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).
Glutamine is a major dietary amino acid that is both a fuel and nitrogen donor for healing tissues damaged by chemotherapy and radiation. Evidence supports the benefit of oral (enteral) glutamine to ...reduce symptoms and improve and/or maintain quality of life of cancer patients. Benefits include not only better nutrition, but also decreased mucosal damage (mucositis, stomatitis, pharyngitis, esophagitis, and enteritis). Glutamine supplementation in a high protein diet (10 grams/day) + disaccharides, such as sucrose and/or trehalose, is a combination that increases glutamine uptake by mucosal cells. This increased topical effect can reduce painful mucosal symptoms and ulceration associated with chemotherapy and radiation in the head and neck region, esophagus, stomach and small intestine. Topical and oral glutamine seem to be the preferred routes for this amino acid to promote mucosal healing during and after cancer treatment.
Soils harbour some of the most diverse microbiomes on Earth and are essential for both nutrient cycling and carbon storage. To understand soil functioning, it is necessary to model the global ...distribution patterns and functional gene repertoires of soil microorganisms, as well as the biotic and environmental associations between the diversity and structure of both bacterial and fungal soil communities
. Here we show, by leveraging metagenomics and metabarcoding of global topsoil samples (189 sites, 7,560 subsamples), that bacterial, but not fungal, genetic diversity is highest in temperate habitats and that microbial gene composition varies more strongly with environmental variables than with geographic distance. We demonstrate that fungi and bacteria show global niche differentiation that is associated with contrasting diversity responses to precipitation and soil pH. Furthermore, we provide evidence for strong bacterial-fungal antagonism, inferred from antibiotic-resistance genes, in topsoil and ocean habitats, indicating the substantial role of biotic interactions in shaping microbial communities. Our results suggest that both competition and environmental filtering affect the abundance, composition and encoded gene functions of bacterial and fungal communities, indicating that the relative contributions of these microorganisms to global nutrient cycling varies spatially.
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KISLJ, NUK, SBMB, UL, UM, UPUK
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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 . . .
Background:
The indications for hip preservation surgery have expanded to include treatment of hip pathology in older adults. While several studies have examined the efficacy of hip arthroscopy in ...the setting of osteoarthritis, there has been no review of outcomes in older adults.
Purpose:
To review the outcomes of hip arthroscopy in older adults and identify factors associated with treatment failures.
Study Design:
Systematic review.
Methods:
PubMed, EMBASE, and the Cochrane Library were searched through March 2016 for studies reporting outcomes of primary hip arthroscopy in patients older than 40 years. Inclusion in the review was based on age, patient-reported outcome (PRO) measures, and duration of follow-up. Two authors screened the results and extracted data for use in this review. Standardized mean difference was calculated to estimate effect size for PRO scores within studies.
Results:
Eight studies with 401 total patients undergoing hip arthroscopy for femoroacetabular impingement (FAI) or labral tears were included in this review. Seven of the 8 studies reported favorable PRO scores and significant postoperative improvement with moderate to large effect size. The included studies demonstrated a trend toward higher effect sizes with an increasing percentage of labral repair compared to isolated labral debridement. The complication rate was comparable to that of previous reports involving younger patients; however, the overall reoperation rate was 20.8%. Conversion to hip arthroplasty ranged from 0% to 30%, with an overall conversion rate of 18.5% at a mean time of 17.5 months following arthroscopy. The most common risk factors for conversion to arthroplasty were low preoperative PRO scores and advanced arthritis.
Conclusion:
Hip arthroscopy appears to be a safe and efficacious treatment for labral tears and FAI in older patients who do not have significant underlying degenerative changes. However, in this population, there is a significant proportion of patients who eventually require hip arthroplasty. Outcomes may be affected by type of treatment (ie, labral debridement vs repair). Additional high-quality studies are needed to understand how these factors affect outcomes.
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FSPLJ, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic ...osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only
Tc-MDP standard bone scans, but also
Tc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na
F), and
FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.
Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple ...myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
•D-RVd improved sCR rates and MRD negativity vs RVd, both of which deepened over time.•No new safety concerns were observed with D-RVd, and no clinically significant impact on stem cell mobilization or engraftment was noted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The coupling between phase transformations and plasticity in shape memory alloys (SMAs) is studied by developing a finite element framework in which the constitutive relation captures both phase ...transformations at the martensite correspondence variant (CV) scale and rate-dependent crystal plasticity in austenite. Load-free and load-biased thermal cycling simulations involving a model cubic-to-tetragonal transformation system are carried out to study how slip in austenite can affect the resulting martensite microstructure. Three key questions are answered. First, where does austenite slip predominantly occur during phase transformation? Second, at what stage during a thermal cycle is plastic deformation most pronounced? Third, what is the effect of plastic deformation on measurable parameters like transformation temperature and subsequent transformation microstructure? The model can also be generalized to study the coupling between phase transformations, twining, and slip.
•We develop a new micromechanical model coupling phase transformation and austenite plasticity in Shape Memory Alloys (SMA).•We model martensite correspondence variant scale phase transformation and reorientation using the phase field method.•We model slip in the austenite phase using a crystal plasticity based framework with a phenomenological hardening rule.•We systematically study the spatial and temporal trends in the interaction between phase transformation and austenite slip.•The model has broader impacts, in that the framework can include other inelastic mechanisms, such as twinning.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 ...antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
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