Cohort study of sleep quality in adult patients with acute pulmonary exacerbations of cystic fibrosis.

BACKGROUND: The impact of an acute pulmonary exacerbation of cystic fibrosis (CF) on sleep quality has not been established. Patients have greater burden of symptoms, higher intensity of therapy and are often admitted to hospital outside of their usual sleeping environment. AIMS: To evaluate the prevalence of, and factors associated with, poor sleep quality in adult patients admitted to hospital with an acute exacerbation of CF lung disease. METHODS: This prospective, observational study determined the prevalence of impaired sleep quality and associated factors in adult patients admitted to a single CF unit with an acute pulmonary exacerbation of CF. Sleep quality was defined by the Pittsburgh Sleep Quality Index (PSQI), with >5 indicating poor sleep quality. Data were obtained through patient questionnaires, chart review and examination. RESULTS: Sixty-six percent of patients had impaired sleep quality. Patients with poor sleep had more sleep disruption due to pain (median response 'mild sleep disruption' vs 'no sleep disruption'; P = 0.003) and insomnia (mean Insomnia Severity Index (ISI) 13 vs 5; P < 0.001). In patients with symptoms of restless legs, poor sleepers had worse symptoms (mean International Restless Legs Severity Score (IRLSS) 15 vs 5; P = 0.029). Univariate modelling showed relationships between PSQI and symptoms of depression and anxiety as well as with sleep disruption due to pain, general noise and nursing observations. In a multivariable model, ISI was the only variable that remained significantly associated with PSQI. Mean PSQI score increased 0.58 units for each 1 unit increase in ISI (95% CI 0.42-0.73; P < 0.001). CONCLUSIONS: Poor sleep quality is common among patients admitted with an acute exacerbation of CF and is strongly associated with insomnia symptoms in this cohort.

Current infection control practices used in Australian and New Zealand cystic fibrosis centers.

BACKGROUND: The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. We aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers. METHODS: Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists. RESULTS: The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room. CONCLUSIONS: Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.

Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy.

BACKGROUND: The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS: From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS: A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test). CONCLUSIONS: In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.).

The impact of front-of-pack nutrition labels on consumer product evaluation and choice: an experimental study.

OBJECTIVE: The present research was an experimental test that aimed to quantify the impact of two dominant front-of-pack (FOP) nutritional label formats on consumer evaluations of food products that carried them. The two FOP label types tested were the traffic light label and the Percentage Daily Intake. DESIGN: A 4×5 partially replicated Latin square design was used that allowed the impact of the FOP labels to be isolated from the effects of the product and the consumers who were performing the evaluations. SETTING: The experiment was conducted on campus at the University of Otago, New Zealand. SUBJECTS: The participants were 250 university students selected at random who met qualifying criteria of independent living and regular purchase of the products used in the research. They were not aware of the purpose of the research. RESULTS: The presence of FOP labels led to significant and positive changes in consumer purchase intentions towards the products that carried them. These changes were not affected by the nature of FOP labels used, their size or the product nutritional status (good/bad) that they were reporting. CONCLUSIONS: The result is consistent with the participants paying attention to the FOP label and then using it as an adimensional cue indicating product desirability. As such, it represents a complete functional failure of both of these FOP label types in this specific instance. This result supports calls for further research on the performance of these FOP labels before any move to compulsory deployment is made.

Human monocyte subsets at homeostasis and their perturbation in numbers and function in filarial infection.

To characterize the function and plasticity of the major human circulating monocyte populations and to explore their role in systemic helminth infection, highly purified (by flow-based sorting) human monocyte subsets (CD14(hi)/CD16(neg) [classical], CD14(+ or hi)/CD16(med) [intermediate], and CD14(neg)/CD16(hi) [nonclassical]) were examined at homeostasis and after activation. Among these three subsets the classical and intermediate subsets were found to be the major sources of inflammatory and regulatory cytokines, as well as cytokines/chemokines associated with alternative activation, whereas the nonclassical and classical populations demonstrated an ability to transmigrate through endothelial monolayers. Moreover, it was primarily the classical subset that was the most efficient in promoting autologous T cell proliferation. The distribution of these subsets changed in the context of a systemic helminth (Wuchereria bancrofti) infection such that patent infection altered the frequency and distribution of these monocyte subsets with the nonclassical monocytes being expanded (almost 2-fold) in filarial infection. To understand further the filarial/monocyte interface, in vitro modeling demonstrated that the classical subset internalized filarial antigens more efficiently than the other two subsets but that the parasite-driven regulatory cytokine interleukin-10 was exclusively coming from the intermediate subset. Our data suggest that monocyte subsets have a differential function at homeostasis and in response to helminth parasites.

A national survey of memory clinics in the Republic of Ireland.

BACKGROUND: This national survey investigates the location, resourcing, staff composition, treatments, waiting time, and numbers of patients attending memory clinics (MCs) in the Republic of Ireland. It also explores Directors' attitudes to future service development including their views about the advantages and disadvantages of quality standards for MCs. METHODS: An audio-taped telephone interview was conducted with the Directors. RESULTS: A total of 14 MCs were identified across the Republic of Ireland, ten of which are hospital-based and most of which offer diagnostic services and are located in Dublin. Nine MCs are medical consultant led and operate under the direction of either Old Age Psychiatrists or Geriatricians. Results show wide variation regarding the location, team size, service availability, and numbers of patients attending. The average number of patients attending in 2011 was 126. Only six clinics employ dedicated Allied Health Professionals. Less than half of the clinics are research active. Whilst most Directors welcomed the availability of national standards, several expressed concern that standards might, in the absence of funding, result in the closure of the most poorly resourced services. CONCLUSIONS: This survey provides valuable data on the main characteristics of all of the 14 MCs delivering services in the Republic of Ireland and raises critical and fundamental questions about the goals and outcomes of MC services. The survey data collected can be used by other countries for cross-national comparison.

Clinical and radiological improvement of cavitary Mycobacteroides abscessus disease in cystic fibrosis following initiation of elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a CFTR modulator therapy that has dramatically improved the health outcomes for many people with cystic fibrosis (pwCF). There is increasing interest in the role of CFTR modulators in the prevention and treatment of respiratory infections in pwCF. A male patient with F508del homozygous cystic fibrosis developed cavitary Mycobacteroides abscessus subspecies bolletii & massiliense respiratory infection. Antimycobacterial treatment was not given as, in discussion with the patient's family, it was deemed unlikely that the intensive regimen would be tolerated by the patient on account of his autism spectrum disorder. Following initiation of ETI, there was a rapid clinical and radiological improvement in this patient's cavitary lung disease. This case adds to the evidence base that suggests CFTR modulators, particularly ETI, may restore innate immune function leading to improved outcomes for pulmonary infection in pwCF.

Phenotypic Evaluation of Rare Cystic Fibrosis Transmembrane Conductance Regulator Mutation Combinations in People with Cystic Fibrosis in Queensland, Australia.

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with 'rare' CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have 'rare' CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority.

Vascular Diseases in Women: Do Women Suffer from Them Differently?

According to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death among women worldwide, yet its magnitude is often underestimated. Biological and gender differences affect health, diagnosis, and healthcare in numerous ways. The lack of sex and gender awareness in health research and healthcare is an ongoing issue that affects not only research but also treatment and outcomes. The importance of recognizing the impacts of both sex and gender on health and of knowing the differences between the two in healthcare is beginning to gain ground. There is more appreciation of the roles that biological differences (sex) and sociocultural power structures (gender) have, and both sex and gender affect health behavior, the development of diseases, their diagnosis, management, and the long-term effects of an illness. An important issue is the knowledge and awareness of women about vascular diseases. The risk of cardiovascular events is drastically underestimated by women themselves, as well as by those around them. The purpose of this review is to draw attention to improving the medical care and treatment of women with vascular diseases.

Diagnosis and disclosure of dementia--a comparative qualitative study of Irish and Swedish General Practitioners.

OBJECTIVES: To explore the attitudes of Irish and Swedish General Practitioners (GPs) to the diagnosis and disclosure of dementia to patients; to investigate GP under-graduate/post-graduate training in dementia; to examine the post-diagnostic support services available to GPs in both countries and to investigate the extent to which dementia is perceived as stigmatising. METHODS: A cross-national exploratory qualitative design was used. In-depth interviews were conducted with five Irish and four Swedish GPs. Interviews were transcribed, translated, thematically coded and categorised. RESULTS: Both Irish and Swedish GPs unequivocally considered the early diagnosis of dementia important but neither group was proactive in making a diagnosis. Both groups relied heavily on family members or patients to bring to their attention memory loss and cognitive impairment problems. Most GPs reported a reluctance to diagnose and several acknowledged going to considerable lengths to avoid using the word 'dementia'. The Swedish GPs had more exposure to dementia-specific training, saw the value in training and were generally very satisfied with post-diagnostic dementia services available to patients, while Irish GPs were less likely to have undergone training, were more equivocal about its value and were very dissatisfied with the community services available. CONCLUSION: Despite the presence of very adequate post-diagnostic support services for people recently diagnosed with dementia, the majority of Swedish GPs like their Irish counterparts displayed therapeutic nihilism and were reluctant to speak overtly to their patients about their dementia. Dementia continues to be a stigmatising illness for both Irish and Swedish GPs.

Care Delivery Interventions for Individuals with Cancer: A Literature Review and Focus on Gastrointestinal Malignancies.

BACKGROUND: Gastrointestinal malignancies represent a particularly challenging condition, often requiring a multidisciplinary approach to management in order to meet the unique needs of these individuals and their caregivers. PURPOSE: In this literature review, we sought to describe care delivery interventions that strive to improve the quality of life and care for patients with a focus on gastrointestinal malignancies. CONCLUSION: We highlight patient-centered care delivery interventions, including patient-reported outcomes, hospital-at-home interventions, and other models of care for individuals with cancer. By demonstrating the relevance and utility of these different care models for patients with gastrointestinal malignancies, we hope to highlight the importance of developing and testing new interventions to address the unique needs of this population.

Functional and phenotypic characteristics of alternative activation induced in human monocytes by interleukin-4 or the parasitic nematode Brugia malayi.

Human monocytes from patients with patent filarial infections are studded with filarial antigen and express markers associated with alternative activation of macrophages (MΦ). To explore the role of filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microfilariae (mf) of Brugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 [IL-4]) or classically (macrophage colony-stimulating factor [MCSF]) activated MΦ. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦ but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4(+) and CD8(+) T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. In contrast to results with MCSF-cultured monocytes, exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted filarial products skew monocytes similarly.

The month of July: an early experience with pandemic influenza A (H1N1) in adults with cystic fibrosis.

BACKGROUND: Pandemic Influenza A (H1N1) 2009 is a novel viral infection that emerged in March 2009. This is the first report addressing the clinical course of patients with cystic fibrosis (CF) and H1N1 infection. METHODS: All patients with an influenza-like illness (ILI) attending our adult centre during July 2009 were identified. Baseline respiratory function, nutritional status, approach to management and short-term clinical course were recorded. RESULTS: Most patients experienced a mild course and were able to be managed with antiviral agents as an outpatient. Robust infection control policies were implemented to limit transmission of H1N1 infection within our CF centre. Patients with severe lung disease, poor baseline nutritional reserve and presenting with more than 48 hours of ILI experienced a more severe course. Prompt antiviral therapy within the first 48 hours of illness may have been important in improving outcomes. CONCLUSIONS: This observational study demonstrates that most adults with CF with H1N1 infection had mild clinical courses and recovered rapidly.

The gastrointestinal microbiota as a site for the biotransformation of drugs.

There are 100 trillion microbes in the human gastrointestinal tract with numbers increasing distally. These microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation. Thus, the objective of this review is the provision of a comprehensive overview of this area; the gastrointestinal microbiota, their drug substrates and metabolic mechanisms, and approaches to studying this further are discussed.

Lack of difference in pulmonary absorption of digoxin, a P-glycoprotein substrate, in mdr1a-deficient and mdr1a-competent mice.

Although in-vitro experiments have suggested that P-glycoprotein (P-gp) may have an important influence on the disposition of inhaled drugs, the effect of P-gp on absorption from the lung in-vivo has not been reported previously. The aim of this study was to compare the pulmonary absorption of digoxin, a well-characterised substrate for P-gp, in mdr1a (-/-) (P-gp-deficient) and mdr1a (+/+) (P-gp-competent) mice. Digoxin was administered by intratracheal instillation over 3-4 s, a method demonstrated to result in dispersion of the dose to all regions of the lung. Drug distribution was determined in the lungs, plasma, brain, heart, liver and kidney of individual mice after 5, 10, 30, 60 and 90 min. Digoxin was cleared rapidly from the lung after intratracheal administration. No differences were observed in the maximum serum concentrations between mdr1a (+/+) and mdr1a (-/-) mice (37.8 +/- 6.9 and 38.8 +/- 15.8 ng mL(-1), respectively). The serum concentration versus time profiles were similar in both strains; the area under the drug serum concentration versus time curve (AUC) was 2010 and 1812 ng mL(-1) min in mdr1a (-/-) and mdr1a (+/+) mice, respectively. For organs harvested at the end of the experiment (90 min), the only significant difference between the strains was the markedly elevated concentration of digoxin in the brains of mdr1a (-/-) mice. In conclusion, digoxin is rapidly absorbed from the mouse lung following tracheal instillation, with no difference in the rate or extent of absorption between mdr1a-deficient and -competent mice. This suggests that, in contrast to the scenario suggested by in-vitro data, P-gp in the respiratory epithelium may have little influence on the disposition of drugs that are well absorbed from the lung.

High permeability of the anionic form restricts accumulation of indomethacin by cultured gastric surface epithelial cells exposed to low apical pH.

The 'ion-trapping' hypothesis suggests that the intracellular concentration of acidic non-steroidal anti-inflammatory drugs in gastric epithelial cells could be much higher than in the gastric lumen, and that such accumulation could contribute to their gastrotoxicity. Our aim was to examine the effect of the pH of the apical medium on the apical to basal transfer of the acidic drug indomethacin (pKa 4.5) across a gastric mucous epithelial cell monolayer, and to determine whether indomethacin accumulated in cells exposed to a low apical pH. Guinea-pig gastric mucous epithelial cells were grown on porous membrane culture inserts (Transwells) for 72 h. Transfer and accumulation of [14C] indomethacin were assessed by scintillation counting. Transfer of [3H]mannitol and measurement of trans-epithelial electrical resistance were used to assess integrity of the monolayer. Distribution of [14C] urea was used to estimate the intracellular volume of the monolayer. The monolayer was not disrupted by exposure of the apical face to media of pH>or=3, or by indomethacin. Transfer of indomethacin (12 microM) to the basal medium increased with decreasing apical medium pH. The apparent permeability of the undissociated acid was estimated to be five times that of the anion. The intracellular concentration of indomethacin was respectively 5.3, 4.1 and 4.3 times that in the apical medium at pH 5.5, 4.5 and 3.0. In conclusion, this study represents the first direct demonstration that indomethacin accumulates in gastric epithelial cells exposed to low apical pH. However, accumulation of indomethacin was moderate and the predictions of the ion-trapping hypothesis were not met, probably due to the substantial permeability of anionic indomethacin across membranes.

A collagen IV matrix is required for guinea pig gastric epithelial cell monolayers to provide an optimal model of the stomach surface for biopharmaceutical screening.

The surface epithelial cells of the stomach represent a major component of the gastric barrier. A cell culture model of the gastric epithelial cell surface would prove useful for biopharmaceutical screening of new chemical entities and dosage forms. Primary cultures of guinea pig gastric mucous epithelial cells were grown on filter inserts (Transwells) for 3 days. Tight-junction formation, assessed by transepithelial electrical resistance (TEER) and permeability of mannitol and fluorescein, was enhanced when collagen IV rather than collagen I was used to coat the polycarbonate filter. TEER for cells grown on collagen IV was close to that obtained with intact guinea pig gastric epithelium in vitro. Differentiation was assessed by incorporation of [3H]glucosamine into glycoprotein and by activity of NADPH oxidase, which produces superoxide. Both of these measures were greater for cells grown on filters coated with collagen I than for cells grown on plastic culture plates, but no major difference was found between cells grown on collagens I and IV. The proportion of cells, which stained positively for mucin with periodic acid Schiff reagent, was greater than 95% for all culture conditions. Monolayers grown on membranes coated with collagen IV exhibited apically polarized secretion of mucin and superoxide, and were resistant to acidification of the apical medium to pH 3.0 for 30 min. A screen of nonsteroidal anti-inflammatory drugs revealed a novel effect of diclofenac and niflumic acid in reversibly reducing permeability by the paracellular route. In conclusion, the mucous cell preparation grown on collagen IV represents a good model of the gastric surface epithelium suitable for screening procedures.

Antibiotic exposure does not influence MRP2 functional expression in Caco-2 cells.

Multidrug resistance-associated protein 2 (MRP2) is associated with active drug efflux and may influence oral bioavailability of common classes of drugs. MRP2 expression demonstrates plasticity. Caco-2 cells, a routine in vitro model for predicting oral bioavailability, are often cultured in media containing antibiotics. We have investigated whether exposure of Caco-2 cells to two common antibiotic regimes alters MRP2 functional expression. Caco-2 cells were grown in the presence or absence of either gentamicin or penicillin-streptomycin for up to 9 weeks. MRP2 functional activity was assessed by calcein efflux across the apical membrane. MRP2 protein expression was determined by immunoblots. Neither antibiotic regime resulted in consistent changes in calcein efflux across the apical membrane (reflecting MRP2 activity) or basolateral membrane (reflecting MRP3 and possibly MRP6 activity) of Caco-2 cells. MRP2 protein expression also showed no change in response to antibiotic exposure. Routine exposure of Caco-2 cells to penicillin-streptomycin or gentamicin does not affect apical MRP2 functional activity in intestinal enterocytic Caco-2 cells. Extrapolating these results to the situation in vivo suggests that the oral bioavailability of MRP substrates is not predicted to be influenced by recent courses of antibiotics.