Factors associated with frequent buprenorphine / naloxone initiation in a national survey of Canadian emergency physicians.

OBJECTIVE: To identify individual and site-related factors associated with frequent emergency department (ED) buprenorphine/naloxone (BUP) initiation. BUP initiation, an effective opioid use disorder (OUD) intervention, varies widely across Canadian EDs. METHODS: We surveyed emergency physicians in 6 Canadian provinces from 2018 to 2019 using bilingual paper and web-based questionnaires. Survey domains included BUP-related practice, demographics, attitudes toward BUP, and site characteristics. We defined frequent BUP initiation (the primary outcome) as at least once per month, high OUD prevalence as at least one OUD patient per shift, and high OUD resources as at least 3 out of the following 5 resources: BUP initiation pathways, BUP in ED, peer navigators, accessible addiction specialists, and accessible follow-up clinics. We excluded responses from sites with <50% participation (to minimize non-responder bias) and those missing the primary outcome. We used univariate analysis to identify associations between frequent BUP initiation and factors of interest, stratifying by OUD prevalence. RESULTS: We excluded 3 responses for missing BUP initiation frequency and 9 for low response rate at one ED. Of the remaining 649 respondents from 34 EDs, 374 (58%) practiced in metropolitan areas, 384 (59%) reported high OUD prevalence, 312 (48%) had high OUD resources, and 161 (25%) initiated BUP frequently. Age, gender, board certification and years in practice were not associated with frequent BUP initiation. Site-specific factors were associated with frequent BUP initiation (high OUD resources [OR 6.91], high OUD prevalence [OR 4.45], and metropolitan location [OR 2.39],) as were individual attitudinal factors (willingness, confidence, and responsibility to initiate BUP.) Similar associations persisted in the high OUD prevalence subgroup. CONCLUSIONS: Individual attitudinal and site-specific factors were associated with frequent BUP initiation. Training to increase physician confidence and increasing OUD resources could increase BUP initiation and benefit ED patients with OUD.

Auditing the AUDIT: A systematic review of cut-off scores for the Alcohol Use Disorders Identification Test (AUDIT) in low- and middle-income countries.

INTRODUCTION: The World Health Organization's (WHO) Alcohol Use Disorders Identification Test (AUDIT) is used extensively across the world, with cut-off scores recommended by the WHO. We reviewed the use and validity of AUDIT cut-off scores in low- and middle-income countries as cultural contexts are expected to influence the detection of alcohol use disorders. MATERIALS AND METHODS: The systematic review was guided by an a priori defined protocol consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We searched Cochrane library, Medline, EMBASE, PsycINFO, CINAHL, Indmed, LILACS, and AJOL databases using appropriate search terms. We conducted a narrative synthesis of the data. RESULTS: We identified 54 distinct studies that used AUDIT cut-off scores which were not in alignment with those recommended by the WHO. India (n = 10), Nigeria (n = 9), and Brazil (n = 9) produced most of these included studies. Most of the studies (n = 42) did not conduct psychometric evaluations of AUDIT cut-off scores. Of the twelve studies which did report psychometric results, a wide range of cut-off scores performed well. In these studies the cut-off scores to detect hazardous drinking ranged from >3 to >5, for harmful drinking from >5 to >16, and for dependent drinking from >7 to >24. DISCUSSION: AUDIT is being widely used in LMICs and non-recommended cut-off scores are considered to be appropriate in these countries. It is important to systematically evaluate the psychometric properties of those cut-off scores to ensure the internal validity of the studies in which they are used.

The onset and progression of alcohol use disorders: A qualitative study from Goa, India.

Quantitative evidence about the burden of alcohol use disorders (AUDs) needs to be complemented with a nuanced qualitative understanding of explanatory models to help supplement public health strategies that are too often steeped uncritically in biomedical models. The aim of this study was to identify the role of various factors in the onset and persistence of AUD and recovery from AUD. This was a qualitative study nested in a population cohort from Goa, India. In-depth interviews of men with incident, recovered, and persistent AUD covered topics such as changes in drinking habits over time, perceptions and experiences about starting/stopping drinking, and so on. Data were analyzed using thematic analysis. Reasons to begin drinking included social drinking, functional use of alcohol, stress, and boredom. Progression to problematic drinking patterns was characterized by drinking alone, alternating between abstinent and heavy drinking periods, and drinking based on the availability of finances. Some enablers to reduce/stop drinking included consequences of drinking lifestyle and personal resolve; some barriers included availability of alcohol at social events and stress. Some reasons for persisting heavy use of alcohol included lack of family support, physical withdrawal symptoms, peer pressure, stress, and easy availability. This article offers a strong conceptualization and nuanced understanding of AUD across a spectrum of developmental courses. This adds to the limited literature on explanatory models of AUD in India and identifies potential targets for prevention and treatment strategies for AUD in low- and middle-income country settings.

Out-of-Pocket and Catastrophic Expenses Incurred by Seeking Pediatric and Adult Surgical Care at a Public, Tertiary Care Centre in Uganda.

BACKGROUND: Surgical care is critical to establish effective healthcare systems in low- and middle-income countries, yet the unmet need for surgical conditions is as high as 65% in Ugandan children. Financial burden and geographical distance are common barriers to help-seeking in adult populations and are unmeasured in the pediatric population. We thus measured out-of-pocket (OOP) expenses and distance traveled for pediatric surgical care in a tertiary hospital in Mbarara, Uganda, as compared to adult surgical and pediatric medical patients. METHODS: Patients admitted to pediatric surgical (n = 20), pediatric medical (n = 18) and adult surgical (n = 18) wards were interviewed upon discharge over a period of 3 weeks. Patient and caregiver-reported expenses incurred for the present illness included prior/future care needed, and travel distance/cost. The prevalence of catastrophic expenses (≥10% of annual income) was calculated and spending patterns compared between wards. RESULTS: Thirty-five percent of pediatric medical patients, 45% of pediatric surgical patients and 55% of adult surgical patients incurred catastrophic expenses. Pediatric surgical patients paid more for their current treatment (p < 0.01)-specifically medications (p < 0.01) and tests (p < 0.01)-than pediatric medical patients, and comparable costs to adults. Adult patients paid more for treatment prior to the hospital (p = 0.04) and miscellaneous expenses (e.g., food while admitted) (p = 0.02). Patients in all wards traveled comparable distances. CONCLUSIONS: Seeking healthcare at a publicly funded hospital is financially catastrophic for almost half of patients. Out-of-stock supplies and broken equipment make surgical care particularly vulnerable to OOP expenses because analgesics, anaesthesia and preoperative imaging are prerequisites to care.

The Association Between Prenatal Stress and Externalizing Symptoms in Childhood: Evidence From the Avon Longitudinal Study of Parents and Children.

BACKGROUND: It has been suggested that prenatal maternal stress may increase the risk of childhood externalizing disorders, yet no large cohort study has investigated this association across a large range of acute stressors. Our objective was to estimate the association between prenatal stressful events and risk of offspring conduct disorder and hyperactivity. METHODS: We used data from 10,184 mother-offspring pairs from the United Kingdom-based Avon Longitudinal Study of Parents and Children. Mothers self-reported 42 prenatal stressful life events at 18 weeks' gestation. Symptoms of conduct disorder and hyperactivity in their offspring were measured at 6, 9, 11, 13, and 16 years of age using the Strengths and Difficulties Questionnaire. The primary outcome was membership in high-symptom trajectories of 1) conduct disorder and 2) hyperactivity throughout childhood, identified using latent class growth modeling. Multinomial logistic regression models estimated the association between prenatal stress and both conduct disorder and hyperactivity, after adjusting for sex, parental education, low birth weight, preterm birth, parental social class, maternal smoking and drinking, maternal mental health, offspring stressful life events, and offspring depressive and anxious symptoms. RESULTS: Those exposed to the highest quartile of prenatal stress were more likely to belong to the high symptom trajectory for hyperactivity (B = 0.46, p < .05) and conduct disorder (B = 0.88, p < .01), respectively. Prenatal stress further demonstrated a positive, dose-response relationship with symptoms of externalizing disorders at independent time points. CONCLUSIONS: The findings suggest that prenatal stressful events may be an independent risk factor for offspring externalizing symptoms, regardless of maternal mental health and offspring internalizing.

Sex-Specific Differences in the Association Between Childhood Adversity and Cardiovascular Disease in Adulthood: Evidence From a National Cohort Study.

BACKGROUND: Childhood adversity increases the risk for cardiovascular disease (CVD) in adulthood. Previously proposed mechanisms suggest that the association is mediated by stress reactivity-known to be higher in women-and is aggravated by adult stress, but this has not yet been confirmed. Therefore, we investigated sex differences to better understand possible pathways from childhood adversity to CVD. METHODS: The National Population Health Survey, a 15-year cohort study of Canadians aged 18-49 years at baseline was used. Logistic regression with interaction terms for sex and stressful life events was used to assess the risk of CVD after childhood adversity. In secondary analyses, we assessed mediation effects of depression, smoking, alcohol, exercise, and diet using the product of coefficient approach. Mediated moderation was subsequently used to explain sex-moderated effects. RESULTS: There was a strong association between childhood adversity and CVD (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.56-2.94) for 3+ childhood adversities. The association was stronger with increasing stressful events, and female patients with 3+ stressful events exhibited the highest risk of CVD (OR, 4.40; 95% CI, 1.98-9.75). No association was found in men. Depression, smoking, and poor diet partially mediated the relationship between childhood adversity and CVD (14%, 9%, and 9%, respectively), but differences in these behaviours did not fully explain the sex-specific differences in the mediated moderation analysis. CONCLUSIONS: The effect of childhood adverse events on CVD is heightened among women, particularly women with stressful adulthoods, and this difference is not mediated by depression, smoking, or poor diet. These findings have important implications for understanding sex differences in CVD risk.

Factors Associated with Suicidal Thought and Help-Seeking Behaviour in Transition-Aged Youth versus Adults.

OBJECTIVE: Suicide is a leading cause of death for transition-aged youth (TAY), and yet few studies examine correlates of suicidal ideation specifically in this age demographic (age 18-24 years). The transition to adulthood is a unique context, marked by novel stressors (e.g., joining the workforce) and increased independence, which may influence risk factors for suicidal ideation. This study examined correlates of suicidal ideation in TAY and adults and contrasted profiles across age. METHODS: We used 4 biannual cycles (2005, 2007, 2009, 2011) of the Canadian Community Health Survey, a population-based cross-sectional survey on health. We used logistic regression to assess the association between suicidal ideation and depression, distress, alcohol use, smoking, exercise, sedentary behaviour, chronic illness, restrictions to daily living, perceived physical and mental health, and perceived social support independently in both TAY ( n = 4427) and adults ( n = 14,452). We subsequently assessed possible interactions with age (18-24 v. 25-44 years) and sex and differences in help-seeking behaviour in a combined model. RESULT: TAY exhibited higher rates of suicidal ideation than adults did ( P < 0.001). Numerous factors were associated with suicidal ideation in TAY. Notably, alcohol abstinence was associated with decreased suicidal ideation in TAY but not for adults. Moreover, when depressed, TAY were significantly less likely to have received professional mental health help than adults (odds ratio = 0.64, 95% CI, 0.43 to 0.94). CONCLUSIONS: Suicidal ideation is more prevalent in TAY than adults, and its consequences may be aggravated by poor treatment-seeking behaviour in at-risk (i.e. depressed) individuals. These different risk profiles substantiate the recent shift toward clinical interventions focusing on transition-aged youth, rather than traditional child (<18 years) and adult (>18 years) services.

Stressful Life Events During Pregnancy and Offspring Depression: Evidence From a Prospective Cohort Study.

OBJECTIVE: The fetal programming hypothesis posits that in utero exposure to stress can alter prenatal brain development and lifelong stress response. However, human studies linking objective prenatal stressors to offspring mental illness, especially depression, are rare. The purpose of this study was to examine the association between mothers' exposure to prenatal stressful life events (SLEs) and offspring depression. METHOD: The sample comprised 10,569 members of a prospective population-based cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers reported on the occurrence and impact of 42 prenatal SLEs. Offspring depressive symptoms were assessed using a computerized version of the Clinical Interview Schedule-Revised (CIS-R) at age 17 to 18, as well as 13 self-report statements from the Short Mood and Feelings Questionnaire (SMFQ) at 6 time points from ages 10 to 11 to 18 to 19. Latent class growth analysis (LCGA) was used to identify trajectories of depressive symptoms across adolescence. RESULTS: After adjusting for potential confounders, a 1-unit increase in maternal SLE scores (range, 0-168) during gestation was associated with increased offspring depressive symptoms (ß = 0.07, p < .01) and major depression (odds ratio [OR] = 1.03, 95% CI 1.01, 1.06) at age 17 to 18. LCGA revealed 4 trajectories of depressive symptoms. High maternal SLEs (fourth quartile) were associated with membership in the trajectory characterized by stable, high levels of depression from age 10 to 11 to 18 to 19 years (OR = 1.72, 95% CI = 1.09, 2.71). CONCLUSION: These results provide support for the fetal programming hypothesis, demonstrating that prenatal exposure to acute stress is associated with offspring depression in adolescence. Stress management may be of benefit for expectant mothers.

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy.

The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies. Cancer Res; 76(16); 4627-36. ©2016 AACR.

Benefit, Risk, and Outcomes in Drug Development: A Systematic Review of Sunitinib.

BACKGROUND: Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total patient burden/benefit in developing a new drug. METHODS: We measured risk using drug-related adverse events that were grade 3 or higher, benefit by objective response rate, and trial outcomes by whether studies met their primary endpoint with acceptable safety. The differences in risk (death rate) and benefit (overall response rate) between industry and nonindustry trials were analyzed with an inverse-variance weighted fixed effects meta-analysis implemented as a weighted regression analysis. All statistical tests were two-sided. RESULTS: We identified 103 primary publications of sunitinib monotherapy, representing 9092 patients and 3991 patient-years of involvement over 10 years and 32 different malignancies. In total, 1052 patients receiving sunitinib monotherapy experienced objective tumor response (15.7% of intent-to-treat population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from drug-related toxicities (1.08%, 95% CI = 1.02% to 1.14%), and at least 1245 experienced grade 3-4 drug-related toxicities (13.7%, 95% CI = 13.3% to 14.1%). Risk/benefit worsened as the development program matured, with several instances of replicated negative studies and almost no positive trials after the first responding malignancies were discovered. CONCLUSIONS: Even for a successful drug, the risk/benefit balance of trials was similar to phase I cancer trials in general. Sunitinib monotherapy development showed worsening risk/benefit, and the testing of new indications responded slowly to evidence that sunitinib monotherapy would not extend to new malignancies. Research decision-making should draw on evidence from whole research programs rather than a narrow band of studies in the same indication.

A meta-analysis of threats to valid clinical inference in preclinical research of sunitinib.

Poor study methodology leads to biased measurement of treatment effects in preclinical research. We used available sunitinib preclinical studies to evaluate relationships between study design and experimental tumor volume effect sizes. We identified published animal efficacy experiments where sunitinib monotherapy was tested for effects on tumor volume. Effect sizes were extracted alongside experimental design elements addressing threats to valid clinical inference. Reported use of practices to address internal validity threats was limited, with no experiments using blinded outcome assessment. Most malignancies were tested in one model only, raising concerns about external validity. We calculate a 45% overestimate of effect size across all malignancies due to potential publication bias. Pooled effect sizes for specific malignancies did not show apparent relationships with effect sizes in clinical trials, and we were unable to detect dose-response relationships. Design and reporting standards represent an opportunity for improving clinical inference.

Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials.

BACKGROUND: Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. OBJECTIVE: To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual. METHODS: We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual. RESULTS: Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001). CONCLUSION: A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging.