS may be perceived in patients who undergo other types of health screening and more benefits for those with internet capable devices.

OBJECTIVE. The purpose of this study was to investigate whether, compared with traditional criteria, the modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapeutics (iRECIST) improves prediction of local tumor control and survival in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS. Fifty-one HCC lesions (mean size, 3.1 cm) treated with SBRT in 41 patients (mean age, 67 years) were retrospectively included. Each patient underwent CT or MRI before SBRT and at least once after SBRT. Best overall response was categorized using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), iRECIST, World Health Organization (WHO) criteria, modified Response Evaluation Criteria in Solid Tumors (mRECIST), and European Association for the Study of the Liver (EASL) criteria. Lesions were then classified as local tumor control (i.e., stable disease, partial response, or complete response) or local treatment failure (i.e., progressive disease) by each tumor response criteria. Proportions of local tumor control were compared using the McNemar exact test. The 1-year overall survival was estimated using the Kaplan-Meier method. RESULTS. The median follow-up after SBRT was 21.0 months. The local tumor control rate was 94.1% (48/51) by iRECIST, 88.2% (45/51) by RECIST 1.1, 72.5% (37/51) by WHO criteria, 80.4% (41/51) by mRECIST, and 72.5% (37/51) by EASL criteria. The local tumor control rate was significantly higher according to iRECIST compared with WHO ( p = 0.0010) and EASL ( p = 0.0225) criteria. The 1-year survival rate for patients with local tumor control according to iRECIST (86.4%) was higher (although not statistically significant) compared with the 1-year survival rate for patients with local tumor control according to the other response criteria. CONCLUSION. iRECIST may provide more robust interpretation of HCC response after SBRT, yielding improved prediction of local tumor control and 1-year survival rates compared with traditional criteria.

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRAS Q61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRAS G12 -driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Clostridium sordellii is a spore-forming anaerobic Gram-positive rod that has rarely been reported to cause disease in humans. Resultant mortality from infection is estimated at nearly 70% and is most often correlated with gynaecological procedures, intravenous drug abuse or trauma. C. sordellii infection often presents similarly to toxic shock syndrome (TSS); notable features of infection include refractory hypotension, haemoconcentration and marked leucocytosis. Although clinically similar to TSS, a notable difference is C. sordellii infections rarely involve fever. The organism's major toxins include haemorrhagic (TcsH) and lethal factor (TcsL), which function to disrupt cytoskeletal integrity. Current literature suggests treating C. sordelli infection with a broad-spectrum penicillin, metronidazole and clindamycin. We present a case of C. sordellii bacteraemia and septic shock in an immunocompromised patient who was recently diagnosed with pleomorphic gluteal sarcoma. Despite presenting in critical condition, the patient improved after aggressive hemodynamic resuscitation, source control and intravenous antibiotic therapy., (2016 BMJ Publishing Group Ltd.)

Purpose: The purpose of this study was to compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia who underwent a myeloablative allogeneic stem cell transplant with and without total body irradiation (TBI)., Methods and Materials: Adult patients with acute myelogenous leukemia undergoing myeloablative allogeneic stem cell transplant at Duke University Medical Center between 1995 and 2012 were included. The primary endpoint was LFS. Secondary outcomes included overall survival (OS), nonrelapse mortality, and the risk of pulmonary toxicity. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed., Results: A total of 206 patients were evaluated: 90 received TBI-based conditioning regimens and 116 received chemotherapy alone. Median follow-up was 36 months. For all patients, 2-year LFS and OS were 36% (95% confidence interval [CI], 29-43) and 39% (95% CI, 32-46), respectively. After adjusting for known prognostic factors using a multivariate analysis, TBI was associated with improved LFS (hazard ratio: 0.63; 95% CI: 0.44-0.91) and OS (hazard ratio: 0.63; 95% CI, 0.43-0.91). There was no difference in nonrelapse mortality between cohorts, but pulmonary toxicity was significantly more common with TBI (2-year incidence 42% vs 12%, P < .001). High-grade pulmonary toxicity predominated with both conditioning strategies (70% and 93% of cases were grade 3-5 with TBI and chemotherapy alone, respectively)., Conclusions: TBI-based regimens were associated with superior LFS and OS but at the cost of increased pulmonary toxicity.

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region., (© The Author 2015. Published by Oxford University Press.)

The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status.

