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Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p

The effect of alcohol on liver disease in HIV infection has not been well characterized.We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with 2 noninvasive indices, "FIB-4," which includes platelets, liver enzymes, and age; and aspartate aminotransferase/platelet ratio index ("APRI"), which includes platelets and liver enzymes. FIB-41.45 and APRI0.5 defined the absence of liver fibrosis. FIB-43.25 and APRI1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (150 kg, 150 to 600 kg,600 kg).Subjects (n = 308) were 73% men, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load1,000 copies/ml, and 18.7% with a CD4 count200 cells/mm(3) . Forty-five percent had lifetime alcohol consumption600 kg, 32.7% 150 to 600 kg, and 22.3%150 kg; 33% had current heavy alcohol use, and 69% had9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses, controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and the absence of liver fibrosis (FIB-41.45) (adjusted odds ratio [AOR] = 1.12 [95% CI: 0.25 to 2.52] for 150 to 600 kg vs.150 kg; AOR = 1.11 [95% CI: 0.52 to 2.36] for600 kg vs.150 kg; global p = 0.95). Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-43.25). Results were similar using APRI, and among those with and without HCV infection.In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and the absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population.

Summary This paper assesses the associations between intimate partner violence (IPV) and sexually transmitted infections (STIs) and sexual risks among HIV-positive female drinkers in St Petersburg, Russia. Survey and STI data were analysed from 285 women in HERMITAGE, a secondary prevention study of HIV-positive heavy drinkers. Logistic and Poisson regression analyses assessed associations of IPV with STI and risky sex. Most women (78%) experienced IPV and 19% were STI positive; 15% sold sex. IPV was not significantly associated with STI, but was with selling sex (adjusted odds ratio = 3.56, 95% confidence interval = 1.02–12.43). In conclusion, IPV is common and associated with sex trade involvement among Russian HIV-positive female drinkers.

In Russia, up to half of premature deaths are attributed to hazardous drinking. The respective roles of alcohol and drug use in premature death among people with HIV in Russia have not been described. Criminalization and stigmatization of substance use in Russia may also contribute to mortality. We explored whether alcohol, drug use and risk environment factors are associated with short-term mortality in HIV-infected Russians who use substances. Secondary analyses were conducted using prospective data collected at baseline, 6 and 12-months from HIV-infected people who use substances recruited between 2007–2010 from addiction and HIV care settings in a single urban setting of St. Petersburg, Russia. We used Cox proportional hazards models to explore associations between 30-day alcohol hazardous drinking, injection drug use, polysubstance use and environmental risk exposures (i.e. past incarceration, police involvement, selling sex, and HIV stigma) with mortality. Among 700 participants, 59% were male and the mean age was 30 years. There were 40 deaths after a median follow-up of 12 months (crude mortality rate 5.9 per 100 person-years). In adjusted analyses, 30-day NIAAA hazardous drinking was significantly associated with mortality compared to no drinking [adjusted Hazard Ratio (aHR) 2.60, 95% Confidence Interval (CI): 1.24–5.44] but moderate drinking was not (aHR 0.95, 95% CI: 0.35–2.59). No other factors were significantly associated with mortality. The high rates of short-term mortality and the strong association with hazardous drinking suggest a need to integrate evidence-based alcohol interventions into treatment strategies for HIV-infected Russians.

Background: Health behavior and weight management interventions for cancer survivors have the potential to prevent future cancer recurrence and improve long-term health; however, their translation can be limited if the intervention is complex and involves high participant burden. Mobile health (mHealth) offers a delivery modality to integrate interventions into daily life routines. Objective: The objective of this study was to evaluate the effects of a one-group trial with a pre-post evaluation design on engagement (use and acceptability), physiological (weight), behavioral (diet and physical activity), and other secondary outcomes. Methods: The 10-week intervention consisted of mHealth components (self-monitoring of selected diet behaviors via daily text messages, wireless devices to automatically track weight and steps) and 4 motivational interviewing–based technology-assisted phone sessions with a nonprofessionally trained counselor. Participants were overweight breast cancer survivors who had completed treatment and owned a smartphone. Weight was measured objectively; diet and physical activity were measured with brief self-reported questionnaires. Results: Ten women participated; they had a mean age of 59 years (SD 6), 50% belonged to a racial or ethnic minority group, 50% had some college or less, and 40% reported using Medicaid health insurance. Engagement was high: out of 70 days in total, the mean number of days recording steps via the wristband pedometer was 64 (SD 7), recording a weight via the scale was 45 (SD 24), and responding to text messages was 60 (SD 13); 100% of participants completed all 4 calls with the counselor. Most (90%) were very likely to participate again and recommend the program to others. Mean weight in pounds decreased (182.5 to 179.1, mean change −3.38 [SD 7.67]), fruit and vegetable daily servings increased (2.89 to 4.42, mean change 1.53 [SD 2.82]), and self-reported moderate physical activity increased in metabolic equivalent of task (MET) minutes per week (2791 to 3336, mean change 545 [SD 1694]). Conclusions: Findings support the conduct of a fully powered trial to evaluate the efficacy of mHealth as a feasible intervention modality for breast cancer survivors. Future research should employ accelerometer-based physical activity assessment and consider development of an all-in-one app to integrate devices, messaging, and educational content and other mHealth approaches to support behavioral counselors conducting weight management interventions. Trial Registration: ClinicalTrials.gov NCT02387671; https://clinicaltrials.gov/ct2/show/NCT02387671 (Archived by WebCite at http://www.webcitation.org/6hGEuttbZ). [JMIR Cancer 2016;2(1):e4]

Importance Atrial fibrillation (AF) during sepsis is associated with an increased risk of ischemic stroke during hospitalization, but risks and benefits associated with anticoagulation for AF during sepsis are unclear. Objective To determine clinician practice patterns and patient risk of stroke and bleeding associated with use of anticoagulation for AF during sepsis. Design, Setting, and Participants A retrospective cohort study using enhanced administrative claims data from approximately 20% of patients hospitalized in the United States July 1, 2010, to June 30, 2013, examined patients with AF during sepsis who did not have additional indications for therapeutic anticoagulation. Propensity score and instrumental variable analyses were used to evaluate risks of in-hospital stroke and bleeding associated with anticoagulation during sepsis. Exposures Parenteral anticoagulants administered in doses greater than those used for prophylaxis of venous thromboembolism. Main Outcomes and Measures Ischemic stroke and clinically significant bleeding events during hospitalization. Results Of 113 511 patients hospitalized with AF and sepsis, 38 582 were included in our primary analysis (18 976 men and 19 606 women; mean [SD] age, 74.9 [11.7] years). A total of 13 611 patients (35.3%) received parenteral anticoagulants, while 24 971 (64.7%) did not. Hospital utilization rates of parenteral anticoagulants for AF during sepsis varied (median, 33%; 25th-75th percentile, 25%-43%). CHA 2 DS 2 VASc scores (congestive heart failure, hypertension, age ≥75 years [doubled], type 1 or type 2 diabetes, stroke or transient ischemic attack or thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) poorly discriminated the risk of ischemic stroke during sepsis (C statistic, 0.526). Among 27 010 propensity score–matched patients, rates of in-hospital ischemic stroke events did not differ significantly between patients who did (174 of 13 505 [1.3%]) and did not (185 of 13 505 [1.4%]) receive parenteral anticoagulation (relative risk [RR], 0.94; 95% CI, 0.77-1.15). Clinically significant bleeding occurred more often among patients who received parenteral anticoagulation (1163 of 13 505 [8.6%]) than patients who did not receive parenteral anticoagulation (979 of 13 505 [7.2%]; RR, 1.21; 95% CI, 1.10-1.32). Risk of ischemic stroke associated with parenteral anticoagulation did not differ significantly between patients with preexisting (RR, 1.12; 95% CI, 0.86-1.44) or newly diagnosed AF (RR, 0.85; 95% CI 0.57-1.27; P = .31 for interaction). Results were robust to multiple sensitivity analyses, including hospital utilization rates of parenteral anticoagulation for AF as an instrument for anticoagulation exposure (RR for stroke, 1.08; 95% CI, 0.62-1.90; RR for bleeding, 1.23; 95% CI, 0.88-1.72). Conclusions and Relevance Among patients with AF during sepsis, parenteral anticoagulation was not associated with reduced risk of ischemic stroke and was associated with higher bleeding rates.

The current study was designed to determine whether SLP perceptions of communication style (passive or active) affect their intervention planning and decision making for young children who require augmentative and alternative communication (AAC). A second goal was to determine whether SLPs who work with young children who use AAC target goals in intervention that promote and/or maintain an active communication style. An original survey was designed for the study. The SLP participants were asked to provide information about the design of AAC systems and the communicative opportunities made available to young children with AAC needs. Participants were recruited through email and were asked to respond to a Web-based survey. Eighty-nine preschool SLPs practicing in 20 states across the United States responded to the survey. Results indicated that many of the SLPs classified young children with AAC needs they have worked with as passive communicators. Furthermore, the SLPs reported differences in their intervention practices for children with AAC needs whom they considered active and passive communicators. The return rate for participants was small, and it is difficult to generalize the results. However, it appears that more emphasis needs to be placed on providing interventions that target communication skills that young children who use AAC need in order to be active communicators and to participate fully in their natural contexts.

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

Summary Background Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3–13·8] vs 4·7 years [3·0–8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). Interpretation Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding US National Institutes of Health and American Lebanese Syrian Associated Charities.

Unhealthy alcohol use (the spectrum of risky use through dependence) is common in HIV-infected persons, yet it can interfere with HIV medication adherence, may lower CD4 cell count, and can cause hepatic injury. Carbohydrate-deficient transferrin (CDT), often measured as %CDT, can detect heavy drinking but whether it does in people with HIV is not well established. We evaluated the operating characteristics of %CDT in HIV-infected adults using cross-sectional data from 300 HIV-infected adults with current or past alcohol problems. Past 30-day alcohol consumption was determined using the Timeline Followback (TLFB), a validated structured recall questionnaire, as the reference standard. Sensitivity and specificity of %CDT (at manufacturer's cut-off point of 2.6%) for detecting both "at-risk" (≥4 drinks in a day or >7 drinks per week for women, ≥5 drinks in a day or >14 per week for men) and "heavy" drinking (≥4 drinks in a day for women, ≥5 drinks in a day for men on at least seven days) were calculated. Receiver operating characteristic (ROC) curves were estimated to summarize the diagnostic ability of %CDT for distinguishing "at risk" and "heavy" levels of drinking. Exploratory analyses that stratified by gender and viral hepatitis infection were performed. Of 300 subjects, 103 reported current consumption at "at-risk" amounts, and 47 reported "heavy" amounts. For "at-risk" drinking, sensitivity of %CDT was 28% (95% confidence interval (CI) 19%, 37%), specificity 90% (95% CI 86%, 94%); area under the ROC curve (AUC) was 0.59. For "heavy" drinking, sensitivity was 36% (95% CI 22%, 50%), specificity 88% (95% CI 84%, 92%); AUC was 0.60. Sensitivity appeared lower among women and those with viral hepatitis; specificity was similar across subgroups. Among HIV-infected adults, %CDT testing yielded good specificity, but poor sensitivity for detecting "at-risk" and "heavy" alcohol consumption, limiting its clinical utility for detecting unhealthy alcohol use in this population.

Individuals with complex communication needs are particularly vulnerable in disaster situations. This paper will describe a community outreach program developed to provide emergency preparedness training for children with complex communication needs. Goals are to acquaint participants with the challenges faced by individuals who used AAC in previous disasters, describe how community education has increased the capacity of stakeholders, and facilitate discussion regarding the application of training programs in additional communities.

BackgroundThe prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. MethodsIn 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data...

To test the hypothesis that quantitative measures of meniscus extrusion predict incident radiographic knee osteoarthritis (KOA), prior to the advent of radiographic disease.206 knees with incident radiographic KOA (Kellgren Lawrence Grade (KLG) 0 or 1 at baseline, developing KLG 2 or greater with a definite osteophyte and joint space narrowing (JSN) grade ≥1 by year 4) were matched to 232 control knees not developing incident KOA. Manual segmentation of the central five slices of the medial and lateral meniscus was performed on coronal 3T DESS MRI and quantitative meniscus position was determined. Cases and controls were compared using conditional logistic regression adjusting for age, sex, BMI, race and clinical site. Sensitivity analyses of early (year [Y] 1/2) and late (Y3/4) incidence was performed.Mean medial extrusion distance was significantly greater for incident compared to non-incident knees (1.56 mean ± 1.12 mm SD vs 1.29 ± 0.99 mm; +21%, P 0.01), so was the percent extrusion area of the medial meniscus (25.8 ± 15.8% vs 22.0 ± 13.5%; +17%, P 0.05). This finding was consistent for knees restricted to medial incidence. No significant differences were observed for the lateral meniscus in incident medial KOA, or for the tibial plateau coverage between incident and non-incident knees. Restricting the analysis to medial incident KOA at Y1/2 differences were attenuated, but reached significance for extrusion distance, whereas no significant differences were observed at incident KOA in Y3/4.Greater medial meniscus extrusion predicts incident radiographic KOA. Early onset KOA showed greater differences for meniscus position between incident and non-incident knees than late onset KOA.

Background and Purpose Oral anticoagulants are highly efficacious for the prevention of stroke in atrial fibrillation, and are the preferred treatment by current guidelines. The purpose of our study was to assess the utilization of antithrombotic drugs in atrial fibrillation patients at the time of ischemic stroke and the factors associated with their use. Methods We enrolled 759 consecutive patients admitted with ischemic stroke at Boston Medical Center, Geisinger Health System, and the University of Alabama. To be eligible, patients had to have electrocardiographically-confirmed atrial fibrillation at the time of admission or within 6months of the index stroke. All stroke events and electrocardiograms were validated by study physicians. Patients with newly diagnosed atrial fibrillation were not eligible. Results The mean age was 78years, 43% were male, 19% black, and the mean CHADS 2 score is 3.0. Atrial fibrillation was paroxysmal in 31%. At presentation, 181 (24%) patients were taking warfarin only, 96 (13%) both warfarin and aspirin, 294 (39%) aspirin alone, and 189 (25%) no antithrombotic therapy. The mean international normalized ratio was 1.6. Among patients with paroxysmal atrial fibrillation, one in five was taking warfarin. Although increasing stroke risk was associated with a greater likelihood of warfarin use, only 39% of highest risk CHADS 2 3–6 were taking warfarin at the time of stroke. Conclusions Among high-risk individuals with atrial fibrillation, only 37% were taking warfarin at the time of stroke. Paroxysmal atrial fibrillation was associated with the highest risk of not receiving warfarin.

Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition., Author Summary Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia. Here we report two unrelated kindreds with inherited mutations in ETV6, the gene encoding the transcription factor ETS variant 6. These families were characterized by a low platelet count (thrombocytopenia) and acute lymphoblastic leukemia (ALL). Sequencing a panel of genes identified germline ETV6 mutations associated with leukemia and thrombocytopenia in multiple individuals tested. In one family, there was a substitution within the DNA binding domain of ETV6, termed L349P, and in the second there were five base pairs missing in ETV6 (N385fs), causing an abnormally truncated protein. We overexpressed the ETV6 mutants in the HeLa cell line and measured protein levels and localization within the cells. Instead of localizing to the nucleus, as expected for a transcription factor, the mutant proteins were found in the cytoplasm. The mutant proteins also showed decreased ability to regulate the expression of other genes typically suppressed by ETV6. These findings suggest that germline ETV6 mutations cause a new type of heritable leukemia. This discovery makes possible the pre-symptomatic diagnosis of leukemia susceptibility in families with germline ETV6 mutations, and also provides new information on the causes of leukemia.

BACKGROUND: Deficits in balance and muscle function are important risk factors for falls in older adults. Aging is associated with significant declines in muscle size and density, but associations of trunk muscle size and density with balance and falls in older adults have not been previously examined. METHODS: Trunk muscle size (cross-sectional area) and attenuation (a measure of tissue density) were measured in computed tomography scans (at the L2 lumbar level) in a cohort of older adults (mean ± SD age of 81.9±6.4) residing in independent living communities. Outcome measures were postural sway measured during quiet standing and Short Physical Performance Battery (SPPB) at baseline, and falls reported by participants for up to 3 years after baseline measurements. RESULTS: Higher muscle density was associated with reduced postural sway, particularly sway velocities, in both men and women, and better Short Physical Performance Battery score in women, but was not associated with falls. Larger muscle size was associated with increased postural sway in men and women and with increased likelihood of falling in men. CONCLUSIONS: The results suggest that balance depends more on muscle quality than on the size of the muscle. The unexpected finding that larger muscle size was associated with increased postural sway and increased fall risk requires further investigation, but highlights the importance of factors besides muscle size in muscle function in older adults. Language: en

Background and Hypothesis: Ischemic stroke (IS) in atrial fibrillation (AF) is associated with high mortality. Inflammation, endothelial dysfunction, and hypercoagulability, in addition to blood stasis in the left atrium, play a critical role in thrombogenesis in AF. Hyperglycemia and chronic kidney disease (CKD) are potent triggers for inflammation, oxidative stress, and thrombogenesis. Statins have been shown to possess anti-inflammatory, anti-oxidant, and anti-thrombotic properties. Accordingly, we assessed the hypothesis that statin use may modulate stroke severity in AF. Methods: Consecutive IS admissions were identified from 2006-2010. All events were subject to CT or MRI and assessed for functional independence at discharge using modified Rankin scale (mRS). AF was confirmed by ECG at presentation or within the prior 6 months in all cases. Covariates were abstracted from the medical record. To account for confounding by treatment, we used multivariable logistic regression analysis adjusted using inverse probability weighting. Results: We identified 1,030 AF-related IS; mean age was 77, 56% were female, mean CHA 2 DS 2 VASC score was 4.8 designating high baseline stroke risk. IS resulted in severe neurological deficit or death (mRS ≥ 4) for 69%; 21% died within 30-days. Severe stroke was associated with older age, diabetes, dementia, prior ischemic stroke, prior venous thromboembolism, and CKD (Table). Baseline statin use was associated with a 33% reduced risk of sustaining a severe stroke. Conclusion: Strokes in AF are associated with high morbidity and mortality. Clinical markers of thrombophilia, including prior IS, DVT, and PE, were significantly associated with severe strokes. Diabetes and CKD independently increased this risk. Statin use resulted in less severe outcomes. Advancing our basic understanding of these interrelated thrombogenic pathways will inform clinical interventions to reduce these devastating outcomes.

Andersen-Tawil syndrome (ATS) is a potassium channelopathy affecting cardiac and skeletal muscle. Periodic paralysis is a presenting symptom in some patients, whereas, in others, symptomatic arrhythmias or prolongation of QT in echocardiographic recordings will lead to diagnosis of ATS. Striking intrafamilial variability of expression of KCNJ2 mutations and rarity of the syndrome may lead to misdiagnosis.We report 15 patients from 8 Polish families with ATS, including 3 with novel KCNJ2 mutations.All patients had dysmorphic features; periodic paralysis affected males more frequently than females (80% vs. 20%), and most attacks were normokalemic. Two patients (with T75M and T309I mutations) had aborted sudden cardiac death. An implantable cardioverter-defibrillator was utilized in 40% of cases.KCNJ2 mutations cause a variable phenotype, with dysmorphic features seen in all patients studied, a high penetrance of periodic paralysis in males and ventricular arrhythmia with a risk of sudden cardiac death.

Background One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use. Methods To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once. Results Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52). Conclusion Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to determine the optimal level of training and whether naloxone rescue kits can meet an over-the-counter standard. With no clear evidence of increased heroin use, this concern should not impede expansion of OEND programs or policies that support them.

Introduction: Drug law enforcement is part of the HIV risk environment among people who inject drugs (PWID). Punitive policing practices such as extrajudicial arrests for needle possession and police planting of drugs have been described anecdotally in Russia, but these experiences and their associations with risky drug behaviours have not been quantified. This study aims to quantify the burden of extrajudicial police arrests among a cohort of HIV-positive PWID in Russia and to explore its links to drug-related health outcomes. Methods: In a cross-sectional study of 582 HIV-positive people with lifetime injection drug use (IDU) in St. Petersburg, Russia, we estimated the prevalence of self-reported extrajudicial police arrests. We used multiple logistic regression to evaluate associations between arrests and the following outcomes: overdose, recent IDU and receptive needle sharing. Findings: This cohort’s mean age was 29.8 years, 60.8% were male; 75.3% reported non-fatal drug overdose, 50.3% recent IDU and 47.3% receptive needle sharing. Extrajudicial arrests were reported by more than half (60.5%, 95% confidence interval [CI]: 56.5–64.5) and were associated with higher odds of non-fatal drug overdose (AOR 1.52, 95% CI: 1.02–2.25) but not with recent IDU (AOR 1.17, arrests were associated with receptive needle sharing (AOR 1.84, 95% CI: 1.09–3.09). Conclusions: Extrajudicial police arrests were common among this cohort of Russian HIV-positive PWID and associated with non-fatal overdose and, among those with recent IDU, receptive needle sharing. As a part of the HIV risk environment of PWIDs, these practices might contribute to HIV transmission and overdose mortality. Further research is needed to relate these findings to the operational environment of law enforcement and to better understand how police interventions among PWIDs can improve the HIV risk environment. Keywords: human rights; police involvement; PLHA; injection drug use; key populations; Russian Federation. (Published: 9 July 2014) Citation: Lunze K et al. Journal of the International AIDS Society 2014, 17 :19043 http://www.jiasociety.org/index.php/jias/article/view/19043 | http://dx.doi.org/10.7448/IAS.17.1.19043

There is increasing evidence for inherited susceptibility to acute lymphoblastic leukemia (ALL) in children. Both common and rare germline genetic variants can significantly influence the risk of developing ALL, often in an age- and/or leukemia subtype-dependent manner (e.g., ARID5B, IKZF1, GATA3, PIP4K2A, PAX5, and TP53). Recently, we and others reported a novel genetic syndrome characterized by damaging germline ETV6 mutations that co-segregate with hereditary thrombocytopenia and increased propensity for hematologic malignancies (especially ALL). Sequencing 4,405 childhood ALL cases, we subsequently identified 30 germline coding ETV6 variants that were potentially responsible for disease predisposition in 35 patients (Lancet Oncol 2015). These findings unequivocally point to ETV6 as a critical ALL risk gene; however, the exact functional consequences of the ALL-related ETV6 variants are largely unknown and the mechanism by which they contribute to leukemogenesis is unclear. To this end, we first systematically evaluated these 30 ETV6 risk variants for their transcriptional repressor activity, ability to bind to target DNA sequences, localize to the nucleus, and also to homo-dimerize. Using PF4 and MMP3 promoter-driven luciferase transcription in HEK293T cells as the model system, we showed that 18 of these 30 ETV6 variants had loss of transcriptional repression activity (median of 53.2% of wildtype ETV6 activity [range 7.1% to 83.9%]). These include 4 of the 5 frameshift variants, all 4 nonsense variants, and also 10 of 11 missense variants in the ETS/DNA binding domain. None of the missense variants outside the ETS domain had significant effects on transcriptional repression function, and surprisingly the E44fs variant showed enhanced activity. Co-expression of wildtype and each of the 18 loss-of-function variants consistently impaired the normal repressor activity of wildtype ETV6, indicating dominant-negative effects. In cells expressing both wildtype and variant ETV6, immunoprecipitation of variant protein pulled down wildtype ETV6, in line with the dominant negative mode of action of variant ETV6 via dimerization with wildtype protein. Cellular fractionation showed significantly increased cytoplasmic localization of 18 loss-of-function ETV6 variants when expressed in HEK293T cells with concomitant reduction in nuclear ETV6. Analysis using EMSA revealed that all 14 variants in the ETS domain resulted in impaired binding to the consensus sequence in ETV6 target genes in vitro, as was also true for all 4 loss-of-function frameshift variants. To examine the role of ETV6 variants on hematopoietic stem and progenitor cell function, we lentivirally transduced murine LSK cells with wildtype or variant murine Etv6 (R355X or R395C). These cells were cultured ex vivo and analyzed for myeloid and pre-B cell differentiation, using colony formation assay. We found no change in the formation of myeloid colonies, whereas the number of pre-B colonies increased slightly with mutant Etv6, although we observed no effects on cell cycle or apoptosis. Focusing on the 18 ETV6 variants with experimentally confirmed deleterious effects, we then evaluated the association of germline ETV6 status with ALL clinical features in 3,906 children from frontline ALL protocols at St. Jude Children's Research Hospital and Children's Oncology Group. Patients with these ETV6 variants were significantly older at ALL diagnosis than those without (13.3 [2.6-21.7] vs 6.8 [0.08-30.7] years, P=0.026) but were more likely to have leukocyte count Disclosures Martin: Novartis: Other: Support of clinical trials; Jazz Pharmaceuticals: Other: One time discussion panel. Evans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Hunger:Patent: Patents & Royalties: Dr. Hunger is a co-inventor of a patent (#8658,964) for the identification of novel subgroups in high risk B-ALL and outcome correlations and diagnostic methods related to the same; Erytech: Honoraria; Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria; Merck: Equity Ownership; Pfizer: Equity Ownership; Amgen: Equity Ownership; Spectrum Pharmaceuticals: Honoraria. Mullighan:Loxo Oncology: Research Funding; Amgen: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.

As international travel increases, many health care professionals are being asked to provide pre-travel advice. We designed an anonymous web-based survey to assess the extent to which primary care providers (PCPs) provide travel medicine advice and how their understanding and delivery of itinerary-specific advice and management compare with that of travel medicine specialists.We surveyed randomly selected US PCPs registered in the Pri-Med Institute (now pmiCME) database and US travel medicine specialists from the International Society of Travel Medicine (ISTM), American Society of Tropical Medicine and Hygiene (ASTMH), and Centers for Disease Control and Prevention (CDC) yellow fever (YF) vaccine provider mailing lists. SAS software (SAS Institute, Cary, NC, USA) was used for all analyses.Of 14,932 e-mails sent to valid e-mail addresses, 902 yielded complete or partially completed surveys (6.0% response rate). Eighty percent of respondents personally provided pre-travel advice (95% of travel medicine specialists versus 73% of PCPs). About two thirds of PCPs (68%) providing pre-travel consultations saw50 travelers per year whereas 30% of travel medicine specialists saw50 travelers per year. More travel medicine specialists (59%) than PCPs (18%) saw500 travelers per year. Familiarity with travel-specific vaccines (YF, Japanese encephalitis) and provision of written educational materials increased as volume of travelers increased. Familiarity with antimalarial side effects and malaria resistance patterns, and knowledge scores based on brief pre-travel scenarios were higher in travel medicine specialists, ASTMH or ISTM certificate holders, and respondents who saw more pre-travel patients.Many PCP survey participants provided pre-travel advice, but most saw few travelers. Volume of travelers and holding an ASTMH or ISTM certificate had the greatest influence on knowledge of travel medicine and provision of appropriate advice and recommendations. Creating easily accessible travel medicine education programs for US providers from a wide range of disciplines is needed to improve the management of travelers.

Background Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers. Methods We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use. Results Detectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05–5.89) and detectable HCV RNA alone (2.95; 1.08–8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90–31.97) and TNF-α (7.70; 1.42–41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84). Conclusions Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.

Objective To evaluate the impact of state supported overdose education and nasal naloxone distribution (OEND) programs on rates of opioid related death from overdose and acute care utilization in Massachusetts. Design Interrupted time series analysis of opioid related overdose death and acute care utilization rates from 2002 to 2009 comparing community-year strata with high and low rates of OEND implementation to those with no implementation. Setting 19 Massachusetts communities (geographically distinct cities and towns) with at least five fatal opioid overdoses in each of the years 2004 to 2006. Participants OEND was implemented among opioid users at risk for overdose, social service agency staff, family, and friends of opioid users. Intervention OEND programs equipped people at risk for overdose and bystanders with nasal naloxone rescue kits and trained them how to prevent, recognize, and respond to an overdose by engaging emergency medical services, providing rescue breathing, and delivering naloxone. Main outcome measures Adjusted rate ratios for annual deaths related to opioid overdose and utilization of acute care hospitals. Results Among these communities, OEND programs trained 2912 potential bystanders who reported 327 rescues. Both community-year strata with 1-100 enrollments per 100 000 population (adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) and community-year strata with greater than 100 enrollments per 100 000 population (0.54, 0.39 to 0.76) had significantly reduced adjusted rate ratios compared with communities with no implementation. Differences in rates of acute care hospital utilization were not significant. Conclusions Opioid overdose death rates were reduced in communities where OEND was implemented. This study provides observational evidence that by training potential bystanders to prevent, recognize, and respond to opioid overdoses, OEND is an effective intervention.

Nondisclosure of one's HIV infection to sexual partners obviates safer sex negotiations and thus jeopardizes HIV transmission prevention. The role of alcohol use in the disclosure decision process is largely unexplored. This study assessed the association between alcohol use and recent nondisclosure of HIV serostatus to sex partners by HIV-infected risky drinkers in St. Petersburg, Russia. Approximately half (317/605; 52.4 %) reported not having disclosed their HIV serostatus to all partners since awareness of infection. Using three separate GEE logistic regression models, we found no significant association between alcohol dependence, risky alcohol use (past 30 days), or alcohol use at time of sex (past 30 days) with recent (past 3 months) nondisclosure (AOR [95 % CI] 0.81 [0.55, 1.20], 1.31 [0.79, 2.17], 0.75 [0.54, 1.05], respectively). Alcohol use at time of sex was associated with decreased odds of recent nondisclosure among seroconcordant partners and among casual partners. Factors associated with nondisclosure were relationship with a casual partner, a serodiscordant partner, multiple sex partners, awareness of HIV diagnosis less than 1 year, and a lifetime history of sexually transmitted disease. Nondisclosure of HIV status to sex partners is common among HIV-infected Russians, however alcohol does not appear to be a predictor of recent disclosure.

Introduction : Police violence against people who inject drugs (PWID) is common in Russia and associated with HIV risk behaviours. Sexual violence from police against women who use drugs has been reported anecdotally in Russia. This mixed-methods study aimed to evaluate sexual violence from police against women who inject drugs via quantitative assessment of its prevalence and HIV risk correlates, and through qualitative interviews with police, substance users and their providers in St. Petersburg, Russia. Methods : Cross-sectional analyses with HIV-positive women who inject drugs ( N =228) assessed the associations between sexual violence from police (i.e. having been forced to have sex with a police officer) and the following behaviours: current drug use, needle sharing and injection frequency using multiple regression models. We also conducted in-depth interviews with 23 key informants, including PWID, police, civil society organization workers, and other stakeholders, to explore qualitatively the phenomenon of sexual violence from police in Russia and strategies to address it. We analyzed qualitative data using content analysis. Results : Approximately one in four women in our quantitative study (24.1%; 95% CI, 18.6%, 29.7%) reported sexual violence perpetrated by police. Affected women reported more transactional sex for drugs or money than those who were not; however, the majority of those reporting sexual violence from police were not involved in these forms of transactional sex. Sexual violence from police was not significantly associated with current drug use or needle sharing but with more frequent drug injections (adjusted incidence rate ratio 1.43, 95% CI 1.04, 1.95). Qualitative data suggested that sexual violence and coercion by police appear to be entrenched as a norm and are perceived insurmountable because of the seemingly absolute power of police. They systematically add to the risk environment of women who use drugs in Russia. Conclusions : Sexual violence from police was common in this cohort of Russian HIV-positive women who inject drugs. Our analyses found more frequent injection drug use among those affected, suggesting that the phenomenon represents an underappreciated human rights and public health problem. Addressing sexual violence from police against women in Russia will require addressing structural factors, raising social awareness and instituting police trainings that protect vulnerable women from violence and prevent HIV transmission. Keywords: sexual violence; gender-based violence; human rights; police involvement; People living with HIV/AIDS (PLHA); injection drug use; key populations; Russian Federation. (Published: 18 July 2016) Citation: Lunze K et al. Journal of the International AIDS Society 2016, 19(Suppl 3) :20877 http://www.jiasociety.org/index.php/jias/article/view/20877 | http://dx.doi.org/10.7448/IAS.19.4.20877

Background Adherences to treatments that require a behavioral action often rely on self-reported recall, yet it is vital to determine whether real time self reporting of adherence using a simple logbook accurately captures adherence. The purpose of this study was to determine whether real time self-reported adherence is an accurate measurement of device usage during a clinical trial by comparing it to electronic recording. Methods Using data collected from older adult men and women (N=135, mean age 82.3 yrs; range 66 to 98 yrs) participating in a clinical trial evaluating a vibrating platform for the treatment of osteoporosis, daily adherence to platform treatment was monitored using both self-reported written logs and electronically recorded radio-frequency identification card usage, enabling a direct comparison of the two methods over one year. Agreement between methods was also evaluated after stratification by age, gender, time in study, and cognition status. Results The two methods were in high agreement (overall intraclass correlation coefficient = 0.96). The agreement between the two methods did not differ between age groups, sex, time in study and cognitive function. Conclusions Using a log book to report adherence to a daily intervention requiring a behavioral action in older adults is an accurate and simple approach to use in clinical trials, as evidenced by the high degree of concordance with an electronic monitor. Trial registration Clinicaltrials.gov NCT00396994

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and the etiology of this aggressive cancer is not fully understood. Common germline polymorphisms in lymphoid development genes and tumor suppressor genes have been associated with ALL susceptibility, although most have modest effects. Only a small fraction of ALL cases are thought to be related to congenital genetic disorders and consequently hereditary predisposition is rarely considered in clinical practice. However, a growing number of rare germline genetic mutations have been discovered in familial ALL (e.g., PAX5, TP53), raising the possibility that the proportion of ALL attributable to inherited predisposition may be higher than currently proposed. In particular, germline ETV6 variations were recently reported in families with hereditary thrombocytopenia and dramatically increased susceptibility to hematologic malignancies (Nat Genet 2015 47: 180 and 535). ETV6 is a transcriptional repressor essential for hematopoiesis and is frequently targeted by somatic genomic aberrations in childhood ALL (e.g., the ETV6-RUNX1 fusion). Therefore, we sought to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which these variants contribute to childhood ALL risk in general. We first identified a family with three cases of childhood ALL at St. Jude Children's Research Hospital. Whole exome sequencing of this family (mother and 2 daughters with ALL, the unaffected father and 1 unaffected daughter) identified a single variant in ETV6 (p.R359X) in the 3 cases with ALL and also in the healthy daughter. This nonsense variant is predicted to create a stop codon within the ETS domain of ETV6, resulting in a truncated protein without DNA-binding function. This highly damaging variant is likely to be responsible for the ALL predisposition in this family with a high albeit incomplete penetrance. To comprehensively determine the prevalence of ALL-predisposing alleles in ETV6, we performed targeted sequencing of this gene in 4,405 children with newly-diagnosed ALL enrolled on the Children's Oncology Group (COG) AALL0232, P9904, P9905 and P9906 protocols and St. Jude Total Therapy XIIIA, XIIIB and XV studies. We identified a total of 43 germline variants in the exonic regions of ETV6. Thirty-one of the 43 ETV6 variants were defined as "ALL-related" because they were not found or extremely rare in non-ALL populations (N=60,706). These ALL risk variants included 4 nonsense, 21 missense, 1 splice site, and 5 frameshift variants occurring in 35 children (0.79% of ALL cases studied). Fifteen of the 31 ALL-relatedvariants (48.4%) were clustered in the ETS DNA-binding domain of ETV6. We used the combined annotation dependent depletion algorithm (CADD) to predict deleterious effects of each variant. ALL-related ETV6 variants were significantly more likely to be damaging compared to germline variants observed in the non-ALL population (mean CADD phred-like score of 25.6 vs 15.2, respectively, p We next analyzed the relationship between germline risk variants in ETV6 and clinical features of ALL in a subset of 2,021 cases enrolled on St. Jude and COG frontline ALL trials. These cases were comprehensively evaluted for ALL charateristics and representative of the US childhood ALL population. Children with ALL-related ETV6 variants were significantly older at the time of diagnosis than those without these variants (9.5 years vs 6.4 years; P=0.009). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (64.3% vs 26.8%; P=0.0045). In contrast, the frequency of somatic ETV6 -RUNX1 fusion was much lower in cases with ETV6 germline risk variants, compared to cases with wildtype ETV6 (7.1% vs 22.7%), even though this difference did not reach statistical significance. Of note, there was also a trend towards overrepresentation of females in carriers of ALL-related ETV6 variants (71.4% vs 45.7%; P=0.063). In conclusion, our findings indicate that germline ETV6 variations are important determinants for genetic predisposition to childhood ALL. Disclosures Martin: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Evans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Hunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Sigma Tau: Consultancy.

Objective: To understand patterns of alcohol consumption and baseline factors associated with favorable drinking patterns among HIV-infected patients. Methods: We studied drinking patterns among HIV-infected patients with current or past alcohol problems. We assessed drinking status in 6-month intervals. Based on National Institute on Alcohol Abuse and Alcoholism guidelines a favorable drinking pattern was defined as not drinking risky amounts at each assessment or decreased drinking over time. All other patterns were defined as unfavorable. Logistic regression models were used to identify baseline factors associated with a favorable pattern. Results: Among 358 subjects, 54% had a favorable drinking pattern with 44% not drinking risky amounts at every assessment, and 11% decreasing consumption over time. Of the 46% with an unfavorable pattern, 4% drank risky amounts each time, 5% increased, and 37% both decreased and increased consumption over time. Current alcohol dependence and recent marijuana use were negatively associated with a favorable pattern, while older age and female gender, and having a primary HIV risk factor of injection drug use were positively associated with a favorable pattern. Conclusion: Many HIV-infected adults with alcohol problems have favorable drinking patterns over time, and alcohol consumption patterns are not necessarily constant. Identifying HIV-infected adults with a pattern of risky drinking may require repeated assessments of alcohol consumption.

Drug and Alcohol Dependence 156 (2015) e183–e245 e197 COCduring conditioning, (3) pre-TAUandTAUduring conditioning, and (4) COC during conditioning. Results: Males and females that were not pre-treated with COC showed a significant preference to the COC-paired chamber. Neither male nor female subjects showed a preference to the TAU-paired chamber. Taurine was effective in inhibiting cocaine preference in both male and female subjects after the preTAU; however, females show a significant preference towards the cocaine-paired chamber when TAU and COC are co-administered. Conclusions:Coc-inducedbehaviors oftenpersist for years after abstinence and the best form of treatment is yet to be determined. This study provides evidence that taurine might deserve study as a treatment for cocaine addiction; however, sex may influence its efficacy. Further studies will be performed to assess possible mechanisms by which taurine inhibits cocaine preference, its relationship to gonadal hormones. Financial support: Supported by NIDA R25DA030310 (KSR); NCRR 5G12RR003060-26, NIMHHD 8G12MD7603-27 (EF, KSR); NIH MARC U*STAR 5T34 GM007639-32 (KU); K05DA015799 (J.C. Anthony, sponsor). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.529 HIV-related stigma and substance use in a Russian cohort of HIV+ risky drinkers Jeffrey Samet1,∗, Karsten Lunze1, Debbie M. Cheng1, Dmitry Lioznov3, Emily Quinn1, Carly Bridden1, Christine Chaisson1, Alexander Y. Walley1, E. Krupitsky3, Anita Raj4, E.J. Edelman2 1 Boston University, Boston, MA, United States 2 Yale, New Haven, CT, United States 3 First St. Petersburg Pavlov State Medical U, St. Petersburg, Russian Federation 4 UCSD, San Diego, CA, United States Aims: To determine whether HIV-related stigma contributes to substance use and dependence among HIV+ Russian individuals with risky alcohol use. Methods: We used data from HERMITAGE, a randomized controlled trial of 700 HIV+ individuals with past 6-month risky sex and risky alcohol use in St. Petersburg, Russia (2007–2011). Demographics, clinical and behavioral characteristics were collected by survey at baseline, 6 and 12 months. We measured HIV-related stigma using the abbreviated Berger HIV-related stigma scale. We assessed past 30 day drug use (modified Risk Behavior Scale), risky alcohol use (Timeline Followback), and substance dependence (CIDI short form). Generalized estimating equations were constructed to examine the association between high HIV-related stigma (score >75th percentile) and substance use over time (any prior 30 days heroin or stimulant or risky alcohol use [per NIAAA criteria]). Secondary outcomes were (1) any prior 30 days heroin or stimulant use; (2) prior 30 days risky alcohol use; and (3) past year alcohol or drug dependence. We adjusted for demographics, education, marital status, intervention group, time since HIV diagnosis, depressive symptoms, antiretroviral therapy use, CD4 count, and social support. Results:At baseline, themean agewas 30 (SD 5) years, with 41% women. Twenty-eight percent reported high HIV-related stigma; 87% reported substanceuse in theprior 30days. In adjustedmodels, high HIV-related stigma (AOR=0.86 [95% CI 0.51, 1.45]) was not significantly associated with substance use. These findings were similar for the secondary outcomes. Conclusions: HIV-related stigma does not appear to be associated with substance use among risky drinkers. Future efforts to identify modifiable factors which contribute to substance use among HIV+ individuals with risky alcohol use are needed. Financial support: R01AA016059; K12DA033312; R25DA013582. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.530 Impact of telehealth in-home-messaging devices on alcohol use in dually diagnosed veterans Elizabeth J. Santa Ana1,∗, Steve Martino2, Mulugeta Gebregziabher1 1 Charleston VAMC and Medical University of South Carolina, Charleston, SC, United States 2 Yale University School of Medicine, West Haven, CT

Germline mutations of transcription factors (e.g. PAX5, CEBPA, GATA2, RUNX1) have been associated with an inherited susceptibility to acute leukemia. Here we report 2 unrelated kindreds harboring germline mutations in ETV6, the gene encoding the transcription factor ETS variants 6. These kindreds were primarily characterized by thrombocytopenia and acute lymphoblastic leukemia (ALL). The first kindred, identified at MSKCC and HMC, includes 9 individuals with thrombocytopenia, and 3 individuals with pre-B ALL. Sequencing a subset of common and somatically altered leukemia genes in this family identified a rare heterozygous non-synonymous missense variation (T>C) in 6 family members with thrombocytopenia and 2 with ALL. Notably, this variant did not segregate in 9 individuals in the kindred without these phenotypes. The amino acid alteration is predicted to lead to an L349P substitution within the DNA binding domain of ETV6 (L349P, NPP_001978). In silico analyses using SIFT and Polyphen assigned pathogenic variant classifications to the L349P variant. The proband of the second family presented to SJCRH with pre-B ALL, a history of thrombocytopenia, and demonstrated hypersensitivity to methotrexate (grade 3 bone marrow suppression). His leukemia transformated to myelodsyplastic syndrome and acute myeloid leukemia, which was treated by unrelated donor transplantation. The proband's mother, maternal aunt and maternal grandfather had thrombocytopenia, and the maternal great grandfather was diagnosed with chronic myeloid leukemia. The proband and his mother were found to carry a heterozygous 5 bp deletion in ETV6, N385fs (c.1153-5_1153_1delAACAG), which is predicted to produce a truncated protein of 389 amino acids with the last 4 residues different from the canonical ETV6 sequence. This variant has not been described in public sequencing data repositories. Finally, a review of 1,120 cases from the SJCRH/Washington University Pediatric Cancer Genome Project, including 588 cases of leukemia (among which 472 were ALL), revealed 3 rare germline ETV6 variants: L442P (n = 1), R181H (n = 1), and V37M (n = 1), with 2 of these variants L442P and R181H predicted to be pathogenic based on prediction and/or genomic location. Notably, these 2 variants each occurred in patients with ALL. Collectively, these findings suggest that germline ETV6 mutations are associated with a novel syndrome of thrombocytopenia with susceptibility to leukemia. Furthermore, these mutations may account for approximately 0.4% (2/472) of pediatric ALL cases. Further phenotypic characterization of affected patients and functional assessment of ETV6 germline variants, in progress, will be required to reveal the clinical effects of these mutations, their incidence in patients with ALL and their role in leukemogenesis. Citation Format: Vijai Joseph, Michael F. Walsh, Sabine Topka, Gang Wu, Rose B. McGee, Emily Quinn, Hiroto Inaba, Christine Hartford, Ching-Hon Pui, Alberto S. Pappo, Michael Edmonson, Lauren Jacobs, Villano Danylo, Kasmintan Schrader, Pragna Gaddam, Zsofia Stadler, Michael Zhang, Polina Stepensky, Peter Steinherz, James Bussel, M Harit, Michael Weintraub, Akiko Shimamura, Jinghui Zhang, James R. Downing, Kenneth Offit, Kim E. Nichols. Germline mutations in ETV6 confer risk of thrombocytopenia and acute lymphocytic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2015-2033

s / Drug and Alcohol Dependence 146 (2015) e2–e33 e15 Characterization of morphine discriminative stimulus properties in C57BL/6 mice D.M. Walentiny, L.S. Harris Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United