The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects.
Pathogenic mutations ...in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome.
Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic.
In addition to the four known common polymorphisms (R34C, H558R, S1103Y, and R1193Q), four relatively ethnic-specific polymorphisms were identified: R481W, S524Y, P1090L, and V1951L. Overall, 39 distinct missense variants (28 novel) were elucidated. Nineteen variants (49%) were found only in the black cohort. Only seven variants (18%) localized to transmembrane-spanning domains. Four variants (F1293S, R1512W, and V1951L cited previously as BrS1-causing mutations and S1787N previously published as a possible LQT3-causing mutation) were identified in this healthy cohort.
This study provides the first comprehensive determination of the prevalence and spectrum of cardiac sodium channel variants in healthy subjects from four distinct ethnic groups. This compendium of SCN5A variants is critical for proper interpretation of SCN5A genetic testing and provides an essential hit list of targets for future functional studies to determine whether or not any of these variants mediate genetic susceptibility for arrhythmias in the setting of either drugs or disease.
•Evaluating incidence and outcome predictors for neurologic injury in spinopelvic dissociation.•Increasing kyphosis is associated with incidence of neurologic injury.•Complete recovery from ...neurologic injury occurs in over half of all patients, with radiculopathy being the most common long-term sequelae.
Traumatic spinopelvic dissociation is a rare injury pattern resulting in discontinuity between the spine and bony pelvis. This injury is associated with a known risk of neurologic compromise which can impact the clinical outcome of these patients. We sought to determine incidence and characteristics of neurologic injury, outcomes following treatment, and predictive factors for neurologic recovery.
We reviewed the clinical documentation and imaging of 270 patients with spinopelvic dissociation from three Level-1 trauma centers treated over a 20-year period. From this cohort, 137 patients fulfilled inclusion criteria with appropriate follow-up. Details surrounding patient presentation, incidence of neurologic injury, and outcome variables were collected for each injury. Neurologic injuries were categorized using the Gibbons criteria. Multivariate analysis was performed to assess for patient and injury factors predictive of neurologic injury and recovery.
The overall incidence of neurologic injury in spinopelvic dissociation injuries was 33% (45/137), with bowel and/or bladder dysfunction (n=16) being the most common presentation. Complete neurologic recovery was seen in 26 cases (58%) and two patients (4%) improved at least one Gibbon stage in clinical follow-up. The most common long-term neurologic sequela at final follow-up was radiculopathy (n=12, 9%). Increased kyphosis was found to be associated with neurologic injury (p=0.002), while location of transverse limb and Roy-Camille type were not predictive of neurologic injury (p=0.31 and p=0.07, respectively). There were no factors found to be predictive of neurologic recovery in this cohort.
Neurologic injury is commonly seen in patients with spinopelvic dissociation and complete neurologic recovery was seen in the majority of patients at final follow-up. When present, long term neurologic dysfunction is most commonly characterized by radiculopathy. While increasing kyphosis was shown to be associated with neurologic injury, no patient or injury factors were predictive of neurologic recovery.
The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some ...cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice.
MYH9‐related disorder diagnosis is still challenging in clinical practice. We analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder and identified 50 patients with a rare variant in MYH9. In the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered.
A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained ...relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant.
The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members.
This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.
•We report a patient with ADA2 deficiency and EBV-driven lymphoproliferative disease.•ADA2 deficiency may predispose to severe EBV-induced disease.•We would recommend that EBV status and viral load is monitored in patients with ADA2 deficiency.
The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with ...antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput ...sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases.
We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes.
We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician.
These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
To review outcomes of spinopelvic dissociation treated with open lumbopelvic fixation.
We reviewed all cases of spinopelvic dissociation treated at three Level-I trauma centers with open lumbopelvic ...fixation, including those with adjunctive percutaneous fixation. We collected demographic data, associated injuries, pre- and postoperative neurologic status, pre- and postoperative kyphosis, and Roy-Camille classification. Outcomes included presence of union, reoperation rates, and complications involving hardware or wound.
From an initial cohort of 260 patients with spinopelvic dissociation, forty patients fulfilled inclusion criteria with a median follow-up of 351 days. Ten patients (25%) had a combination of percutaneous iliosacral and open lumbopelvic repair. Average pre- and postoperative kyphosis was 30 degrees and 26 degrees, respectively. Twenty patients (50%) had neurologic deficit preoperatively, and eight (20%) were unknown or unable to be assessed. All patients presenting with bowel or bladder dysfunction (n = 12) underwent laminectomy at time of surgery, with 3 patients (25%) having continued dysfunction at final follow-up. Surgical site infection occurred in four cases (10%) and wound complications in two (5%). All cases (100%) went on to union and five patients (13%) required hardware removal.
Open lumbopelvic fixation resulted in a high union rate in the treatment of spinopelvic dissociation. Approximately 1 in 6 patients had a wound complication, the majority of which were surgical site infections. Bowel and bladder dysfunction at presentation were common with the majority of cases resolving by final follow-up when spinopelvic dissociation had been treated with decompression and stable fixation.
1. Typically in resource selection studies, the spatial extent of a home range is defined first and then the available resources within that perimeter are estimated. However, the home ranges (or ...habitats) of some animals are constrained by linear environmental features (e.g. rivers, shorelines). Traditional home range estimators often overestimate home range extent for such species, which can lead to spurious estimation of resource availability and selection. 2. We used a synoptic model of space use to explicitly account for resource selection of a species constrained by linear features in its environment to compare with traditional home range estimators. We used the endangered Blakiston's fish owl Bubo blakistoni in the Russian Far East as our example. 3. Mean annual home range size (± standard error) was more than three times larger when using kernel methods (30·3 ± 15·1 km²) than when using the synoptic model (9·4 ± 2·0 km², n = 7). 4. Fish owls showed strong selection for areas within valleys, closer to waterways, closer to patches of permanently open water and with greater channel complexity than available sites. 5. Synthesis and applications. The synoptic model solves a long-standing problem in home range and resource selection studies because it provides an objective way to estimate the space use of a species whose habitat is constrained by linear features in its environment. Improvements in the accuracy of such estimations can lead to identification of important resources across landscapes, the development of more rigorous site-specific or landscape-scale management plans, and to scientifically defensible conservation or threat mitigation measures.
Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be ...reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.
To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.
Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.
Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).
Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).
NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.
Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism.
Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.
MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.
Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.
Apixaban (Eliquis
, Bristol-Myers Squibb, USA; Pfizer, USA) 5 mg bd (twice daily) was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana
, Daiichi Sankyo, Japan) 60 mg od (once daily) was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.
NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.
These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.
Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.
This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.
The National Institute for Health Research Health Technology Assessment programme.
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