Activity of Bdellovibrio Hit Locus Proteins, Bd0108 and Bd0109, Links Type IVa Pilus Extrusion/Retraction Status to Prey-Independent Growth Signalling

Bdellovibrio bacteriovorus are facultatively predatory bacteria that grow within gram-negative prey, using pili to invade their periplasmic niche. They also grow prey-independently on organic nutrients after undergoing a reversible switch. The nature of the growth switching mechanism has been elusive, but several independent reports suggested mutations in the hit (host-interaction) locus on the Bdellovibrio genome were associated with the transition to preyindependent growth. Pili are essential for prey entry by Bdellovibrio and sequence analysis of the hit locus predicted that it was part of a cluster of Type IVb pilus-associated genes, containing bd0108 and bd0109. In this study we have deleted the whole bd0108 gene, which is unique to Bdellovibrio, and compared its phenotype to strains containing spontaneous mutations in bd0108 and the common natural 42 bp deletion variant of bd0108. We find that deletion of the whole bd0108 gene greatly reduced the extrusion of pili, whereas the 42 bp deletion caused greater pilus extrusion than wild-type. The pili isolated from these strains were comprised of the Type IVa pilin protein; PilA. Attempts to similarly delete gene bd0109, which like bd0108 encodes a periplasmic/secreted protein, were not successful, suggesting that it is likely to be essential for Bdellovibrio viability in any growth mode. Bd0109 has a sugar binding YD- repeat motif and an N-terminus with a putative pilin-like fold and was found to interact directly with Bd0108. These results lead us to propose that the Bd0109/Bd0108 interaction regulates pilus production in Bdellovibrio (possibly by interaction with the pilus fibre at the cell wall), and that the presence (and possibly retraction state) of the pilus feeds back to alter the growth state of the Bdellovibrio cell. We further identify a novel small RNA encoded by the hit locus, the transcription of which is altered in different bd0108 mutation background

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Datasheet1_The social return on investment of physical activity and nutrition interventions—a scoping review.pdf

IntroductionScarcity of resources and mounting pressures on health systems make it critical to evaluate new and existing public health interventions related to physical activity and nutrition. The Social Return on Investment (SROI) framework has gained prominence for capturing traditional variables such as economic costs and returns, as well as wider beneficial social and environmental outcomes. A scoping review was conducted to present the existing evidence on the SROI of physical activity and nutrition interventions, demonstrating the wider benefits of these interventions.MethodologyExisting peer-reviewed evidence and grey literature was collated to identify physical activity and nutrition interventions that were evaluated using the SROI framework between January 1996 up until February 2022. Only literature published in the English language, interventions that were conducted in high-income countries were considered for inclusion. Study information and economic data was entered into a pre-prepared data extraction sheet and eligible studies were quality assessed using a 12-point quality assessment framework for SROI studies.ResultsThis review identified a total of 21 SROI studies, with only four deriving from peer-reviewed literature sources. In total, 18 studies evaluated physical activity interventions, one study was purely focused on nutrition, whereas the two remaining studies presented a mix of physical activity and nutrition. The majority of studies derived from the United Kingdom (n = 16) with very few of the studies published prior to 2010 (n = 1). In total, four studies were classified as low quality based on the 12-point quality assessment framework used for this review. Outcomes of the relevant studies show that the benefits of these interventions have added value to families, communities and the wider environments of the target groups.ConclusionThis scoping review is adding to research conducted to understand the wider value of public health interventions such as physical activity and nutrition interventions using the SROI framework. This is important so that the development and implementation of public health interventions have the greatest value to people and society, which also benefits decision-makers to effectively and sustainably allocate scarce resources.</p

Data_Sheet_1_Understanding health inequalities in Wales using the Blinder-Oaxaca decomposition method.docx

BackgroundThroughout Wales and the world, health inequality remains a problem that is interconnected with a wider and complex social, economic and environmental dynamic. Subsequently, action to tackle inequality in health needs to take place at a structural level, acknowledging the constraints affecting an individual's (or community's) capability and opportunity to enable change. While the ‘social determinants of health' is an established concept, fully understanding the composition of the health gap is dependent on capturing the relative contributions of a myriad of social, economic and environmental factors within a quantitative analysis.MethodThe decomposition analysis sought to explain the differences in the prevalence of these outcomes in groups stratified by their ability to save at least £10 a month, whether they were in material deprivation, and the presence of a limiting long-standing illness, disability of infirmity. Responses to over 4,200 questions within the National Survey for Wales (n = 46,189; 2016–17 to 2019–20) were considered for analysis. Variables were included based on (1) their alignment to a World Health Organization (WHO) health equity framework (“Health Equity Status Report initiative”) and (2) their ability to allow for stratification of the survey sample into distinct groups where considerable gaps in health outcomes existed. A pooled Blinder-Oaxaca model was used to analyse inequalities in self-reported health (fair/poor health, low mental well-being and low life satisfaction) and were stratified by the variables relating to financial security, material deprivation and disability status.ResultsThe prevalence of fair/poor health was 75% higher in those who were financially insecure and 95% higher in those who are materially deprived. Decomposition of the outcome revealed that just under half of the health gap was “explained” i.e., 45.5% when stratifying by the respondent's ability to save and 46% when stratifying by material deprivation status. Further analysis of the explained component showed that “Social/Human Capital” and “Income Security/Social Protection” determinants accounted the most for disparities observed; it also showed that “Health Services” determinants accounted the least. These findings were consistent across the majority of scenarios modeled.ConclusionThe analysis not only quantified the significant health gaps that existed in the years leading up to the COVID-19 pandemic but it has also shown what determinants of health were most influential. Understanding the factors most closely associated with disparities in health is key in identifying policy levers to reduce health inequalities and improve the health and well-being across populations.</p

Erbium-doped fibre ring laser based on microfibre coupler

A compact erbium-doped fibre (EDF) laser is demonstrated which uses a microfibre coupler and a highly concentrated EDF loop. The coupler functions to inject the pump light and tap out the output. The EDF laser operates at 1526.3 nm, with a signal-to-noise ratio of about 26 dB. The maximum output power 20 µW is obtained at the pump power 18.6mW. We have obtained the slope efficiencies of the laser 0.12, 0.06, 0.04 and 0.02% at the EDF lengths fixed at 90, 78, 66 and 51 cm, respectively. The lowest lasing-pump power threshold is achieved at 3.8 mW

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease