A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or ...placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab 0·82 0·71-0·95, p = 0·008 and sarilumab 0·80 0·61-1·04, p = 0·09 compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 95%CI 0·81-1·32, p = 0·80. The p-value for the global test of inconsistency was 0·28. Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.
Background: Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other ...components of the MetS. Objective: This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS. Design: A free-living, single-blinded dietary intervention study. Subjects and Methods: MetS subjects (n=417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined. Results: In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P<0.01), particularly in men. Conclusion: There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.
This paper proposes a DC microgrid system, comprising multiple locally available renewable energy sources in an off-grid rural community, based on a commissioned field study carried out in a rural, ...off-grid village in Nepal, which has solar and wind resource available. Using estimated solar data for the site's location, wind data measured locally, household and population data collected over the course of several months and typical measured domestic demand profiles, DC microgrid system models have been constructed using HOMER and Simulink software to represent the DC system proposed.
This work is innovative in using a range of on-site data collected and measured locally in a commissioned field study carried out over several months to quantify current local resources and loads and estimating future ones based on the local population's current economic and domestic activities, and intended ones. This data is used in determining both the optimal size of the generation and storage elements through HOMER based on long term system behaviour, and to model shorter term system response to changes in generation and load using Simulink, ensuring system stability and grid voltage is maintained. Further novel aspects of this study are that power flow is controlled using adaptive DC droop control on each individual energy source to enable optimal power sharing with minimum power dissipation across distribution lines, and the droop control has been further adapted to the case of storage which can act as a source or a load.
•DC microgrid simulated for Nepali off-grid community with field study data as input.•Combination of HOMER and Simulink used as simulation tools.•Droop control used to share power amongst sources and storage elements.•HOMER Optimisation used to determine optimum component sizes.•Evaluation over full day using variable weather to establish suitability.
Background
Low muscularity and malnutrition at intensive care unit (ICU) admission have been associated with negative clinical outcomes. There are limited data available evaluating the validity of ...bedside techniques to measure muscle mass in critically ill adults. We aimed to compare bedside methods for muscle mass assessment bioimpedance spectroscopy (BIS), arm anthropometry and subjective physical assessment against reference technology computed tomography (CT) at ICU admission.
Methods
Adults who had CT scanning at the third lumbar area <72 h after ICU admission were prospectively recruited. Bedside methods were performed within 48 h of the CT scan. Pearson’s correlation compared CT muscle area with BIS‐derived fat‐free mass (FFM) (kg) and FFM‐Chamney (kg) (adjusted for overhydration), mid‐upper arm circumference (cm) and mid‐arm muscle circumference (cm). Depleted muscle stores were determined using published thresholds for each method. Cohen’s kappa (κ) was used to evaluate the agreement between bedside and CT assessment of muscularity status (normal or low).
Results
Fifty participants were enrolled. There were strong correlations between CT muscle area and FFM values and mid‐arm muscle circumference (P < 0.001). Using FFM‐Chamney, all six (100%) participants with low CT muscle area were detected (κ = 0.723). FFM‐BIS, arm anthropometry and subjective physical assessment methods detected 28%–38% of participants with low CT muscle area.
Conclusions
BIS‐derived FFM using an adjustment algorithm for overhydration was correlated with CT muscle area and had good agreement with muscularity status assessed by CT image analysis. Arm anthropometry and subjective physical assessment techniques were not able to reliably detect participants with low CT muscle area.
•A review to determine if exercise interventions are effective in promoting PA in CF.•A systematic approach to evidence appraisal was used.•Improvements in PA in short- and long-term interventions ...were seen in 11/15 studies.•Aerobic training and activity counselling most consistently improved PA.
Physical activity (PA) and exercise have numerous benefits in Cystic Fibrosis (CF) including improved lung function, exercise capacity and quality of life. Despite these benefits, the effectiveness of interventions to promote PA in this population are still largely unknown. The objective of this review was to synthesise existing research and determine whether exercise interventions are effective in promoting PA in people with CF. Using the PRISMA guidelines, a comprehensive search was conducted. Fifteen studies (463 participants) met the inclusion criteria. Eleven studies demonstrated improvements in PA in both short- and long-term interventions. However, the interventions were variable across the included studies, with a large inconsistency in PA assessment tools used. Aerobic training and activity counselling were the two elements identified in this review which most consistently improved PA. Future research should consider larger sample sizes and the use of accurate instruments to assess and track PA levels longitudinally.
The Fermi Gamma-ray Burst Monitor (GBM) has detected over 1400 gamma-ray bursts (GRBs) since it began science operations in 2008 July. We use a subset of over 300 GRBs localized by instruments such ...as Swift, the Fermi Large Area Telescope, INTEGRAL, and MAXI, or through triangulations from the InterPlanetary Network, to analyze the accuracy of GBM GRB localizations. We find that the reported statistical uncertainties on GBM localizations, which can be as small as 1degrees, underestimate the distance of the GBM positions to the true GRB locations and we attribute this to systematic uncertainties. The distribution of systematic uncertainties is well represented (68% confidence level) by a 3degrees.7 Gaussian with a non-Gaussian tail that contains about 10% of GBM-detected GRBs and extends to approximately 14degrees. A more complex model suggests that there is a dependence of the systematic uncertainty on the position of the GRB in spacecraft coordinates, with GRBs in the quadrants on the Y axis better localized than those on the X axis.
Epstein-Barr virus (EBV), which is ubiquitous in the adult population, is causally associated with human malignancies. Like many infectious agents, EBV has evolved strategies to block host cell ...death, including through expression of viral homologues of cellular BCL-2 pro-survival proteins (vBCL-2s), such as BHRF1. Small molecule inhibitors of the cellular pro-survival BCL-2 family proteins, termed 'BH3-mimetics', have entered clinical trials for blood cancers with the BCL-2 inhibitor venetoclax already approved for treatment of therapy refractory chronic lymphocytic leukaemia and acute myeloid leukaemia in the elderly. The generation of BH3-mimetics that could specifically target vBCL-2 proteins may be an attractive therapeutic option for virus-associated cancers, since these drugs would be expected to only kill virally infected cells with only minimal side effects on normal healthy tissues. To achieve this, a better understanding of the contribution of vBCL-2 proteins to tumorigenesis and insights into their biochemical functions is needed. In the context of Burkitt lymphoma (BL), BHRF1 expression conferred strong resistance to diverse apoptotic stimuli. Furthermore, BHRF1 expression in mouse haematopoietic stem and progenitor cells accelerated MYC-induced lymphoma development in a model of BL. BHRF1 interacts with the cellular pro-apoptotic BCL-2 proteins, BIM, BID, PUMA and BAK, but its capability to inhibit apoptosis could not be mapped solely to one of these interactions, suggesting plasticity is a key feature of BHRF1. Site-directed mutagenesis revealed a site in BHRF1 that was critical for its interaction with PUMA and blocking DNA-damage-induced apoptosis, identifying a potentially therapeutically targetable vulnerability in BHRF1.
Background While behavioural abnormalities are fundamental features of Rett syndrome (RTT), few studies have examined the RTT behavioural phenotype. Most of these reports have focused on autistic ...features, linked to the early regressive phase of the disorder, and few studies have applied standardised behavioural measures. We used a battery of standardised measures of behaviour and functioning to test the following hypotheses: (1) autistic behaviour is prominent throughout childhood in RTT; (2) autistic features are more salient in individuals with milder presentation; (3) severity of autistic behaviour is associated with a wider range of behavioural problems; and (4) specific MECP2 mutations are linked to more severe autistic behaviour.
Methods Eighty MECP2 mutation‐positive girls with RTT (aged 1.6–14.9 years) were administered: (1) the Screen for Social Interaction (SSI), a measure of autistic behaviour suited for individuals with severe communication and motor impairment; (2) the Rett Syndrome Behaviour Questionnaire (RSBQ), covering a wide range of abnormal behaviours in RTT; (3) the Vineland Adaptive Behavior Scales (VABS); and (4) a modified version of the Rett Syndrome Severity Scale (RSSS). Regression analyses examined the predictive value of age and RSSS on autistic behaviour and other behavioural abnormalities. T‐tests further characterised the behavioural phenotype of individual MECP2 mutations.
Results While age had no significant effect on SSI or RSBQ total scores in RTT, VABS Socialization and Composite scores decreased over time. Clinical severity (i.e. RSSS) also increased with age. Surprisingly, SSI performance was not related to either RSSS or VABS Composite scores. Autistic behaviour was weakly linked with the RSBQ Hand behaviour factor scores, but not with the RSBQ Fear/Anxiety factor. Clinical (neurological) severity did not predict RSBQ scores, as evidenced by the analysis of individual MECP2 mutations (e.g. p.R106W, p.R270X and p.R294X).
Conclusions Our data suggest that in RTT, autistic behaviour persists after the period of regression. It also demonstrated that neurological and behavioural impairments, including autistic features, are relatively independent of one another. Consistent with previous reports of the RTT phenotype, individual MECP2 mutations demonstrate complex associations with autistic features. Evidence of persistent autistic behaviour throughout childhood, and of a link between hand function and social skills, has important implications not only for research on the RTT behavioural phenotype, but also for the clinical management of the disorder.
Data from massively parallel sequencing or ‘Next Generation Sequencing’ of the human exome has reached a critical mass in both public and private databases, in that these collections now allow ...researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith–Lemli–Opitz Syndrome (SLOS), the 7‐dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening.
The Gamma‐ray Burst Monitor (GBM) on board the Fermi Gamma‐ray Space Telescope has triggered on over 300 terrestrial gamma‐ray flashes (TGFs) since its launch in June 2008. With 14 detectors, GBM ...collects on average ∼100 counts per triggered TGF, enabling unprecedented studies of the time profiles of TGFs. Here we present the first rigorous analysis of the temporal properties of a large sample of TGFs (278), including the distributions of the rise and fall times of the individual pulses and their durations. A variety of time profiles are observed with 19% of TGFs having multiple pulses separated in time and 31 clear cases of partially overlapping pulses. The effect of instrumental dead time and pulse pileup on the temporal properties are also presented. As the observed gamma ray pulse structure is representative of the electron flux at the source, TGF pulse parameters are critical to distinguish between relativistic feedback discharge and lightning leader models. We show that at least 67% of TGFs at satellite altitudes are significantly asymmetric. For the asymmetric pulses, the rise times are almost always shorter than the fall times. Those which are not are consistent with statistical fluctuations. The median rise time for asymmetric pulses is ∼3 times shorter than for symmetric pulses while their fall times are comparable. The asymmetric shapes observed are consistent with the relativistic feedback discharge model when Compton scattering of photons between the source and Fermi is included, and instrumental effects are taken into account.
Key Points
First rigorous analysis of the temporal properties of a large sample of TGFs
Asymmetric pulses always have longer fall than rise
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