Summary Background Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and ...cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk. Methods In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40–80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1 ) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1 ) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov , number NCT01313676. Findings Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio HR 0·88 95% CI 0·74–1·04; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 0·77–1·08; p=0·284; vilanterol, 0·96 0·81–1·14; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year SE 2·4 vs 46 mL per year 2·5 for placebo, difference 8 mL per year 95% CI 1–15) with similar findings for fluticasone furoate (difference 8 mL per year 95% CI 1–14), but not vilanterol (difference −2 mL per year 95% CI −8 to 5). Combination therapy had no effect on composite cardiovascular events (HR 0·93 95% CI 0·75–1·14) with similar findings for fluticasone furoate (0·90 0·72–1·11) and vilanterol (0·99 0·80–1·22). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups. Interpretation In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline. Funding GlaxoSmithKline.
Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late ...1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk.
Determine whether ...AECOPD events are associated with increased risk of subsequent CVD.
We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD.
Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7-5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6-14.9).
In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).
The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in ...mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.
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•The duration of eating/fasting varies based on diet type and feeding protocol•Meal feeding and CR, unlike AL, show high metabolic flexibility in male mice•Eating patterns rather than diet composition influence longevity regulation•A prolonged daily fasting is associated with delayed onset of liver pathologies
Mitchell et al. show that a long daily period of fasting improves the health and survival of male mice, regardless of caloric intake, diet composition, and body weight.
Background In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and ...cardiovascular events among adults with chronic kidney disease (CKD). Study Design Prospective cohort. Setting & Participants 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictors 4 lifestyle factors (regular physical activity, body mass index BMI of 20-<25 kg/m2 , nonsmoking, and “healthy diet”), individually and in combination. Outcomes CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. Measurements Multivariable-adjusted Cox proportional hazards. Results During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI ≥ 25 kg/m2 and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 95% CI, 0.58-0.97 and 0.61 95% CI, 0.45-0.82 for BMIs of 25 to <30 and ≥30 kg/m2 , respectively, versus 20 to <25 kg/m2 ; HR for nonsmoking of 0.68 95% CI, 0.55-0.84 compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 95% CI, 0.46-0.96 for BMI of 25-<30 vs 20-<25 kg/m2 and 0.55 95% CI, 0.40-0.75 vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 95% CI, 0.52-0.79 vs inactive), BMI ≥ 30 kg/m2 (HR, 0.64 95% CI, 0.43-0.96 vs 20-<25 kg/m2 ), and nonsmoking (HR, 0.45 95% CI, 0.34-0.60 vs current smoker). BMI < 20 kg/m2 was associated with increased all-cause mortality risk (HR, 2.11 95% CI, 1.13-3.93 vs 20-<25 kg/m2 ). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). Limitations Lifestyle factors were measured only once. Conclusions Regular physical activity, nonsmoking, and BMI ≥ 25 kg/m2 were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.
Summary
The structure and function of microbial communities inhabiting the subseafloor near hydrothermal systems are influenced by fluid geochemistry, geologic setting and fluid flux between vent ...sites, as well as biological interactions. Here, we used genome‐resolved metagenomics and metatranscriptomics to examine patterns of gene abundance and expression and assess potential niche differentiation in microbial communities in venting fluids from hydrothermal vent sites at the Mid‐Cayman Rise. We observed similar patterns in gene and transcript abundance between two geochemically distinct vent fields at the community level but found that each vent site harbours a distinct microbial community with differing transcript abundances for individual microbial populations. Through an analysis of metabolic pathways in 64 metagenome‐assembled genomes (MAGs), we show that MAG transcript abundance can be tied to differences in metabolic pathways and to potential metabolic interactions between microbial populations, allowing for niche‐partitioning and divergence in both population distribution and activity. Our results illustrate that most microbial populations have a restricted distribution within the seafloor, and that the activity of those microbial populations is tied to both genome content and abiotic factors.
This trial involving more than 6000 patients with chronic obstructive pulmonary disease (COPD) compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and ...fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate; this fell short of the study's prespecified goals. There were improved clinical outcomes among patients treated with the combination regimen.
This trial involving more than 6000 patients with COPD compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate, which fell short of the prespecified goal.
Chronic obstructive pulmonary disease (COPD) is a major cause of illness, death, and the use of health care resources globally.
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The disease causes approximately 2.75 million deaths annually, and the number is projected to increase.
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Treatment for COPD is focused on minimizing risk factors, improving symptoms, and preventing exacerbations.
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With the exception of smoking-cessation programs for patients with early disease,
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home oxygen treatment for persistent hypoxemia,
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and lung-reduction surgery for selected patients with emphysema,
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no treatment has been shown to reduce mortality.
Pulmonary inflammation is prominent in COPD.
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Antiinflammatory drugs such as inhaled corticosteroids have little or no . . .
To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC).
PK dependencies in OS were ...evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL
), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL
subgroups.
A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma HR = 0.98; 95% confidence interval (CI), 0.94-1.02 and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL
-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL
paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL
-OS association (multivariate-adjusted CL
HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC).
These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL
with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.
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Little is known about evolutionary drivers of microbial populations in the warm subseafloor of deep-sea hydrothermal vents. Here we reconstruct 73 metagenome-assembled genomes (MAGs) from two ...geochemically distinct vent fields in the Mid-Cayman Rise to investigate patterns of genomic variation within subseafloor populations. Low-abundance populations with high intra-population diversity coexist alongside high-abundance populations with low genomic diversity, with taxonomic differences in patterns of genomic variation between the mafic Piccard and ultramafic Von Damm vent fields. Populations from Piccard are significantly enriched in nonsynonymous mutations, suggesting stronger purifying selection in Von Damm relative to Piccard. Comparison of nine Sulfurovum MAGs reveals two high-coverage, low-diversity MAGs from Piccard enriched in unique genes related to the cellular membrane, suggesting these populations were subject to distinct evolutionary pressures that may correlate with genes related to nutrient uptake, biofilm formation, or viral invasion. These results are consistent with distinct evolutionary histories between geochemically different vent fields, with implications for understanding evolutionary processes in subseafloor microbial populations.
The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD ...severity staging on the effectiveness of SFC, particularly in patients with milder disease.
TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: >or= 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).
Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval CI: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio HR 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.
In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages. Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease. The effects were similar to those reported for the study as a whole. Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.
Clinicaltrial.gov registration NCT00268216; Study number: SCO30003.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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