PspF-binding domain PspA1-144 and the PspA·F complex: New insights into the coiled-coil-dependent regulation of AAA+ proteins.

Phage shock protein A (PspA) belongs to the highy conserved PspA/IM30 family and is a key component of the stress inducible Psp system in Escherichia coli. One of its central roles is the regulatory interaction with the transcriptional activator of this system, the σ54 enhancer binding protein PspF, a member of the AAA+ protein family. The PspA/F regulatory system has been intensively studied and serves as a paradigm for AAA+ enzyme regulation by trans-acting factors. However, the molecular mechanism of how exactly PspA controls the activity of PspF and hence σ54-dependent expression of the psp genes is still unclear. To approach this question, we identified the minimal PspF-interacting domain of PspA, solved its structure, determined its affinity to PspF and the dissociation kinetics, identified residues that are potentially important for PspF regulation and analyzed effects of their mutation on PspF in vivo and in vitro. Our data indicate that several characteristics of AAA+ regulation in the PspA·F complex resemble those of the AAA+ unfoldase ClpB, with both proteins being regulated by a structurally highly conserved coiled-coil domain. The convergent evolution of both regulatory domains points to a general mechanism to control AAA+ activity for divergent physiological tasks via coiled-coil domains

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients

\ua9 2024, European Respiratory Society. All rights reserved.Background Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods A systematic review was performed identifying studies that reported in-hospital mortality, postdischarge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisation

Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade

Objectives: As myocardial fibrosis might be an important contributor to the association of obesity with left ventricular (LV) dysfunction and heart failure, we investigated the effects of spironolactone on LV function and serological fibrosis markers (procollagen type III N-terminal propeptide (PIIINP) and procollagen type I C-terminal propeptide (PICP)) in patients with obesity and abnormal LV performance. Design: A prospective, randomised, double-blind, placebo-controlled study. Setting: A university hospital. Patients: and intervention 113 patients (mean±SD age 58±8 years) with body mass index≥30, without any comorbidities, with impaired early diastolic mitral annular velocity, randomised to spironolactone 25 mg/day or placebo for 6 months. Main outcome measures: Echocardiographically derived indices of LV systolic (strain and strain rate) and diastolic (E velocity, tissue e and E/e ratio) function, myocardial reflectivity (calibrated integrated backscatter (IB)), and serum PICP and PIIINP. Results: In the spironolactone group, significant improvements in myocardial deformation, peak early diastolic velocity (Em), E/e and IB were noted with a simultaneous decrease in PICP and PIIINP. No corresponding alterations were found with placebo. Improvement in LV systolic function (increase in strain) was independently associated with baseline strain (β=-0.43,

PspF binding domain PspA 1 144 and the PspA center dot F complex New insights into the coiled coil dependent regulation of AAA plus proteins

Phage shock protein A (PspA) belongs to the highy conserved PspA/IM30 family and is a key component of the stress inducible Psp system in Escherichia coli. One of its central roles is the regulatory interaction with the transcriptional activator of this system, the σ54 enhancer binding protein PspF, a member of the AAA+ protein family. The PspA/F regulatory system has been intensively studied and serves as a paradigm for AAA+ enzyme regulation by trans-acting factors. However, the molecular mechanism of how exactly PspA controls the activity of PspF and hence σ54-dependent expression of the psp genes is still unclear. To approach this question, we identified the minimal PspF-interacting domain of PspA, solved its structure, determined its affinity to PspF and the dissociation kinetics, identified residues that are potentially important for PspF regulation and analyzed effects of their mutation on PspF in vivo and in vitro. Our data indicate that several characteristics of AAA+ regulation in the PspA·F complex resemble those of the AAA+ unfoldase ClpB, with both proteins being regulated by a structurally highly conserved coiled-coil domain. The convergent evolution of both regulatory domains points to a general mechanism to control AAA+ activity for divergent physiological tasks via coiled-coil domains

The likelihood of improving physical activity after pulmonary rehabilitation is increased in patients with COPD who have better exercise tolerance

Purpose: Pulmonary rehabilitation (PR) enhances exercise tolerance in patients with COPD; however, improvements in physical activity (PA) are not guaranteed. This study explored the relationship between baseline exercise tolerance and changes in PA after PR. Materials and methods: Patient data from prospective clinical trials in the PR settings of Athens and Leuven (2008-2016) were analyzed. Validated PA monitors were worn for 1 week before and after a 12-week program. The proportion of patients who improved PA levels ≥1,000 steps/day (“PA responders”) after PR was compared between those with initial 6-minute walk distance [6MWDi] <350 m and ≥350 m. Baseline predictors of PA change were evaluated via univariate and multivariate logistic regression analyses. Results: Two hundred thirty-six patients with COPD (median [IQR] FEV 1 44 [33-59] % predicted, age 65±8 years, 6MWDi 416 [332-486] m) were included. The proportion of “PA responders” after PR was significantly greater in those with higher vs lower 6MWDi (37.9% vs 16.4%, respectively; P<0.001). 6MWDi group classification was the strongest baseline independent predictor of PA improvement (univariate OR 3.10, 95% CI 1.51-6.36). Conclusion: The likelihood of improving PA after PR is increased with greater 6MWDi. Baseline exercise tolerance appears as an important stratification metric for future research in this field. © 2018 Osadnik et al

Survival after pulmonary rehabilitation in patients with COPD: impact of functional exercise capacity and its changes

Carlos A Camillo,1,2 Daniel Langer,1,2 Christian R Osadnik,1,3–5 Lisa Pancini,2 Heleen Demeyer,1,2 Chris Burtin,1,6 Rik Gosselink,1,2 Marc Decramer,2 Wim Janssens,2 Thierry Troosters1,2 1KU Leuven, Department of Rehabilitation Sciences, Leuven, Belgium; 2University Hospital Leuven, Respiratory Division and Rehabilitation, Leuven, Belgium; 3Monash University, Department of Physiotherapy, Melbourne, VIC, Australia; 4Institute for Breathing and Sleep, Melbourne, VIC, Australia; 5Monash Health, Monash Lung and Sleep, Melbourne, VIC, Australia; 6Hasselt University, Rehabilitation Research Centre, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium Abstract: The impact of rehabilitation-induced changes in 6-minute walk distance (6MWD) on the survival of patients with chronic obstructive pulmonary disease (COPD) has not been fully elucidated. This study sought to determine the association of baseline 6MWD and its changes after pulmonary rehabilitation (PR) with 5-year survival in patients with COPD. Patients who were referred to a 12-week outpatient PR program were followed up for 5 years postcompletion, and survival status was verified. Survival was analyzed according to four groups based upon initial 6MWD (6MWDi) and its changes (Δ6MWD) after PR (Group 1: 6MWDi ≥350 m and Δ6MWD ≥30 m; Group 2: 6MWDi ≥350 m and Δ6MWD <30 m; Group 3: 6MWDi <350 m and Δ6MWD ≥30 m; and Group 4: 6MWDi <350 m and Δ6MWD <30 m) via Kaplan–Meier analysis and log rank test. Cox regression was performed to identify possible confounders of mortality estimates. In total, 423 patients (with mean ± standard deviation of forced expiratory volume in the first second [FEV1] 43±16% predicted, age 65±8 years, and 6WMDi 381±134 m) underwent PR between 1999 and 2010. Survival rates decreased progressively from Group 1 to Group 4 (Group 1, 81%; Group 2, 69%; Group 3, 47%; Group 4, 27%; log rank test, P<0.05). 6MWDi ≥350 m (hazard ratio [HR] 0.39 [95% confidence interval {CI} 0.30–0.50]) and Δ6MWD ≥30 m (HR 0.66 [95% CI 0.51–0.85]) were strongly and independently associated with survival. Compared with Group 1, mortality risks progressively increased in Group 2 (HR 1.36 [95% CI 0.92–2.00]; not significant), Group 3 (HR 1.90 [95% CI 1.28–2.84]; P=0.001), and Group 4 (HR 3.28 [95% CI 2.02–5.33]; P,0.0001). Both poor 6MWD and lack of improvement >30 m after PR are associated with worse 5-year survival in patients with COPD. Keywords: pulmonary disease, chronic obstructive, exercise training, mortality, 6-minute walk test, minimally important differenc

Association of body mass index and long-term mortality in patients from nationwide LIPIDOGRAM 2004–2015 cohort studies: no obesity paradox?

Abstract Background An obesity paradox has been described in relation to adverse clinical outcomes (e.g., mortality) with lower body mass index (BMI). Aims We sought to evaluate the association between BMI and weight loss with long-term all-cause mortality in adult populations under the care of family physicians. Methods LIPIDOGRAM studies were conducted in primary care in Poland in 2004, 2006, and 2015 and enrolled a total of 45,615 patients. The LIPIDOGRAM Plus study included 1627 patients recruited in the LIPIDOGRAM 2004 and repeated measurements in 2006 edition. Patients were classified by BMI categories as underweight, normal weight, overweight and class I, II, or III (obesity). Follow-up data up to December 2021 were obtained from the Central Statistical Office. Differences in all-cause mortality were analyzed using Kaplan‒Meier and Cox regression analyses. Results Of 45,615 patients, 10,987 (24.1%) were normal weight, 320 (0.7%) were underweight, 19,134 (41.9%) were overweight, and 15,174 (33.2%) lived with obesity. Follow-up was available for 44,620 patients (97.8%, median duration 15.3 years, 61.7% females). In the crude analysis, long-term all-cause mortality was lowest for the normal-weight group (14%) compared with other categories. After adjusting for comorbidities, the highest risk of death was observed for the class III obesity and underweight categories (hazard ratio, HR 1.79, 95% CI [1.55–2.05] and HR 1.57, 95% CI [1.22–2.04]), respectively. The LIPIDOGRAM Plus analysis revealed that a decrease in body weight (by 5 and 10%) over 2 years was associated with a significantly increased risk of death during long-term follow-up—HR 1.45 (95% CI 1.05–2.02, p = 0.03) and HR 1.67 (95% CI 1.02–2.74, p < 0.001). Patients who experienced weight loss were older and more burdened with comorbidities. Conclusions Being underweight, overweight or obese is associated with a higher mortality risk in a population of patients in primary care. Patients who lost weight were older and more burdened with cardiometabolic diseases, which may suggest unintentional weight loss, and were at higher risk of death in the long-term follow-up. In nonsmoking patients without comorbidities, the lowest mortality was observed in those with a BMI < 25 kg/m2, and no U-curve relationship was observed

Pulmonary function testing during SARS-CoV-2: An ANZSRS/TSANZ position statement.

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases