Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.This study was funded by The Dunhill Medical Trust, Addenbrooke’s Charitable Trust, Isaac Newton Trust , and Prader-Willi Association UK. Funding bodies had no role in study design, data collection, data analysis, data interpretation, writing of the report or the decision to submit for publication. We are grateful to the NIHR Collaborations for Leadership in Applied Health Care Research and Care (CLAHRC) East of England for financial support to AJH and HAR and to the Health Foundation for support of AJH. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final version of the article. It first appeared from Taylor & Francis via http://dx.doi.org/10.1111/jir.1220

Investigation of the link between fluid shift and airway collapsibility as a mechanism for obstructive sleep apnea in congestive heart failure

The increased prevalence of obstructive sleep apnea (OSA) in congestive heart failure (CHF) may be associated with rostral fluid shift. We investigated the effect of overnight rostral fluid shift on pharyngeal collapsibility (Pcrit), pharyngeal caliber (APmean), and apnea‐hypopnea index (AHI) in CHF patients. Twenty‐three optimally treated systolic CHF patients were studied. Neck circumference was measured immediately prior to sleep in the evening and immediately after waking in the morning as a marker of rostral fluid shift. Pcrit was measured during sleep, early and late in the night. APmean was measured using acoustic reflection at the same times as neck circumference measurements. 15/23 CHF patients experienced an overnight increase in neck circumference; overall neck circumference significantly increased overnight (mean±SD, evening: 41.7 ± 3.2 cm; morning: 42.3 ± 3.1 cm; P = 0.03). Pcrit increased significantly overnight (early‐night: −3.8 ± 3.3 cmH2O; late‐night: −2.6 ± 3.0 cmH2O; P = 0.03) and APmean decreased (evening: 4.2 ± 1.3 cm2; morning: 3.7 ± 1.3 cm2; P = 0.006). The total AHI correlated with neck circumference (r = 0.4; P = 0.04) and Pcrit (r = 0.5; P = 0.01). APmean correlated with neck circumference (r = −0.47; P = 0.02). There was no significant change in AHI between the first and second half of the night (first‐half: 12.9 ± 12.4/h; second‐half: 13.7 ± 13.3/h; P = 0.6). Overnight rostral fluid shift was associated with increased pharyngeal collapsibility and decreased pharyngeal caliber during sleep in CHF patients. Rostral fluid shift may be an important mechanism of OSA in this patient group

Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency

BACKGROUND: Preclinical evidence implicates neutrophil elastase (NE) in PAH pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. RESEARCH QUESTION: Are circulating NE and elafin levels abnormal in PAH and associated with clinical severity? STUDY DESIGN/METHODS: . In an observational Stanford University PAH cohort (N=249), plasma NE and elafin were measured in comparison to healthy controls (N=106) then related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (N=75, N=357). Mixed effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE/elafin balance on pulmonary artery endothelial cells (PAECs) from PAH patients. RESULTS: Relative to controls, patients had increased NE (205.1 [123.6-387.3] vs. 97.6 [74.4-126.6] ng/mL, P168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (HR 2.52, CI 1.36-4.65, P=0.003) or prognostic cytokines (HR 2.63, CI 1.42-4.87, P=0.001), and NE added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH-PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients. INTERPRETATION: NE is increased and elafin deficient across PAH subtypes. NE associates with disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin

Visual Pigment Gene Changes in Adrenoleukodystrophy

Purpose. The gene for X-linked adrenoleukodystrophy, a neurodegenerative disorder, is closely linked to the red/green color pigment genes on the distal X-chromosome Xq28 and one kindred is known to have a genetic change affecting both loci. The purpose of this article is to perform a systematic assessment of the frequency of this situation in many affected kindreds. Methods. Recombinant DNA probes were used in blot hybridization studies to determine the structure of the color pigment genes in affected males from 59 different adrenoleukodystrophy kindreds. Whenever possible, color vision was measured using the Farnsworth 100-Hue test. Results. Eleven of the 59 kindreds had abnormal color pigment gene clusters; these included fusion genes and changes in gene number. Only one kindred had a deletion of sequences immediately 5' to the color pigment genes. Conclusions. The incidence of color pigment gene changes in our 59 adrenoleukodystrophy kindreds is approximately twice the frequency of defective color vision reported in historic studies but is about the same as that found in studies of the actual genes in large populations. However, the range of changes in the color pigment genes in adrenoleukodystrophy is broader than encountered in most populations. Changes in the highly conserved color pigment genes reflect reorganizations in the Xq28 chromosomal region, some of which involve the contiguous gene for adrenoleukodystrophy. Invest Ophthalmol Vis Sci. 1993;34:2634-2637 -?k-linked Adrenoleukodystrophy (ALD) is a devastating neurodegenerative disease affecting boys 6 to 12 years old. Although the underlying metabolic abnormality is unknown, ALD is associated with diagnostic accumulations of very long chain fatty acids. 1 To localize the ALD gene on the human X-chromosome we showed that ALD and the anonymous Xq28 DNA fragment DXS52 cosegregate with a lod score >13 at d = 0.0 in seven kindreds

Mind the gap? The platform trial as a working environment

BACKGROUND: Trials have become bigger and more complicated due to the complexity introduced by biomarker stratification, and the advent of multi-arm multi-stage trials, and umbrella and basket platform designs. The trials unit at University College London has been at the forefront of this work, with ground-breaking trials such as STAMPEDE and FOCUS4. The trial management and data management teams on these trials have summarised the operational challenges, to enable the broader clinical trials community to learn from their experiences. In a small-scale qualitative study, we examined the personal experience of individual researchers working on these trials. COMMENTARY: We found reports of high workloads, with potentially significant stress for individuals and with an impact on their career choices. We conclude that there was an initial underestimation of the work required and of the inherent, largely unanticipated, challenges. We discuss the importance of fully understanding these trials' resource requirements, both for those writing grant applications and critically, for those with responsibility for deciding on funding. The working environment was characterised by three features: complexity, scale and heightened expectations. These features are highly attractive for professional development and engender high levels of loyalty and commitment. We observed a trade-off between these intrinsic rewards and the continuous demands of overlapping tasks, balancing a mix of routine and high-profile work, and the changing nature of pivotal roles. Such demands present challenges for colleague relationships, by enhancing the potential for competition and by disrupting the natural opportunities to pause, review and celebrate team achievements. In addition, molecular stratification in effect brings the patient into the trial office, as a specific individual, despite anonymisation, who is owed test results and a treatment decision. We discuss these observations with a view to interconnecting the need for compassion for patients with caring for the researchers engaged in the research ecosystem who are aiming to produce much hoped-for advances in medical science. CONCLUSIONS: There is a need for increased awareness of the challenge these studies place on those throughout the team delivering the study. Such considerations must influence leaders and funders, both in their initial budget considerations and throughout delivery

Exploring the usability of a connected autonomous vehicle human machine interface designed for older adults

Users of Level 4–5 connected autonomous vehicles (CAVs) should not need to intervene with the dynamic driving task or monitor the driving environment, as the system will handle all driving functions. CAV human-machine interface (HMI) dashboards for such CAVs should therefore offer features to support user situation awareness (SA) and provide additional functionality that would not be practical within non-autonomous vehicles. Though, the exact features and functions, as well as their usability, might differ depending on factors such as user needs and context of use. The current paper presents findings from a simulator trial conducted to test the usability of a prototype CAV HMI designed for older adults and/or individuals with sensory and/or physical impairments: populations that will benefit enormously from the mobility afforded by CAVs. The HMI was developed to suit needs and requirements of this demographic based upon an extensive review of HMI and HCI principles focused on accessibility, usability and functionality [1, 2], as well as studies with target users. Thirty-one 50-88-year-olds (M 67.52, three 50–59) participated in the study. They experienced four seven-minute simulated journeys, involving inner and outer urban settings with mixed speed-limits and were encouraged to explore the HMI during journeys and interact with features, including a real-time map display, vehicle status, emergency stop, and arrival time. Measures were taken pre-, during- and post- journeys. Key was the System Usability Scale [3] and measures of SA, task load, and trust in computers and automation. As predicted, SA decreased with journey experience and although cognitive load did not, there were consistent negative correlations. System usability was also related to trust in technology but not trust in automation or attitudes towards computers. Overall, the findings are important for those designing, developing and testing CAV HMIs for older adults and individuals with sensory and/or physical impairments

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH