Primary care and medication management characteristics among patients receiving office-based opioid treatment with buprenorphine.

BACKGROUND: Office-based opioid treatment (OBOT) is an evidence-based treatment model for opioid use disorder (OUD) offered by both addiction and general primary care providers (PCPs). Calls exist for more PCPs to offer OBOT. Few studies have been conducted on the primary care characteristics of OBOT patients. OBJECTIVE: To characterize medical conditions, medications, and treatment outcomes among patients receiving OBOT with buprenorphine for OUD, and to describe differences among patients by age and by time in care. METHODS: This study is a retrospective review of medical records on or before 4/29/2019 at an outpatient primary care clinic within a nonprofit addiction treatment setting. Inclusion criterion was all clinic patients actively enrolled in the OBOT program. Patients not prescribed buprenorphine or with no OBOT visits were excluded. RESULTS: Of 355 patients, 42.0% had another PCP. Common comorbid conditions included chronic pain and psychiatric diagnosis. Few patients had chronic viral hepatitis or HIV. Patients reported a median of 4 medications. Common medications were cardiovascular, antidepressant, and nonopioid pain agents. Older patients had a higher median number of medications. There was no significant difference in positive opioid urine toxicology (UT) based on age, chronic pain status, or psychoactive medications. Patients retained >1 year were less likely to have positive opioid UT. CONCLUSION: Clinical needs of many patients receiving OBOT are similar to those of the general population, supporting calls for PCPs to provide OBOT.

Primary varicella zoster infection compared to varicella vaccine reactivation associated meningitis in immunocompetent children.

We diagnosed varicella zoster virus (VZV) meningitis in a healthy adolescent boy who presented without a rash or fever. We aim to compare VZV reactivation meningitis in children after primary VZV infection and VZV vaccination. We reviewed the literature up until June 2020 using Pubmed/MEDLINE and EMBASE databases using 'varicella zoster', 'meningitis' and 'children' as keywords. Only English articles were included. Twenty-five cases were included in this review. Children who had VZV reactivation meningitis after vaccination were younger (7 ± 3.4 years vs. 11.9 ± 3.6 years, P = 0.0038), had a shorter interval between first exposure to reactivation (5.6 ± 2.9 years vs. 8.8 ± 3.2 years, P = 0.018) and more likely to have a rash (100% vs. 55%, P = 0.04). VZV reactivation meningitis occurs after both primary VZV infection and VZV vaccination. The absence of exanthem, fever or meningism does not rule out VZV meningitis.

Fifty-Five Years Follow-Up of 111 Adult Survivors After Biventricular Repair of PAIVS and PS.

There is paucity of long-term data on adult survivors after biventricular repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS). This study aimed to determine the cardiac and non-cardiac outcomes of adult survivors after biventricular repair of PAIVS and PS. The cardiac, neurodevelopmental and liver problems of 111 adults, 40 with PAIVS and 71 with PS, were reviewed. The median follow-up duration of our patients was 26.5 years (range 14.8-55 years). The freedom from reintervention at 30 years was 17.4% and 73.3% for PAIVS and PS patients (p < 0.001), respectively. Compared with PS patients, PAIVS patients had significantly greater prevalence of right atrial and right ventricular (RV) dilatation, and moderate to severe tricuspid and pulmonary regurgitation (all p < 0.05), and cardiac arrhythmias (22.5% vs. 8.5%, p = 0.047). The freedom from development of cardiac arrhythmias at 30 years of 68.4% and 91.6%, respectively, in PAIVS and PS patients (p = 0.03). Cox proportional hazards model identified PAIVS as an independent risk factor for reintervention (HR 4.0, 95% CI 2.1-7.6, p < 0.001) and development of arrhythmias (HR 4.1, 95% CI 1.1-14.4, p = 0.03). Neurodevelopmental problems were found in 17.5% of PAIVS patients and 7.0% of PS patients (p = 0.11). Liver problems occurred in 2 (5%) PAIVS patients, both of whom required conversion to 1.5 ventricular repair. In conclusion, long-term problems, including the need for reinterventions, cardiac arrhythmias, RV dilation, pulmonary regurgitation, and neurodevelopmental and liver issues are more prevalent in adult PAIVS than PS survivors.

Randomized pilot trial of Web-based cognitive-behavioral therapy adapted for use in office-based buprenorphine maintenance.

Background: Despite the clear success of office-based buprenorphine treatment in increasing availability of effective treatment for opioid use disorder, constraints on its effectiveness include high attrition and limited high-quality behavioral care in many areas. Web-based interventions may be a novel strategy for providing evidence-based behavioral care to individuals receiving office-based buprenorphine maintenance. This report describes modification and initial pilot testing of Web-based training in cognitive-behavioral therapy (CBT4CBT) specifically for use with individuals in office-based buprenorphine. Methods: Twelve-week randomized pilot trial evaluating effects of CBT4CBT-Buprenophine in retaining participants and reducing drug use with respect to standard office-based buprenorphine alone was carried out. Twenty individuals meeting DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria for current opioid use disorder were randomized to standard buprenorphine treatment or buprenorphine plus access to CBT4CBT-Buprenorphine. Results: There were promising findings regarding rates of urine toxicology screens negative for opioids (91% versus 64%; P = .05, effect size d = 0.88) and all drugs (82% versus 30%; P = .004, d = 1.2). Individuals randomized to CBT4CBT-Buprenorphine completed a mean of 82.6 (SD = 4.4) days of treatment (of a possible 84) compared with 68.6 (SD = 32.6) for those assigned to standard buprenorphine treatment. Conclusions: Although preliminary and limited by the small sample size, this trial suggests the feasibility and promise of validated, Web-based interventions, tailored for this specific patient population, for improving outcomes in office-based buprenorphine.

Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings.

BACKGROUND: Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). METHODS: This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2 mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n = 44). All participants had completed a parent varenicline study evaluating alcohol self-administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08 g/dl) or a nonalcoholic control beverage, order counterbalanced. RESULTS: Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2 mg/d varenicline versus placebo. CONCLUSIONS: These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs.

N-methyl-D-aspartate receptor antagonism has differential effects on alcohol craving and drinking in heavy drinkers.

BACKGROUND: The objective of this study was to determine the effects of the N-methyl-d-aspartate (NMDA) receptor antagonist, memantine (0, 20, 40 mg/d), upon alcohol drinking and craving in heavy drinkers with or without a family history (FH) of alcoholism, and to explore the modulatory influence of the presence of impulsivity on these outcomes. METHODS: Ninety-two, nontreatment-seeking, heavy drinkers received memantine or placebo for 8 days. On the eighth day, they received a priming dose of alcohol followed by a 3-hour period of alcohol access. RESULTS: Memantine at a dose of 20 mg reduced alcohol craving but did not influence alcohol drinking. No effects of FH were observed. In participants with higher baseline levels of impulsivity, 40 mg of memantine reduced alcohol craving but increased alcohol drinking and alcohol-induced stimulation. CONCLUSIONS: NMDA receptor signaling may play divergent roles in mediating alcohol cue-induced craving and alcohol drinking in heavy drinkers. The potential efficacy of memantine as monotherapy for alcohol use disorders may be limited by its tendency to disinhibit drinking in some individuals.

Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials.

BACKGROUND: The ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), are biomarkers of recent alcohol consumption that provide objective measures of abstinence. Our goals are to better understand the impact of cutoff concentration on test interpretation, the need for measuring both metabolites, and how best to integrate test results with self-reports in clinical trials. METHODS: Subjects (n = 18) were administered, 1 week apart, 3 alcohol doses calibrated to achieve blood concentrations of 20, 80, and 120 mg/dl, respectively. Urinary EtG/EtS was measured at timed intervals during a 24-hour hospitalization and twice daily thereafter. In addition, participants from 2 clinical trials provided samples for EtG/EtS and drinking histories. Cutoffs for EtG/EtS of 100/50, 200/100, and 500/250 ng/ml were evaluated. RESULTS: Twelve hours following each challenge, EtG was always positive at the 100 and 200 cutoffs, but at 24 hours sensitivity was poor at all cutoffs following the low dose, and poor after 48 hours regardless of dose or cutoff. Similarly, in the clinical trials EtG sensitivity was good for detecting any drinking during the last 24 hours at the 2 lowest cutoffs, but under 40% during the last 24 to 48 hours. Sensitivity was reduced at the 500 ng/ml cutoff. Discrepancies between EtG and EtS were few. Comparison of self-reports of abstinence and EtG-confirmed abstinence indicated underreporting of drinking. CONCLUSIONS: Any drinking the night before should be detectable the following morning with EtG cutoffs of 100 or 200 ng/ml. Twenty-four hours after drinking, sensitivity is poor for light drinking, but good for heavier consumption. At 48 hours, sensitivity is low following 6 drinks or less. Increasing the cutoff to 500 ng/ml leads to substantially reduced sensitivity. Monitoring both EtG and EtS should usually be unnecessary. We recommend EtG-confirmed self-reports of abstinence for evaluation of outcomes in clinical trials.

Whole genome sequencing in paediatric channelopathy and cardiomyopathy.

Background: Precision medicine in paediatric cardiac channelopathy and cardiomyopathy has a rapid advancement over the past years. Compared to conventional gene panel and exome-based testing, whole genome sequencing (WGS) offers additional coverage at the promoter, intronic regions and the mitochondrial genome. However, the data on use of WGS to evaluate the genetic cause of these cardiovascular conditions in children and adolescents are limited. Methods: In a tertiary paediatric cardiology center, we recruited all patients diagnosed with cardiac channelopathy and cardiomyopathy between the ages of 0 and 18 years old, who had negative genetic findings with prior gene panel or exome-based testing. After genetic counselling, blood samples were collected from the subjects and both their parents for WGS analysis. Results: A total of 31 patients (11 cardiac channelopathy and 20 cardiomyopathy) were recruited. Four intronic splice-site variants were identified in three cardiomyopathy patients, which were not identified in previous whole exome sequencing. These included a pathogenic variant in TAFAZZIN:c.284+5G>A (Barth syndrome), a variant of unknown significance (VUS) in MYBPC3:c.1224-80G>A and 2 compound heterozygous LP variants in LZTR1 (LZTR1:c.1943-256C>T and LZTR1:c1261-3C>G) in a patient with clinical features of RASopathy. There was an additional diagnostic yield of 1.94% using WGS for identification of intronic variants, on top of conventional gene testing. Conclusion: WGS plays a role in identifying additional intronic splice-site variants in paediatric patients with isolated cardiomyopathy. With the demonstrated low extra yield of WGS albeit its ability to provide potential clinically important information, WGS should be considered in selected paediatric cases of cardiac channelopathy and cardiomyopathy in a cost-effective manner.

Financial toxicity in breast cancer patients receiving regional nodal irradiation: Variation by cancer subtype.

BACKGROUND: We evaluated sociodemographic and clinical predictors of financial toxicity (FT) among patients with breast cancer with higher risk clinical factors warranting regional nodal irradiation (RNI). METHODS: Among 183 participants in a clinical trial of conventional vs. hypofractionated treatment with RNI, 125 (68 %) completed a pilot survey of FT measured using the validated Economic Strain and Resilience in Cancer (ENRICh) instrument, scored from 0 (minimal) to 10 (severe) FT. Associations with predictors were evaluated using Pearson correlation coefficients and Kruskal Wallis, Mann-Whitney U, and Jonckheere-Terpstra tests. Predictors of severe FT (ENRICh≥5) were tested using multivariable logistic regression with odds ratios converted to relative risks (RR). RESULTS: Of the sample, all received RNI, 92 % chemotherapy, 67 % axillary dissection, 26 % mastectomy without reconstruction, and 32 % mastectomy with reconstruction. At a median follow up of 1.48 years, median FT score was 2.13 (IQR 0.93-4.6), with 20.8 % of patients experiencing severe FT. Unadjusted worse FT score was associated with younger age (P = 0.003), Hispanic ethnicity (P = 0.006), lower income (P = 0.02), shorter interval from diagnosis to FT assessment (P = 0.02), and chemotherapy receipt (P = 0.05), but not with breast surgery type (P = 0.42), axillary surgery type (P = 0.33), or pathologic T (P = 0.68) or N stage (P = 0.47). In multivariable analysis, triple negative subtype was the sole clinical factor predicting severe FT (RR = 3.38; 95 % CI 1.48-4.99; P = 0.01). CONCLUSION: Among patients with breast cancer receiving RNI, triple negative subtype was associated with severe FT, suggesting that tumor receptor subtype may help identify a key breast cancer subpopulation for early FT intervention.

A preliminary study on the effect of combined nicotine replacement therapy on alcohol responses and alcohol self-administration.

BACKGROUND AND OBJECTIVES: Limiting alcohol consumption may help prevent alcohol-mediated smoking relapse in heavy drinking smokers. This pilot study examined whether combining a nicotine patch with nicotine nasal spray has stronger attenuating effects on alcohol response and consumption than a nicotine patch alone. METHODS: Twenty-two non-alcohol dependent heavy drinking smokers completed the double-blind cross-over, placebo-controlled study (21 mg nicotine patch + nicotine or placebo nasal spray). Six hours after 21 mg nicotine patch application, subjective and physiological responses to a priming drink (0.3 g/kg) were assessed, followed by two 1-hr alcohol self-administration periods, with possible consumption of up to 4 drinks per period (each 0.15 g/kg). Nasal spray (1 mg [active] or 0 mg [placebo] per dose) was administered 10 min prior to the priming dose and each self-administration period. RESULTS: Active nasal spray did not increase serum nicotine levels, compared with placebo administration. The number of drinks consumed did not differ by the nasal spray conditions. However, positive subjective responses to the priming drink were lower in the active nasal spray condition than the placebo nasal spray condition. During the self-administration period, urge to drink was also lower in the active spray condition than the placebo condition. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Augmenting the nicotine patch with nicotine nasal spray attenuated positive subjective alcohol response and craving and suggests that future studies should investigate whether these findings translate to a clinical setting.

Socioeconomic Barriers to Randomized Clinical Trial Retention in Patients Treated With Adjuvant Radiation for Early-Stage Breast Cancer.

PURPOSE: Socioeconomic barriers contribute to breast cancer clinical trial enrollment disparities. We sought to identify whether socioeconomic disadvantage also is associated with decreased trial retention. METHODS AND MATERIALS: We performed a secondary analysis of 253 (of 287) patients enrolled in a randomized phase 3 trial of conventionally fractionated versus hypofractionated whole-breast irradiation. The outcome of trial retention versus dropout was defined primarily based on whether the patient completed breast cosmesis outcomes assessment at 3-year follow-up, and secondarily, at 5-year follow-up. Associations of retention with severity of socioeconomic disadvantage, quantified by patients' home neighborhood area deprivation index (ADI) rank (1 [least] to 100 [most deprivation]), were tested using the Kruskal-Wallis test and multivariate logistic regression. Associations of retention with patients' use of social resource assistance were analyzed using the χ2 test. RESULTS: In total, 21.7% (n = 55) of patients dropped out by 3 years and 36.7% (n = 92) by 5 years. Median ADI was 36.5 (interquartile range, 22-57) for retained and 46.0 (interquartile range, 29-60) for dropout patients. Dropout was associated with more severe socioeconomic deprivation (ADI ≥45 vs <45) at 3 years (odds ratio, 3.63; 95% confidence interval, 1.62-8.15; P = .002) and 5 years (odds ratio, 2.55; 95% confidence interval, 1.37-4.76; P = .003). While on study, patients who ultimately dropped out were more likely to require resource assistance for practical (transportation, housing, financial) than psychological needs (distress, grief) or advance care planning (P = .03). CONCLUSIONS: In this study, ADI was associated with disparities in clinical trial retention of patients with breast cancer receiving adjuvant radiation treatment. Results suggest that developing multidimensional interventions that extend beyond routine social determinants needs screening are needed, not only to enhance initial clinical trial access and enrollment but also to enable robust long-term retention of socioeconomically disadvantaged patients and improve the validity and generalizability of reported long-term trial clinical and patient-reported outcomes.

A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor.

PURPOSE: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. RESULTS: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. CONCLUSIONS: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

Financial toxicity in cancer patients and subsequent risk of repeat acute care utilization.

Background: Acute care (AC) visits by cancer patients are costly sources of healthcare resources and can exert a financial burden of oncology care both for individuals with cancer and healthcare systems. We sought to identify whether cancer patients who reported more severe initial financial toxicity (FT) burdens shouldered excess risks for acute care utilization. Methods: In 225 adult patients who participated in the Economic Strain and Resilience in Cancer (ENRICh) survey study of individuals receiving ambulatory cancer care between March and September 2019, we measured the baseline FT (a multidimensional score of 0-10 indicating the least to most severe global, material, and coping FT burdens). All AC visits, including emergency department (ED) and unplanned hospital admissions, within 1-year follow-up were identified. The association between the severity of FT and the total number of AC visits was tested using Poisson regression models. Results: A total of 18.6% (n = 42) of patients had any AC visit, comprising 64.3% hospital admissions and 35.7% ED visits. Global FT burden was associated with the risk of repeat AC visits within 1-year follow-up (RR = 1.17, 95% CI 1.07-1.29, P < 0.001 for every unit increase), even after adjusting for sociodemographic and disease covariates. When examining subdimensions of FT, the burden of depleted FT coping resources (coping FT) was strongly associated with the risk of repeat AC visits (RR = 1.27, 95% CI 1.15-1.40, P < 0.001) while material FT burden showed a trend toward association (RR = 1.07, 95% CI 0.99-1.15, P = 0.07). Conclusion: In this prospective study of acute oncology care utilization outcomes among adult cancer patients, FT was a predictor of a higher burden of acute care visits. Patients with severely depleted material and also practical and social coping resources were at particular risk for repeated visits. Future studies are needed to identify whether early FT screening and intervention efforts may help to mitigate urgent acute care utilization burdens.

Pilot study of a Spanish language measure of financial toxicity in underserved Hispanic cancer patients with low English proficiency.

Background: Financial toxicity (FT) reflects multi-dimensional personal economic hardships borne by cancer patients. It is unknown whether measures of FT-to date derived largely from English-speakers-adequately capture economic experiences and financial hardships of medically underserved low English proficiency US Hispanic cancer patients. We piloted a Spanish language FT instrument in this population. Methods: We piloted a Spanish version of the Economic Strain and Resilience in Cancer (ENRICh) FT measure using qualitative cognitive interviews and surveys in un-/under-insured or medically underserved, low English proficiency, Spanish-speaking Hispanics (UN-Spanish, n = 23) receiving ambulatory oncology care at a public healthcare safety net hospital in the Houston metropolitan area. Exploratory analyses compared ENRICh FT scores amongst the UN-Spanish group to: (1) un-/under-insured English-speaking Hispanics (UN-English, n = 23) from the same public facility and (2) insured English-speaking Hispanics (INS-English, n = 31) from an academic comprehensive cancer center. Multivariable logistic models compared the outcome of severe FT (score > 6). Results: UN-Spanish Hispanic participants reported high acceptability of the instrument (only 0% responded that the instrument was "very difficult to answer" and 4% that it was "very difficult to understand the questions"; 8% responded that it was "very difficult to remember resources used" and 8% that it was "very difficult to remember the burdens experienced"; and 4% responded that it was "very uncomfortable to respond"). Internal consistency of the FT measure was high (Cronbach's α = 0.906). In qualitative responses, UN-Spanish Hispanics frequently identified a total lack of credit, savings, or income and food insecurity as aspects contributing to FT. UN-Spanish and UN-English Hispanic patients were younger, had lower education and income, resided in socioeconomically deprived neighborhoods and had more advanced cancer vs. INS-English Hispanics. There was a higher likelihood of severe FT in UN-Spanish (OR = 2.73, 95% CI 0.77-9.70; p = 0.12) and UN-English (OR = 4.13, 95% CI 1.13-15.12; p = 0.03) vs. INS-English Hispanics. A higher likelihood of severely depleted FT coping resources occurred in UN-Spanish (OR = 4.00, 95% CI 1.07-14.92; p = 0.04) and UN-English (OR = 5.73, 95% CI 1.49-22.1; p = 0.01) vs. INS-English. The likelihood of FT did not differ between UN-Spanish and UN-English in both models (p = 0.59 and p = 0.62 respectively). Conclusion: In medically underserved, uninsured Hispanic patients with cancer, comprehensive Spanish-language FT assessment in low English proficiency participants was feasible, acceptable, and internally consistent. Future studies employing tailored FT assessment and intervention should encompass the key privations and hardships in this population.

Developing and validating a human laboratory model to screen medications for smoking cessation.

INTRODUCTION: To facilitate translational work in medications development for smoking cessation, we have developed a human laboratory analogue of smoking lapse behavior. Our paradigm models 2 critical features of smoking lapse: the ability to resist the first cigarette and subsequent ad libitum smoking. In this paper we present the results of 2 studies designed to develop and validate the effect of nicotine deprivation on smoking lapse behavior. METHODS: Study 1 (n = 30) was designed to develop the model parameters by examining varying levels of nicotine deprivation (1, 6, and 18 hr; within-subject) and identifying optimum levels of monetary reinforcement to provide while modeling the ability to resist smoking. Study 2 was designed to validate the model by screening smoking cessation medications with known clinical efficacy. Subjects (n = 62) were randomized to either varenicline 2 mg/day, bupropion 300 mg/day, or placebo, and we then modeled their ability to resist smoking and subsequent ad libitum smoking. RESULTS: In Study 1, increasing levels of nicotine deprivation and decreasing levels of monetary reinforcement decreased the ability to resist smoking. In Study 2, the lapse model was found to be sensitive to medication effects among smokers who demonstrated a pattern of heavy, uninterrupted, and automated smoking (i.e., smoked within 5 min of waking). Ratings of craving, mood, withdrawal, and subjective cigarette effects are presented as secondary outcomes with results mirroring clinical findings. CONCLUSIONS: Our smoking lapse model demonstrates promise as a translational tool to screen novel smoking cessation medications. Next steps in this line of research will focus on evaluating predictive validity.

Primary Care Associated With Follow Up Viral Load Testing in Patients Cured of Hepatitis C Infection With Direct Acting Antivirals at a Multidisciplinary Addiction Treatment Program: Insights From a Real-World Setting.

OBJECTIVES: Treatment of hepatitis C virus infection (HCV) with direct acting antiviral therapy is encouraged regardless of substance use status. Patients with substance use disorder are at risk of HCV reinfection after cure. Follow up viral load testing (FUVL) with HCV RNA is recommended. We investigated factors associated with adoption of FUVL in real-world clinical settings. METHODS: Medical records of all patients with SUD who achieved HCV cure with direct acting antivirals at a multidisciplinary addiction treatment program between 2014 and 2019 were reviewed as part of a quality improvement initiative. Demographic and clinical characteristics including SUD treatment, urine toxicology results, and medical service use were collected. Factors associated with FUVL were analyzed and the rate of HCV reinfection was determined. RESULTS: Among 149 patients, 58.4% received FUVL. Receipt of FUVL was associated with engagement in ongoing primary medical care after cure (AOR 4.39, 95% CI [1.67, 11.49]). The HCV reinfection rate among those who received FUVL was 1.95 per 100 person-years of follow up (95% CI [0.64, 5.98]). There was no significant difference in the percentage of negative urine toxicology results before and after cure. CONCLUSIONS: Over half of a cohort of patients with substance use disorder cured of HCV received FUVL. The relationship between FUVL and engagement in primary medical and substance use treatment highlights the importance of integrated systems in providing longitudinal care for patients cured of HCV. Standardized interventions that facilitate FUVL testing and management of infectious complications of SUD in addiction treatment settings are needed.

Common genetic determinants of vitamin D insufficiency: a genome-wide association study.

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Microarray Profiling Reveals Distinct Circulating miRNAs in Aged Male and Female Mice Subjected to Post-stroke Social Isolation.

Social isolation (SI) increases ischemic injury and significantly delays recovery after experimental stroke. Changes in circulating microRNAs (miRNAs) have been implicated in several neurological disorders, including stroke. However, potential biomarkers to elucidate the mechanisms that underlie the detrimental effects of post-stroke isolation are unknown. Aged C57BL/6 male and female mice (18-20 months) were subjected to a 60-min middle cerebral artery occlusion followed by reperfusion and were assigned to either isolation (SI) or continued pair housing (PH) immediately after stroke. On day 15, mice were sacrificed, and plasma samples were collected for miRNAome analysis. Top candidate miRNAs and their biological functions were identified using integrated bioinformatics. The miRNAome analysis revealed a total of 21 differentially expressed miRNAs across both sexes with fold change of 3 or higher. Within the female cohort, miR-206-3p, -376a-3p, -34b-5p, -133a-5p, -466f, and -671-3p were highly altered relative to the PH housing condition. Similarly in males, miR-376c-3p, -181d-5p, -712-5p, -186-5p, -21a-3p, -30d-3p, -495-3p, -669c-5p, -335-5p, -429-3p, -31-3p, and -217-5p were identified. Following Kyoto Encyclopedia of Genes and Genomes analysis, the identified miRNAs effected distinct subset of pathways within sexes. Interactional network analysis revealed miR-495-3p (male) and miR-34b-5p (female) as pivotal nodes that targeted the largest subset of genes. We identified several sex-specific miRNAs as candidate biomarkers for post-stroke SI in aged male and female mice. Additionally, these results suggest that there is potential to use plasma-based circulating miRNAs as a source of novel biomarkers to identify biological pathways involved in post-stroke SI.

Saracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants.

More effective treatments to reduce pathological alcohol drinking are needed. The glutamatergic system and the NMDA receptor (NMDAR), in particular, are implicated in behavioral and molecular consequences of chronic alcohol use, making the NMDAR a promising target for novel pharmacotherapeutics. Ethanol exposure upregulates Fyn, a protein tyrosine kinase that indirectly modulates NMDAR signaling by phosphorylating the NR2B subunit. The Src/Fyn kinase inhibitor saracatinib (AZD0530) reduces ethanol self-administration and enhances extinction of goal-directed ethanol-seeking in mice. However, less is known regarding how saracatinib affects habitual ethanol-seeking. Moreover, no prior studies have assessed the effects of Src/Fyn kinase inhibitors on alcohol-seeking or consumption in human participants. Here, we tested the effects of saracatinib on alcohol consumption and craving/seeking in two species, including the first trial of an Src/Fyn kinase inhibitor to reduce drinking in humans. Eighteen male C57BL/6NCrl mice underwent operant conditioning on a variable interval schedule to induce habitual responding for 10% ethanol/0.1% saccharin. Next, mice received 5 mg/kg saracatinib or vehicle 2 h or 30 min prior to contingency degradation to measure habitual responding. In the human study, 50 non-treatment seeking human participants who drank heavily and met DSM-IV criteria for alcohol abuse or dependence were randomized to receive 125 mg/day saracatinib (n = 33) or placebo (n = 17). Alcohol Drinking Paradigms (ADP) were completed in a controlled research setting: before and after 7-8 days of treatment. Each ADP involved consumption of a priming drink of alcohol (0.03 mg%) followed by ad libitum access (3 h) to 12 additional drinks (0.015 g%); the number of drinks consumed and craving (Alcohol Urge Questionnaire) were recorded. In mice, saracatinib did not affect habitual ethanol seeking or consumption at either time point. In human participants, no significant effects of saracatinib on alcohol craving or consumption were identified. These results in mice and humans suggest that Fyn kinase inhibition using saracatinib, at the doses tested here, may not reduce alcohol consumption or craving/seeking among those habitually consuming alcohol, in contrast to reports of positive effects of saracatinib in individuals that seek ethanol in a goal-directed manner. Nevertheless, future studies should confirm these negative findings using additional doses and schedules of saracatinib administration.