The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease

Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency

From Wiley via Jisc Publications RouterHistory: received 2019-12-09, rev-recd 2020-08-28, accepted 2020-08-29, pub-electronic 2020-09-15, pub-print 2021-06Article version: VoRPublication status: PublishedFunder: Medical Research Council Clinical Research Training Fellowship; Grant(s): MR/N001427/1Funder: European Society of Paediatric Infectious Diseases FellowshipFunder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269; Grant(s): 202865/Z/16/ZAbstract: The glucose‐6‐phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss‐of‐function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra‐hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony‐stimulating factor (G‐CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency‐associated IBD. G6PC3 deficiency was associated with early‐onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G‐CSF treatment. In vitro studies on the patients’ blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL‐8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro‐inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G‐CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency‐associated IBD refractory to immune suppressants

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Modelling an integrated impact of fire, explosion and combustion products during transitional events caused by an accidental release of LNG

In a complex processing facility, there is likelihood of occurrence of cascading scenarios, i.e. hydrocarbon release, fire, explosion and dispersion of combustion products. The consequence of such scenarios, when combined, can be more severe than their individual impact. Hence, actual impact can be only representedby integration of above mentioned events. A novel methodology is proposed to model an evolving accident scenario during an incidental release of LNG in a complex processing facility. The methodology is applied to a case study considering transitional scenarios namely spill, pool formation and evaporation of LNG, dispersion of natural gas, and the consequent fire, explosion and dispersion of combustion products using Computational Fluid Dynamics (CFD). Probit functions are employed to analyze individual impacts and a ranking method is used to combine various impacts to identify risk during the transitional events.The results confirmed that in a large and complex facility, an LNG fire can transit to a vapor cloud explosion ifthe necessary conditions are met, i.e.the flammable range, ignition source with enough energy and congestion/confinement level. Therefore, the integrated consequences are more severe than those associated with the individual ones, and need to be properly assessed. This study would provide an insight for an effective analysis of potential consequences of an LNG spill in any LNG processing facility and it can be useful for the safety measured design of process facilities

Cross-sectional relationship between physical fitness components and functional performance in older persons living in long-term care facilities

BACKGROUND: The age-related deterioration of physiological capacities such as muscle strength and balance is associated with increased dependence. Understanding the contribution of physical fitness components to functional performance facilitates the development of adequate exercise interventions aiming at preservation of function and independence of older people. The aim of the study was to investigate the relationship between physical fitness components and functional performance in older people living in long-term care facilities. METHODS: Design cross-sectional study Subjects 226 persons living in long-term care facilities (mean age: 81.6 ± 5.6). Outcome measures Physical fitness and functional performance were measured by performance-based tests. RESULTS: Knee and elbow extension strength were significantly higher in men (difference = 44.5 and 50.0 N, respectively), whereas women were more flexible (difference sit & reach test = 7.2 cm). Functional performance was not significantly different between the genders. In men, motor coordination (eye-hand coordination) and measures of strength were the main contributors to functional performance, whereas in women flexibility (sit and reach test) and motor coordination (tandem stance and eye-hand coordination) played a major role. CONCLUSION: The results of this study show that besides muscle strength, fitness components such as coordination and flexibility are associated with functional performance of older people living in long-term care facilities. This suggests that men and women living in long-term care facilities, differ considerably concerning the fitness factors contributing to functional performance. Women and men may, therefore, need exercise programs emphasizing different fitness aspects in order to improve functional performance

Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations

BACKGROUND: The Mini Mental State Examination (MMSE) is a cognitive test that is commonly used as part of the evaluation for possible dementia. OBJECTIVES: To determine the diagnostic accuracy of the Mini‐Mental State Examination (MMSE) at various cut points for dementia in people aged 65 years and over in community and primary care settings who had not undergone prior testing for dementia. SEARCH METHODS: We searched the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), LILACS (BIREME), ALOIS, BIOSIS previews (Thomson Reuters Web of Science), and Web of Science Core Collection, including the Science Citation Index and the Conference Proceedings Citation Index (Thomson Reuters Web of Science). We also searched specialised sources of diagnostic test accuracy studies and reviews: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). We attempted to locate possibly relevant but unpublished data by contacting researchers in this field. We first performed the searches in November 2012 and then fully updated them in May 2014. We did not apply any language or date restrictions to the electronic searches, and we did not use any methodological filters as a method to restrict the search overall. SELECTION CRITERIA: We included studies that compared the 11‐item (maximum score 30) MMSE test (at any cut point) in people who had not undergone prior testing versus a commonly accepted clinical reference standard for all‐cause dementia and subtypes (Alzheimer disease dementia, Lewy body dementia, vascular dementia, frontotemporal dementia). Clinical diagnosis included all‐cause (unspecified) dementia, as defined by any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM); International Classification of Diseases (ICD) and the Clinical Dementia Rating. DATA COLLECTION AND ANALYSIS: At least three authors screened all citations.Two authors handled data extraction and quality assessment. We performed meta‐analysis using the hierarchical summary receiver‐operator curves (HSROC) method and the bivariate method. MAIN RESULTS: We retrieved 24,310 citations after removal of duplicates. We reviewed the full text of 317 full‐text articles and finally included 70 records, referring to 48 studies, in our synthesis. We were able to perform meta‐analysis on 28 studies in the community setting (44 articles) and on 6 studies in primary care (8 articles), but we could not extract usable 2 x 2 data for the remaining 14 community studies, which we did not include in the meta‐analysis. All of the studies in the community were in asymptomatic people, whereas two of the six studies in primary care were conducted in people who had symptoms of possible dementia. We judged two studies to be at high risk of bias in the patient selection domain, three studies to be at high risk of bias in the index test domain and nine studies to be at high risk of bias regarding flow and timing. We assessed most studies as being applicable to the review question though we had concerns about selection of participants in six studies and target condition in one study. The accuracy of the MMSE for diagnosing dementia was reported at 18 cut points in the community (MMSE score 10, 14‐30 inclusive) and 10 cut points in primary care (MMSE score 17‐26 inclusive). The total number of participants in studies included in the meta‐analyses ranged from 37 to 2727, median 314 (interquartile range (IQR) 160 to 647). In the community, the pooled accuracy at a cut point of 24 (15 studies) was sensitivity 0.85 (95% confidence interval (CI) 0.74 to 0.92), specificity 0.90 (95% CI 0.82 to 0.95); at a cut point of 25 (10 studies), sensitivity 0.87 (95% CI 0.78 to 0.93), specificity 0.82 (95% CI 0.65 to 0.92); and in seven studies that adjusted accuracy estimates for level of education, sensitivity 0.97 (95% CI 0.83 to 1.00), specificity 0.70 (95% CI 0.50 to 0.85). There was insufficient data to evaluate the accuracy of the MMSE for diagnosing dementia subtypes.We could not estimate summary diagnostic accuracy in primary care due to insufficient data. AUTHORS' CONCLUSIONS: The MMSE contributes to a diagnosis of dementia in low prevalence settings, but should not be used in isolation to confirm or exclude disease. We recommend that future work evaluates the diagnostic accuracy of tests in the context of the diagnostic pathway experienced by the patient and that investigators report how undergoing the MMSE changes patient‐relevant outcomes