128 research outputs found
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The Pulmonary Vascular Research Institute celebrates its first decade.
Virtual consultations for patients with Obstructive Sleep Apnoea:systematic review and meta-analysis
Background: The COVID-19 pandemic has accelerated the adoption of virtual care strategies for the management of patients with Obstructive Sleep Apnoea/Hypopnoea Syndrome. Research question: What is the effectiveness of virtual consultations compared to in-person consultations for the management of Continuous Positive Airway Pressure therapy in adult patients with Obstructive Sleep Apnoea/Hypopnoea Syndrome? Methods: A systematic review and meta-analysis (PROSPERO; CRD42022297532) based on six electronic databases plus manually selected journals was conducted in January 2022. Two researchers independently selected, quality appraised, and extracted data. The co-primary outcomes were patient-reported sleepiness, assessed by the Epworth Sleepiness Scale, and reported cost-effectiveness. Findings: 12 studies (n=1823 adults) were included in the review. Seven studies (n=1089) were included in the meta-analysis which showed no difference in the magnitude of improvement in patient-reported sleepiness scores between virtual and in-person consultations (MD [95%CI], -0.39 [-1.38 to 0.60]; p=0.4), though Epworth Sleepiness Scale scores improved in both groups. Virtual care strategies modestly increased Continuous Positive Airway Pressure therapy adherence and were found to be less costly than in-person care strategies in the three Spanish trials that reported cost-effectiveness. Conclusion: The findings of this review suggest that virtual care delivered by telephone or video consultations is as effective as in-person consultations for improving subjective sleepiness in patients with Obstructive Sleep Apnoea/Hypopnoea Syndrome treated with Continuous Positive Airway Pressure. This clinical management strategy may also improve Continuous Positive Airway Pressure adherence without increasing the costs, supporting its potential as a follow-up management strategy, where patients prefer this approach
A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO)
Rationale Mandibular advancement devices (MADs)
are used to treat obstructive sleep apnoea-hypopnoea
syndrome (OSAHS) but evidence is lacking regarding
their clinical and cost-effectiveness in less severe disease.
Objectives To compare clinical- and cost-effectiveness
of a range of MADs against no treatment in mild to
moderate OSAHS.
Measurements and methods This open-label,
randomised, controlled, crossover trial was undertaken at
a UK sleep centre. Adults with Apnoea-Hypopnoea Index
(AHI) 5–<30/h and Epworth Sleepiness Scale (ESS) score
≥9 underwent 6 weeks of treatment with three nonadjustable
MADs: self-moulded (SleepPro 1; SP1);
semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD
(bMAD); and 4 weeks no treatment. Primary outcome
was AHI scored by a polysomnographer blinded to
treatment. Secondary outcomes included ESS, quality of
life, resource use and cost.
Main results 90 patients were randomised and 83
were analysed. All devices reduced AHI compared with
no treatment by 26% (95% CI 11% to 38%, p=0.001)
for SP1, 33% (95% CI 24% to 41%) for SP2 and 36%
(95% CI 24% to 45%, p<0.001) for bMAD. ESS was
1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37
(95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no
treatment (p<0.001 for all). Compliance was lower for
SP1, which was the least preferred treatment at trial exit.
All devices were cost-effective compared with no
treatment at a £20 000/quality-adjusted life year (QALY)
threshold. SP2 was the most cost-effective up to
£39 800/QALY.
Conclusions Non-adjustable MADs achieve clinically
important improvements in mild to moderate OSAHS and
are cost-effective
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation
Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.
Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype
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Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Background:
Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (
BMPR2
) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (
EIF2AK4
) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.
Methods:
Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in
BMPR2
and biallelic
EIF2AK4
variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and
sorting intolerant from tolerant
predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.
Results:
Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in
BMPR2
were identified in 130 patients (14.8%). Biallelic mutations in
EIF2AK4
were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic
EIF2AK4
mutations. These patients had a reduced transfer coefficient for carbon monoxide (K
co
; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without
EIF2AK4
mutations. However, radiological assessment alone could not accurately identify biallelic
EIF2AK4
mutation carriers. Patients with PAH with biallelic
EIF2AK4
mutations had a shorter survival.
Conclusions:
Biallelic
EIF2AK4
mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K
co
and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge
Cancer Centre and Medical Research Council Infrastructure Award. The
University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre
The influence of recent social experience and physical environment on courtship and male aggression
Prolonged rote learning produces delayed memory facilitation and metabolic changes in the hippocampus of the ageing human brain
Background: Repeated rehearsal is one method by which verbal material may be transferred from short- to long-term memory. We hypothesised that extended engagement of memory structures through prolonged rehearsal would result in enhanced efficacy of recall and also of brain structures implicated in new learning. Twenty-four normal participants aged 55-70 (mean = 60.1) engaged in six weeks of rote learning, during which they learned 500 words per week every week (prose, poetry etc.). An extensive battery of memory tests was administered on three occasions, each six weeks apart. In addition, proton magnetic resonance spectroscopy (H-1-MRS) was used to measure metabolite levels in seven voxels of interest (VOIs) (including hippocampus) before and after learning.Results: Results indicate a facilitation of new learning that was evident six weeks after rote learning ceased. This facilitation occurred for verbal/episodic material only, and was mirrored by a metabolic change in left posterior hippocampus, specifically an increase in NAA/(Cr+Cho) ratio.Conclusion: Results suggest that repeated activation of memory structures facilitates anamnesis and may promote neuronal plasticity in the ageing brain, and that compliance is a key factor in such facilitation as the effect was confined to those who engaged fully with the training
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