The reduction in small ribosomal subunit abundance in ethanol-stressed cells of Bacillus subtilis is mediated by a SigB-dependent antisense RNA

One of the best-characterized general stress responses in bacteria is the sigma(B)-mediated stress response of the Gram-positive soil bacterium Bacillus subtilis. The sigma(B) regulon contains approximately 200 protein-encoding genes and 136 putative regulatory RNAs. One of these sigma(B)-dependent RNAs, named S1136-S1134, was recently mapped as being transcribed from the S1136 promoter on the opposite strand of the essential rpsD gene, which encodes the ribosomal primary-binding protein S4. Accordingly, S1136-S1134 transcription results in an rpsD-overlapping antisense RNA (asRNA). Upon exposure of B. subtilis to ethanol, the S1136 promoter was found to be induced, while rpsD transcription was downregulated. By quantitative PCR, we show that the activation of transcription from the S1136 promoter is directly responsible for the downregulation of rpsD upon ethanol exposure. We also show that this downregulation of rpsD leads to a reduced level of the small (30S) ribosomal subunit upon ethanol stress. The activation of the S1136 promoter thus represents the first example of antisense transcription-mediated regulation in the general stress response of B. subtilis and implicates the reduction of ribosomal protein abundance as a new aspect in the sigma(B)-dependent stress response. We propose that the observed reduction in the level of the small ribosomal subunit, which contains the ribosome-decoding center, may protect B. subtilis cells against misreading and spurious translation of possibly toxic aberrant peptides under conditions of ethanol stress. (C) 2015 Elsevier B.V. All rights reserved.</p

Impact of the Southwark and Lambeth Integrated Care Older People's Programme on hospital utilisation and costs: controlled time series and cost-consequence analysis.

OBJECTIVES: To estimate the impact on hospital utilisation and costs of a multi-faceted primary care intervention for older people identified as being at risk of avoidable hospitalisation. DESIGN: Observational study: controlled time series analysis and estimation of costs and cost consequences of the Programme. General practitioner (GP)'s practice level data were analysed from 2009 to 2016 (intervention operated from 2012 to 2016). Mixed-effect Poisson regression models of hospital utilisation included comparisons with control practices and background trends in addition to within-practice comparisons. Cost estimation used standard tariff values. SETTING: 94 practices in Southwark and Lambeth and 263 control practices from other parts of England. MAIN OUTCOME MEASURES: Hospital utilisation: emergency department attendance, emergency admissions, emergency admissions for ambulatory sensitive conditions, outpatient attendance, elective admission and length of stay. RESULTS: By the fourth year of the Programme, there were reductions in accident and emergency (A&E) attendance (rate ratio 0.944, 95% CI 0.913 to 0.976), outpatient attendances (rate ratio 0.938, 95% CI 0.902 to 0.975) and elective admissions (rate ratio 0.921, 95% CI 0.908 to 0.935) but there was no evidence of reduced emergency admissions. The costs of the Programme were £149 per resident aged 65 and above but savings in hospital costs were only £86 per resident aged 65 and above, equivalent to a net increase in health service expenditure of £64 per resident though the Programme was nearly cost neutral if set-up costs were excluded. Holistic assessments carried out by GPs and consequent Integrated Care Management (ICM) plans were associated with increases in elective activity and costs; £126 increase in outpatient attendance and £936 in elective admission costs per holistic assessment carried out, and £576 increase in outpatient and £5858 in elective admission costs per patient receiving ICM. CONCLUSIONS: The Older People's Programme was not cost saving. Some aspects of the Programme were associated with increased costs of elective care, possibly through the identification of unmet need

Salivary testosterone and cortisol levels in borderline personality disorder before and after a 12-week group dialectical behavior therapy intervention

BackgroundBorderline Personality Disorder (BPD) is a chronic, debilitating, and difficult to treat condition. BPD has recently been linked to steroid hormone dysregulation and medical conditions characterized by disturbed androgen metabolism. This study aimed to investigate cortisol and testosterone levels in BPD, and changes in hormones following psychological treatment.MethodsParticipants with BPD (n = 33) completed a 12-week Dialectical Behavior Therapy group program. Pre and post salivary testosterone and cortisol were analyzed. Baseline hormones in the BPD group were compared to age-and-sex matched controls (n = 33). Non-parametric tests were utilized to investigate group differences, pre-post treatment hormone and symptom changes, and associations between symptoms and hormone levels.ResultsParticipants with BPD had significantly higher testosterone levels than controls. Mean testosterone levels in females with BPD were double that of female controls. Testosterone and cortisol levels were related, and some BPD symptoms were associated with with hormone levels. BPD symptoms reduced significantly with treatment, however pre to post hormone levels did not change.ConclusionsThis study supports an association between BPD symptoms and neuroendocrine dysfunction at baseline, however we found no reduction in hormone dysfunction post treatment. Further research into relationships between stress signaling and neuroendocrine disturbances in BPD may inform aetiological and treatment models.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12618000477224. Registered on 3 April 2018

An Angiotensin I-Converting Enzyme Mutation (Y465D) Causes a Dramatic Increase in Blood ACE via Accelerated ACE Shedding

Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE.HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE--between Arg1203 and Ser1204--was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another.The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase)

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Background and ObjectivesDisease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).MethodsC9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer\u27s Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.ResultsA total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.DiscussionWe confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment

Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds

As the development of new classes of antibiotics slows, bacterial resistance to existing antibiotics is becoming an increasing problem. A potential solution is to develop treatment strategies with an alternative mode of action. We consider one such strategy: anti-adhesion therapy. Whereas antibiotics act directly upon bacteria, either killing them or inhibiting their growth, anti-adhesion therapy impedes the binding of bacteria to host cells. This prevents bacteria from deploying their arsenal of virulence mechanisms, while simultaneously rendering them more susceptible to natural and artificial clearance. In this paper, we consider a particular form of anti-adhesion therapy, involving biomimetic multivalent adhesion molecule 7 coupled polystyrene microbeads, which competitively inhibit the binding of bacteria to host cells. We develop a mathematical model, formulated as a system of ordinary differential equations, to describe inhibitor treatment of a Pseudomonas aeruginosa burn wound infection in the rat. Benchmarking our model against in vivo data from an ongoing experimental programme, we use the model to explain bacteria population dynamics and to predict the efficacy of a range of treatment strategies, with the aim of improving treatment outcome. The model consists of two physical compartments: the host cells and the exudate. It is found that, when effective in reducing the bacterial burden, inhibitor treatment operates both by preventing bacteria from binding to the host cells and by reducing the flux of daughter cells from the host cells into the exudate. Our model predicts that inhibitor treatment cannot eliminate the bacterial burden when used in isolation; however, when combined with regular or continuous debridement of the exudate, elimination is theoretically possible. Lastly, we present ways to improve therapeutic efficacy, as predicted by our mathematical model

Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans.

BACKGROUND: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. METHODS: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. RESULTS: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. CONCLUSION: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Dark Triad personality traits, second-to-forth digit ratio (2D:4D) and circulating testosterone and cortisol levels

Introduction: Dark Triad (DT) personality traits (psychopathy, Machiavellianism, and narcissism) show sex differences and associations with hormones. Understanding aetiology may assist in mitigating the harm of these potentially adverse characteristics. Low second-to-fourth digit ratio (2D:4D) is hypothesised to be a marker of high prenatal testosterone exposure and may provide important information about organisational hormones. The aim of the present study was to measure Dark Triad and Big 5 personality traits in relation to digit ratio, salivary testosterone, and cortisol. Methods: A non-clinical sample (N = 268; 49.25% Female, age M25.20 ± 8.77 yrs) completed the Short Dark Triad and International Personality Inventory Pool - Mini. Afternoon saliva was analysed for testosterone and cortisol, and 2D:4D finger ratios were measured. Results: Males scored higher on DT traits than females. Females scored higher on Big 5 agreeableness and neuroticism. Males had higher testosterone and cortisol levels and lower 2D:4D than females. Digit ratio correlated inversely with salivary testosterone, Machiavellianism, and psychopathy. Testosterone levels correlated positively with cortisol levels and psychopathy and negatively with agreeableness, neuroticism, and Machiavellianism. Conclusions: These results provide indications that Machiavellianism and psychopathy (Dark Triad) traits, but not narcissism or Big 5 traits, are linked to markers of prenatal testosterone exposure. Results also replicate sex differences seen in 2D:4D digit ratios, with males having a shorter second-relative-to-forth finger. Links between circulating testosterone, digit ratios, cortisol and personality traits provide further information about potential biological bases of personality