Head-to-head trials of antibiotics for bronchiectasis

Background The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer‐term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost‐effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions. Objectives To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis. Search methods We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies. Selection criteria We included RCTs reported as full‐text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high‐resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method. Data collection and analysis Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs). Main results Four randomised trials were eligible for inclusion in this systematic review ‐ two studies with 83 adults comparing fluoroquinolones with β‐lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations ‐ one of our primary outcomes. Included studies reported no serious adverse events ‐ another of our primary outcomes ‐ and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β‐lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low‐quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low‐quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low‐quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low‐quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low‐quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. Authors' conclusions Limited low‐quality evidence favours short‐term oral fluoroquinolones over beta‐lactam antibiotics for patients hospitalised with exacerbations. Very low‐quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head‐to‐head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short‐term or long‐term therapy. More research on this topic is needed

Pro-inflammatory flagellin proteins of prevalent motile commensal bacteria are variably abundant in the intestinal microbiome of elderly humans

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Stochastic Modeling Of Physical Drag Coefficient – Its Impact On Orbit Prediction And Space Traffic Management

Ambitious satellite constellation projects by commercial entities and the ease of access to space in recent times have led to a dramatic proliferation of low-Earth space traffic. It jeopardizes space safety and long-term sustainability, necessitating better space domain awareness (SDA). Correct modeling of uncertainties in force models and orbital states, among other things, is an essential part of SDA. For objects in the low-Earth orbit (LEO) region, the uncertainty in the orbital dynamics mainly emanate from limited knowledge of the atmospheric drag-related parameters and variables. In this paper, which extends the work by Paul et al. (2021), we develop a feed-forward deep neural network model for the prediction of the satellite drag coefficient for the full range of satellite attitude (i.e., satellite pitch ∈ (-90°, +90°) and satellite yaw ∈ (0°, +360°)). The model simultaneously predicts the mean and the standard deviation and is well-calibrated. We use numerically simulated physical drag coefficient data for training our neural network. The numerical simulations are carried out using the test particle Monte Carlo method using the diffuse reflection with incomplete accommodation gas-surface interaction model. Modeling is carried out for the well-known Challenging Minisatellite Payload (CHAMP) satellite. Finally, we use the Monte Carlo approach to propagate CHAMP over a three-day period under various modeling scenarios to investigate the distribution of radial, along-track, and cross-track orbital errors caused by drag coefficient uncertainty. The key takeaways of this paper are - (a) a constant drag coefficient cannot be used for reliable SDA purposes, and (b) stochastic machine learning models allow for the computation of drag coefficients in a timely manner while providing reliable uncertainty estimates

Polysaccharide utilization loci and nutritional specialization in a dominant group of butyrate-producing human colonic Firmicutes

Acknowledgements The Rowett Institute of Nutrition and Health (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). POS is a PhD student supported by the Scottish Government (RESAS) and the Science Foundation Ireland, through a centre award to the APC Microbiome Institute, Cork, Ireland. Data Summary The high-quality draft genomes generated in this work were deposited at the European Nucleotide Archive under the following accession numbers: 1. Eubacterium rectale T1-815; CVRQ01000001–CVRQ0100 0090: http://www.ebi.ac.uk/ena/data/view/PRJEB9320 2. Roseburia faecis M72/1; CVRR01000001–CVRR010001 01: http://www.ebi.ac.uk/ena/data/view/PRJEB9321 3. Roseburia inulinivorans L1-83; CVRS01000001–CVRS0 100 0151: http://www.ebi.ac.uk/ena/data/view/PRJEB9322Peer reviewedPublisher PD

Heterologous gene expression in the human gut bacteria Eubacterium rectale and Roseburia inulinivorans by means of conjugative plasmids

Acknowledgements The Rowett Institute (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). POS was a PhD student supported by the Scottish Government (RESAS) and the Science Foundation Ireland, through a centre award (12/RC/2273) to APC Microbiome Ireland, Cork, Ireland.Peer reviewedPostprin

Protein-Pacing and Multi-Component Exercise Training Improves Physical Performance Outcomes in Exercise-Trained Women: The PRISE 3 Study

The beneficial cardiometabolic and body composition effects of combined protein-pacing (P; 5-6 meals/day at 2.0 g/kg BW/day) and multi-mode exercise (resistance, interval, stretching, endurance; RISE) training (PRISE) in obese adults has previously been established. The current study examines PRISE on physical performance (endurance, strength and power) outcomes in healthy, physically active women. Thirty exercise-trained women (\u3e4 days exercise/week) were randomized to either PRISE (n = 15) or a control (CON, 5-6 meals/day at 1.0 g/kg BW/day; n = 15) for 12 weeks. Muscular strength (1-RM bench press, 1-RM BP) endurance (sit-ups, SUs; push-ups, PUs), power (bench throws, BTs), blood pressure (BP), augmentation index, (AIx), and abdominal fat mass were assessed at Weeks 0 (pre) and 13 (post). At baseline, no differences existed between groups. Following the 12-week intervention, PRISE had greater gains (p \u3c 0.05) in SUs, PUs (6 ± 7 vs. 10 ± 7, 40%; 8 ± 13 vs. 14 ± 12, 43% ∆reps, respectively), BTs (11 ± 35 vs. 44 ± 34, 75% ∆watts), AIx (1 ± 9 vs. -5 ± 11, 120%), and DBP (-5 ± 9 vs. -11 ± 11, 55% ∆mmHg). These findings suggest that combined protein-pacing (P; 5-6 meals/day at 2.0 g/kg BW/day) diet and multi-component exercise (RISE) training (PRISE) enhances muscular endurance, strength, power, and cardiovascular health in exercise-trained, active women

Unique Organization of Extracellular Amylases into Amylosomes in the Resistant Starch-Utilizing Human Colonic Firmicutes Bacterium Ruminococcus bromii

ACKNOWLEDGMENTS We acknowledge support from BBSRC grant no. BB/L009951/1, from the Scottish government Food, Land and People program, and from the Society for Applied Microbiology. E.A.B. is supported by a grant (no. 1349/13) from the Israel Science Foundation (ISF), Jerusalem, Israel, and by a grant from the United States-Israel Binational Science Foundation (BSF). E.A.B. is the incumbent of the Maynard I. and Elaine Wishner Chair of Bio-organic Chemistry. Thanks are due to Fergus Nicol for proteomic analysis and to Auriane Bernard for enzyme assays on stationary-phase cultures. We also thank Julian Parkhill and Keith Turner (Wellcome Trust Sanger Institute, Cambridge, United Kingdom) for making the R. bromii L2-63 genome sequence available for analysis.Peer reviewedPublisher PD

Distribution, organization and expression of genes concerned with anaerobic lactate utilization in human intestinal bacteria

Lactate accumulation in the human gut is linked to a range of deleterious health impacts. However, lactate is consumed and converted to the beneficial short-chain fatty acids butyrate and propionate by indigenous lactate-utilizing bacteria. To better understand the underlying genetic basis for lactate utilization, transcriptomic analyses were performed for two prominent lactate-utilizing species from the human gut, Anaerobutyricum soehngenii and Coprococcus catus , during growth on lactate, hexose sugar or hexose plus lactate. In A. soehngenii L2-7 six genes of the lactate utilization (lct) cluster, including NAD-independent d-lactate dehydrogenase (d-iLDH), were co-ordinately upregulated during growth on equimolar d- and l-lactate (dl-lactate). Upregulated genes included an acyl-CoA dehydrogenase related to butyryl-CoA dehydrogenase, which may play a role in transferring reducing equivalents between reduction of crotonyl-CoA and oxidation of lactate. Genes upregulated in C. catus GD/7 included a six-gene cluster (lap) encoding propionyl CoA-transferase, a putative lactoyl-CoA epimerase, lactoyl-CoA dehydratase and lactate permease, and two unlinked acyl-CoA dehydrogenase genes that are candidates for acryloyl-CoA reductase. A d-iLDH homologue in C. catus is encoded by a separate, partial lct, gene cluster, but not upregulated on lactate. While C. catus converts three mols of dl-lactate via the acrylate pathway to two mols propionate and one mol acetate, some of the acetate can be re-used with additional lactate to produce butyrate. A key regulatory difference is that while glucose partially repressed lct cluster expression in A. soehngenii , there was no repression of lactate-utilization genes by fructose in the non-glucose utilizer C. catus . This suggests that these species could occupy different ecological niches for lactate utilization in the gut, which may be important factors to consider when developing lactate-utilizing bacteria as novel candidate probiotics

Multi-Modal Exercise Training and Protein-Pacing Enhances Physical Performance Adaptations Independent of Growth Hormone and BDNF but May Be Dependent on IGF-1 in Exercise-Trained Men

OBJECTIVE: Protein-pacing (P; 5-6meals/day @ 2.0g/kgBW/day) and multi-mode exercise (RISE; resistance, interval, stretching, endurance) training (PRISE) improves muscular endurance, strength, power and arterial health in exercise-trained women. The current study extends these findings by examining PRISE on fitness, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and brain-derived neurotrophic factor (BDNF) response, cardiometabolic health, and body composition in exercise-trained men. DESIGN: Twenty active males (\u3e4daysexercise/week) completed either: PRISE (n=11) or RISE (5-6meals/day @ 1.0g/kgBW/day; n=9) for 12weeks. Muscular strength (1-repetition maximum bench and leg press, 1-RM BP, and 1-RM LP), endurance (sit-ups, SU; push-ups, PU), power (squat jump, SJ, and bench throw, BT), flexibility (sit-and-reach, SR), aerobic performance (5km cycling time-trial, TT), GH, IGF-1, BDNF, augmentation index, (AIx), and body composition, were assessed at weeks 0 (pre) and 13 (post). RESULTS:At baseline, no differences existed between groups except for GH (RISE, 230±13 vs. PRISE, 382±59pg/ml, p CONCLUSIONS: Exercise-trained men consuming a P diet combined with multi-component exercise training (PRISE) enhance muscular power, strength, aerobic performance, and flexibility which are not likely related to GH or BDNF but possibly to IGF-1 response

Impact of carbohydrate substrate complexity on the diversity of the human colonic microbiota.

The diversity of the colonic microbial community has been linked with health in adults and diet composition is one possible determinant of diversity. We used carefully controlled conditions in vitro to determine how the complexity and multiplicity of growth substrates influence species diversity of the human colonic microbiota. In each experiment, five parallel anaerobic fermenters that received identical faecal inocula were supplied continuously with single carbohydrates (either arabinoxylan-oligosaccharides (AXOS), pectin or inulin) or with a '3-mix' of all three carbohydrates, or with a '6-mix' that additionally contained resistant starch, β-glucan and galactomannan as energy sources. Inulin supported less microbial diversity over the first 6 d than the other two single substrates or the 3- and 6-mixes, showing that substrate complexity is key to influencing microbiota diversity. The communities enriched in these fermenters did not differ greatly at the phylum and family level, but were markedly different at the species level. Certain species were promoted by single substrates, whilst others (such as Bacteroides ovatus, LEfSe P = 0.001) showed significantly greater success with the mixed substrate. The complex polysaccharides such as pectin and arabinoxylan-oligosaccharides promoted greater diversity than simple homopolymers, such as inulin. These findings suggest that dietary strategies intended to achieve health benefits by increasing gut microbiota diversity should employ complex non-digestible substrates and substrate mixtures