Burden of hereditary transthyretin amyloidosis on quality of life

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study we examine the impact of hATTR amyloidosis on quality of life (QOL). METHODS: Neuropathy-specific QOL, measured with the Norfolk QOL-Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36-item Short Form Health Survey version 2 (SF-36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases. RESULTS: Neuropathy-specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure. DISCUSSION: Patients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169-175, 201

Adverse childhood experiences and mental health in young adults: a longitudinal survey

BACKGROUND: Adverse childhood experiences (ACEs) have been consistently linked to psychiatric difficulties in children and adults. However, the long-term effects of ACEs on mental health during the early adult years have been understudied. In addition, many studies are methodologically limited by use of non-representative samples, and few studies have investigated gender and racial differences. The current study relates self-reported lifetime exposure to a range of ACEs in a community sample of high school seniors to three mental health outcomes–depressive symptoms, drug abuse, and antisocial behavior–two years later during the transition to adulthood. METHODS: The study has a two-wave, prospective design. A systematic probability sample of high school seniors (N = 1093) was taken from communities of diverse socioeconomic status. They were interviewed in person in 1998 and over the telephone two years later. Gender and racial differences in ACE prevalence were tested with chi-square tests. Each mental health outcome was regressed on one ACE, controlling for gender, race/ethnicity, and SES to obtain partially standardized regression coefficients. RESULTS: Most ACEs were strongly associated with all three outcomes. The cumulative effect of ACEs was significant and of similar magnitude for all three outcomes. Except for sex abuse/assault, significant gender differences in the effects of single ACEs on depression and drug use were not observed. However, boys who experienced ACEs were more likely to engage in antisocial behavior early in young adulthood than girls who experienced similar ACEs. Where racial/ethnic differences existed, the adverse mental health impact of ACEs on Whites was consistently greater than on Blacks and Hispanics. CONCLUSION: Our sample of young adults from urban, socio-economically disadvantaged communities reported high rates of adverse childhood experiences. The public health impact of childhood adversity is evident in the very strong association between childhood adversity and depressive symptoms, antisocial behavior, and drug use during the early transition to adulthood. These findings, coupled with evidence that the impact of major childhood adversities persists well into adulthood, indicate the critical need for prevention and intervention strategies targeting early adverse experiences and their mental health consequences

Male reproductive aging arises via multifaceted mating-dependent sperm and seminal proteome declines, but is postponable in Drosophila

I.S. and S.W. were supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Fellowship to S.W. (BB/K014544/1) and S.W. additionally by a Dresden Senior Fellowship. B.M.K., P.D.C., and R.F. were supported by the Kennedy Trust and John Fell Funds. R.D. was supported by Marie Curie Actions (Grant 655392). B.R.H. was funded by the EP Abraham Cephalosporin-Oxford Graduate Scholarship with additional support from the BBSRC Doctoral Training Programme. M.F.W. was supported by a NIH Grant R01HD038921. Work in the J.S. Laboratory was supported by NIH Grant R15HD080511.Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, be-tween reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending inter-ventions could ameliorate the declining performance of the ejacu-late as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration con-tributes to male reproductive decline via mating-dependent mech-anisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproduc-tive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling re-sults in improved late-life ejaculate performance, indicating simul-taneous amelioration of both somatic and reproductive aging.Publisher PDFPeer reviewe

Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic Juvenile Idiopathic Arthritis

Objective Systemic juvenile idiopathic arthritis (JIA) is characterized by fevers, rash, and arthritis, for which interleukin‐1 (IL‐1) and IL‐6 inhibitors appear to be effective treatments. Pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and alveolar proteinosis (AP) have recently been reported with increased frequency in systemic JIA patients. Our aim was to characterize and compare systemic JIA patients with these complications to a larger cohort of systemic JIA patients. Methods Systemic JIA patients who developed PAH, ILD, and/or AP were identified through an electronic Listserv and their demographic, systemic JIA, and pulmonary disease characteristics as well as their medication exposure information were collected. Patients with these features were compared to a cohort of systemic JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. Results The patients (n = 25) were significantly ( P < 0.05) more likely than the CARRA registry cohort (n = 389) to be female; have more systemic features; and have been exposed to an IL‐1 inhibitor, tocilizumab, corticosteroids, intravenous immunoglobulin, cyclosporine, and cyclophosphamide. Twenty patients (80%) were diagnosed with pulmonary disease after 2004. Twenty patients (80%) had macrophage activation syndrome (MAS) during their disease course and 15 patients (60%) had MAS at pulmonary diagnosis. Sixteen patients had PAH, 5 had AP, and 7 had ILD. Seventeen patients (68%) were taking or recently discontinued (<1 month) a biologic agent at pulmonary symptom onset; 12 patients (48%) were taking anti–IL‐1 therapy (primarily anakinra). Seventeen patients (68%) died at a mean of 10.2 months from the diagnosis of pulmonary complications. Conclusion PAH, AP, and ILD are underrecognized complications of systemic JIA that are frequently fatal. These complications may be the result of severe uncontrolled systemic disease activity and may be influenced by medication exposure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97453/1/21889_ftp.pd

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

A randomised controlled trial of computerised cognitive behaviour therapy for the treatment of depression in primary care: the Randomised Evaluation of the Effectiveness and Acceptability of Computerised Therapy (REEACT) trial.

BACKGROUND: Computerised cognitive behaviour therapy (cCBT) has been developed as an efficient form of therapy delivery with the potential to enhance access to psychological care. Independent research is needed which examines both the clinical effectiveness and cost-effectiveness of cCBT over the short and longer term. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of cCBT as an adjunct to usual general practitioner (GP) care against usual GP care alone, for a free-to-use cCBT program (MoodGYM; National Institute for Mental Health Research, Australian National University, Canberra, Australia) and a commercial pay-to-use cCBT program (Beating the Blues(®); Ultrasis, London, UK) for adults with depression, and to determine the acceptability of cCBT and the experiences of users. DESIGN: A pragmatic, multicentre, three-armed, parallel, randomised controlled trial (RCT) with concurrent economic and qualitative evaluations. Simple randomisation was used. Participants and researchers were not blind to treatment allocation. SETTING: Primary care in England. PARTICIPANTS: Adults with depression who scored ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9). INTERVENTIONS: Participants who were randomised to either of the two intervention groups received cCBT (Beating the Blues or MoodGYM) in addition to usual GP care. Participants who were randomised to the control group were offered usual GP care. MAIN OUTCOME MEASURES: The primary outcome was depression at 4 months (PHQ-9). Secondary outcomes were depression at 12 and 24 months; measures of mental health and health-related quality of life at 4, 12 and 24 months; treatment preference; and the acceptability of cCBT and experiences of users. RESULTS: Clinical effectiveness: 210 patients were randomised to Beating the Blues, 242 patients were randomised to MoodGYM and 239 patients were randomised to usual GP care (total 691). There was no difference in the primary outcome (depression measured at 4 months) either between Beating the Blues and usual GP care [odds ratio (OR) 1.19, 95% confidence interval (CI) 0.75 to 1.88] or between MoodGYM and usual GP care (OR 0.98, 95% CI 0.62 to 1.56). There was no overall difference across all time points for either intervention compared with usual GP care in a mixed model (Beating the Blues versus usual GP care, p = 0.96; and MoodGYM versus usual GP care, p = 0.11). However, a small but statistically significant difference between MoodGYM and usual GP care at 12 months was found (OR 0.56, 95% CI 0.34 to 0.93). Free-to-use cCBT (MoodGYM) was not inferior to pay-to-use cCBT (Beating the Blues) (OR 0.91, 90% CI 0.62 to 1.34; p = 0.69). There were no consistent benefits of either intervention when secondary outcomes were examined. There were no serious adverse events thought likely to be related to the trial intervention. Despite the provision of regular technical telephone support, there was low uptake of the cCBT programs. Cost-effectiveness: cost-effectiveness analyses suggest that neither Beating the Blues nor MoodGYM appeared cost-effective compared with usual GP care alone. Qualitative evaluation: participants were often demotivated to access the computer programs, by reason of depression. Some expressed the view that a greater level of therapeutic input would be needed to promote engagement. CONCLUSIONS: The benefits that have previously been observed in developer-led trials were not found in this large pragmatic RCT. The benefits of cCBT when added to routine primary care were minimal, and uptake of this mode of therapy was relatively low. There remains a clinical and economic need for effective low-intensity psychological treatments for depression with improved patient engagement. TRIAL REGISTRATION: This trial is registered as ISRCTN91947481. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme