81 research outputs found
Diagnosing idiopathic learning disability: a cost-effectiveness analysis of microarray technology in the National Health Service of the United Kingdom
Array based comparative genomic hybridisation (aCGH) is a powerful technique for detecting clinically relevant genome imbalance and can offer 40 to > 1000 times the resolution of karyotyping. Indeed, idiopathic learning disability (ILD) studies suggest that a genome-wide aCGH approach makes 10–15% more diagnoses involving genome imbalance than karyotyping. Despite this, aCGH has yet to be implemented as a routine NHS service. One significant obstacle is the perception that the technology is prohibitively expensive for most standard NHS clinical cytogenetics laboratories. To address this, we investigated the cost-effectiveness of aCGH versus standard cytogenetic analysis for diagnosing idiopathic learning disability (ILD) in the NHS. Cost data from four participating genetics centres were collected and analysed. In a single test comparison, the average cost of aCGH was £442 and the average cost of karyotyping was £117 with array costs contributing most to the cost difference. This difference was not a key barrier when the context of follow up diagnostic tests was considered. Indeed, in a hypothetical cohort of 100 ILD children, aCGH was found to cost less per diagnosis (£3,118) than a karyotyping and multi-telomere FISH approach (£4,957). We conclude that testing for genomic imbalances in ILD using microarray technology is likely to be cost-effective because long-term savings can be made regardless of a positive (diagnosis) or negative result. Earlier diagnoses save costs of additional diagnostic tests. Negative results are cost-effective in minimising follow-up test choice. The use of aCGH in routine clinical practice warrants serious consideration by healthcare providers
Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study
Background Pain is a common symptom in patients with
multiple myeloma (MM). Many patients are dependent on
analgesics and in particular opioids, but there is limited information
on the impact of these drugs and their side effects on
health-related quality of life (HRQoL).
Method In a cross-sectional study, semi-structured interviews
were performed in 21 patients attending the hospital with
symptomatic MM on pain medications. HRQoL was measured
using items 29 and 30 of the European Organisation for
Research and Treatment of Cancer (EORTC) QLQ-C30.
Results Patients were able to recall a median of two (range
0–4) analgesics. They spontaneously identified a median
of two (range 1–5) side effects attributable to their analgesic
medications. Patients’ assessment of HRQoL based on
the EORTC QLQ-C30 questions 29/30 was mean 48.3
(95 % CI; 38.7–57.9) out of 100. Patients’ assessment of
their HRQoL in the hypothetical situation, in which they
would not experience any side effects from analgesics, was
significantly higher: 62.6 (53.5–71.7) (t test, p=0.001).
Conclusion This study provides, for the first time, evidence
that side effects of analgesics are common in symptomatic
MM and may result in a statistically and clinically significant
reduction of self-reported HRQoL
The Simons Observatory: Magnetic Sensitivity Measurements of Microwave SQUID Multiplexers
The Simons Observatory (SO) will be a cosmic microwave background (CMB)
survey experiment with three small-aperture telescopes and one large-aperture
telescope, which will observe from the Atacama Desert in Chile. In total, SO
will field 70,000 transition-edge sensor (TES) bolometers in six spectral
bands centered between 27 and 280 GHz in order to achieve the sensitivity
necessary to measure or constrain numerous cosmological quantities. The SO
Universal Focal Plane Modules (UFMs) each contain a 150 mm diameter TES
detector array, horn or lenslet optical coupling, cold readout components, and
magnetic shielding. SO will use a microwave SQUID multiplexing (MUX)
readout at an initial multiplexing factor of 1000; the cold (100 mK)
readout components are packaged in a MUX readout module, which is part of
the UFM, and can also be characterized independently. The 100 mK stage TES
bolometer arrays and microwave SQUIDs are sensitive to magnetic fields, and
their measured response will vary with the degree to which they are
magnetically shielded. We present measurements of the magnetic pickup of test
microwave SQUID multiplexers as a study of various shielding configurations for
the Simons Observatory. We discuss how these measurements motivated the
material choice and design of the UFM magnetic shielding.Comment: 5 pages, 6 figures, conference proceedings submitted to IEEE
Transactions on Applied Superconductivit
The Simons Observatory microwave SQUID multiplexing detector module design
Advances in cosmic microwave background (CMB) science depend on increasing
the number of sensitive detectors observing the sky. New instruments deploy
large arrays of superconducting transition-edge sensor (TES) bolometers tiled
densely into ever larger focal planes. High multiplexing factors reduce the
thermal loading on the cryogenic receivers and simplify their design. We
present the design of focal-plane modules with an order of magnitude higher
multiplexing factor than has previously been achieved with TES bolometers. We
focus on the novel cold readout component, which employs microwave SQUID
multiplexing (mux). Simons Observatory will use 49 modules containing
60,000 bolometers to make exquisitely sensitive measurements of the CMB. We
validate the focal-plane module design, presenting measurements of the readout
component with and without a prototype detector array of 1728
polarization-sensitive bolometers coupled to feedhorns. The readout component
achieves a yield and a 910 multiplexing factor. The median white noise
of each readout channel is 65 . This impacts the
projected SO mapping speed by , which is less than is assumed in the
sensitivity projections. The results validate the full functionality of the
module. We discuss the measured performance in the context of SO science
requirements, which are exceeded.Comment: Accepted to The Astrophysical Journa
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.
Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein
Purpose
Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.
Methods
We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments.
Results
We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity.
Conclusion
Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping
BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription
Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.This article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.Wellcome Trust (grant number WT098051)Published (open access
A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
Purpose
Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned.
Methods
Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted.
Results
We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency).
Conclusion
The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock
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