Loss of a water-mediated network results in reduced agonist affinity in a β2-adrenergic receptor clinical variant.
Biochim Biophys Acta Proteins Proteom. 2021 Jan 13;:140605
Authors: Nikte SV, Sonar K, Tandale A, Joshi M, Sengupta D
The β2-adrenergic receptor (β2AR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly "non-deleterious" substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response. We are able to identify hydration sites in the transmembrane domain that are essential to maintain the integrity of the binding site but are absent in the variant. The loss of these hydration sites in the variant correlates with perturbations in the intra-protein interaction network and rearrangements in the orthosteric ligand binding site. In conjunction, we observe an altered binding and reduced free energy of a series of agonists, in line with experimental trends. Our work identifies a functional allosteric pathway connected by specific hydration sites in β2AR that has not been reported before and provides insight into water-mediated networks in GPCRs in general. Overall, the work is one of the first step towards developing variant-specific potent and selective agonists.
PMID: 33453412 [PubMed - as supplied by publisher]
Clinical outcomes and costs associated with procalcitonin utilization in hospitalized patients with pneumonia, heart failure, viral respiratory infection, or chronic obstructive pulmonary disease.
Intern Emerg Med. 2021 Jan 16;:
Authors: Johnson SA, Rupp AB, Rupp KL, Reddy S
Lower respiratory tract infections (LRTIs) due to bacterial pneumonia are common among hospitalized patients and are frequently treated with antibiotics. Viral illnesses and exacerbations of heart failure or COPD may present with symptoms mimicking a LRTI, resulting in unnecessary antibiotic utilization. Procalcitonin testing may be useful in these clinical scenarios. We attempted to assess the utility of procalcitonin testing versus not testing, and positive versus negative results among hospitalized patients with suspected LRTI. We performed a retrospective cohort study using multivariable analysis comparing clinical outcomes of patients with and without procalcitonin testing. Patients were 18 years or older, hospitalized for pneumonia, heart failure, COPD, or a viral respiratory illness between October 2014 and October 2015 (n = 2353). All patients received at least one dose of antibiotics. Major outcomes were duration of antibiotic therapy, length of hospital stay, C. difficile testing and infections, and normalized total direct costs. Procalcitonin testing occurred in 14.0% of patients and pneumonia (70.6%) was the most common diagnosis. After covariate adjustments, mean length of stay (5.61 vs. 6.67 days, p < 0.001) and duration of antibiotics (3.95 vs. 4.47 days, p < 0.001) were shorter among tested patients. Fewer 30-day readmissions (OR 0.62, 95% CI 0.40-0.95) were observed, and total direct healthcare costs were 34% lower (0.66, 95% CI 0.58-0.74) among tested patients. Negative procalcitonin results were associated with further reductions in some outcomes. In conclusion, procalcitonin testing among hospitalized patients with suspected LRTI is associated with reductions in antibiotic duration, length of stay, 30-day readmission, and healthcare costs.
PMID: 33453013 [PubMed - as supplied by publisher]
Low BMI and weight loss aggravate COPD mortality in men, findings from a large prospective cohort: the JACC study.
Sci Rep. 2021 Jan 15;11(1):1531
Authors: Wada H, Ikeda A, Maruyama K, Yamagishi K, Barnes PJ, Tanigawa T, Tamakoshi A, Iso H
To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009. A total of 45,837 male residents were observed for a median period of 19.1 years. Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019. During follow-up, 268 participants died from COPD. The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41-0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59-0.68). These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years. Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality.
PMID: 33452329 [PubMed - as supplied by publisher]
Prevalence of different comorbidities in chronic obstructive pulmonary disease among Shahrekord PERSIAN cohort study in southwest Iran.
Sci Rep. 2021 Jan 15;11(1):1548
Authors: Kiani FZ, Ahmadi A
Comorbidities are common in chronic obstructive pulmonary disease (COPD) patients. This study was conducted to determine the prevalence of common comorbidities in patients with COPD compared with people without COPD. This cross-sectional, population-based study was performed on 6961 adults aged 35-70 years enrolled in the Shahrekord PERSIAN cohort study. Data (demographic and clinical characteristics, comorbidities, anthropometric and blood pressure measurements, laboratory, and spirometry tests) collection was performed according to the cohort protocol from 2015 to 2019. In the present study, 215 (3.1%) patients were diagnosed with COPD and 1753 (25.18%) ones with restrictive lung patterns. The mean age of COPD patients was 52.5 ± 9.76 years. 55.8% of patients were male, 17.7% were current smokers and 12.1% had a history of smoking or were former smokers. 5.6% of patients had no comorbidity and 94.5% had at least one comorbidity. The most common comorbidities in COPD patients were dyslipidemia (70.2%), hypertension (30.2%), metabolic syndrome (22.8%), and diabetes (16.7%). The most common comorbidities in individuals with a restrictive spirometry pattern were dyslipidemia (68.9%), metabolic syndrome (27.2%), hypertension (26.1%), depression (17.6%), and fatty liver (15.5%). The logistic regression analysis with 95% confidence interval (95%CI) of odds ratio (OR) showed that comorbidities of chronic lung diseases (OR = 2.12, 95% CI 1.30-3.44), diabetes (OR = 1.54, 95%CI 1.03-2.29), cardiovascular disease (OR = 1.52, 95%CI 1.17-2.43), and hypertension (OR = 1.4, 95%CI 1.02-1.99) were more likely to occur in COPD patients than in healthy individuals. Knowing these prevalence rates and related information provides new insights on comorbidities to reduce disease burden and develop preventive interventions and to regulate health care resources to meet the needs of patients in primary health care.
PMID: 33452286 [PubMed - as supplied by publisher]
Impact of statin on long-term outcome among patients with end-stage renal disease with acute myocardial infarction (AMI): a nationwide case-control study.
Postgrad Med J. 2021 Jan 15;:
Authors: Kuo FY, Huang WC, Tang PL, Cheng CC, Chiang CH, Lin HC, Chuang TJ, Wann SR, Mar GY, Liu CP, Cheng JT, Wu MC, whole study team
BACKGROUND: Use of statin has been associated with reduced risk of cardiovascular diseases events and mortality. However, in patients with end-stage renal disease (ESRD), the protective effects of statin are controversial. To evaluate the impact of chronic statin use on clinical outcomes of patients with acute myocardial infarction (AMI) with ESRD.
METHODS: We enrolled 8056 patients with ESRD who were initially diagnosed and admitted for first AMI from Taiwan's National Health Insurance Research Database. Of which, 2134 patients underwent statin therapy. We randomly selected and use age, sex, hypertension, diabetes mellitus (DM), peripheral vascular diseases (PVD), heart failure (HF), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease, matched with the study group as controls (non-stain user). We compared the effects of statin use in term of all-cause death among patients with AMI with ESRD.
RESULTS: Statin use resulted in a significantly higher survival rate in patients ith AMI with ESRD compared with non-statin users. After adjusted the comorbidities the male patients and patients with DM, PVD, HF and CVA had lower long-term survival rate (all p<0.001). Patients who underwent percutaneous coronary intervention (p<0.001), ACE inhibitors/angiotensin II receptor blockers (p<0.001), β receptor blockers (p<0.001) and statin therapy (p=0.007) had better long-term survival rate. Patients with AMI with ESRD on statin therapy exhibited a significantly lower risk of mortality compared with non-statin users (p<0.0001).
CONCLUSION: Among patients with ESRD with AMI, statin therapy was associated with reduced all-cause mortality.
PMID: 33452152 [PubMed - as supplied by publisher]