Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

Background Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent. Methods and Findings This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged >= 40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA(1c) between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12-18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [Cl]: 0.05-0.27%) in all COPD patients, and 0.25% (95% Cl: 0.10-0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (> 250 mg) had greater odds of increased HbA(1c) and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses ( Conclusion For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICS may be at greater risk of diabetes progression

Pulmonary oxygen uptake and muscle deoxygenation kinetics during recovery in trained and untrained male adolescents

Previous studies have demonstrated faster pulmonary oxygen uptake ( V ˙ O 2 ) kinetics in the trained state during the transition to and from moderate-intensity exercise in adults. Whilst a similar effect of training status has previously been observed during the on-transition in adolescents, whether this is also observed during recovery from exercise is presently unknown. The aim of the present study was therefore to examine V ˙ O 2 kinetics in trained and untrained male adolescents during recovery from moderate-intensity exercise. 15 trained (15 ± 0.8 years, V ˙ O 2max 54.9 ± 6.4 mL kg−1 min−1) and 8 untrained (15 ± 0.5 years, V ˙ O 2max 44.0 ± 4.6 mL kg−1 min−1) male adolescents performed two 6-min exercise off-transitions to 10 W from a preceding “baseline” of exercise at a workload equivalent to 80% lactate threshold; V ˙ O 2 (breath-by-breath) and muscle deoxyhaemoglobin (near-infrared spectroscopy) were measured continuously. The time constant of the fundamental phase of V ˙ O 2 off-kinetics was not different between trained and untrained (trained 27.8 ± 5.9 s vs. untrained 28.9 ± 7.6 s, P = 0.71). However, the time constant (trained 17.0 ± 7.5 s vs. untrained 32 ± 11 s, P < 0.01) and mean response time (trained 24.2 ± 9.2 s vs. untrained 34 ± 13 s, P = 0.05) of muscle deoxyhaemoglobin off-kinetics was faster in the trained subjects compared to the untrained subjects. V ˙ O 2 kinetics was unaffected by training status; the faster muscle deoxyhaemoglobin kinetics in the trained subjects thus indicates slower blood flow kinetics during recovery from exercise compared to the untrained subjects

Adjuvant breast cancer chemotherapy during late-trimester pregnancy: not quite a standard of care

<p>Abstract</p> <p>Background</p> <p>Diagnosis of breast cancer during pregnancy was formerly considered an indication for abortion. The pendulum has since swung to the other extreme, with most reviews now rejecting termination while endorsing immediate anthracycline-based therapy for any pregnant patient beyond the first trimester. To assess the evidence for this radical change in thinking, a review of relevant studies in the fields of breast cancer chemotherapy, pregnancy, and drug safety was conducted.</p> <p>Discussion</p> <p>Accumulating evidence for the short-term safety of anthracycline-based chemotherapy during late-trimester pregnancy represents a clear advance over the traditional norm of therapeutic abortion. Nonetheless, the emerging orthodoxy favoring routine chemotherapy during gestation should continue to be questioned on several grounds: (1) the assumed difference in maternal survival accruing from chemotherapy administered earlier – i.e., during pregnancy, rather than after delivery – has not been quantified; (2) the added survival benefit of adjuvant cytotoxic therapy prescribed within the hormone-rich milieu of pregnancy remains presumptive, particularly for ER-positive disease; (3) the maternal survival benefit associated with modified adjuvant regimens (e.g., weekly schedules, omission of taxanes, etc.) has not been proven equivalent to standard (e.g., post-delivery) regimens; and (4) the long-term transplacental and transgenerational hazards of late-trimester chemotherapy are unknown.</p> <p>Summary</p> <p>Although an incrementally increased risk of cancer-specific mortality is impossible to exclude, mothers who place a high priority on the lifelong well-being of their progeny may be informed that deferring optimal chemotherapy until after delivery is still an option to consider, especially in ER-positive, node-negative and/or last-trimester disease.</p

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

BACKGROUND: Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR). Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. METHODS: We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh) to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. RESULTS: The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. CONCLUSION: These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR

New treatments addressing the pathophysiology of hereditary angioedema

Hereditary angioedema is a serious medical condition caused by a deficiency of C1-inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation

The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty

BACKGROUND: Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes. METHODS/DESIGN: The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934-1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004-2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65-70 years old subjects will be surveyed in 2009 (birth year 1939-1943) and in 2014 (birth year 1944-1948). DISCUSSION: The Lc65+ study focuses on the sequence "Determinants --&gt; Components --&gt; Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War

A supramolecular helix that disregards chirality

The functions of complex crystalline systems derived from supramolecular biological and non-biological assemblies typically emerge from homochiral programmed primary structures via first principles involving secondary, tertiary and quaternary structures. In contrast, heterochiral and racemic compounds yield disordered crystals, amorphous solids or liquids. Here, we report the self-assembly of perylene bisimide derivatives in a supramolecular helix that in turn self-organizes in columnar hexagonal crystalline domains regardless of the enantiomeric purity of the perylene bisimide. We show that both homochiral and racemic perylene bisimide compounds, including a mixture of 21 diastereomers that cannot be deracemized at the molecular level, self-organize to form single-handed helical assemblies with identical single-crystal-like order. We propose that this high crystalline order is generated via a cogwheel mechanism that disregards the chirality of the self-assembling building blocks. We anticipate that this mechanism will facilitate access to previously inaccessible complex crystalline systems from racemic and homochiral building blocks

DNA methylation and the epigenetic clock in relation to physical frailty in older people:The Lothian Birth Cohort 1936

Background: The biological mechanisms underlying frailty in older people are poorly understood. There is some evidence to suggest that DNA methylation patterns may be altered in frail individuals. Methods: Participants were 791 people aged 70 years from the Lothian Birth Cohort 1936. DNA methylation was measured in whole blood. Biological age was estimated using two measures of DNA methylation-based age acceleration - extrinsic and intrinsic epigenetic age acceleration. We carried out an epigenome-wide association study of physical frailty, as defined by the Fried phenotype. Multinomial logistic regression was used to calculate relative risk ratios for being physically frail or pre-frail according to epigenetic age acceleration. Results: There was a single significant (P=1.16x10-7) association in the epigenome-wide association study comparing frail versus not frail. The same CpG was not significant when comparing pre-frail versus not frail. Greater extrinsic epigenetic age acceleration was associated with an increased risk of being physically frail, but not of being pre-frail. For a year increase in extrinsic epigenetic age acceleration, age- and sex-adjusted relative risk ratios (95% CI) for being physically frail or pre-frail were 1.06 (1.02, 1.10) and 1.02 (1.00, 1.04) respectively. After further adjustment for smoking and chronic disease, the association with physical frailty remained significant. Intrinsic epigenetic age acceleration was not associated with physical frailty status.Conclusions: People who are biologically older, as indexed by greater extrinsic epigenetic age acceleration, are more likely to be physically frail. Future research will need to investigate whether epigenetic age acceleration plays a causal role in the onset of physical frailty

Deterministic processes structure bacterial genetic communities across an urban landscape

Land-use change is predicted to act as a driver of zoonotic disease emergence through human exposure to novel microbial diversity, but evidence for the effects of environmental change on microbial communities in vertebrates is lacking. We sample wild birds at 99 wildlife-livestock-human interfaces across Nairobi, Kenya, and use whole genome sequencing to characterise bacterial genes known to be carried on mobile genetic elements (MGEs) within avian-borne Escherichia coli (n=241). By modelling the diversity of bacterial genes encoding virulence and antimicrobial resistance (AMR) against ecological and anthropogenic forms of urban environmental change, we demonstrate that communities of avian-borne bacterial genes are shaped by the assemblage of co-existing avian, livestock and human communities, and the habitat within which they exist. In showing that non-random processes structure bacterial genetic communities in urban wildlife, these findings suggest that it should be possible to forecast the effects of urban land-use change on microbial diversity