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Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18–65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was −0·254% per year (95% CI −0·422 to −0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing. The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

IntroductionDue to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D.Methods and analysisIn this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18–74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5–10.5% (48–91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks’ add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial.Ethics and disseminationThe present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.Trial registration numbersNCT05078255 and U1111-1259-1491.

This paper presents a novel, publicly available repository of anatomically segmented brain images of healthy subjects as well as patients with mild cognitive impairment and Alzheimer's disease. The underlying magnetic resonance images have been obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. T1-weighted screening and baseline images (1.5T and 3T) have been processed with the multi-atlas based MAPER procedure, resulting in labels for 83 regions covering the whole brain in 816 subjects. Selected segmentations were subjected to visual assessment. The segmentations are self-consistent, as evidenced by strong agreement between segmentations of paired images acquired at different field strengths (Jaccard coefficient: 0.802±0.0146). Morphometric comparisons between diagnostic groups (normal; stable mild cognitive impairment; mild cognitive impairment with progression to Alzheimer's disease; Alzheimer's disease) showed highly significant group differences for individual regions, the majority of which were located in the temporal lobe. Additionally, significant effects were seen in the parietal lobe. Increased left/right asymmetry was found in posterior cortical regions. An automatically derived white-matter hypointensities index was found to be a suitable means of quantifying white-matter disease. This repository of segmentations is a potentially valuable resource to researchers working with ADNI data. ► Free repository of MR-based anatomical brain image segmentations. ► Based on ADNI, covering normals and patients. ► Volumetric analysis corroborates previous findings. ► Asymmetry measures correlating with disease progression. ► Automatically derived quantitative index of white-matter disease.

Background According to the World Health Organization, drowning is the 3rd leading cause of unintentional injury-related deaths worldwide, accounting for 370,000 annual deaths and 7% of all injury-related deaths. Low- and middle-income countries are the most affected, accounting for 91% of unintentional drowning deaths. Methods The authors performed a systematic review of literature indexed in EMBASE, PubMed, Web of Science, Cochrane Library, and Traumatology journals formerly indexed in PubMed in January 2014 and again in September 2016. Abstracts were limited to human studies in English, conducted in low- and middle-income countries, and containing quantitative data on drowning epidemiology. Results A total of 62 articles met inclusion criteria. The majority of articles originate from Asia (56%) and Africa (26%). Risk factors for drowning included young age (<17–20 years old), male gender (75% vs. 25% female), rural environment (84% vs. 16% urban), occurring in the daytime (95% vs. 5% night time), lack of adult supervision (76% vs. 18% supervised), and limited swimming ability (86% vs. 10% with swimming ability). There was almost equal risk of drowning in a small body of water versus a large body of water (42% ponds, ditches, streams, wells; 46% lakes, rivers, sea, ocean). Conclusion Drowning is a significant cause of injury-related deaths, especially in LMICs. Young males who are unsupervised in rural areas and have limited formal swimming instruction are at greatest risk of drowning in small bodies of water around their homes. Preventative strategies include covering wells and cisterns, fencing off ditches and small ponds, establishing community daycares, providing formal swimming lessons, and increasing awareness of the risks of drowning.

Abstract Context Despite evidence of possible glucagonotropic effects, the role of the gut hormone glucagon-like peptide 2 (GLP-2) in glucose metabolism is unclear. Objective This work aimed to evaluate the effect of exogenous GLP-2 on plasma glucagon levels during hypoglycemia, euglycemia, and hyperglycemia in healthy male volunteers. Methods A randomized, double-blind, placebo-controlled, crossover study was conducted with supportive ex vivo human islet experiments. Participants included 10 lean, healthy men, median (interquartile range) aged 22 (21-23) years, with body mass index of 23.5 (23.3-23.8) and glycated hemoglobin A1c of 4.8 (4.6-5.1)% (29 (26.5-32.5) mmol/mol). During 6 separate study days, GLP-2 (6 pmol/kg/min for 10 minutes and 2 pmol/kg/min for the following 90 minutes) and placebo (saline), respectively, were infused intravenously during insulin-induced hypoglycemia (∼2.5 mmol/L), euglycemia (∼5 mmol/L), or hyperglycemia (∼10 mmol/L). Primary outcome was baseline-subtracted area under the curve for plasma glucagon, and secondary outcomes were serum insulin and C-peptide concentrations. Exploratory outcomes included norepinephrine, growth hormone, and bone homeostatic markers carboxy-terminal collagen crosslinks (CTX) and procollagen type I amino-terminal propeptide (PINP). Results During GLP-2 infusions, steady-state plasma GLP-2 concentrations were 50-fold higher than during placebo. Compared to placebo, GLP-2 increased glucagon secretion slightly during euglycemia, and not during insulin-induced hypoglycemia or hyperglycemia. Ex vivo, GLP-2 did not affect glucagon secretion from isolated human islets. GLP-2 did not affect circulating concentrations of insulin, C-peptide, growth hormone, norepinephrine, or CTX during hypoglycemia, euglycemia, or hyperglycemia. GLP-2 decreased PINP during euglycemia and hyperglycemia. Conclusion Exogenous GLP-2 increased glucagon secretion slightly during euglycemia and not during insulin-induced hypoglycemia or hyperglycemia in healthy young men.

Rates of brain atrophy derived from serial magnetic resonance (MR) studies may be used to assess therapies for Alzheimer's disease (AD). These measures may be confounded by changes in scanner voxel sizes. For this reason, the Alzheimer's Disease Neuroimaging Initiative (ADNI) included the imaging of a geometric phantom with every scan. This study compares voxel scaling correction using a phantom with correction using a 9 degrees of freedom (9DOF) registration algorithm. We took 129 pairs of baseline and 1-year repeat scans, and calculated the volume scaling correction, previously measured using the phantom. We used the registration algorithm to quantify any residual scaling errors, and found the algorithm to be unbiased, with no significant (p=0.97) difference between control (n=79) and AD subjects (n=50), but with a mean (SD) absolute volume change of 0.20 (0.20) % due to linear scalings. 9DOF registration was shown to be comparable to geometric phantom correction in terms of the effect on atrophy measurement and unbiased with respect to disease status. These results suggest that the additional expense and logistic effort of scanning a phantom with every patient scan can be avoided by registration-based scaling correction. Furthermore, based upon the atrophy rates in the AD subjects in this study, sample size requirements would be approximately 10–12% lower with (either) correction for voxel scaling than if no correction was used.

Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease. In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012–003641–15), and is completed. Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was –2·29 mL (95% CI –6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group. 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods. Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Matthew Hemming and colleagues describe the ex vivo gene delivery of an Aβ-degrading protease that reduces amyloid plaque burden in transgenic mice expressing human amyloid precursor protein.

Objective To assess the relationship between MRI-derived changes in whole-brain and ventricular volume with change in cognitive scores in Alzheimer’s disease (AD), mild cognitive impairment (MCI) and control subjects. Material and methods In total 131 control, 231 MCI and 99 AD subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with T1-weighted volumetric MRIs from baseline and 12-month follow-up were used to derive volume changes. Mini mental state examination (MMSE), Alzheimer’s disease assessment scale (ADAS)-cog and trails test changes were calculated over the same period. Results Brain atrophy rates and ventricular enlargement differed between subject groups ( p  < 0.0005) and in MCI and AD were associated with MMSE changes. Both measures were additionally associated with ADAS-cog and trails-B in MCI patients, and ventricular expansion was associated with ADAS-cog in AD patients. Brain atrophy ( p  < 0.0005) and ventricular expansion rates ( p  = 0.001) were higher in MCI subjects who progressed to AD within 12 months of follow-up compared with MCI subjects who remained stable. MCI subjects who progressed to AD within 12 months had similar atrophy rates to AD subjects. Conclusion Whole-brain atrophy rates and ventricular enlargement differed between patient groups and healthy controls, and tracked disease progression and psychological decline, demonstrating their relevance as biomarkers.

Understanding the mechanisms of amyloid-beta protein (Abeta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Abeta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Abeta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Abeta levels in AD. The objective of this study was to determine if enhancing the clearance of Abeta in the brain by ex vivo gene delivery of an Abeta-degrading protease can reduce amyloid plaque burden. We generated a secreted form of the Abeta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Abeta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). Ex vivo gene delivery of an Abeta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Abeta-degrading proteases as a means to therapeutically lower Abeta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.