Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% ...of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1), appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1) is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the "risk genotypes" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a ...novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C-S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor-acceptor complex in synthesis.
Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols.
During the year following New Zealand's first COVID-19 lockdown, a 33% reduction in chronic obstructive pulmonary disease (COPD)-related admissions occurred and persisted beyond this period at ...Christchurch Hospital.
To identify contributing factors which may have resulted in a persistent decrease in COPD hospitalisation rates at Christchurch Hospital following the 2020 COVID-19 lockdown.
Using an explanatory sequential mixed-methods research design, we (i) retrospectively analysed hospital admissions and primary healthcare access by people with COPD (n = 1358) in Canterbury before, during and after COVID lockdown (24 March 2019 to 2021) and (ii) undertook individual interviews from a sample of patients (n = 14).
Patients who were not re-admitted following the COVID-19 lockdown had fewer general practice encounters, acute primary care access, antibiotic and prednisone prescriptions. Proportionally fewer Māori and more Pacific patients were admitted with COPD following lockdown. Positive contributing factors at a primary care level included improvements in primary care interactions and medication management. At a patient and community level, there were improvements in lifestyle, self-management practices, social support and contact precautions. However, a subgroup of patients described negative effects such as social isolation.
A combination of patient, primary care and community-level factors led to an overall persistent decrease in COPD admissions following the COVID-19 lockdown. Future targeted and individualised measures focusing on these modifiable factors may decrease future COPD-related hospital admissions. The study design facilitated further explanation about factors that contributed to the persistent decrease in hospital admissions among people living with COPD and has underscored the importance of social support, patient empowerment and reduction in barriers in accessing care in admission reduction.
Much remains unknown about the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult lungs. We hypothesized that VLBW adults would have impaired lung function ...compared with controls, and those with a history of BPD would have worse lung function than those without.
At age 26 to 30 years, 226 VLBW survivors of the New Zealand VLBW cohort and 100 term controls born in 1986 underwent lung function tests including spirometry, plethysmographic lung volumes, diffusing capacity of the lung for carbon monoxide, and single-breath nitrogen washout (SBN
).
An obstructive spirometry pattern was identified in 35% VLBW subjects versus 14% controls, with the majority showing mild obstruction. Compared with controls, VLBW survivors demonstrated significantly lower forced expiratory volume in 1 second (FEV
), FEV
/forced vital capacity (FVC) ratio (FEV
/FVC), forced expiratory flow at 25% to 75% of FVC and higher residual volume (RV), RV/total lung capacity (TLC) ratio (RV/TLC), decreased diffusing capacity of the lung for carbon monoxide, and increased phase III slope for SBN
. The differences persisted after adjustment for sex and smoking status. Within the VLBW group, subjects with BPD showed significant reduction in FEV
, FEV
/FVC, and forced expiratory flow at 25% to 75% of FVC, and increase in RV, RV/TLC, and phase III slope for SBN
, versus subjects without. The differences remained after adjustment for confounders.
Adult VLBW survivors showed a higher incidence of airflow obstruction, gas trapping, reduced gas exchange, and increased ventilatory inhomogeneity versus controls. The findings suggest pulmonary effects due to VLBW persist into adulthood, and BPD is a further insult on small airway function.
Indole-ynones have been established as general substrates for radical dearomatizing spirocyclization cascade reactions. Five distinct and varied synthetic protocols have been ...developedcyanomethylation, sulfonylation, trifluoromethylation, stannylation and borylationusing a variety of radical generation modes, ranging from photoredox catalysis to traditional AIBN methods. The simple and easily prepared indole-ynones can be used to rapidly generate diverse, densely functionalized spirocycles and have the potential to become routinely used to explore radical reactivity. Experimental and computational investigations support the proposed radical cascade mechanism and suggest that other new methods are now primed for development.
Population-based data regarding the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult exercise capacity are limited.
To compare exercise capacity in a ...national VLBW cohort with term-born controls and explore factors contributing to the differences.
At 26-30 years of age, 228 VLBW survivors and 100 controls underwent lung function tests, cardiopulmonary exercise testing, and assessment of resting cardiac structure and function using echocardiography. Data on self-reported physical activity were collected.
Compared with controls, adults with VLBW demonstrated reduced oxygen uptake, work rate, and oxygen pulse at peak exercise (9.3%, 10.7%, and 10.8% lower, respectively) and earlier anaerobic threshold (all
< 0.0001), with all mean values within normal range. VLBW survivors showed reduced physical activity, impaired lung function (reduced FEV
, FEV
/FVC, and Dl
), altered left ventricular structure and function (reduced mass, size, stroke volume, and cardiac output), and reduced right atrial and ventricular size. Adjustment for the combination of three sets of covariates (physical activity with body mass index, lung function, and cardiac structure and function) explained most of the exercise group differences. Beyond the effects of physical activity and body mass index, lung function and cardiac structure and function contributed approximately equally. BPD with other prematurity-related perinatal factors (ventilation, antenatal steroids, extremely low birth weight, and extreme preterm) were not associated with a reduced exercise capacity.
Exercise capacity was significantly reduced in adults with VLBW, which we speculate is from combined effects of impaired lung function, altered heart structure and function, and reduced physical activity. Perinatal factors including BPD were not associated with a reduced exercise capacity.
Aims
To evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with healthy volunteers and using ...the modified Inje drug cocktail.
Methods
This was a single‐centre pharmacokinetic study with 12 healthy participants and 7 participants with GOLD D COPD. Midazolam 1 mg, dextromethorphan 30 mg, losartan 25 mg, omeprazole 20 mg, caffeine 130 mg and paracetamol 1000 mg were simultaneously administered and intensive pharmacokinetic sampling was conducted over 8 hours. Drug metabolism by CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, UGT1A6 and UGT1A9 in participants with COPD were compared with phenotypes in healthy controls.
Results
The oral clearance (95% confidence interval) in participants with COPD relative to controls was: midazolam 63% (60–67%); dextromethorphan 72% (40–103%); losartan 53% (52–55%); omeprazole 35% (31–39%); caffeine 52% (50–53%); and paracetamol 73% (72–74%). There was a 5‐fold increase in AUC for omeprazole and approximately 2‐fold increases for caffeine, losartan, dextromethorphan, and midazolam. The AUC of paracetamol, which is mostly glucuronidated, was increased by about 60%.
Conclusion
Severe COPD is associated with a clinically significant reduction in oral drug clearance. This may be greater for cytochrome P450 substrates than for glucuronidated drugs. This supports reduced starting doses when prescribing for patients with severe COPD.
Higher maternal intake of vitamin D during pregnancy is associated with a lower risk of wheezing in offspring. The relationship between cord-blood levels of 25-hydroxyvitamin D (25OHD) and childhood ...wheezing is unknown. We hypothesized that cord-blood levels would be inversely associated with risk of respiratory infection, wheezing, and asthma.
Cord blood from 922 newborns was tested for 25(OH)D. Parents were asked if their child had a history of respiratory infection at 3 months of age or a history of wheezing at 15 months of age and then annually thereafter. Incident asthma was defined as doctor-diagnosed asthma by the time the child was 5 years old and reported inhaler use or wheezing since the age of 4 years.
The median cord-blood level of 25(OH)D was 44 nmol/L (interquartile range: 29-78). Follow-up was 89% at the age of 5 years. Adjusting for the season of birth, 25(OH)D had an inverse association with risk of respiratory infection by 3 months of age (odds ratio: 1.00 reference for ≥75 nmol/L, 1.39 for 25-74 nmol/L, and 2.16 95% confidence interval: 1.35-3.46 for <25 nmol/L). Likewise, cord-blood 25(OH)D levels were inversely associated with risk of wheezing by 15 months, 3 years, and 5 years of age (all P < .05). Additional adjustment for more than 12 potential confounders did not materially change these results. In contrast, we found no association between 25(OH)D levels and incident asthma by the age of 5 years.
Cord-blood levels of 25(OH)D had inverse associations with risk of respiratory infection and childhood wheezing but no association with incident asthma.
Self-management interventions are considered effective in patients with COPD, but trials have shown inconsistent results and it is unknown which patients benefit most. This study aimed to summarize ...the evidence on effectiveness of self-management interventions and identify subgroups of COPD patients who benefit most.
Randomized trials of self-management interventions between 1985 and 2013 were identified through a systematic literature search. Individual patient data of selected studies were requested from principal investigators and analyzed in an individual patient data meta-analysis using generalized mixed effects models.
Fourteen trials representing 3,282 patients were included. Self-management interventions improved health-related quality of life at 12 months (standardized mean difference 0.08, 95% confidence interval CI 0.00-0.16) and time to first respiratory-related hospitalization (hazard ratio 0.79, 95% CI 0.66-0.94) and all-cause hospitalization (hazard ratio 0.80, 95% CI 0.69-0.90), but had no effect on mortality. Prespecified subgroup analyses showed that interventions were more effective in males (6-month COPD-related hospitalization: interaction P=0.006), patients with severe lung function (6-month all-cause hospitalization: interaction P=0.016), moderate self-efficacy (12-month COPD-related hospitalization: interaction P=0.036), and high body mass index (6-month COPD-related hospitalization: interaction P=0.028 and 6-month mortality: interaction P=0.026). In none of these subgroups, a consistent effect was shown on all relevant outcomes.
Self-management interventions exert positive effects in patients with COPD on respiratory-related and all-cause hospitalizations and modest effects on 12-month health-related quality of life, supporting the implementation of self-management strategies in clinical practice. Benefits seem similar across the subgroups studied and limiting self-management interventions to specific patient subgroups cannot be recommended.
Calprotectin, the major neutrophil protein, is a critical alarmin that modulates inflammation and plays a role in host immunity by strongly binding trace metals essential for bacterial growth. It has ...two cysteine residues favourably positioned to act as a redox switch. Whether their oxidation occurs in vivo and affects the function of calprotectin has received little attention. Here we show that in saliva from healthy adults, and in lavage fluid from the lungs of patients with respiratory diseases, a substantial proportion of calprotectin was cross-linked via disulfide bonds between the cysteine residues on its S100A8 and S100A9 subunits. Stimulated human neutrophils released calprotectin and subsequently cross-linked it by myeloperoxidase-dependent production of hypochlorous acid. The myeloperoxidase-derived oxidants hypochlorous acid, taurine chloramine, hypobromous acid, and hypothiocyanous acid, all at 10 μM, cross-linked calprotectin (5 μM) via reversible disulfide bonds. Hypochlorous acid generated A9-A9 and A8-A9 cross links. Hydrogen peroxide (10 μM) did not cross-link the protein. Purified neutrophil calprotectin existed as a non-covalent heterodimer of A8/A9 which was converted to a heterotetramer - (A8/A9)
- with excess calcium ions. Low level oxidation of calprotectin with hypochlorous acid produced substantial proportions of high order oligomers, whether oxidation occurred before or after addition of calcium ions. At high levels of oxidation the heterodimer could not form tetramers with calcium ions, but prior addition of calcium ions afforded some protection for the heterotetramer. Oxidation and formation of the A8-A9 disulfide cross link enhanced calprotectin's susceptibility to proteolysis by neutrophil proteases. We propose that reversible disulfide cross-linking of calprotectin occurs during inflammation and affects its structure and function. Its increased susceptibility to proteolysis will ultimately result in a loss of function.
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