Citations

Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55–200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X‐associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune‐mediated disorders. Here we present a case of a 58‐year‐old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter‐ and intra‐tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

Objective To assess the impact of primary or progressive status on recurrence‐free survival ( RFS ), cancer‐specific mortality ( CSM ) and overall mortality ( OM ) after radical cystectomy ( RC ) for muscle‐ invasive bladder cancer ( MIBC ). Patients and Methods A total of 768 consecutive patients underwent RC as treatment for MIBC at our institution between 2000 and 2012. Primary MIBC was defined as no previous history of bladder cancer and progressive was defined as recorded previous treated non‐ MIBC ( NMIBC ) that had progressed to MIBC . The median follow‐up was 85 (60–109) months. Univariate and multivariate Cox regression models were used to compare RFS , CSM and OM between these two cohorts. Results In all, 475 (61.8%) patients had primary and 293 (38.2%) patients had progressive MIBC . There were no differences between the two groups in terms of demographics, pathological and peri‐operative complications (all P > 0.1). The 10‐year RFS , CSM and OM rates for primary vs progressive status were 43 vs 36% ( P = 0.01), 43 vs 37% ( P = 0.01), and 35 vs 28% ( P = 0.03), respectively. On multivariable Cox regression analyses, progressive status remained significantly associated with a higher rate of recurrence (hazard ratio [ HR ] 1.47, 95% confidence interval [ CI ] 1.12–1.79; P = 0.03), CSM ( HR 1.42, 95% CI 1.07–1.89; P = 0.01) and OM ( HR 1.42, 95% CI 1.13–1.65; P = 0.02). Conclusions Among patients treated with RC for MIBC , progressive status was associated with a higher CSM , OM and recurrence rate after RC . The present study thus provides an impetus to improve risk sub‐stratification when bladder cancer is still at the NMIBC stage, be it through new biomarkers or improved imaging, as a subset of patients with NMIBC are likely to benefit from early RC .

AbstractThe majority of kidney transplant recipients die from cardiovascular events. Physical activity may be a modifiable risk factor for cardiovascular disease following transplant. The goal of our study was to examine adherence to a physical activity intervention following kidney transplant and its impact on metabolic parameters. All patients who received a kidney transplant at our center between 12/2010 and 12/2011 received usual care (n = 162), while patients transplanted between 12/2011 and 1/2013 received a 90‐day pedometer‐based physical activity intervention (n = 145). Metabolic parameters were assessed at four and 12 months post‐transplant. Baseline demographics and clinical management were similar between cohorts. Adherence to the prescription was 36.5%. Patients in the physical activity cohort had lower systolic and diastolic blood pressure four months post‐transplant compared to the usual care cohort (122 ± 18 vs. 126 ± 16 mmHg, p = 0.049 and 73 ± 10 vs. 77 ± 9, p = 0.004) and less impaired fasting glucose (20.7% vs. 30.9%, p = 0.04). Twelve‐month outcomes were not different between cohorts. Over one‐third of our cohort adhered to a pedometer‐based physical activity intervention following kidney transplant, and the intervention was associated with improved metabolic parameters. Further study of post‐transplant exercise interventions and methods to optimize long‐term adherence are needed.

ObjectiveTo examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.MethodsIn 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).ResultsA novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.ConclusionsA newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.

Background— Chronic disease can contribute to functional disability, which can degrade quality of life. However, the prevalence of functional disability and its association with outcomes among patients with heart failure requires further study. Methods and Results— Southeastern Minnesota residents with heart failure were enrolled from September 2003 through January 2012 into a cohort study with follow-up through December 2012. Difficulty with 9 activities of daily living (ADLs) was assessed by a questionnaire. Patients were divided into 3 categories of ADL difficulty (no/minimal, moderate, severe). The associations of ADL difficulty with mortality and hospitalization were assessed using Cox and Andersen-Gill models. Among 1128 patients (mean age, 74.7 years; 49.2% female), a majority (59.4%) reported difficulty with one or more ADLs at enrollment, with 272 (24.1%) and 146 (12.9%) experiencing moderate and severe difficulty, respectively. After a mean (SD) follow-up of 3.2 (2.4) years, 614 patients (54.4%) had died. Mortality increased with increasing ADL difficulty; the hazard ratio (95% confidence interval) for death was 1.49 (1.22–1.82) and 2.26 (1.79–2.86) for those with moderate and severe difficulty, respectively, compared to those with no/minimal difficulty ( P trend <0.001). Patients with moderate and severe difficulty were at an increased risk for all-cause and noncardiovascular hospitalization. In a second assessment, 17.7% of survivors reported more difficulty with ADLs and patients with persistently severe or worsening difficulty were at an increased risk for death (hazard ratio, 2.10; 95% confidence interval, 1.71–2.58; P <0.001) and hospitalization (hazard ratio, 1.51; 95% confidence interval, 1.31–1.74; P <0.001). Conclusions— Functional disability is common in patients with heart failure, can progress over time, and is associated with adverse prognosis.

Cost-effectiveness modeling studies of global endometrial ablation (GEA) for treatment of abnormal uterine bleeding (AUB) from a US perspective are lacking. The objective of this study was to model the cost-effectiveness of GEA vs. hysterectomy for treatment of AUB in the United States from both commercial and Medicaid payer perspectives. The study team developed a 1-, 3-, and 5-year semi-Markov decision-analytic model to simulate 2 hypothetical patient cohorts of women with AUB—1 treated with GEA and the other with hysterectomy. Clinical and economic data (including treatment patterns, health care resource utilization, direct costs, and productivity costs) came from analyses of commercial and Medicaid claims databases. Analysis results show that cost savings with simultaneous reduction in treatment complications and fewer days lost from work are achieved with GEA versus hysterectomy over almost all time horizons and under both the commercial payer and Medicaid perspectives. Cost-effectiveness metrics also favor GEA over hysterectomy from both the commercial payer and Medicaid payer perspectives—evidence strongly supporting the clinical-economic value about GEA versus hysterectomy. Results will interest clinicians, health care payers, and self-insured employers striving for cost-effective AUB treatments. ( Population Health Management 2015;18:373–382)

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.