Background: Salvage surgical resection for non-small cell lung cancer (NSCLC) patients initially treated with definitive chemotherapy and radiotherapy can be performed safely, but the long-term benefits are not well characterized., Methods: Perioperative complications and long-term survival of all patients with NSCLC who received curative-intent definitive radiotherapy, with or without chemotherapy, followed by lobectomy from 1995 to 2012 were evaluated., Results: During the study period, 31 patients met the inclusion criteria. Clinical stage distribution was stage I in 2 (6%), stage II in 5 (16%), stage IIIA in 15 (48%), stage IIIB in 5 (16%), stage IV in 3 (10%), and unknown in 1 (3%). The reasons surgical resection was initially not considered were: patients deemed medically inoperable (5 [16%]); extent of disease was considered unresectable (21 [68%]); small cell lung cancer misdiagnosis (1 [3%]), and unknown (4 [13%]). Definitive therapy was irradiation alone in 2 (6%), concurrent chemoradiotherapy in 28 (90%), and sequential chemoradiotherapy in 1 (3%). The median radiation dose was 60 Gy. Patients were subsequently referred for resection because of obvious local relapse, medical tolerance of surgical intervention, or posttherapy imaging suggesting residual disease. The median time from radiation to lobectomy was 17.7 weeks. There were no perioperative deaths, and morbidity occurred in 15 patients (48%). None of the 3 patients with residual pathologic nodal disease survived longer than 37 months, but the 5-year survival of pN0 patients was 36%. Patients who underwent lobectomy for obvious relapse (n = 3) also did poorly, with a median overall survival of 9 months., Conclusions: Lobectomy after definitive radiotherapy can be done safely and is associated with reasonable long-term survival, particularly when patients do not have residual nodal disease., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Several studies documented that lower scores on the Morningness-Eveningness Questionnaire (MEQ) are associated with a higher global seasonality of mood (GSS). As for the Modern Man artificial lighting predominantly extends evening activity and exposure to light, and as evening bright light phase is known to delay circadian rhythms, this chronic exposure could potentially lead to both lower Morningness as well as higher GSS. The aim of the study was to investigate if the MEQ-GSS relationship holds in the Old Order Amish of Lancaster County, PA, a population that does not use network electrical light., Methods: 489 Old Order Amish adults (47.6% women), with average (SD) age of 49.7 (14.2) years, completed both the Seasonal Pattern Assessment Questionnaire (SPAQ) for the assessment of GSS, and MEQ. Associations between GSS scores and MEQ scores were analyzed using linear models, accounting for age, gender and relatedness by including the relationship matrix in the model as a random effect., Results: GSS was inversely associated with MEQ scores (p=0.006, adjusted)., Limitations: include a potential recall bias associated with self-report questionnaires and no actual light exposure measurements., Conclusion: We confirmed the previously reported inverse association between MEQ scores and lower seasonality of mood, for the first time in a population that does not use home network electrical lighting. This result suggests that the association is not a byproduct of exposure to network electric light, and calls for additional research to investigate mechanisms by which Morningness is negatively associated with seasonality., (Published by Elsevier B.V.)

Wnt-1 inducible signalling pathway protein 1 (WISP-1/CCN4) is an extracellular matrix protein that belongs to the Cyr61 (cysteine-rich protein 61), CTGF (connective tissue growth factor) and NOV (CCN) family and plays a role in multiple cellular processes. No specific WISP-1 receptors have been identified but emerging evidence suggests WISP-1 mediates its downstream effects by binding to integrins. Here we describe a functional analysis of integrin receptor usage by WISP-1. Truncated WISP-1 proteins were produced using a baculovirus expression system. Full length WISP-1 and truncated proteins were evaluated for their ability to induce adhesion in A549 epithelial cells and β-catenin activation and CXCL3 secretion in fibroblasts (NRK49-F cells). Subsequent inhibition of these responses by neutralising integrin antibodies was evaluated. A549 cells demonstrated adhesion to full-length WISP-1 whilst truncated proteins containing VWC, TSP or CT domains also induced adhesion, with highest activity observed with proteins containing the C-terminal TSP and CT domains. Likewise the ability to induce β-catenin activation and CXCL3 secretion was retained in truncations containing C-terminal domains. Pre-treatment of A549s with either integrin αVβ5, αVβ3 or β1 neutralising antibodies partially inhibited full length WISP-1 induced adhesion whilst combining integrin αVβ5 and β1 antibodies increased the potency of this effect. Incubation of NRK49-F cells with integrin neutralising antibodies failed to effect β-catenin translocation or CXCL3 secretion. Analysis of natural WISP-1 derived from human lung tissue showed the native protein is a high order oligomer. Our data suggest that WISP-1 mediated adhesion of A549 cells is an integrin-driven event regulated by the C-terminal domains of the protein. Activation of β-catenin signalling and CXCL3 secretion also resides within the C-terminal domains of WISP-1 but are not regulated by integrins. The oligomeric nature of native WISP-1 may drive a high avidity interaction with these receptors in vivo.

Introduction: Tobacco use is a complex behavior. The Old Order Amish community offers unique advantages for the study of tobacco use because of homogenous ancestral background, sociocultural similarity, sex-specific social norms regarding tobacco use, and large family size. Tobacco use in the Old Order Amish community is almost exclusively confined to males., Methods: We examined characteristics of tobacco use and familial aggregation among 1,216 Amish males from cross-sectional prospectively collected data. Outcomes examined included ever using tobacco regularly, current use, quantity of use, duration of use, and frequency of use., Results: Sixteen percent of Amish men were current tobacco users, with the majority reporting cigar use only. Higher rates of tobacco use were found among sons of fathers who smoked compared with sons of fathers who did not smoke (46% vs. 22%, p < .001) as well as among brothers of index cases who smoked compared with brothers of index cases who did not smoke (61% vs. 29%, p < .001). After controlling for shared household effects and age, heritability accounted for 66% of the variance in ever smoking regularly (p = .045)., Conclusions: The familial patterns of tobacco use observed among Amish men highlight the important role of family in propagating tobacco use and support the usefulness of this population for future genetic studies of nicotine addiction., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies have shown associations between single nucleotide polymorphisms (SNPs) in gamma aminobutyric acid receptor alpha 2 (GABRA2) and adolescent conduct disorder (CD) and alcohol dependence in adulthood, but not adolescent alcohol dependence. The present study was intended as a replication and extension of this work, focusing on adolescent CD, adolescent alcohol abuse and dependence (AAD), and adult AAD. Family based association tests were run using Hispanics and non-Hispanic European American subjects from two independent longitudinal samples. Although the analysis provided nominal support for an association with rs9291283 and AAD in adulthood and CD in adolescence, the current study failed to replicate previous associations between two well replicated GABRA2 SNPs and CD and alcohol dependence. Overall, these results emphasize the utility of including an independent replication sample in the study design, so that the results from an individual sample can be weighted in the context of its reproducibility.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype., (© 2013 WILEY PERIODICALS, INC.)

Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy.

Background/objective: We examined seasonality and winter seasonal affective disorder (SAD) in the Old Order Amish of Lancaster County, Pennsylvania, a unique population that prohibits use of network electric light in their homes., Methods: We estimated SAD using the seasonal pattern assessment questionnaire (SPAQ) in 1306 Amish adults and compared the frequencies of SAD and total SAD (i.e., presence of either SAD or subsyndromal-SAD) between men and women, young and old, and awareness of (ever vs. never heard about) SAD. Heritability of global seasonality score (GSS) was estimated using the maximum likelihood method, including a household effect to capture shared environmental effects., Results: The mean (±SD) GSS was 4.36 (±3.38). Prevalence was 0.84% (95% CI: 0.36-1.58) for SAD and 2.59% (95% CI: 1.69-3.73) for total SAD. Heritability of GSS was 0.14±0.06 (SE) (p=0.002) after adjusting for age, gender, and household effects., Limitations: Limitations include likely overestimation of the rates of SAD by SPAQ, possible selection bias and recall bias, and limited generalizability of the study., Conclusions: In the Amish, GSS and SAD prevalence were lower than observed in earlier SPAQ-based studies in other predominantly Caucasian populations. Low heritability of SAD suggests dominant environmental effects. The effects of awareness, age and gender on SAD risk were similar as in previous studies. Identifying factors of resilience to SAD in the face of seasonal changes in the Amish could suggest novel preventative and therapeutic approaches to reduce the impact of SAD in the general population., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968., Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking., Data Sources: Primary data., Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy., Data Extraction: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum., Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01)., Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Multiple studies have provided evidence for genetic associations between single nucleotide polymorphisms (SNPs) located on the CHRNA5/A3/B4 gene cluster and various phenotypes related to Nicotine Dependence (Greenbaum et al. 2009). Only a few studies have investigated other substances of abuse. The current study has two aims, (1) to extend previous findings by focusing on associations between the CHRNA5/A3/B4 gene cluster and age of initiation of several different substances, and (2) to investigate heterogeneity in age of initiation across the different substances. All analyses were conducted with a subset of the Add Health study with available genetic data. The first aim was met by modeling onset of tobacco, alcohol, cannabis, inhalants, and other substance use using survival mixture analysis (SMA). Ten SNPs in CHRNA5/A3/B4 were used to predict phenotypic differences in the risk of onset, and differences between users and non-users. The survival models aim at investigating differences in the risk of initiation across the 5-18 age range for each phenotype separately. Significant or marginally significant genetic effects were found for all phenotypes. The genetic effects were mainly related to the risk of initiation and to a lesser extent to discriminating between users and non-users. To address the second goal, the survival analyses were complemented by a latent class analysis that modeled all phenotypes jointly. One of the ten SNPs was found to predict differences between the early and late onset classes. Taken together, our study provides evidence for a general role of the CHRNA5/A3/B4 gene cluster in substance use initiation that is not limited to nicotine and alcohol.

There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.

Background: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies., Methods: Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia., Results: The rs3087454 SNP, located at position -1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia., Conclusions: The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia.