Search

It has long been recognized that sample size calculations for cluster randomized trials require consideration of the correlation between multiple observations within the same cluster. When measurements are taken at anything other than a single point in time, these correlations depend not only on the cluster but also on the time separation between measurements and additionally, on whether different participants (cross-sectional designs) or the same participants (cohort designs) are repeatedly measured. This is particularly relevant in trials with multiple periods of measurement, such as the cluster cross-over and stepped-wedge designs, but also to some degree in parallel designs. Several papers describing sample size methodology for these designs have been published, but this methodology might not be accessible to all researchers. In this article we provide a tutorial on sample size calculation for cluster randomized designs with particular emphasis on designs with multiple periods of measurement and provide a web-based tool, the Shiny CRT Calculator, to allow researchers to easily conduct these sample size calculations. We consider both cross-sectional and cohort designs and allow for a variety of assumed within-cluster correlation structures. We consider cluster heterogeneity in treatment effects (for designs where treatment is crossed with cluster), as well as individually randomized group-treatment trials with differential clustering between arms, for example designs where clustering arises from interventions being delivered in groups. The calculator will compute power or precision, as a function of cluster size or number of clusters, for a wide variety of designs and correlation structures. We illustrate the methodology and the flexibility of the Shiny CRT Calculator using a range of examples. [ABSTRACT FROM AUTHOR]

Aims: Interventional cardiology procedures may expose patients and staff to considerable radiation doses. We aimed to assess whether exposure to ionizing radiation during catheter ablation of supraventricular tachycardia (SVT) can be completely avoided.Methods and Results: In this prospective randomized study, patients with SVT (atrioventricular re-entrant tachycardia n = 94, typical atrial flutter n = 29) were randomly assigned in a 1:1 ratio to catheter ablation with conventional fluoroscopic guidance (CF group) or with the EnSite Precision mapping system [zerofluoro (ZF) group]. Acute procedural parameters, increased stochastic risk of cancer incidence and 6-month follow-up data were assessed. Between May 2019 and August 2020, 123 patients were enrolled. Clinical parameters were comparable. Median procedural time was 60.0 and 58.0 min, median fluoroscopy time and estimated median effective dose were 240 s vs. 0 and 0.38 mSv vs. 0 and arrhythmia recurrence was 5% and 7.9% in the CF and ZF groups, respectively. The acute success rate was 98.4% in both groups. No procedure-related complications were reported. At an average age of 55.5 years and median radiation exposure of 0.38 mSv, the estimate of increased incidence was approximately 1 in 14 084. The estimated mortality rate was 1 per 17 857 exposed persons.Conclusions: The procedural safety and efficacy of the zero-fluoroscopic approach are similar to those of conventional fluoroscopy-based ablation for atrioventricular nodal re-entrant tachycardia and atrial flutter. Under the assumption of low radiation dose, the excessive lifetime risk of malignancy in the CF group due to electrophysiology procedure is reasonably small, whilst totally reduced in zero fluoroscopy procedures. [ABSTRACT FROM AUTHOR]

Background: The female sex is associated with poorer outcomes after myocardial infarction (MI), although current evidence in older patients is limited and mixed. We sought to evaluate sex-based differences in outcome after MI in older patients.Method: Consecutive older (≥70 years) all-comer patients with out-of-hospital MI admitted to 20 hospitals in Finland between 2005 and 2014 were studied using national registries (n = 40 654, mean age 80 years, 50% women). The outcome of interest was death within 1 year after MI. Differences between sexes (age, baseline features, medication, comorbidities, revascularization, and treating hospital) were balanced by inverse probability weighting.Results: Adjusted all-cause case fatality was lower in women than in men at 30 days (16.0% vs 19.0%, respectively) and at 1 year (27.7% vs 32.4%, respectively) after MI (hazard ratio: 0.83; confidence interval [CI]: 0.80-0.86; p < .0001). Excess 1-year case fatality after MI compared to the corresponding general population was 22.1% (CI: 21.4%-22.8%) in women and 24.1% (CI: 23.4%-24.9%) in men. Women had a lower adjusted hazard of death after MI in subgroups of patients aged 70-79 years and ≥80 years, patients with and without ST elevation MI, revascularized and non-revascularized patients, patients with and without atrial fibrillation, and patients with and without diabetes. The sex difference in case fatality remained similar during the study period.Conclusions: Older women were found to have a lower hazard of death after an out-of-hospital MI when compared to older men with similar features and treatments. This finding was consistent in several subgroups. [ABSTRACT FROM AUTHOR]

With the availability of limited resources, innovation for improved statistical method for the design and analysis of randomized controlled trials (RCTs) is of paramount importance for newer and better treatment discovery for any therapeutic area. Although clinical efficacy is almost always the primary evaluating criteria to measure any beneficial effect of a treatment, there are several important other factors (e.g., side effects, cost burden, less debilitating, less intensive, etc.), which can permit some less efficacious treatment options favorable to a subgroup of patients. This leads to non-inferiority (NI) testing. The objective of NI trial is to show that an experimental treatment is not worse than an active reference treatment by more than a pre-specified margin. Traditional NI trials do not include a placebo arm for ethical reason; however, this necessitates stringent and often unverifiable assumptions. On the other hand, three-arm NI trials consisting of placebo, reference, and experimental treatment, can simultaneously test the superiority of the reference over placebo and NI of experimental treatment over the reference. In this article, we proposed both novel Frequentist and Bayesian procedures for testing NI in the three-arm trial with Poisson distributed count outcome. RCTs with count data as the primary outcome are quite common in various disease areas such as lesion count in cancer trials, relapses in multiple sclerosis, dermatology, neurology, cardiovascular research, adverse event count, etc. We first propose an improved Frequentist approach, which is then followed by it's Bayesian version. Bayesian methods have natural advantage in any active-control trials, including NI trial when substantial historical information is available for placebo and established reference treatment. In addition, we discuss sample size calculation and draw an interesting connection between the two paradigms. [ABSTRACT FROM AUTHOR]

Background: Rectal gonorrhoea is a common sexually transmitted infection with increasing antimicrobial resistance requiring optimization of available treatments.Objectives: This systematic review aimed to assess the efficacy of current treatments, previously trialled treatments and new emerging treatments for rectal Neisseria gonorrhoeae (NG).Methods: Online bibliographic databases were search from 1 January 1946 to 14 August 2020. All randomized controlled trials (RCTs) with rectal NG data among participants aged 15 years or above and published in English were included. Random effects meta-analyses were used to estimate overall treatment efficacy, defined as microbiological cure. Sub-group analyses included stratifying by diagnostic assay, by dual versus monotherapy, and by currently recommended treatments (e.g. ceftriaxone ± azithromycin) versus previously trialled but not recommended treatments (e.g. amoxicillin) versus emerging treatments (e.g. zoliflodacin). The study protocol was registered on PROSPERO (CRD42020202998).Results: 54 studies including 1813 participants and 44 treatment regimens were identified. The overall summary treatment efficacy for rectal NG was 100.0% (95% CI: 99.9%-100.0%; I2 = 0.0%; P = 0.86). Efficacy estimates for monotherapies (100.0%; 95% CI: 99.88%-100.0%; I2 = 0.00%; P = 0.97) and dual therapies (100.0%; 95% CI: 97.65%-100.0%; I2 = 56.24%; P = 0.03) were similar. Efficacy was highest for current treatments (100.00%; 95% CI: 99.96%-100.00%; I2 = 0.00%; P = 0.98) versus emerging treatments (97.16%; 95% CI: 86.79%-100.00%; I2 = 0.00%; P = 0.84). There were no trials exclusively investigating rectal NG and small sample size was a limitation in most trials.Conclusions: Currently recommended treatments containing ceftriaxone, as mono or dual therapy, are effective. Emerging drugs such as zoliflodacin may be potentially useful for rectal NG but further data are needed. [ABSTRACT FROM AUTHOR]

Introduction: While large proportions of smokers attempt to quit, rates of relapse remain high and identification of valid prognostic markers is of high priority. Delayed reward discounting (DRD) is a behavioral economic index of impulsivity that has been associated with smoking cessation, albeit inconsistently. This systematic review sought to synthesize the empirical findings on DRD as a predictor of smoking cessation treatment outcome, to critically appraise the quality of the literature, and to propose directions for future research.Aims and Methods: A total of 734 articles were identified, yielding k = 14 studies that met the eligibility criteria. The Quality in Prognosis Studies (QUIPS) tool was used to assess methodological quality of the included studies.Results: Individual study methods were highly heterogeneous, including substantial variation in research design, DRD task, clinical subpopulation, and treatment format. The predominant finding was that steeper DRD (higher impulsivity) was associated with significantly worse smoking cessation outcomes (10/14 studies). Negative results tended to be in pregnant and adolescent subpopulations. The QUIPS results suggested low risk of bias across studies; 11/14 studies were rated as low risk of bias for 5/6 QUIPS domains.Conclusions: This review revealed consistent low-bias evidence for impulsive DRD as a negative prognostic predictor of smoking cessation treatment outcome in adults. However, methodological heterogeneity was high, precluding meta-analysis and formal tests of small study bias. The prospects of targeting impulsive DRD as a potentially modifiable risk factor or providing targeted treatment for smokers exhibiting high levels of discounting are discussed.Implications: These findings indicate consistent evidence for DRD as a negative prognostic factor for smoking cessation outcome in adults. As such, DRD may be a useful as a novel treatment target or for identifying high-risk populations requiring more intensive treatment. [ABSTRACT FROM AUTHOR]

This multicountry prospective study investigated whether persistent systemic inflammation, measured by 8 plasma biomarkers, in HIV-1-infected Africans during suppressive antiretroviral therapy (ART) (viral load <50 copies/mL), was associated with CD4+ T-cell recovery and viral rebound (>1000 copies/mL) during long-term treatment. On-ART sCD14 and C-reactive protein concentrations were inversely associated with subsequent CD4+ T-cell counts. Risk of viral rebound was increased for participants with higher on-ART CXCL10 concentrations and reduced for those with a greater sCD163 decline during the first year of ART. Persistent systemic inflammation predicted CD4+ T-cell recovery and viral rebound, warranting further mechanistic research in relation to clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: During the period of hospitalization, patients can develop functional decline. The main aim of our study was to assess the natural trajectory of each activity of daily living (ADL) and to assess how in-hospital exercise could influence short-term trajectory of ADLs.Method: Acutely hospitalized patients (n = 297, 56.5% women) were randomly assigned to the intervention or control (usual care) group within the first 48 hours of admission. An exercise training program was prescribed in 2 daily sessions (morning and evening) of 20 minutes duration during 5-7 consecutive days for the intervention group. The primary endpoint was the change in every ADL (assessed with the Barthel Index) from 2 weeks before admission to hospital discharge.Results: Acute hospitalization per se led to significant in-patient's functional ability impairment in ADLs during hospitalization, whereas the exercise intervention reversed this trend (3.7 points; 95% CI: 0.5-6.8 points). After analyzing the trajectory of each one of the ADLs, patients in the control group significantly worsened all activities, but with a different degree of loss. For the between-group analysis, significant differences were obtained in many ADLs including bathing, dressing, grooming, bladder control, toilet use, transfers, mobility, and climbing stairs (p < .05). The control group had the greatest impairment in all domains analyzed (ie, feeding, bathing, dressing, grooming, bowel control, bladder control, toilet use, transfers, mobility, and climbing stairs; p < .05).Conclusions: An individualized multicomponent exercise training program in older adults is effective to reverse the loss of specific ADLs that frequently occurs during hospitalization. Each patient profile should receive an individualized prescription of exercise during hospitalizations.Clinical Trials Registration Number: NCT02300896. [ABSTRACT FROM AUTHOR]

Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention. [ABSTRACT FROM AUTHOR]

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Self-monitoring is a key component of behavioral weight loss (BWL) interventions. Past research suggests that individuals may avoid self-monitoring in certain contexts (e.g., skipping self-weighing after higher-than-usual calorie intake). However, no studies have attempted to quantify individuals' inclination to avoid information about their weight control ("weight-related information avoidance"; WIA) or prospectively examined its implications for treatment engagement and outcomes in BWL programs.Purpose: Characterize WIA using a validated questionnaire among adults enrolled in BWL treatment and examine whether WIA prospectively predicts self-monitoring adherence, session attendance, treatment discontinuation, or weight loss.Methods: Participants (N = 87; MBMI = 34.9 kg/m2, 83% female) completed a measure of WIA prior to starting a 12 week, group-based BWL intervention. Participants were given digital self-monitoring tools and instructed to self-monitor their food intake daily, physical activity daily, and body weight weekly (Weeks 1-10) and then daily (Weeks 11-12). Session attendance and treatment discontinuation were recorded. Weight was measured in-clinic pretreatment and posttreatment.Results: While mean WIA was low (M = 2.23, standard deviation [SD] = 0.95; potential scale range: 1-7), greater WIA predicted poorer attendance (r = -.23; p = .03) and poorer self-monitoring of physical activity (r = -.28; p = .009) and body weight (r = -.32; p = .003). WIA did not predict food monitoring (p = .08), treatment discontinuation (p = .09), or 12 week weight loss (p = .91).Conclusions: Greater WIA, as assessed via a brief questionnaire, may place individuals at risk for poorer self-monitoring and treatment engagement during BWL. Further research on the implications of WIA in the context of weight management is warranted, including evaluation of correlates, moderators, and mechanisms of action of WIA.Clinical Trial Registration: NCT03337139. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of common treatments for polycystic ovary syndrome (PCOS) on a panel of hormones (reproductive/metabolic).Design: Secondary analysis of blood from a randomized controlled trial of three 16-week preconception interventions designed to improve PCOS-related abnormalities: continuous oral contraceptive pills (OCPs, N = 34 subjects), intensive lifestyle modification (Lifestyle, N = 31), or a combination of both (Combined, N = 29).Materials and Methods: Post-treatment levels of activin A and B, inhibin B, and follistatin (FST), as well as Insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 2 (IGFBP-2), glucagon, glucagon-like peptide 1 (GLP-1) and 2, and oxyntomodulin were compared to baseline, and the change from baseline in these parameters were correlated with outcomes.Results: Oral contraceptive pill use was associated with a significant suppression in activin A, inhibin A, and anti-mullerian hormone (AMH), but a significant increase in FST. IGF-1, IGFBP-2, glucagon, and GLP-2 levels were significantly decreased. Oxyntomodulin was profoundly suppressed by OCPs (ratio of geometric means: 0.09, 95% confidence interval [CI]: 0.05, 0.18, P < 0.001). None of the analytes were significantly affected by Lifestyle, whereas the effects of Combined were similar to OCPs alone, although attenuated. Oxyntomodulin was significantly positively associated with the change in total ovarian volume (rs = 0.27; 95% CI: 0.03, 0.48; P = 0.03) and insulin sensitivity index (rs = 0.48; 95% CI: 0.27, 0.64; P < 0.001), and it was inversely correlated with change in area under the curve (AUC) glucose [rs = -0.38; 95% CI: -0.57, -0.16; P = 0.001]. None of the hormonal changes were associated with live birth, only Activin A was associated with ovulation (risk ratio per 1 ng/mL increase in change in Activin A: 6.0 [2.2, 16.2]; P < 0.001).Conclusions: In women with PCOS, OCPs (and not Lifestyle) affect a wide variety of reproductive/metabolic hormones, but their treatment response does not correlate with live birth. [ABSTRACT FROM AUTHOR]

Background: In the United States, human papillomavirus (HPV) vaccination has been recommended for young adult men who have sex with men (MSM) since 2011.Methods: The Vaccine Impact in Men study surveyed MSM and transgender women aged 18-26 years in 3 US cities during 2016-2018. Self-collected anal swab and oral rinse specimens were assessed for 37 types of HPV. We compared HPV prevalence among vaccinated and unvaccinated participants and determined adjusted prevalence ratios (aPR) and 95% confidence intervals (CI).Results: Among 1767 participants, 704 (39.8%) self-reported receiving HPV vaccine. Median age at vaccination (18.7 years) was older than age at first sex (15.7 years). Quadrivalent vaccine-type HPV was detected in anal or oral specimens from 475 (26.9%) participants. Vaccine-type HPV prevalence was lower among vaccinated (22.9%) compared with unvaccinated (31.6%) participants; aPR for those who initiated vaccination at age ≤18 years was 0.41 (CI, 0.24-0.57) and at age >18 years was 0.82 (CI, 0.67-0.98). Vaccine effectiveness of at least 1 HPV vaccine dose at age ≤18 years or >18 years was 59% and 18%, respectively.Conclusions: Findings suggest real-world effectiveness of HPV vaccination among young adult MSM. This effect was stronger with younger age at vaccination. [ABSTRACT FROM AUTHOR]

Nonobstructive azoospermia, (NOA) is the most common cause of azoospermia. NOA is characterized by hypergonadotropic hypogonadism, testicular failure, and impaired spermatogenesis. The recent development of surgical sperm retrieval techniques such as microsurgical testicular sperm extraction (mTESE) has, for the first time, allowed some men with NOA to father biological children. It is common practice for endocrine stimulation therapies such as gonadotropins, selective estrogen receptor modulators (SERMs), and aromatase inhibitors to be used prior to mTESE to increase intratesticular testosterone synthesis with the aim of improving sperm retrieval rates; however, there is currently a paucity of data underpinning their safety and efficacy. We present 2 cases of men with NOA undergoing endocrine stimulation therapy and mTESE. We also discuss the current evidence and controversies associated with the use of hormonal stimulation therapy in couples affected by this severe form of male infertility. [ABSTRACT FROM AUTHOR]

Poor mental health is a pressing global health problem, with high prevalence among poor populations from low-income countries. Existing studies of conditional cash transfer (CCT) effects on mental health have found positive effects. However, there is a gap in the literature on population-wide effects of cash transfers on mental health and if and how these vary by the severity of mental illness. We use the Malawian Longitudinal Study of Family and Health containing 790 adult participants in the Malawi Incentive Programme, a year-long randomized controlled trial. We estimate average and distributional quantile treatment effects and we examine how these effects vary by gender, HIV status and usage of the cash transfer. We find that the cash transfer improves mental health on average by 0.1 of a standard deviation. The effect varies strongly along the mental health distribution, with a positive effect for individuals with worst mental health of about four times the size of the average effect. These improvements in mental health are associated with increases in consumption expenditures and expenditures related to economic productivity. Our results show that CCTs can improve adult mental health for the poor living in low-income countries, particularly those with the worst mental health. [ABSTRACT FROM AUTHOR]

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution. [ABSTRACT FROM AUTHOR]

Context: Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20% and 40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect.Objective: The objective of this work is to determine whether MS disease progression following alemtuzumab treatment differs in patients who develop AITD compared to those who do not.Design, Setting, and Patients: A retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 was conducted at a tertiary referral center.Main Outcome Measures: Thyroid status, new relapses, Expanded Disability Status Scale (EDSS) score change, and disability progression following alemtuzumab were evaluated.Results: Twenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [interquartile range]; AITD: -0.25 [-1 to 0.5] vs non-AITD: 0 [1-0]. P = .007]. Multivariable regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (P = .011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (P = .023). There was no difference in the number of new focal T2 lesions and contrast-enhancing magnetic resonance imaging lesions developed following alemtuzumab between the 2 groups.Conclusion: Graves disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate. [ABSTRACT FROM AUTHOR]

Context: It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting.Objective: The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk.Design: VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median).Setting: This is a nationwide study.Participants: Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study.Interventions: Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design.Main Outcome Measures: Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit.Results: Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points.Conclusion: Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population. [ABSTRACT FROM AUTHOR]

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants. [ABSTRACT FROM AUTHOR]

Introduction: This study examined relations of two affective vulnerabilities, high anxiety sensitivity (AS) and low distress tolerance (DT), with tobacco dependence, withdrawal, smoking cessation, and pharmacotherapy response.Methods: Smokers interested in quitting (N = 1067; 52.2% female, 28.1% African American) were randomized to 12 weeks of nicotine patch, nicotine patch plus nicotine lozenge, or varenicline. Baseline questionnaires assessed AS, DT, negative affect, anxiety, and dependence. Withdrawal was assessed the first-week post-quit via ecological momentary assessment.Results: DT, but not AS, predicted biochemically confirmed point-prevalence abstinence at multiple endpoints: weeks 4, 12, 26, and 52 post-quit (ps < .05); relations remained after controlling for pharmacotherapy treatment, AS, baseline negative affect, anxiety, and anxiety disorder history (ps < .05). Additional exploratory analyses examining week 4 abstinence showed DT predicted abstinence (p = .004) even after controlling for baseline dependence, post-quit withdrawal (craving and negative affect), and treatment. DT moderated treatment effects on abstinence in exploratory analyses (interaction p = .025); those with high DT were especially likely to be abstinent at week 4 with patch plus lozenge versus patch alone.Conclusions: DT, but not AS, predicted abstinence over 1 year post-quit (higher DT was associated with higher quit rates), with little overlap with other affective measures. DT also predicted early abstinence independent of dependence and withdrawal symptoms. Results suggest low DT may play a meaningful role in motivation to use tobacco and constitute an additional affective risk factor for tobacco cessation failure beyond negative affect or clinical affective disorders.Implications: People in a stop-smoking study who reported a greater ability to tolerate distress were more likely to quit smoking and remain smoke-free 1 year later. Smokers with high DT were more likely to be smoke-free 4 weeks after their target quit day if they received nicotine patch plus nicotine lozenge rather than nicotine patch alone.Trial Registration: NCT01553084. [ABSTRACT FROM AUTHOR]

Individuals often respond differently to identical treatments, and characterizing such variability in treatment response is an important aim in the practice of personalized medicine. In this article, we describe a nonparametric accelerated failure time model that can be used to analyze heterogeneous treatment effects (HTE) when patient outcomes are time-to-event. By utilizing Bayesian additive regression trees and a mean-constrained Dirichlet process mixture model, our approach offers a flexible model for the regression function while placing few restrictions on the baseline hazard. Our nonparametric method leads to natural estimates of individual treatment effect and has the flexibility to address many major goals of HTE assessment. Moreover, our method requires little user input in terms of model specification for treatment covariate interactions or for tuning parameter selection. Our procedure shows strong predictive performance while also exhibiting good frequentist properties in terms of parameter coverage and mitigation of spurious findings of HTE. We illustrate the merits of our proposed approach with a detailed analysis of two large clinical trials (N = 6769) for the prevention and treatment of congestive heart failure using an angiotensin-converting enzyme inhibitor. The analysis revealed considerable evidence for the presence of HTE in both trials as demonstrated by substantial estimated variation in treatment effect and by high proportions of patients exhibiting strong evidence of having treatment effects which differ from the overall treatment effect. [ABSTRACT FROM AUTHOR]

Clinical management of chronic diseases requires periodic evaluations. Subjects transition between various levels of severity of a disease over time, one of which may trigger an intervention that requires treatment. For example, in diabetic retinopathy, patients with type 1 diabetes are evaluated yearly for either the onset of proliferative diabetic retinopathy (PDR) or clinically significant macular edema (CSME) that would require immediate treatment to preserve vision. Herein, we investigate methods for the selection of personalized cost-effective screening schedules and compare them with a fixed visit schedule (e.g., annually) in terms of both cost and performance. The approach is illustrated using the progression of retinopathy in the DCCT/EDIC study. [ABSTRACT FROM AUTHOR]

Background: Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide-treated nets remain the main interventions for prevention of malaria in human immunodeficiency virus (HIV)-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these interventions, and new ones are needed.Methods: We conducted a double-blinded, randomized, placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide had recently been implemented. Participants were enrolled between gestation weeks 12 and 28 and given an insecticide-treated net. The primary outcome was detection of active or past placental malarial infection by histopathologic analysis. Secondary outcomes included incidence of malaria, parasite prevalence, and adverse birth outcomes.Result: All 200 women enrolled were followed through delivery, and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of histopathologically detected placental malarial infection between the daily TMP-SMX plus DP arm and the daily TMP-SMX alone arm (6.1% vs. 3.1%; relative risk, 1.96; 95% confidence interval, .50-7.61; P = .50). Similarly, there were no differences in secondary outcomes.Conclusions: Among HIV-infected pregnant women in the setting of indoor residual spraying of insecticide, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes.Clinical Trials Registration: NCT02282293. [ABSTRACT FROM AUTHOR]

Introduction: Converging clinical and biological evidence suggest sex is an important factor when selecting a pharmacological intervention for smoking cessation. The current investigation used network meta-analyses to estimate sex differences in the comparative efficacy of transdermal nicotine (TN), varenicline, and sustained release (SR) bupropion for smoking cessation.Methods: Systematically searched previously published reviews and databases (Medline, PsycINFO, Embase) of randomized, double-blind, placebo-controlled trials of bupropion-SR, TN, and varenicline for cigarette smoking cessation in primary care/general community samples were included.Results: Thirty-two studies met all criteria and 28 (88%) were included in the final analyses, representing 14 389 smokers (51% female). Results of the full sample (women and men combined) mirrored those from a Cochrane Tobacco Addiction Group network meta-analysis of smoking cessation pharmacotherapy, showing VAR>TN=BUP. All medications improved quit rates over placebo for both women and men. Relative to placebo, varenicline efficacy was similar for women and men. Significant sex differences were evident when comparing varenicline versus TN and varenicline versus bupropion. For women, varenicline was more efficacious than TN (RR = 1.41; 95% CI = 1.12,1.76) and bupropion (RR = 1.38; 95% CI = 1.08,1.77). For men, outcomes for those treated with TN and bupropion were similar to those treated with varenicline. There were no differences in efficacy when comparing bupropion versus TN.Conclusions: The advantage of varenicline over bupropion SR and TN is greater for women than men. Clinicians should strongly consider varenicline as the first option treatment for women. Among men, the advantage of varenicline over TN or bupropion is less clear.Implications: This study provides information for the sex-informed treatment of nicotine addiction among cigarette smokers. Relative to placebo, women and men achieved similar outcomes when treated with varenicline; however the advantages of varenicline over transdermal patch and bupropion were greater for women compared to men. [ABSTRACT FROM AUTHOR]

Background: Fractional-dose administration of inactivated poliovirus vaccine (fIPV) could increase IPV affordability and stretch limited supplies. We assessed immune responses following fIPV administered intradermally, compared with full-dose IPV administered intramuscularly, among adults with a history of oral poliovirus vaccine (OPV) receipt.Methods: We conducted a randomized, controlled noninferiority trial in Cuba. fIPV or IPV were administered on days 0 and 28; serum was collected on days 0, 7, 28, and 56 for analysis by a neutralization assay. The primary end point was seroconversion or a ≥4-fold rise in antibody titer. The noninferiority limit was 10%. The secondary end point was safety, assessed by the number and intensity of adverse reactions.Results: A total of 503 of 534 enrolled participants (94.2%) completed all study requirements. Twenty-eight days after the first dose, 94.8%, 98.0%, and 98.0% of fIPV recipients had an immune response to poliovirus types 1, 2, and 3, respectively, compared with 98.1% (P = .06), 98.0% (P = 1.00), and 99.2% (P = .45) in the IPV arm. Noninferiority was achieved on days 7, 28, and 56 for all serotypes. No serious adverse events were reported.Conclusion: fIPV induced similar boosting immune responses, compared with full-dose IPV. This suggests that fIPV would be an effective strategy to boost population immunity in an outbreak situation.Clinical Trials Registration: ACTRN12615000305527. [ABSTRACT FROM AUTHOR]

Illicit drug use is common among patients admitted following burn injury. The authors sought to evaluate whether drug abuse results in worse outcomes. The National Burn Repository (NBR) was queried for data on all patients with drug testing results available. Outcomes included mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, and duration of ventilator support. Propensity score weighting was performed to control for age, alcohol use, burn size, gender, and etiology of burn. A total of 20,989 patients had drug screen data available; 11,642 (55.5%) tested positive for at least one drug of abuse. Illicit drug use was associated with a higher proportion of patients with flame burn (53.2 vs 48.4%) and larger average burn size (11.2 vs 9.5% TBSA, P < .001). Attempted suicide was more likely if the patient had used drugs (2.8 vs 1.7%, P < .001). Drug use resulted in longer hospital and ICU LOS (14.2 vs 11.4 and 8.5 vs 5.6 days, P < .001), but did not increase the risk of mortality (5.7 vs 5.2, P = .08). After propensity score weighting, drug use did not affect mortality, hospital LOS, or duration of ventilator support, but did increase the average ICU LOS by 1.2 days (P = .001). Drug use does not affect mortality, hospital LOS, or duration of ventilator support among burned patients. After controlling for burn size, age, mechanism of injury, and gender, patients with a positive drug screen had an average increase in ICU LOS by 1 day. [ABSTRACT FROM AUTHOR]

Objectives: Optimizing antiretroviral drug combination on an individual basis in resource-limited settings is challenging because of the limited availability of drugs and genotypic resistance testing. Here, we describe our latest computational models to predict treatment responses, with or without a genotype, and compare the potential utility of global and local models as a treatment tool for South Africa.Methods: Global random forest models were trained to predict the probability of virological response to therapy following virological failure using 29 574 treatment change episodes (TCEs) without a genotype, 3179 of which were from South Africa and were used to develop local models. In addition, 15 130 TCEs including genotypes were used to develop another set of models. The 'no-genotype' models were tested with an independent global test set (n = 1700) plus a subset from South Africa (n = 222). The genotype models were tested with 750 independent cases.Results: The global no-genotype models achieved area under the receiver-operating characteristic curve (AUC) values of 0.82 and 0.79 with the global and South African tests sets, respectively, and the South African models achieved AUCs of 0.70 and 0.79. The genotype models achieved an AUC of 0.84. The global no-genotype models identified more alternative, locally available regimens that were predicted to be effective for cases that failed their new regimen in the South African clinics than the local models. Both sets of models were significantly more accurate predictors of outcomes than genotyping with rules-based interpretation.Conclusions: These latest global models predict treatment responses accurately even without a genotype, out-performed the local South African models and have the potential to help optimize therapy, particularly in resource-limited settings. [ABSTRACT FROM AUTHOR]

Objectives: Usability and pilot testing of a web intervention (BeInCharge.org [BIC]) of behavior plus nutrition intervention for children with cystic fibrosis (CF) ages 4-9 years.Methods: Think Aloud methodology was used with five mothers to assess usability and refine the intervention. A pilot trial was then conducted with 10 mothers of children with CF ages 4-9 years randomized to the web-based BIC or a Standard Care Control (STC). Change in weight gain for each group was compared in a pre-to-post design.Results: Mothers rated the usability and clarity of BIC highly. The pilot trial showed children of mothers who received BIC had a significant change in weight pre-to-post-treatment (0.67 kg, p = .04). Change for the STC was not significant (0.41 kg, p = .10).Conclusions: A web-based behavior plus nutrition intervention appears promising in increasing weight gain in children with CF. [ABSTRACT FROM AUTHOR]

Background: One billion children live in war-affected regions of the world. We conducted the first cost-effectiveness analysis of an intervention for war-affected youth in sub-Saharan Africa, as well as a broader cost analysis.Methods: The Youth Readiness Intervention (YRI) is a behavioural treatment for reducing functional impairment associated with psychological distress among war-affected young persons. A randomized controlled trial was conducted in Freetown, Sierra Leone, from July 2012 to July 2013. Participants (n = 436, aged 15-24) were randomized to YRI (n = 222) or care as usual (n = 214). Functional impairment was indexed by the World Health Organization Disability Assessment Scale; scores were converted to quality-adjusted life years (QALYs). An 'ingredients approach' estimated financial and economic costs, assuming a societal perspective. Incremental cost-effectiveness ratios (ICERs) were also expressed in terms of gains across dimensions of mental health and schooling. Secondary analyses explored whether intervention effects were largest among those worst-off (upper quartile) at baseline.Results: Retention at 6-month follow-up was 85% (n = 371). The estimated economic cost of the intervention was $104 per participant. Functional impairment was lower among YRI recipients, compared with controls, following the intervention but not at 6-month follow-up, and yielded an ICER of $7260 per QALY gained. At 8-month follow-up, teachers' interviews indicated that YRI recipients observed higher school enrolment [P < 0.001, odds ratio (OR) 8.9], denoting a cost of $431 per additional school year gained, as well as better school attendance (P = 0.007, OR 34.9) and performance (P = 0.03, effect size = -1.31). Secondary analyses indicated that the intervention was cost-effective among those worst-off at baseline, yielding an ICER of $3564 per QALY gained.Conclusions: The YRI is not cost-effective at a willingness-to-pay threshold of three times average gross domestic product per capita. However, results indicate that the YRI translated into a range of benefits, such as improved school enrolment, not captured by cost-effectiveness analysis. We also outline areas for modification to improve cost-effectiveness in future trials.Trial Registration: clinicaltrials.gov Identifier: RPCGA-YRI-21003. [ABSTRACT FROM AUTHOR]

Introduction: Relapse prevention (RP) remains a major challenge to smoking cessation. Previous research found that a set of self-help RP booklets significantly reduced smoking relapse. This study tested the effectiveness of RP booklets when added to the existing services of a telephone quitline.Methods: Quitline callers (N = 3458) were enrolled after their 2-week quitline follow-up call and randomized to one of three interventions: (1) Usual Care: standard intervention provided by the quitline, including brief counseling and nicotine replacement therapy; (2) Repeated Mailings (RM): eight Forever Free RP booklets sent to participants over 12 months; and (3) Massed Mailings: all eight Forever Free RP booklets sent upon enrollment. Follow-ups were conducted at 6-month intervals, through 24 months. The primary outcome measure was 7-day-point-prevalence-abstinence.Results: Overall abstinence rates were 61.0% at baseline, and 41.9%, 42.7%, 44.0%, and 45.9% at the 6-, 12-, 18- and 24-month follow-ups, respectively. Although RM produced higher abstinence rates, the differences did not reach significance for the full sample. Post-hoc analyses of at-risk subgroups revealed that among participants with high nicotine dependence (n = 1593), the addition of RM materials increased the abstinence rate at 12 months (42.2% vs. 35.2%; OR = 1.38; 95% CI = 1.03% to 1.85%; P = .031) and 24 months (45% vs. 38.8%; OR = 1.31; 95% CI = 1.01% to 1.73%; P = .046).Conclusions: Sending self-help RP materials to all quitline callers appears to provide little benefit to deterring relapse. However, selectively sending RP booklets to callers explicitly seeking assistance for RP and those identified as highly dependent on nicotine might still prove to be worthwhile. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV)-infected persons have higher rates of herpes zoster than HIV-uninfected individuals. We assessed whether twice daily treatment with 400 mg of oral acyclovir reduces the incidence of herpes zoster in a randomized, double-blind, placebo-controlled trial among 3408 persons coinfected with HIV and herpes simplex virus type 2. During 5175 person-years of follow-up, 26 cases of herpes zoster occurred among those assigned acyclovir, compared with 69 cases among those assigned placebo (rates, 1.00 and 2.68/100 person-years, respectively), a relative decrease of 62% (hazard ratio, 0.38; 95% confidence interval, .24-.67; P < .001). Daily acyclovir prophylaxis significantly reduced herpes zoster incidence among HIV-infected persons. [ABSTRACT FROM AUTHOR]

Background: The Tobacco Longitudinal Care study was a randomized controlled trial for smoking cessation. It demonstrated that longitudinal care for smoking cessation, in which telephone-based counseling and nicotine replacement therapy were offered for 12 months, was more effective than the standard 8-week treatment.Purpose: This study aims to identify for whom and how longitudinal care increased the likelihood of abstinence.Methods: Mediated moderation analyses were utilized across three time points.Results: There was a trend towards smokers who did not respond to treatment (i.e., were still smoking) by 21 days being more likely to be abstinent at 6 months if they received longitudinal care rather than usual care. Similarly, those who did not respond to treatment by 3 months were more likely to be abstinent at 12 months if they received longitudinal care. At both time points, the likelihood of abstinence did not differ across treatment conditions among participants who responded to treatment (i.e., quit smoking). The effect on 6-month outcomes was mediated by satisfaction and readiness to quit. Cessation self-efficacy, satisfaction, and readiness to quit mediated the effect on 12-month outcomes. The effect of treatment condition on the likelihood of abstinence at 18 months was not moderated by response to treatment at 6 months.Conclusions: Smokers who did not respond to initial treatment benefited from longitudinal care. Differential effects of treatment condition were not observed among those who responded to early treatment. Conditional assignment to longitudinal care may be useful. Determining for whom and how interventions work over time will advance theory and practice. [ABSTRACT FROM AUTHOR]

Background: Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIV-exposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age.Methods: Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months.Results: Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16).Conclusions: Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden. [ABSTRACT FROM AUTHOR]

Background: Women at risk for breast cancer report elevated psychological distress, which has been adversely associated with cancer-relevant behaviors and biology.Purpose: The present study sought to examine the effects of a 10-week cognitive behavioral stress management (CBSM) group intervention on distress among women with a family history of breast cancer.Methods: Participants were randomly assigned to CBSM (N = 82) or a wait-list comparison group (N = 76). Baseline to postintervention effects of CBSM on depressive symptoms and perceived stress were examined using hierarchical regression.Results: CBSM participants reported significantly lower posttreatment depressive symptoms (β = -0.17, p < 0.05) and perceived stress (β = -0.23, p < 0.05) than wait-list comparison participants. Additionally, greater relaxation practice predicted lower distress.Conclusions: Group-based CBSM intervention is feasible and can reduce psychological distress among women with a family history of breast cancer. The present findings represent an encouraging avenue for the future application of CBSM. ( Clinicaltrials.gov number NCT00121160). [ABSTRACT FROM AUTHOR]

Introduction: Understanding the mechanisms by which bupropion promotes smoking cessation may lead to more effective treatment. To the extent that reduced smoking reinforcement is one such mechanism, a longer duration of pre quit bupropion treatment should promote extinction of smoking behavior. We evaluated whether 4 weeks of pre quit bupropion (extended run-in) results in greater pre quit reductions in smoking rate and cotinine and, secondarily, greater short-term abstinence, than standard 1 week of pre quit bupropion (standard run-in).Methods: Adult smokers (n = 95; 48 females) were randomized to a standard run-in group (n = 48; 3-week placebo, then 1-week bupropion pre quit) or an extended run-in group (4-week pre quit bupropion; n = 47). Both groups received group behavioral counseling and 7 weeks of post quit bupropion. Smoking rate (and craving, withdrawal, and subjective effects) was collected daily during the pre quit period; biochemical data (cotinine and carbon monoxide) were collected at study visits.Results: During the pre quit period, the extended run-in group exhibited a greater decrease in smoking rate, compared to the standard run-in group, interaction p = .03. Cigarette craving and salivary cotinine followed a similar pattern, though the latter was evident only among women. Biochemically verified 4-week continuous abstinence rates were higher in the extended run-in group (53%) than the standard run-in group (31%), p = .033.Conclusions: The extended use of bupropion prior to a quit attempt reduces smoking behavior during the pre quit period and improved short-term abstinence rates. The data are consistent with an extinction-of-reinforcement model and support further investigation of extended run-in bupropion therapy for smoking cessation. [ABSTRACT FROM AUTHOR]

Objective: To develop a reliable coding scheme for components of group-based behavioral support for smoking cessation, to establish the frequency of inclusion in English Stop-Smoking Service (SSS) treatment manuals of specific components, and to investigate the associations between inclusion of behavior change techniques (BCTs) and service success rates.Methods: A taxonomy of BCTs specific to group-based behavioral support was developed and reliability of use assessed. All English SSSs (n = 145) were contacted to request their group-support treatment manuals. BCTs included in the manuals were identified using this taxonomy. Associations between inclusion of specific BCTs and short-term (4-week) self-reported quit outcomes were assessed.Results: Fourteen group-support BCTs were identified with >90% agreement between coders. One hundred and seven services responded to the request for group-support manuals of which 30 had suitable documents. On average, 7 BCTs were included in each manual. Two were positively associated with 4-week quit rates: "communicate group member identities" and a "betting game" (a financial deposit that is lost if a stop-smoking "buddy" relapses).Conclusion: It is possible to reliably code group-specific BCTs for smoking cessation. Fourteen such techniques are present in guideline documents of which 2 appear to be associated with higher short-term self-reported quit rates when included in treatment manuals of English SSSs. [ABSTRACT FROM AUTHOR]

Background: IVF treatments carry a high risk of twin pregnancy which confers a higher risk to the mother and child than singletons. Increased use of elective single embryo transfer (eSET) can reduce this twin rate. We aimed to utilize a previously published data set and statistical model based on routinely collected clinical data to predict the outcomes of policies that increase the proportion of eSET.Methods: The models allow simultaneous prediction of outcomes from double embryo transfer (DET) and SET. These models were used to predict outcomes for different scenarios using SET in both the initial (fresh) transfer and over a complete cycle (transfer of all embryos created, with cryopreservation). A total of 16 096 cycles (12 487 fresh and 3609 frozen) from 9040 couples treated between 2000 and 2005 were included in the final analyses.Results: For any transfer, SET has about a one-third lower live birth rate relative to DET: this can be partially mitigated by appropriate patient and treatment cycle selection, with several realistic policies performing similarly. However, if we consider complete cycles with embryo cryopreservation, it is possible for repeat SET to produce more live births per egg retrieval than repeat DET.Conclusions: All patients receiving SET would have a higher chance of successful treatment in that cycle if they received DET. The selection of appropriate patients for SET can partially ameliorate the overall loss. For complete cycles, repeat SET could produce more live births per egg retrieval than repeat DET. All treatments involving SET will increase the number of treatments required to achieve a successful outcome and this extra treatment burden will be a significant barrier to the implementation of such treatments. [ABSTRACT FROM AUTHOR]

Background: In order to optimize IVF strategies, particularly with the use of single embryo transfer, good predictive models are required. Here, we develop a model to allow such prediction, and the structure of the models point to more general conclusions about the mode of action of prognostic factors.Methods: Anonymized data from consecutive embryo transfers in five IVF centres in the UK for the 2000-2005 period were extracted and the morphological grade based on common scoring criteria was included. There were 16 096 (12 487 fresh and 3609 frozen) transfers, for 8775 couples, available for analysis. Live birth data were fitted to a model with separate sub-models for embryo and recipient effects [the 'Embryo-Uterus' (EU) model]. All covariates were included, with sub-model selection using Akaike's information criterion.Results: Age, number of embryos created, attempt number, previous history of pregnancy, duration of infertility, day of transfer and tubal diagnosis were all identified as significant prognostic factors, along with embryo grade and growth rate. Frozen transfers were substantially less likely to lead to a live birth with odds ratios of 1/3 to 1/2 compared with fresh transfers, with no evidence of differential loss for any particular patient group. Age acts predominantly through the embryo component with only a weak effect on the uterus. The embryo number, attempt number, previous pregnancies and duration of infertility act predominantly through the uterine environment. Both sub-models show significant heterogeneity between centres.Conclusions: The EU modelling framework has generated a model for predicting outcomes of embryo-transfer procedures, subject to the limitations of routinely collected data. With this large data set, the model allows identification of factors that act specifically on embryo viability or maternal receptivity. Variability in the two components between centres with similar overall outcomes suggests scope for further optimization of IVF treatment. [ABSTRACT FROM AUTHOR]

This study assessed the cost-effectiveness of two low-intensity programs for quitting smokeless tobacco, based on results of a randomized trial with 1,069 volunteer participants. Cost data were collected for two levels of intervention: manual only (a self-help manual) and assisted self-help (the manual plus a videotape and two supportive phone calls from tobacco cessation counselors). Incremental cost-effectiveness ratios were calculated for assisted self-help vs. quitting on one's own, using the manual-only quit rate and data from another study as alternative proxies for no intervention. A threshold analysis was conducted to determine the spontaneous quit rate at which the manual-only intervention becomes more cost-effective than assisted self-help. The cost to provide and receive the assisted self-help intervention averaged US $56 per participant vs. $20 for the manual-only intervention (societal perspective, Year 2000 dollars). Estimates for incremental cost per quit for the assisted self-help intervention ranged from $922 to $1,758, depending on the proxy used for no intervention. The manual-only intervention was more cost-effective than assisted self-help if quitting among motivated chewers who do not receive treatment does not exceed 3.4%. Support from a wife or partner added little cost to a quit attempt for male chewers ($3-$4). Providing a manual, video, and brief phone counseling to smokeless tobacco users who want to quit is a reasonable use of health care resources. The self-help quitting guide also may be a cost-effective treatment, but it remains to be demonstrated whether it is more effective than quitting on one's own. [ABSTRACT FROM AUTHOR]

Although bupropion is known to be an effective aid to smoking cessation, little is known about its mode of action. In the present study we tested the hypothesis that bupropion reduces the likelihood that a smoking lapse, or slip, leads to a subsequent relapse. This hypothesis was tested in the context of a clinical trial of bupropion as a smoking cessation aid, using Cox regression and representing lapse history as a discrete time-varying covariate. Bupropion treatment reduced the probability of relapse during the treatment phase (hazard ratio, or HR=.421, p< or =.000) but not during the follow-up phase (end of treatment to 6 months, HR=.896, p< or=.67). As anticipated, having small lapses during treatment contributed to or predicted subsequent relapse, both during treatment (HR=2.897, p< or =.000) and during follow-up (HR=2.320, p< or=.008). Although an interaction was found between drug treatment and lapse history in predicting subsequent failure during the treatment phase, the finding suggested that drug slightly increased the effect of lapse on eventual failure during treatment (HR=1.706, p