Update of the best practice dietetic management of overweight and obese children and adolescents: a systematic review protocol

To update an existing systematic review series of randomized controlled trials (RCT) that include a dietary intervention for the management of overweight or obesity in children or adolescents.Specifically, the review questions are: In randomized controlled trials of interventions which include a dietary intervention for the management of overweight or obesity in children or adolescents

The self-reference effect on perception: Undiminished in adults with autism and no relation to autism traits

Memory for (and perception of) information about the self is superior to memory for (and perception of) other kinds of information. This self-reference effect (SRE) in memory appears diminished in ASD and related to the number of ASD traits manifested by neurotypical individuals (fewer traits = larger SRE). Here, we report the first experiments exploring the relation between ASD and the SRE in perception. Using a “Shapes” Task (Sui et al., 2012), participants learned to associate three different shapes (triangle, circle, square) with three different labels representing self, a familiar other, or an unfamiliar other (e.g., “you”, “mother”, “stranger”). Participants then completed trials during which they were presented with one shape and one label for 100ms, and made judgements about whether the shape and label were a match. In Experiment 1, neurotypical participants (n=124) showed the expected SRE, detecting self-related matches more reliably and quickly than matches involving familiar or unfamiliar other. Most important, number of ASD traits was unrelated to the size of the SRE for either accuracy or RT. Bayesian association analyses strongly supported the null hypothesis. In Experiment 2, there were no differences between 22 adults with ASD and 21 matched comparison adults in performance on the Shapes Task. Despite showing large and significant theory of mind impairments, participants with ASD showed the typical SRE and there were no associations with ASD traits in either group. In every case, Bayesian analyses favoured the null hypothesis. These findings challenge theories about self-representation in ASD, as discussed in the paper

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Effectiveness of lifestyle interventions in child obesity: systematic review with meta-analysis

Background and objectives: The effects of lifestyle interventions on cardio-metabolic outcomes in overweight children have not been reviewed systematically. The objective of the study was to examine the impact of lifestyle interventions incorporating a dietary component on both weight change and cardio-metabolic risks in overweight/obese children. Methods: English-language articles from 1975 to 2010, available from 7 databases, were used as data sources. Two independent reviewers assessed articles against the following eligibility criteria: randomized controlled trial, participants overweight/obese and ≤18 years, comparing lifestyle interventions to no treatment/wait-list control, usual care, or written education materials. Study quality was critically appraised by 2 reviewers using established criteria; Review Manager 5.1 was used for meta-analyses.Results: Of 38 eligible studies, 33 had complete data for meta-analysis on weight change; 15 reported serum lipids, fasting insulin, or blood pressure. Lifestyle interventions produced significant weight loss compared with no-treatment control conditions: BMI (−1.25kg/m², 95% confidence interval [CI] −2.18 to −0.32) and BMI z score (−0.10, 95% CI −0.18 to −0.02). Studies comparing lifestyle interventions to usual care also resulted in significant immediate (−1.30kg/m², 95% CI −1.58 to −1.03) and posttreatment effects (−0.92 kg/m², 95% CI −1.31 to −0.54) on BMI up to 1 year from baseline. Lifestyle interventions led to significant improvements in low-density lipoprotein cholesterol (−0.30 mmol/L, 95% CI −0.45 to −0.15), triglycerides (−0.15 mmol/L, 95% CI −0.24 to −0.07), fasting insulin (−55.1 pmol/L, 95% CI −71.2 to −39.1) and blood pressure up to 1 year from baseline. No differences were found for high-density lipoprotein cholesterol. Conclusions: Lifestyle interventions can lead to improvements in weight and cardio-metabolic outcomes. Further research is needed to determine the optimal length, intensity, and long-term effectiveness of lifestyle interventions

Outcomes of Sub-threshold Abdominal Aortic Aneurysms Undergoing Surveillance in Patients Aged 85 Years or Over

Objective Despite an increasing elderly population there is limited evidence regarding the surveillance and management of small abdominal aortic aneurysms (AAAs) in octogenarians. This study investigated outcomes of patients aged ≥85 years undergoing AAA surveillance to identify whether discontinuation of surveillance might be safe. Methods This was a retrospective cohort study of all patients aged 85 years undergoing surveillance with a small (30–54 mm) AAA between January 2007 and November 2017. Patients were stratified depending on aneurysm diameter at index ( 50 mm). A threshold of 55 mm was used to decide intervention in all patients. Subsequent management of threshold aneurysms, aneurysm related and all cause mortality were also collected. Results One hundred and one patients were included (88 male, mean diameter at index 45 mm, median follow up 56.0 months). The majority of patients (72.3%) undergoing surveillance had not reached threshold at the end of follow up. Only one patient in the 50 mm groups, respectively (p 50 mm index group). Conclusion The present data suggests that discontinuation of aneurysm surveillance in patients aged 85 years with aneurysms < 40 mm might be safe. In patients with a larger aneurysm or those approaching threshold, early assessment of fitness for surgery may prevent unnecessary surveillance. The decision to treat aneurysms reaching threshold is complex but is appropriate in selected patients

CaMKK2 facilitates Golgi-associated vesicle trafficking to sustain cancer cell proliferation

Abstract Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates cell and whole-body metabolism and supports tumorigenesis. The cellular impacts of perturbing CAMKK2 expression are, however, not yet fully characterised. By knocking down CAMKK2 levels, we have identified a number of significant subcellular changes indicative of perturbations in vesicle trafficking within the endomembrane compartment. To determine how they might contribute to effects on cell proliferation, we have used proteomics to identify Gemin4 as a direct interactor, capable of binding CAMKK2 and COPI subunits. Prompted by this, we confirmed that CAMKK2 knockdown leads to concomitant and significant reductions in δ-COP protein. Using imaging, we show that CAMKK2 knockdown leads to Golgi expansion, the induction of ER stress, abortive autophagy and impaired lysosomal acidification. All are phenotypes of COPI depletion. Based on our findings, we hypothesise that CAMKK2 sustains cell proliferation in large part through effects on organelle integrity and membrane trafficking

Impact of dietary macronutrient distribution on BMI and cardiometabolic outcomes in overweight and obese children and adolescents: a systematic review

The present systematic review examined the effectiveness of weight management interventions comparing diets with varying macronutrient distributions on BMI and cardiometabolic risk factors in overweight or obese children and adolescents. A systematic search of seven databases for the period 1975−2013 identified 14 eligible randomized or quasi-randomized controlled trials conducted with 6–18-year-old subjects. Seven trials compared a low-fat (≤33% energy or <40 g/day) to an isocaloric (n = 2) or ad libitum (n = 5) low-carbohydrate diet (<20% energy or <60 g/day). Meta-analysis indicated a greater reduction in BMI in the low-carbohydrate group immediately after dietary intervention; however, the quality of the studies was limited and cardiometabolic benefits were inconsistent. Six trials compared increased-protein diets (19–30% energy) to isocaloric standard-protein diets (15–20% energy) and one compared an increased-fat diet (40% energy) to an isocaloric standard-fat diet (27% energy); there were no differences in outcomes in these studies. Current evidence suggests that improved weight status can be achieved in overweight or obese children and adolescents irrespective of the macronutrient distribution of a reduced-energy diet. Tailoring the macronutrient content to target specific cardiometabolic risk factors, such as a low-carbohydrate diet to treat insulin resistance, may be possible, but further research is needed before specific recommendations can be made