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In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two‐stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non‐responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug‐only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT‐A study data to assess the benefit of low‐dose aripiprazole adjunctive to antidepressant therapy treatment. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether testosterone therapy (TTh) in men with hypogonadism and type 2 diabetes mellitus (T2DM) improves glycaemic control and insulin sensitivity, and results in remission of T2DM. Material and Methods: A total of 356 men who had total testosterone levels ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism were included in the study and followed up for 11 years. All patients received standard diabetes treatment and 178 patients additionally received parenteral testosterone undecanoate 1000 mg every 12 weeks following an initial 6-week interval. A control group comprised 178 hypogonadal patients who opted not to receive TTh. Results: Patients with hypogonadism and T2DM treated with testosterone had significant progressive and sustained reductions in fasting glucose, glycated haemoglobin (HbA1c) and fasting insulin over the treatment period. In the control group, fasting glucose, HbA1c and fasting insulin increased. Among the patients treated with testosterone 34.3% achieved remission of their diabetes and 46.6% of patients achieved normal glucose regulation. Of the testosterone-treated group, 83.1% reached the HbA1c target of 47.5 mmol/mol (6.5%) and 90% achieved the HbA1c target of 53.0 mmol/mol (7%). In contrast, no remission of diabetes or reductions in glucose or HbA1c levels were noted in the control group. There were fewer deaths, myocardial infarctions, strokes and diabetic complications in the testosterone-treated group. Conclusions: Long-term TTh in men with T2DM and hypogonadism improves glycaemic control and insulin resistance. Remission of diabetes occurred in one-third of the patients. TTh is potentially a novel additional therapy for men with T2DM and hypogonadism. [ABSTRACT FROM AUTHOR]

Summary: Severity of cardiac involvement remains the leading determinant of survival in light chain (AL) amyloidosis. Until recently, cardiac response after treatment relied on reduction of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). In this study, 94 patients with AL amyloidosis (baseline BNP ≥150 pg/ml) had BNP measured at 6 months following treatment. Median overall survival was not reached for cardiac response (≥50 pg/ml and ≥ 30% decrease in BNP), 9·2 years for cardiac stability (<50 pg/ml and <30% change in BNP) and 2·8 years for cardiac progression (≥50 pg/ml or ≥30% increase in BNP) (log‐rank P < 0·001). Cardiac response and progression, as measured by BNP values, are significantly associated with survival in AL amyloidosis. [ABSTRACT FROM AUTHOR]

Two‐way enriched design (TED) is a novel approach addressing placebo response in clinical trials. It is a two‐stage, randomized, placebo‐controlled trial design with enrichment in placebo non‐responders and treatment responders at the second stage. All data from the first stage and data from placebo non‐responders and treatment responders in the second stage are used for the final analysis of the treatment effect. The existing methods for the analysis of TED data include score tests with one, two, and three degrees of freedom. All these methods are only applicable to binary outcomes. However, there is an interest in continuous outcomes in clinical trials in psychiatry. In this manuscript, we apply some novel methods, including a repeated measures model, a weighted repeated measures model with weights from propensity score, and weights from K‐means clustering, to analyze TED data for both binary outcomes and continuous outcomes. The simulation study indicates that the repeated measures model performs consistently well in preserving the type I error and achieving the minimum mean standard error as well as a higher power. The performance of the weighted repeated measures model with weights from K‐means clustering improves with increasing sample size. Investigators can choose from these analytic approaches under different scenarios. [ABSTRACT FROM AUTHOR]

Aims: Guidelines for management of patients with heart failure with mid‐range ejection fraction [HFmrEF; left ventricular EF (LVEF) 41–49%] do not exist. Disagreement exists whether HFmrEF should be considered a distinct group. The aim of this study is to examine characteristics of patients with HFmrEF with HF with reduced EF (HFrEF; LVEF ≤ 40%) or preserved EF (HFpEF; LVEF ≥ 50%). Methods and results: We examined data collected in the American College of Cardiology's National Cardiovascular Data Registry (NCDR) Practice Innovation and Clinical Excellence (PINNACLE) Registry® for first HF patient visits between 1 May 2008 and 30 June 2016. Analysis was performed using ANOVA F‐tests (or Kruskal–Wallis tests for non‐normally distributed variables) for continuous parameters and χ2 tests for nominal covariates at the first diagnosed HF visit. Given the NCDR PINNACLE Registry® is a US‐based registry, we opted to define HFmrEF as per the US guidelines, which define HFmrEF as LVEF 41–49% in contrast to European guidelines, which define HFmrEF as LVEF 40–49%. Among 1 103 386 patients with available data, 36.1% (N = 398 228) had HFrEF, 7.5% (N = 82 292) had HFmrEF, and 56.5% (N = 622 866) had HFpEF. Compared with patients with HFrEF or HFpEF, patients with HFmrEF had more prevalent coronary and peripheral artery disease and more history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery (all P < 0.001). Patients with HFmrEF were also more likely to have atrial fibrillation/flutter, diabetes, and chronic kidney disease and to have a history of tobacco use (both P < 0.001). Among those with EF assessment prior to this analysis, only 4.8% (N = 1032) previously had HFrEF that improved to HFmrEF; 32.9% (N = 7072) had HFpEF previously and progressed to HFmrEF. Those patients who transitioned from HFpEF to HFmrEF had considerably more complex profiles and were less aggressively managed compared with those who remained with HFmrEF (all P < 0.001). Conclusions: In this large descriptive analysis, patients with HFmrEF had an atherothrombotic phenotype distinct from other forms of HF. Interventions aimed at treating coronary ischaemia and addressing prevalent risk factors may play a particularly important role in the management of patients with HFmrEF. [ABSTRACT FROM AUTHOR]

Introduction: The HeartLight laser balloon ablation system was US Food and Drug Administration approved in 2016 for the treatment of paroxysmal atrial fibrillation (AF), but there have been numerous single‐center and multicenter studies published reporting its outcomes, in addition to a few randomized trials. We aimed to systematically review and synthesize currently published outcome data on AF ablation using the laser balloon ablation system. Methods and Results: We performed a systematic review and meta‐analysis of published studies of AF ablation performed using the laser balloon ablation system. Human studies reporting acute procedural results with a minimum of 6 months follow‐up were included. Outcomes of interest included acute and 12‐month procedural efficacy, safety, and procedure duration. Aggregated data were analyzed with random effects models, using a Bayesian hierarchical approach. We identified 17 published manuscripts comprising a sample of 1188 patients (mean age 61 years, 80% paroxysmal). At procedure end, 98.8% of targeted pulmonary veins were successfully isolated. The pooled estimate for 12‐month freedom from atrial arrhythmia without use of antiarrhythmic drugs for patients with paroxysmal AF was 74.3% (95% confidence interval [CI], 59.9% to 86.4%), and for all AF types combined was 72.9% (65.3% to 79.9%). The most commonly reported procedural complication was phrenic nerve injury (pooled incidence 2.6%; 95% CI, 1.4% to 3.9%), which resolved during follow‐up in most cases. Conclusion: Laser balloon ablation is highly effective at achieving pulmonary vein isolation. Although comparisons are mainly indirect, safety and 12‐month efficacy compare favorably with those observed using other currently used AF ablation technologies. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Wild‐type transthyretin (ATTRwt) cardiac amyloidosis has emerged as an important cause of heart failure in the elderly. Atrial fibrillation (AF) commonly affects older adults with heart failure and is associated with reduced survival, but its role in ATTRwt is unclear. We sought to explore the clinical impact of AF in ATTRwt. Methods and results: Patients with biopsy‐proven ATTRwt cardiac amyloidosis (n = 146) were retrospectively identified, and clinical, echocardiographic, and biochemical data were collected. Patients were classified as AF or non‐AF and followed for survival for a median of 41.4 ± 27.1 months. Means testing, univariable, and multivariable regression models were employed. A systematic review was performed. AF was observed in 70% (n = 102). Mean age was similar (AF, 75 ± 6 vs. non‐AF, 74 ± 5 years, P = 0.22). Anticoagulant treatment of patients with AF was as follows: 78% warfarin, 17% novel anticoagulant, and 6% no anticoagulation. Amiodarone was prescribed to 24%. There were no differences in left ventricular ejection fraction (P = 0.09) or left atrial volume (P = 0.87); however, mean diastolic dysfunction grade was higher in AF (mean 2.7 ± 0.5 vs. 2.4 ± 0.5, P = 0.01). While creatinine (P = 0.52) and B‐type natriuretic peptide (P = 0.48) were similar, patients with AF had lower serum transthyretin concentrations (221 ± 51 vs. 250 ± 52 μg/mL, P < 0.01). Survival between groups was similar (P = 0.46). Conclusions: These data provide an evidence basis for clinical management and demonstrate that AF in ATTRwt does not negatively impact survival. Further analysis of the relationship between transthyretin concentration and AF development is warranted. [ABSTRACT FROM AUTHOR]

Household contact studies, a mainstay of tuberculosis transmission research, often assume that tuberculosis-infected household contacts of an index case were infected within the household. However, strain genotyping has provided evidence against this assumption. Understanding the household versus community infection dynamic is essential for designing interventions. The misattribution of infection sources can also bias household transmission predictor estimates. We present a household-community transmission model that estimates the probability of community infection, that is, the probability that a household contact of an index case was actually infected from a source outside the home and simultaneously estimates transmission predictors. We show through simulation that our method accurately predicts the probability of community infection in several scenarios and that not accounting for community-acquired infection in household contact studies can bias risk factor estimates. Applying the model to data from Vitória, Brazil, produced household risk factor estimates similar to two other standard methods for age and sex. However, our model gave different estimates for sleeping proximity to index case and disease severity score. These results show that estimating both the probability of community infection and household transmission predictors is feasible and that standard tuberculosis transmission models likely underestimate the risk for two important transmission predictors. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The six-minute walk test (6 MWT) has been widely used as an objective evaluation of functional exercise capacity and response to medical intervention in cardiopulmonary diseases. However, little is known about the 6 MWT in evaluating patients with AL amyloidosis. We performed a retrospective study of 120 adults with systemic AL amyloidosis (60 with cardiac involvement and 60 without cardiac involvement) who had their initial evaluation at the Amyloidosis Center between 2013 and 2015 and had undergone 6 MWT as a measure of functional exercise capacity. Forty-seven patients with cardiac involvement and 41 patients without cardiac involvement were included in the final analysis. The six-minute walk distances (6 MWD) were 368 ± 105 m and 420 ± 116 m (mean ± SD), respectively ( P = 0·03). Among AL amyloidosis patients with cardiac involvement, the 6 MWD was associated with New York Heart Association class ( P < 0·001), B-type natriuretic peptide ( P = 0·003) and overall survival (hazard ratio 0·381, 95% confidence interval 0·215-0·676, P = 0·001). In conclusion, the 6 MWT is a valuable tool in assessing functional exercise capacity in patients with AL amyloidosis. [ABSTRACT FROM AUTHOR]

In this observational analysis from the Practice Innovation and Clinical Excellence Registry®, we examined changes in guideline‐directed medical therapies relative to changes in symptom severity in ambulatory patients with heart failure with reduced ejection fraction, finding change in medication more often occurring when patients were changing their New York Heart Association symptom severity, rather than during periods of stable symptoms. Additionally, despite being available for a year during the time of our analysis, the use of sacubitril/valsartan was extremely low, and most often added in the context of worsening symptoms, not how this drug was studied and not how the guidelines articulate its use. [ABSTRACT FROM AUTHOR]

Purpose: Magnetic resonance imaging (MRI) is a high-cost imaging modality, and an optimized encounter ideally provides high-quality care, patient satisfaction, and capacity utilization. Our purpose was to assess the effectiveness of team training and its impact on patient show-up and completion rates for their MRI examinations.Materials and Methods: A total of 97,712 patient visits from three tertiary academic medical centers over 1-year intervals were evaluated, totaling 49,733 visits at baseline and 47,979 after training. Each center's MRI team received team training skill training including advanced communication and team training techniques training. This training included onsite instruction including case simulation with scenarios requiring appropriate behavioral and communicative interventions. Orientation and training also utilized customized online tools and proctoring. The study completion rate and patient show-up rate during consecutive year-long intervals before and after team training were compared to assess its effectiveness. Two-sided chi-square tests for proportions using were applied at a 0.05 significance level.Results: Despite differing no-show rates (5-22.2%) and study incompletion rates (0.7-3.7%) at the three academic centers, the combined patients' data showed significant (P < 0.0001) improvement in the patients' no-show rates (combined decreases from 11.2% to 8.7%) and incompletion rates (combined decreases from 2.3% to 1.4%).Conclusion: Our preliminary results suggest training of the imaging team can improve the no-show and incompletion rates of the MRI service, positively affecting throughput and utilization. Team training can be readily implemented and may help address the needs of the current cost-conscious and consumer-sensitive healthcare environment. J. MAGN. RESON. IMAGING 2016;44:1040-1047. [ABSTRACT FROM AUTHOR]

Objectives: : To update the imaging literature regarding spleen appearances in young patients with sickle cell disease (SCD). Methods: We conducted a retrospective study and included 112 patients age 0 to 21 years with SCD who had at least 1 abdominal sonogram at our institution between 1999 and 2011. Radiologic findings were compared between risk groups by χ2 analysis. Findings were correlated with other imaging modalities when available. Results: In our cohort, 35.7% of patients had autosplenectomy, and 8.0% had undergone surgical splenectomy. Only 5.0% of individuals age 0 to 5 years had autosplenectomy. In those who had not undergone surgical splenectomy or autosplenectomy, 76.2% had echogenic spleens, heterogeneous‐appearing spleens, or both, and patients with the homozygous sickle cell anemia (HbSS) genotype were more likely to have an abnormal spleen echo texture. Patients treated with transfusions had echogenic spleens and had a higher frequency of splenic regeneration nodules. Most patients (80%) with splenomegaly did not require surgical splenectomy after 5.7 years of follow‐up. Conclusions: Twenty years ago, children with HbSS SCD were expected to have autosplenectomy by age 5 years. There have been changes in the radiologic appearance of the spleen in patients with SDC, likely due to improved supportive care and the use of acute and chronic transfusion therapy. We found that autosplenectomy is rare by age 5 years, and during childhood and adolescence, the spleen typically appears echogenic, heterogeneous, or both, depending on disease severity. [ABSTRACT FROM AUTHOR]

Background Neuromuscular electrical stimulation (NMES) is a highly sought after but poorly studied treatment for dysphagia among patients with head and neck cancer with dysphagia. This study investigated the efficacy of NMES in this patient population. Methods In this double-blinded, randomized controlled trial, 170 patients with head and neck cancer experiencing posttreatment dysphagia were randomized into active NMES + swallow exercise versus sham NMES + swallow exercise groups. Outcomes after a 12-week program included changes in fluoroscopy measures, diet, and quality of life. Results After the 12-week program, the active NMES group had significantly worse Penetration Aspiration Scale scores than the sham group. Both groups reported significantly better diet and quality of life. No other measures were significant. Conclusion NMES did not add benefit to traditional swallow exercises. Unfortunately, swallow exercises were not effective by themselves either. For patients with head and neck cancer with moderate to severe dysphagia caused by radiation therapy, current behavioral therapies are of limited help in reversing long-term dysphagia. © 2015 Wiley Periodicals, Head Neck 38: E1221-E1231, 2016 [ABSTRACT FROM AUTHOR]

Objective In addition to primary and secondary ('classical') hypogonadism, hypogonadism occurring in middle-aged and elderly men has been recognized. There is evidence that restoring T levels to normal improves body weight, serum lipids and glucose levels. Design Observational registry study. Patients Two hundred and sixty-two hypogonadal, middle-aged and elderly, men received testosterone replacement treatment (TRT). After having been on TRT for a mean duration of 65.5 months, TRT was temporarily intermitted in 147 patients for a mean of 16.9 months (Group I) due to cost reimbursement issues and in seven men due to prostate cancer. All these men resumed TRT for a mean period of 14.5 months. Of the cohort, 115 men were treated continuously (designated as Group C). To compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). For proper comparison, the same periods were analysed for those patients who continued TRT throughout (Group C). Measurements Variables of body weight, glucose metabolism, lipids, blood pressure and C-reactive protein (CRP). Results In Group C there was a continuous improvement of body weight, serum lipids, glucose, HbA1c, blood pressure and CRP. In Group I there was a similar initial improvement which was reversed upon intermission of T administration but which appeared again when T treatment was reinstated. Conclusions Our observation indicates that T administration improves body weight and metabolic factors in men with hypogonadism but withdrawal of T reverses these beneficial effects to appear again when TRT is resumed. [ABSTRACT FROM AUTHOR]

The Sequential Parallel Comparison Design (SPCD) is one of the novel approaches addressing placebo response. The analysis of SPCD data typically classifies subjects as 'placebo responders' or 'placebo non-responders'. Most current methods employed for analysis of SPCD data utilize only a part of the data collected during the trial. A repeated measures model was proposed for analysis of continuous outcomes that permitted the inclusion of information from all subjects into the treatment effect estimation. We describe here a new approach using a weighted repeated measures model that further improves the utilization of data collected during the trial, allowing the incorporation of information that is relevant to the placebo response, and dealing with the problem of possible misclassification of subjects. Our simulations show that when compared to the unweighted repeated measures model method, our approach performs as well or, under certain conditions, better, in preserving the type I error, achieving adequate power and minimizing the mean squared error. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective Huntington's disease ( HD) is a rare neurodegenerative disease caused by the expansion of an N-terminal repeat in the huntingtin protein. The protein is expressed in all cells in the body; hence, peripheral tissues, such as blood, may recapitulate processes in the brain. The plasma metabolome may provide a window into active processes that influence brain health and a unique opportunity to noninvasively identify processes that may contribute to neurodegeneration. Alterations in metabolic pathways in brain have been shown to profoundly impact HD. Therefore, identification and quantification of critical metabolomic perturbations could provide novel biomarkers for disease onset and disease progression. Methods We analyzed the plasma metabolomic profiles from 52 premanifest ( PHD), 102 early symptomatic HD, and 140 healthy controls (NC) using liquid chromatography coupled with a highly sensitive electrochemical detection platform. Results Alterations in tryptophan, tyrosine, purine, and antioxidant pathways were identified, including many related to energetic and oxidative stress and derived from the gut microbiome. Multivariate statistical modeling demonstrated mutually distinct metabolomic profiles, suggesting that the processes that determine onset were likely distinct from those that determine progression. Gut microbiome-derived metabolites particularly differentiated the PHD metabolome, while the symptomatic HD metabolome was increasingly influenced by metabolites that may reflect mutant huntingtin toxicity and neurodegeneration. Interpretation Understanding the complex changes in the delicate balance of the metabolome and the gut microbiome in HD, and how they relate to disease onset, progression, and phenotypic variability in HD are critical questions for future research. [ABSTRACT FROM AUTHOR]

Missing data pose a serious challenge to the integrity of randomized clinical trials, especially of treatments for prolonged illnesses such as schizophrenia, in which long-term impact assessment is of great importance, but the follow-up rates are often no more than 50%. Sensitivity analysis using Bayesian modeling for missing data offers a systematic approach to assessing the sensitivity of the inferences made on the basis of observed data. This paper uses data from an 18-month study of veterans with schizophrenia to demonstrate this approach. Data were obtained from a randomized clinical trial involving 369 patients diagnosed with schizophrenia that compared long-acting injectable risperidone with a psychiatrist's choice of oral treatment. Bayesian analysis utilizing a pattern-mixture modeling approach was used to validate the reported results by detecting bias due to non-random patterns of missing data. The analysis was applied to several outcomes including standard measures of schizophrenia symptoms, quality of life, alcohol use, and global mental status. The original study results for several measures were confirmed against a wide range of patterns of non-random missingness. Robustness of the conclusions was assessed using sensitivity parameters. The missing data in the trial did not likely threaten the validity of previously reported results. [ABSTRACT FROM AUTHOR]

Objectives To determine whether oral health is better in centenarians than in a published birth cohort-matched sample and to compare oral health in centenarian offspring with a case-controlled reference sample. Design Observational cross-sectional study. Setting New England Centenarian Study ( NECS). Participants Seventy-three centenarians, 467 offspring, and 251 offspring generation-reference cohort subjects from the NECS. Measurements A self-report questionnaire was administered to measure oral health in all three groups, with edentulous rate as the primary outcome measure. The NECS made information on sociodemographic characteristics and medical history available. Centenarian results were compared with published birth cohort-matched results. Data from offspring and reference cohorts were analyzed to determine differences in oral health and associations between oral health measures and specific medical conditions. Results The edentulous rate of centenarians (36.5%) was lower than that of their birth cohort (46%) when they were aged 65 to 74 in 1971 to 1974 (according to National Center of Health Statistics). Adjusting for confounding factors, the reference cohort was more likely to be edentulous (adjusted odds ratio ( AOR) = 2.78, 95% confidence interval CI = 1.17-6.56), less likely to have all or more than half of their own teeth (AOR = 0.48, 95% CI = 0.3-0.76), and less likely to report excellent or very good oral health (AOR = 0.65, 95% CI = 0.45-0.94) than the centenarian offspring. Conclusion Centenarians and their offspring have better oral health than their respective birth cohorts. Oral health may prove to be a helpful marker for systemic health and healthy aging. [ABSTRACT FROM AUTHOR]

To investigate effects of long-term testosterone (T) therapy in obese men with T deficiency (TD) and type 2 diabetes mellitus (T2DM), data were collected from two observational, prospective, and cumulative registry studies of 561 men with TD receiving T therapy for up to 6 years. A subgroup of obese hypogonadal men with T2DM was analyzed. Weight, height, waist circumference (WC), fasting blood glucose (FBG), glycated haemoglobin (HbA1c) blood pressure, lipid profile, C-reactive protein (CRP), and liver enzymes were measured. A total of 156 obese, diabetic men with T deficiency, aged 61.17 ± 6.18 years, fulfilled selection criteria. Subsequent to T therapy, WC decreased by 11.56 cm and weight declined by 17.49 kg (15.04%). Fasting glucose declined from 7.06 ± 1.74 to 5.59 ± 0.94 mmol/L (P < 0.0001 for all). HbA1c decreased from 8.08 to 6.14%, with a mean change of 1.93%. Systolic and diastolic blood pressure, lipid profiles including total cholesterol: HDL ratio, CRP, and liver enzymes all improved (P < 0.0001). Long-term T therapy for up to 6 years resulted in significant and sustained improvements in weight, T2DM, and other cardiometabolic risk factors in obese, diabetic men with TD and this therapy may play an important role in the management of obesity and diabetes (diabesity) in men with T deficiency. [ABSTRACT FROM AUTHOR]

Testosterone deficiency leads to bone loss and testosterone treatment has a beneficial effect. This study investigated the effects of normalizing serum testosterone on bone mineral density in 45 men with osteoporosis, diagnosed with testosterone deficiency (serum testosterone levels < 12.1 nmol/L, T-scores: (mean ± SD) -3.12 ± 0.45, minimum: -4.10, and maximum: -2.60). In a cumulative, prospective, registry study of hypogonadal men (mean age: 53 ± 7 years) they received parenteral testosterone undecanoate of 1000 mg/12 weeks for up to six years. After one year 44 men were included in the registry, after two years 36 men, after three years 32 men, after four years 25 men, after five years 10 men and after six years 4 men. The declining numbers do not reflect drop-out rates but are a result of the registry design. Over the 6 year period there was a significant and progressive improvement of the T-scores in these men. Normalizing of serum testosterone leads to an improvement of bone mineral density and this improvement was progressive with the time period of testosterone administration. In this study of 6-years many men with testosterone deficiency suffered from classical diagnoses (Klinefelter's syndrome and testicular pathology) hitherto undiagnosed. [ABSTRACT FROM AUTHOR]

Objective This study analyzed the effects of normalization of serum testosterone (T) levels on anthropometric parameters in hypogonadal men. Design and Methods Open-label, single-center, cumulative, prospective registry study of 255 men (aged 33-69 years, mean 58.02 ± 6.30 years), with T levels below 12.13 nmol/L (mean: 9.93±1.38). 215 men for at least 2 years, 182 for 3 years, 148 for 4, and 116 for at least 5 years were studied. They received parenteral T undecanoate 1,000 mg/12 weeks after an initial interval of 6 weeks. Results Body weight (BW) decreased from 106.22 ± 16.93 kg to 90.07 ± 9.51 kg. Waist circumference (WC) reduced from 107.24 ± 9.14 cm to 98.46 ± 7.39 cm. BMI (m/kg2) declined from 33.9 ± 5.51 m/kg2 to 29.13 ± 3.09 m/kg2. All parameters examined were statistically significant with P < 0.0001 versus baseline and versus the previous year over 5 years indicating a continuous weight loss over the full observation period. The mean per cent weight loss after 1 year was 4.16 ± 0.31%, after 2 years 7.54 ± 0.32%, after 3 years 9.23 ± 0.33%, after 4 years 11.42 ± 0.35% and after 5 years 13.57 ± 0.37%. Conclusions In an uncontrolled, observational cohort, normalizing serum T to normal physiological levels produced consistent loss of BW, WC, and BMI. These improvements were progressive over the full 5 years of the study. [ABSTRACT FROM AUTHOR]

Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease. We scanned 22 patients with Huntington's disease at approximately 1-year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex. There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate the separate and combined effects of caregiver status and high stress on mortality risk over 8 years in elderly women. DESIGN: Prospective cohort study conducted in four U.S. communities followed from 1999/01 (baseline) to December 31, 2007. SETTING: Home-based interviews. PARTICIPANTS: Three hundred seventy-five caregiver and 694 noncaregiver participants from the Caregiver-Study of Osteoporotic Fractures (Caregiver-SOF) who participated in the baseline Caregiver-SOF interview. MEASUREMENTS: Caregiver status was based on SOF respondents' self-report of performing one or more instrumental or basic activities of daily living for a relative or friend with impairments. Two measures of stress were used: Perceived Stress Scale and stress related to caregiving tasks. All-cause mortality was the outcome. RESULTS: Caregivers were more stressed than noncaregivers; 19.7% of caregivers and 27.4% of noncaregivers died. Mortality was lower in caregivers than noncaregivers (adjusted hazard ratio, (AHR)=0.74, 95% confidence interval (CI)=0.56–0.89). High-stress respondents had greater mortality risk than low-stress respondents over the first 3 years of follow-up (AHR=1.81, 95% CI=1.16–2.82) but not in later years. Likewise, high-stress caregivers and noncaregivers had higher mortality risk than low-stress noncaregivers, although low-stress caregivers had significantly lower mortality than did noncaregivers, whether perceived stress or caregiving-related stress was measured (AHR=0.67 and 0.57). Similar results were observed in analyses comparing spouse caregivers with married noncaregivers. CONCLUSION: Short-term effects of stress, not caregiving per se, may increase the risk of health decline in older caregivers. [ABSTRACT FROM AUTHOR]

The article discusses a study on the soft tissue, joint and bone manifestations of AL amyloidosis. The study showed that soft tissue and bone involvement occurred in 42.9% of the patients with submandibular gland enlargement, macroglossia and carpal tunnel syndrome as the most common manifestations. Survival time of VL gene was found to be longer in patients with dominant soft tissue and bone involvement compared to those with other dominant organ involvement.

A response from the author of the article "Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes" that was published in the previous issue is presented.

Background: Despite higher thromboembolism risk, women with atrial fibrillation have lower oral anticoagulation (OAC) use compared to men. The influence of the CHA 2 DS 2 -VASc score or the introduction of non-vitamin K OACs on this relationship is not known., Methods and Results: Using the PINNACLE National Cardiovascular Data Registry from 2008 to 2014, we compared the association of sex with OAC use (warfarin or non-vitamin K OACs) overall and by CHA 2 DS 2 -VASc score and examined temporal trends in OAC use by sex. Multivariable regression models assessed the association between sex and OAC use in those with CHA 2 DS 2 -VASc scores ≥2. Temporal analyses assessed changes in OAC use by sex over time. Of the 691 906 atrial fibrillation patients, 48.5% were women. Women were significantly less likely than men to use any OAC overall (56.7% versus 61.3%; P <0.001) and at all levels of CHA 2 DS 2 -VASc score (adjusted risk ratio 9% to 33% lower, all P <0.001). Compared to other thromboembolic risk factors, female sex was associated with lower use of OAC (risk ratio 0.90, 95%CI 0.90-0.91). Over time, non-vitamin K OAC use increased at a slightly higher rate in women (56.2% increase per year, 95%CI 54.6% to 57.9%) compared to men (53.6% increase per year, 95%CI 52.0% to 55.2%), yet women remained less likely to receive any OAC at all time points ( P <0.001)., Conclusions: Among patients with atrial fibrillation, women were significantly less likely to receive OAC at all levels of the CHA 2 DS 2 -VASc score. Despite increasing non-vitamin K OAC use, women had persistently lower rates of OAC use compared to men over time., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain-related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (ECM) homeostasis, which is partly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We therefore tested the hypothesis that circulating levels of MMPs and TIMPs in patients with AL-CMP and TTR-related CMP (TTR-CMP) are dissimilar and indicative of cardiac amyloid disease type., Methods and Results: Fifty AL-CMP patients were compared with 50 TTR-CMP patients (composed of 38 SSA and 12 ATTR patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were determined by ELISA. Compared with TTR-CMP patients, AL-CMP patients had higher levels of brain natriuretic peptide (BNP), troponin I (TnI), MMP-2, TIMP-1, and MMP-2/TIMP-2 ratio, despite less left ventricular (LV) hypertrophy and better preserved LV ejection fraction. Mortality was worse in AL-CMP patients than in TTR-CMP patients (log-rank P<0.01). MMP-2/TIMP-2 plus BNP and TnI showed the highest discriminative ability for distinguishing AL-CMP from TTR-CMP. Female sex (HR, 2.343; P=0.049) and BNP (HR, 1.041; P<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only BNP was a predictor of death in AL-CMP patients (HR, 1.090; P<0.01). There were no prognostic factors for all-cause death in TTR-CMP patients., Conclusions: Circulating concentrations of MMPs and TIMPs may be useful in differentiating patients with AL-CMP from those with TTR-CMP, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated BNP level, female sex increased the risk of death in patients with cardiac amyloidoses.