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Quorum sensing plays a vital role in the environmental and host life cycles of Vibrio cholerae. The quorum-sensing circuit involves the consorted action of autoinducers, small RNAs, and regulatory proteins to control a plethora of physiological events in this bacterium. Among the regulatory proteins, LuxO is considered a low-cell-density master regulator. It is a homolog of NtrC, a two-component response regulator. NtrC belongs to an evolving protein family that works with the alternative sigma factor σ54 to trigger gene transcription. Structurally, these proteins comprise 3 domains: a receiver domain, a central AAA+ATPase domain, and a C-terminal DNA-binding domain (DBD). LuxO communicates with its cognate promoters by employing its DNA binding domain. In the present study, we desired to identify the critical residues in the DBD of LuxO. Our combined mutagenesis and biochemical assays resulted in the identification of eleven residues that contribute significantly to LuxO regulatory function. [ABSTRACT FROM AUTHOR]

Key Points: Question: For people with chronic obstructive pulmonary disease (COPD) at high risk of exacerbations, does bisoprolol reduce the number of exacerbations? Finding: In this randomized double-blind placebo-controlled trial of 515 people with COPD, the number of exacerbations requiring treatment with oral corticosteroids, antibiotics, or both did not differ significantly with use of bisoprolol (mean exacerbations, 2.03/y) vs placebo (mean exacerbations, 2.01/y). Meaning: Treatment with bisoprolol did not reduce COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. This randomized clinical trial examines whether the addition of bisoprolol to treatment of people with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation reduces the rate of moderate to severe exacerbations. Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P =.72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P =.96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306 [ABSTRACT FROM AUTHOR]

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability–defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with (NCT 03480347). [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease.Methods: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers.Discussion: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally.Trial Registration: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018. [ABSTRACT FROM AUTHOR]

Ageing is defined as a progressive decline of homeostasis that occurs after the reproductive phase of life is complete, which is thought to arise because of impaired DNA repair following damage. This leads to an increased risk of disease or death. Ageing is one of the most important risk factors for most chronic diseases. Chronic obstructive pulmonary disease (COPD) represents an important component of the increasingly prevalent multiple chronic debilitating diseases that are a major cause of morbidity and mortality, particularly in the elderly. There is increasing evidence that the pathogenesis of COPD is linked to an accelerated ageing process. This review discusses the evidence supporting a number of mechanisms, including oxidative stress and ageing, in the pathogenesis of COPD. Greater understanding of these mechanisms leads to novel therapeutic interventions targeted at this heterogeneous disease. [ABSTRACT FROM PUBLISHER]

Background. The 2007 InfectiousDisease Society of America/American Thoracic Society (IDSA/ATS) guidelines for community-acquired pneumonia (CAP) recommended new criteria to guide admission to the intensive care unit (ICU) for patients with this condition. Although the major criteria (requirement for mechanical ventilation or septic shock requiring vasopressor support) are well established, the value of the minor criteria alone have not been fully validated. Methods. We performed a prospective observational study of consecutive adult patients with CAP admitted to NHS Lothian (Scotland, United Kingdom). Patients meeting the IDSA/ATS major criteria on admission were excluded, along with patients not suitable for ICU care owing to advanced directives or major comorbid illnesses. Performance characteristics for the IDSA/ATS minor criteria were calculated and compared with those for alternative scoring systems identified in the literature. Two definitions of severe CAP were used as primary end points: ICU admission, and subsequent requirement for mechanical ventilation or vasopressor support (MV/VS); 30-day mortality was a secondary outcome. Results. The study included 1062 patients with CAP potentially eligible for ICU admission. Each of the 9 minor criteria was associated with increased risk of MV/VS and 30-day mortality in univariate analysis. Two hundred seven patients had ⩾3 minor criteria (19.5%). The IDSA/ATS 2007 criteria had an area under the receiver operating characteristic curve of 0.85 (0.82-0.88) for prediction of MV/VS, 0.85 (0.82-0.88) for prediction of ICU admission, and 0.78 (0.74-0.82) for prediction of 30-day mortality. The IDSA/ATS 2007 criteria were at least equivalent to more established scoring systems for prediction of MV/VS and ICU admission and equivalent to alternative scoring systems for predicting 30-day mortality in this patient population. Conclusions. In a population of patients with CAP without contraindications to ICU care, the IDSA/ATS minor criteria predict subsequent requirement for MV/VS, ICU admission, and 30-day mortality. [ABSTRACT FROM AUTHOR]

Background: The aim of this meta-analysis was to determine if severity assessment tools can be used to guide decisions regarding intensive care unit (ICU) admission of patients with community-acquired pneumonia. Methods: A search of PUBMED and EMBASE (1980-2009) was conducted to identify studies reporting pneumonia severity scores and prediction of ICU admission. Two reviewers independently collected data and assessed study quality. Performance characteristics were pooled using a random-effects model. Results: Sufficient data were collected to perform a meta-analysis on five current scoring systems: the Pneumonia Severity Index (PSI), the CURB65 score, the CRB65 score, the American Thoracic Society (ATS) 2001 criteria and the Infectious Disease Society of America/ATS (IDSA/ATS) 2007 criteria. The analysis was limited due to large variations in the ICU admission criteria, ICU admission rates and patient characteristics between different studies and different healthcare systems. In the pooled analysis, PSI, CURB65 and CRB65 performed similarly in terms of sensitivity and specificity across a range of cut-offs. Patients in CURB65 group 0 were at lowest risk of ICU admission (negative likelihood ratio 0.14; 95% confidence interval 0.06-0.34) while the ATS 2001 criteria had the highest positive likelihood ratio (7.05; 95% confidence interval 4.39-11.3). Conclusion: Large variations exist in the use of ICU resources between different studies and different healthcare systems. Scoring systems designed to predict 30-day mortality perform less well when ICU admission is taken into account. Further studies of dedicated ICU admission scores are required. [ABSTRACT FROM AUTHOR]

Background. The recently introduced concept of health care-associated pneumonia (HCAP), referring to patients with frequent healthcare contacts and at higher risk of contracting resistant pathogens, is controversial. Methods. This prospective observational study recorded the clinical features, microbiology, and outcomes in a UK cohort of hospitalized patients with pneumonia. The primary outcome was 30-day mortality. Logistic regression was used to adjust for confounders when determining the impact of HCAP on clinical outcomes. Results. A total of 20.5% of patients met the HCAP criteria. HCAP patients were older than patients with community-acquired pneumonia (CAP) (median 76 y, IQR 65-83 vs 65 y, IQR 48-77; P < .0001) and more frequently had major comorbidities (62.1% vs 45.2%; P < .0001). Patients with HCAP had higher initial severity compared to CAP patients (Pneumonia Severity Index, mean 3.7 [SD 1.1] vs mean 3.1 [SD 1.3]; P < .0001) but also worse functional status using the Eastern Cooperative Oncology Group scale (mean 2.4 [SD 1.44] vs mean 1.4 [SD 1.13]; P < .0001) and more frequently had treatment restrictions such as do not resuscitate orders (59.9% vs 29.8%; P < .0001). Consequently mortality was increased (odds ratio [OR] 2.15 [1.44-3.22]; P = .002) in HCAP patients on univariate analysis. Multivariate analysis suggested this relationship was primarily due to confounders rather than a higher frequency of treatment failure due to resistant organisms (adjusted OR .97 [.61-1.55]; P = .9). The frequencies of Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Gram-negative Enterobacteriaceae were low in both cohorts. Conclusions. HCAP is common in the United Kingdom and is associated with a high mortality. This increased mortality was primarily related to underlying patient-related factors rather than the presence of antibiotic-resistant pathogens. This study did not establish a clear indication to change prescribing practices in a UK cohort. [ABSTRACT FROM AUTHOR]

Objectives To determine whether the introduction of a community-acquired pneumonia (CAP) severity assessment tool to guide antibiotic selection could reduce broad-spectrum antibiotic prescribing without compromising patient safety. Methods A prospective before and after evaluation study. Empirical antibiotic prescribing was studied for 18 months from June 2006 to January 2008 (pre-intervention) and then for 18 months following the implementation of a CURB65-guided antibiotic therapy guideline in June 2008. The primary outcome was the use of broad-spectrum antibiotics (cephalosporin, amoxicillin plus clavulanic acid and macrolides) in patients with CAP. Safety outcomes were 30 day mortality, requirement for mechanical ventilation and/or vasopressor support (MV/VS), development of complicated pneumonia, time to clinical stability (TCS) and length of hospital stay. Results The introduction of CURB65-guided therapy resulted in an overall reduction in the prescription of cephalosporins (from 27.1% of patients receiving this agent in the overall pre-intervention cohort to 8.0% in the post-intervention cohort, P < 0.0001) and macrolides (72.8% to 58.7%, P < 0.0001), particularly among low-risk patients. There was a corresponding increase in the prescription of the narrower-spectrum agent amoxicillin (29.7% to 41.7%, P < 0.0001) and an increase in the use of amoxicillin monotherapy (10.4% to 29.9%, P < 0.0001). Co-amoxiclav use increased slightly as this agent replaced cephalosporins as first-line treatment for severe CAP. The guideline had no impact on 30 day mortality, MV/VS, complicated pneumonia, TCS or length of stay. Following the intervention, adherence to national guidelines increased from 25.4% of prescriptions to 61.9%, suggesting the potential for further improvements. Conclusions CURB65-guided antibiotic therapy was associated with a significant decrease in broad-spectrum antibiotic use. The intervention was safe with no impact on mortality, treatment failure or clinical response. [ABSTRACT FROM PUBLISHER]

The article discusses a study on the incidence of acute kidney injury (AKI) in community-acquired pneumonia (CAP) patients on hospital admission. Patients were assessed based on their risk, injury, failure, loss and end-stage kidney (RIFLE) disease assessment using hospital admission creatinine and baseline creatinine. The study found that the RIFLE assessment tool is able to evaluate and classify AKI during admission and to provide a 30-day mortality prediction.