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Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available. Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.

BackgroundThe brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS.MethodsWe conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression.Results383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0–6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW.ConclusionLarger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS.Trail registration numberNCT01910259.

A 31-year old male with a background of occasional Migraine without aura and mechanical lower back pain, presented with recurrent transient episodes of generalised headache, speech impairment, confusional state, and hemi-body sensory-motor symptoms. He had 9-10 episodes over a 2-week period. These were sudden, non-stereotypical, and lasted between 30-120 minutes. He was well in between and the very first episode happened just before his travel to the Canaries for holidays. He had 3 separate admissions with these episodes.Routine blood tests were normalContrast CT head and MRI brain showed transient generalised leptome- ningeal enhancement, CSF showed sequential WCC of 420 and 200 before returning to normal. Repeat EEG showed no epileptiform abnormality. Extensive tests for infectious agents including viral serology were all either negative or suggestive of previous exposure. Only HSV-7 PCR was positive. Inflammatory and paraneoplastic tests were negative. He fully recovered from these in 2 months with no sequelae.The clinical Syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lympho- cytosis (HaNDL) is well described, rarely seen and poorly understood. Proposed mechanisms include migraine pathophysiology, post-infectious and immunological phenomenon. This is the first report of an active HSV-7 infection, causing HaNDL.

Objective The role of CSF lymphocytic pleocytosis in predicting the clinical outcome of multiple sclerosis is unclear. We explored the impact of CSF pleocytosis at diagnosis on long-term disease progression in a large UK cohort. Methods We extracted demographic, clinical and CSF data of people with MS attending the MS clinics between 1996 and 2014 at two MS centres from the English Midlands. We compared EDSS at onset, follow up EDSS and progression indices Multiple Sclerosis Severity Score (MSSS), annualized change in EDSS and transition to secondary progression in the presence/absence of pleocytosis. Two-tailed student t -test, Mann–Whitney U test, Chi-Square or Fisher’s exact tests were used for detecting the differences. Results A total of 247 patients with MS (178 females; mean age 42.4; 217 with relapsing onset) were followed up for an average of 13.56 years (median 12 years). Almost 18% had lymphocytic CSF ≥ 5 per microliter. CSF pleocytosis was not associated with higher EDSS at the time of LP or at follow up, and other progression indices like MSSS, annualized change in EDSS or transition to secondary progression. Discussion CSF pleocytosis at MS diagnosis does not predict higher long-term disability and has no long-term prognostic value in routine clinical circumstances. Differences between MS populations and potential differences in disease activity at the time of CSF analysis may account for differences between studies.

Postextubation, the patient became restless, tachypnoeic and started desaturating. 100% O 2 delivery was tried with anatomical face mask but because of inadequate seal, the continuous positive airway pressure could not be achieved. Type I is of sudden onset following upper airway obstruction and Type II develops after surgical relief of chronic upper airway obstruction.

Introduction Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. Methods In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. Results The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0–100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. Conclusions Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

Phenytoin infusion was stopped;, patient's vitals were closely monitored and following investigations were done-: -complete haemogram, renal function tests, blood glucose, liver function tests, serum albumin, serum sodium, potassium, magnesium, phosphorus and calcium. Causes of hypocalcaemia can be many, e.g. chronic and acute renal failure, post-thyroidectomy [3] post- parathyroidectomy, primary hypoparathyroidism, [4] vitamin D deficiency, massive blood transfusion, hypoalbuminaemia, alkalosis, chemotherapy, acute pancreatitis, etc.

BackgroundTo assist neurologists with effectively planning multiple sclerosis (MS) services in the NHS, this study quantified the administration and monitoring time burden associated with selected high-efficacy disease-modifying therapies (DMTs; alemtuzumab, cladribine tablets [CladT], fingolimod, natalizumab, and ocrelizumab) for highly-active relapsing MS in the UK.MethodsA time and motion study was conducted across four MS centres over 3–4 months per-site (Aug 2019–Feb 2021). Time dedicated by healthcare professionals (HCPs) to pre-specified drug administration and monitoring activities was assessed for each of the selected DMTs. Data were extrapolated over 4 years per-patient, based on the relevant Summaries of Product Characteristics, and analysed descriptively.ResultsFor oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 12.3 hours for CladT and 15.9 hours for fingolimod. For infusion DMTs, total time (administration and monitoring) was 35.5 hours for alemtuzumab (6.1 and 29.4 hours), 46.5 hours for natalizumab (17.2 and 29.3 hours), and 21.6 hours for ocrelizumab (6.2 and 15.4 hours).ConclusionsWhile active HCP time varies across sites, infusion DMTs are projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs.

This case report highlights the anaesthetic management of a patient who had residual muscle paralysis following neuromuscular blockade, which was attributed to hypothermia and corrected by administration of amino acid solution. The various causes of residual neuromuscular blockade should be considered when treating such a patient. Amino acid infusion has been found to hasten the recovery from neuromuscular block due to vecuronium bromide aggravated by hypothermia.