A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Systematic meta-review of supported self-management for asthma: a healthcare perspective

BACKGROUND: Supported self-management has been recommended by asthma guidelines for three decades; improving current suboptimal implementation will require commitment from professionals, patients and healthcare organisations. The Practical Systematic Review of Self-Management Support (PRISMS) meta-review and Reducing Care Utilisation through Self-management Interventions (RECURSIVE) health economic review were commissioned to provide a systematic overview of supported self-management to inform implementation. We sought to investigate if supported asthma self-management reduces use of healthcare resources and improves asthma control; for which target groups it works; and which components and contextual factors contribute to effectiveness. Finally, we investigated the costs to healthcare services of providing supported self-management. METHODS: We undertook a meta-review (systematic overview) of systematic reviews updated with randomised controlled trials (RCTs) published since the review search dates, and health economic meta-analysis of RCTs. Twelve electronic databases were searched in 2012 (updated in 2015; pre-publication update January 2017) for systematic reviews reporting RCTs (and update RCTs) evaluating supported asthma self-management. We assessed the quality of included studies and undertook a meta-analysis and narrative synthesis. RESULTS: A total of 27 systematic reviews (n = 244 RCTs) and 13 update RCTs revealed that supported self-management can reduce hospitalisations, accident and emergency attendances and unscheduled consultations, and improve markers of control and quality of life for people with asthma across a range of cultural, demographic and healthcare settings. Core components are patient education, provision of an action plan and regular professional review. Self-management is most effective when delivered in the context of proactive long-term condition management. The total cost (n = 24 RCTs) of providing self-management support is offset by a reduction in hospitalisations and accident and emergency visits (standard mean difference 0.13, 95% confidence interval -0.09 to 0.34). CONCLUSIONS: Evidence from a total of 270 RCTs confirms that supported self-management for asthma can reduce unscheduled care and improve asthma control, can be delivered effectively for diverse demographic and cultural groups, is applicable in a broad range of clinical settings, and does not significantly increase total healthcare costs. Informed by this comprehensive synthesis of the literature, clinicians, patient-interest groups, policy-makers and providers of healthcare services should prioritise provision of supported self-management for people with asthma as a core component of routine care. SYSTEMATIC REVIEW REGISTRATION: RECURSIVE: PROSPERO CRD42012002694 ; PRISMS: PROSPERO does not register meta-reviews

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Statistical analysis of northward IMF phenomena, transpolar arcs and horse collar aurora

Some auroral phenomena occur primarily during quiet geomagnetic conditions when the interplanetary magnetic field (IMF) is directed northward; these auroral features tend to occur poleward of the main auroral oval. The Special Sensor Ultraviolet Spectrographic Imager (SSUSI) instrument on-board Defense Meteorological Satellite Program (DMSP) provides a way to observe the auroral regions on the Earth almost simultaneously in northern and southern hemispheres which allows these phenomena to be studied in detail. This thesis presents statistical analyses of transpolar arcs (TPAs) and horse collar aurora (HCA). Firstly, a detection algorithm is created to identify TPAs in the DMSP/SSUSI data based on peaks in the average radiance intensity poleward of 12.5° colatitude. TPAs are found to be observed more frequently in the winter hemisphere. A preference for TPAs to be detected at dawn is also seen. These findings are discussed in relation to current TPA formation models. Similar statistical analysis is performed on HCA identified visually in the DMSP/SSUSI data. As expected, HCA form when the interplanetary magnetic field (IMF) clock angle is small. The occurrence of HCA does not appear to be dependent on season or the IMF Bx component. It is found that the dawn arc of the HCA is usually brighter than the dusk arc. It is suggested that this could lead to the unexpected predominance of TPAs at dawn, and that these are possibly misidentified HCA. Finally, 11 HCA events are studied in further detail with the use of all-sky cameras (ASC) to track the formation and motion of the HCA. The arcs follow the predicted theory and move dawnward (duskward) in the northern hemisphere if the IMF becomes dominated by a negative (positive) By. TPAs and HCA are also seen to occur simultaneously.</p

Signatures of wedgelets over Fennoscandia during the St Patrick s Day Storm 2015

During the long main phase of the St Patrick's Day storm on March 17, 2015, we found three separate enhancements of the westward electrojet. These enhancements are observed in the ionospheric equivalent currents computed using geomagnetic data over Fennoscandia. Using data from the IMAGE magnetometer network, we identified localised field-aligned current (FAC) systems superimposed on the pre-existing ionospheric current system. We suggest that these localised current systems are wedgelets and that they can potentially contribute to a larger-scale structure of a substorm current wedge (SCW). Each wedgelet is associated with a negative BX spike. Each spike is recorded at a higher latitude than the former one and all three are very localised over Fennoscandia. The first spike occurred at 17:34 UT and was observed at Lycksele, R rvik and Nurmij rvi, the second spike was recorded at 17:41 UT and located at Lycksele and R rvik, whereas the last spike occurred at 17:47 UT and was observed at Kevo and Abisko. Simultaneous optical auroral data and electron injections at the geosynchronous orbit indicate that one or more substorms took place in the polar ionosphere at the time of the wedgelets. This study demonstrates the occurrence of small and short-lived structures such as wedgelets at different locations over a short time scale, 15 min in this case

Signatures of wedgelets over Fennoscandia during the St Patrick’s Day Storm 2015

During the long main phase of the St Patrick’s Day storm on March 17, 2015, we found three separate enhancements of the westward electrojet. These enhancements are observed in the ionospheric equivalent currents computed using geomagnetic data over Fennoscandia. Using data from the IMAGE magnetometer network, we identified localised field-aligned current (FAC) systems superimposed on the pre-existing ionospheric current system. We suggest that these localised current systems are wedgelets and that they can potentially contribute to a larger-scale structure of a substorm current wedge (SCW). Each wedgelet is associated with a negative BX spike. Each spike is recorded at a higher latitude than the former one and all three are very localised over Fennoscandia. The first spike occurred at 17:34 UT and was observed at Lycksele, Rørvik and Nurmijärvi, the second spike was recorded at 17:41 UT and located at Lycksele and Rørvik, whereas the last spike occurred at 17:47 UT and was observed at Kevo and Abisko. Simultaneous optical auroral data and electron injections at the geosynchronous orbit indicate that one or more substorms took place in the polar ionosphere at the time of the wedgelets. This study demonstrates the occurrence of small and short-lived structures such as wedgelets at different locations over a short time scale, 15 min in this case

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease