Expanded central role of the respiratory physiotherapists in the community setting.

The development of community hubs through the Slaintecare initiative will rely on respiratory physiotherapists and clinical nurse specialists for the management of chronic respiratory diseases. The role of the respiratory physiotherapist has evolved dramatically over the last decade. We review the increasing scope of practice of the physiotherapist and the evidence base for same. We pay particular attention to the role of the physiotherapist in areas such as pulmonary rehabilitation, sputum clearance, neuromuscular disease, chronic respiratory failure, ambulatory oxygen assessments and dysfunctional breathing. We give an in depth review of sputum clearance techniques. We also address areas of potential future expansion for the role of the physiotherapist such as prescription and initiation of non-invasive ventilation.

LacOp: A free web-based lac operon simulation that enhances student learning of gene regulation concepts.

Here, we describe a free, web-based simulation of the lac operon, "LacOp," that is designed to enhance the learning of prokaryotic gene regulation and pathways in advanced high school and undergraduate genetics courses. This new electronic resource was created by a team of students in an advanced undergraduate course and is hosted online (http://flask-env.rnwhymamqf.us-west-2.elasticbeanstalk.com/lacop). LacOp has a simple web interface compatible with a range of devices, including smartphones. To determine whether the LacOp simulation enhances student learning from traditional instruction, we introduced the lac operon to undergraduate genetics students through a traditional classroom experience followed by use of the LacOp simulation. Students worked on their own using the included tutorial to create and test the effect of various genotypes on E. coli lactose metabolism and regulation. Upon completion of the tutorial, students showed measurable gains in conceptual understanding of the lac operon. These students also reported a generally favorable opinion of the LacOP simulation as a use of their instructional time.

Thrombocytosis during Stable State Predicts Mortality in Bronchiectasis.

Rationale: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored. Objectives: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes. Methods: Patients with bronchiectasis have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. The primary outcome was 5-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at 1, 2, and 3-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables. Results: Among the 1,771 patients (median age, 67 yr; 63.4% female) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significantly higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both 3-year (23 [22.8%] vs. 83 [8.5%], respectively; P < 0.01) and 5-year (26 [35.1%] vs. 116 [15.9%], respectively; P < 0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations because of severe exacerbations (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.20-2.79; P = 0.01) after 1-year follow-up, as well as increased 3-year (OR, 3.06; 95% CI, 1.74-5.39; P < 0.01) and 5-year (OR, 2.46; 95% CI, 1.39-4.37; P < 0.01) mortality. Conclusions: Platelets represent a cheap and easy-to-evaluate biomarker, and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations because of exacerbations, poor quality of life, and mortality in adults with bronchiectasis.

Is the GOLD guideline for diagnosing obstruction in COPD discriminatory in predicting severe future COPD-related exacerbations and death?

Journal club commentary on the discriminative accuracy of FEV1: FVC thresholds for COPD-related hospitalisation and mortality https://bit.ly/3BaWWY7.

Mummichog (Fundulus heteroclitus) are less sensitive to 17α-ethinylestradiol (EE2) than other common model teleosts: A comparative review of reproductive effects.

The environmental estrogen 17α-ethinylestradiol (EE2) will depress or completely inhibit egg production in many common model teleosts at low concentrations (≤0.5 ng/L; Runnalls et al., 2015). This inhibition is not seen in the estuarine killifish, or mummichog (Fundulus heteroclitus), even when exposed to 100 ng/L EE2. This relative insensitivity to EE2 exposure indicates species-specific mechanisms for compensating for exogenous estrogenic exposure. This review compares various reproductive responses elicited by EE2 in mummichog to other common model teleosts, such as zebrafish (Danio rerio) and fathead minnow (Pimephales promelas), identifying key endpoints where mummichog differ from other studied fish. For example, EE2 accumulates primarily in the liver/gall bladder of mummichog, which is different than zebrafish and fathead minnow in which accumulation is predominantly in the carcass. Despite causing species-specific differences in fecundity, EE2 has been shown to consistently induce hepatic vitellogenin in males and cause feminization/sex reversal during gonadal differentiation in larval mummichog, similar to other species. In addition, while gonadal steroidogenesis and plasma steroid levels respond to exogenous EE2, it is generally at higher concentrations than observed in other species. In mummichog, production of 17ß-estradiol (E2) by full grown ovarian follicles remains high; unlike other teleost models where E2 synthesis decreases as 17α,20ß-dihydroxy-4-prenen-3-on levels increase to induce oocyte maturation. New evidence in mummichog indicates some dissimilarity in gonadal steroidogenic gene expression responses compared to gene expression responses in zebrafish and fathead minnow exposed to EE2. The role of ovarian physiology continues to warrant investigation regarding the tolerance of mummichog to exogenous EE2 exposure. Here we present a comprehensive review, highlighting key biological differences in response to EE2 exposure between mummichog and other commonly used model teleosts.

Current therapies for gastro-oesophageal reflux in the setting of chronic lung disease: state of the art review.

The inter-relationship between chronic respiratory disease and reflux disease in the airway reflux paradigm is extremely complex and remains poorly characterised. Reflux disease is reported to cause or contribute to the severity of a number of respiratory tract diseases including laryngeal disorders, sinusitis, chronic cough, asthma, COPD, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis and bronchiolitis obliterans post lung transplant. It is now appreciated that reflux disease is not simply caused by liquid acid reflux but rather by a variety of chemical refluxates originating from the stomach and duodenum due to a number of different mechanisms. Reflux disease can be challenging to diagnose, particularly proving its role in the causation of direct respiratory epithelial damage. Significant advances in oesophageal assessment and gastric biomarkers have emerged in recent years as our understanding increases. There are a number of treatments available for reflux disease, both medical and surgical, but there is a paucity of large randomised trials to evaluate their efficacy in the setting of chronic respiratory disease. Everyday clinical practice, however, informs us that treatment failure in reflux disease is common. This clinical review summarises associations between reflux disease in the setting of chronic respiratory diseases and examines available evidence regarding potential therapeutic strategies.

Physiological effects of 5α-dihydrotestosterone in male mummichog (Fundulus heteroclitus) are dose and time dependent.

Numerous anthropogenic sources, such as pulp mill and sewage treatment effluents, contain androgenic endocrine disrupting compounds that alter the reproductive status of aquatic organisms. The current study injected adult male mummichog (Fundulus heteroclitus) with 0 (control), 1 pg/g, 1 ng/g or 1 µg/g body weight of the model androgen 5α-dihydrotestosterone (DHT) with the intent to induce a period of plasma sex hormone depression, a previously-observed effect of DHT in fish. A suite of gonadal steroidogenic genes were assessed during sex hormone depression and recovery. Fish were sampled 6, 12, 16, 18, 24, 30 and 36 h post-injection, and sections of testis tissue were either snap frozen immediately or incubated for 24 h at 18 °C to determine in vitro gonadal hormone production and then frozen. Plasma testosterone (T) and 11-ketotestosterone (11KT) were depressed beginning 24 h post-injection. At 36 h post-injection plasma T remained depressed while plasma 11KT had recovered. In snap frozen tissue there was a correlation between plasma sex hormone depression and downregulation of key steroidogenic genes including steroidogenic acute regulatory protein (star), cytochrome P450 17a1 (cyp17a1), 3ß-hydroxysteroid dehydrogenase (3ßhsd), 11ß-hydroxysteroid dehydrogenase (11ßhsd) and 17ß-hydroxysteroid dehydrogenase (17ßhsd). Similar to previous studies, 3ßhsd was the first and most responsive gene during DHT exposure. Gene responses from in vitro tissue were more variable and included the upregulation of 3ßhsd, 11ßhsd and star during the period of hormone depression. The differential expression of steroidogenic genes from the in vitro testes compared to the snap frozen tissues may be due to the lack of regulators from the hypothalamo-pituitary-gonadal axis present in whole-animal systems. Due to these findings it is recommended to use snap frozen tissue, not post-incubation tissue from in vitro analysis, for gonadal steroidogenic gene expression to more accurately reflect in vivo responses.

Bronchiectasis in India: results from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India Registry.

BACKGROUND: Bronchiectasis is a common but neglected chronic lung disease. Most epidemiological data are limited to cohorts from Europe and the USA, with few data from low-income and middle-income countries. We therefore aimed to describe the characteristics, severity of disease, microbiology, and treatment of patients with bronchiectasis in India. METHODS: The Indian bronchiectasis registry is a multicentre, prospective, observational cohort study. Adult patients (≥18 years) with CT-confirmed bronchiectasis were enrolled from 31 centres across India. Patients with bronchiectasis due to cystic fibrosis or traction bronchiectasis associated with another respiratory disorder were excluded. Data were collected at baseline (recruitment) with follow-up visits taking place once per year. Comprehensive clinical data were collected through the European Multicentre Bronchiectasis Audit and Research Collaboration registry platform. Underlying aetiology of bronchiectasis, as well as treatment and risk factors for bronchiectasis were analysed in the Indian bronchiectasis registry. Comparisons of demographics were made with published European and US registries, and quality of care was benchmarked against the 2017 European Respiratory Society guidelines. FINDINGS: From June 1, 2015, to Sept 1, 2017, 2195 patients were enrolled. Marked differences were observed between India, Europe, and the USA. Patients in India were younger (median age 56 years [IQR 41-66] vs the European and US registries; p<0·0001]) and more likely to be men (1249 [56·9%] of 2195). Previous tuberculosis (780 [35·5%] of 2195) was the most frequent underlying cause of bronchiectasis and Pseudomonas aeruginosa was the most common organism in sputum culture (301 [13·7%]) in India. Risk factors for exacerbations included being of the male sex (adjusted incidence rate ratio 1·17, 95% CI 1·03-1·32; p=0·015), P aeruginosa infection (1·29, 1·10-1·50; p=0·001), a history of pulmonary tuberculosis (1·20, 1·07-1·34; p=0·002), modified Medical Research Council Dyspnoea score (1·32, 1·25-1·39; p<0·0001), daily sputum production (1·16, 1·03-1·30; p=0·013), and radiological severity of disease (1·03, 1·01-1·04; p<0·0001). Low adherence to guideline-recommended care was observed; only 388 patients were tested for allergic bronchopulmonary aspergillosis and 82 patients had been tested for immunoglobulins. INTERPRETATION: Patients with bronchiectasis in India have more severe disease and have distinct characteristics from those reported in other countries. This study provides a benchmark to improve quality of care for patients with bronchiectasis in India. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society, and the British Lung Foundation.

Bendopnoea in exercise limited patients with COPD.

Dyspnoea on bending over (bendopnoea) is most commonly associated with systolic heart failure. COPD patients often also complain of bendopnoea but little is known about this symptom in this patient group. We objectively assessed 44 COPD patients attending pulmonary rehabilitation for bendopnoea in a tertiary referral centre to determine the potential mechanism and clinical implications of this symptom. Bendopnoea was assessed by timing the duration of onset to breathlessness on bending forward at the waist for 30 s. BORG score, oxygen saturations and blood pressure measurements were obtained before and after. Of 44 patients (mean age±SD 66.7 ±â€¯8.4 years; 22 male, BMI 28.1 ±â€¯6.4), bendopnoea was present in 23 (52.3%) patients. This was significantly associated with a lower FEV1% (p = 0.02) and TLCO% (<0.001) and higher CAT score (p = 0.03). A strong trend was also noted with higher waist/hip ratio (p = 0.06). There were no associations with age, BMI, oxygen saturation, static lung volumes, exercise capacity or non-invasive haemodynamic markers such as pro-BNP, physiological changes or echocardiography findings.

Comparison of steroidogenic gene expression in mummichog (Fundulus heteroclitus) testis tissue following exposure to aromatizable or non-aromatizable androgens.

Androgens are a recognized class of endocrine disrupting compounds with the ability to impact reproductive status in aquatic organisms. The current study utilized in vitro exposure of mummichog (Fundulus heteroclitus) testis tissue to either the aromatizable androgen 17α-methyltestosterone (MT) or the non-aromatizable androgen 5α-dihydrotestosterone (DHT) over the course of 24 h to determine if there were differential effects on steroidogenic gene expression. Testis tissue was exposed to androgen concentrations of 10-12 M, 10-9 M and 10-6 M for 6, 12, 18 or 24 h, after which a suite of steroidogenic genes, including steroidogenic acute regulatory protein, 3ß-hydroxysteroid dehydrogenase (3ßhsd) and cytochrome P450 17A1 (cyp17a1), were quantified using real-time polymerase chain reaction. Both androgens affected steroidogenic gene expression, with most alterations occurring at the 24-hour time point. The gene with the highest fold-change, and shortest interval to expression alteration, was 3ßhsd for both androgens. Potential differences between the two model androgens were observed in increased expression of cyp17a1 and 11ß-hydroxysteroid dehydrogenase (11ßhsd), which were only altered after exposure to DHT and in expression levels of cytochrome P450 11A1 (cyp11a1), which was upregulated by MT but not altered by DHT. Results from this study show both androgens interact at the gonadal level of the hypothalamus-pituitary-gonadal axis and may possess some distinct gene expression impacts. These data strengthen the current research initiatives of establishing in vitro test systems that allow toxic potential of untested chemicals to be predicted from molecular perturbations.

Characterization of the "Frequent Exacerbator Phenotype" in Bronchiectasis.

RATIONALE: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. OBJECTIVES: To establish if there is a "frequent exacerbator phenotype" in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. METHODS: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. MEASUREMENTS AND MAIN RESULTS: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype. The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P < 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P < 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P < 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during follow-up. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. CONCLUSIONS: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up.

Patterns of Disease in Patients with Middle-Lobe Predominant Bronchiectasis.

BACKGROUND: Middle-lobe predominant bronchiectasis affecting the right middle-lobe and/or lingula (RMLP) is classically described in asthenic, elderly females with skeletal abnormalities or associated nontuberculous mycobacterial (NTM) infection. OBJECTIVES: We aimed to evaluate the frequency and clinical characteristics of patients with an RMLP phenotype in a cohort of newly diagnosed bronchiectasis patients and determine associations with disease severity. METHODS: A retrospective observational cross-sectional cohort study of consecutive bronchiectasis patients in our institution was performed. Data were collected on baseline variables, microbiology status, lung function, and radiology according to the modified Bhalla score. Disease severity was assessed using bronchiectasis severity index (BSI) and FACED severity scores. RESULTS: Of 81 patients (mean age [SD] 62.6 [12.4], females 55 [67.9%], BMI 26.9 [5.7%]), 20 (24.7%) had RMLP disease. These patients were significantly younger, female, and with lower BMIs than patients with the classical bronchiectasis phenotype (p = 0.03, 0.01, and p <0.01, respectively). Fewer symptoms of cough and daily sputum (p = 0.01 and <0.01), prior exacerbation frequency (p = 0.03), and higher baseline forced expiratory volume (p = 0.04) were noted. A higher incidence of NTM at diagnosis was demonstrated (p = 0.01). BSI and FACED severity scores in RMLP patients were significantly lower than their counterparts (both p < 0.001). CONCLUSIONS: The RMLP phenotype is associated with younger patients than classically described in the literature. An increased rate of NTM infection in this phenotype was noted, particularly in females, but much lower than previously described. Lung function and disease severity scores in this patient group are relatively normal, suggesting a milder phenotype in patients with this form of the disease.

Bronchiectasis Rheumatoid Overlap Syndrome Is an Independent Risk Factor for Mortality in Patients With Bronchiectasis: A Multicenter Cohort Study.

BACKGROUND: This study assessed if bronchiectasis (BR) and rheumatoid arthritis (RA), when manifesting as an overlap syndrome (BROS), were associated with worse outcomes than other BR etiologies applying the Bronchiectasis Severity Index (BSI). METHODS: Data were collected from the BSI databases of 1,716 adult patients with BR across six centers: Edinburgh, United Kingdom (608 patients); Dundee, United Kingdom (n = 286); Leuven, Belgium (n = 253); Monza, Italy (n = 201); Galway, Ireland (n = 242); and Newcastle, United Kingdom (n = 126). Patients were categorized as having BROS (those with RA and BR without interstitial lung disease), idiopathic BR, bronchiectasis-COPD overlap syndrome (BCOS), and "other" BR etiologies. Mortality rates, hospitalization, and exacerbation frequency were recorded. RESULTS: A total of 147 patients with BROS (8.5% of the cohort) were identified. There was a statistically significant relationship between BROS and mortality, although this relationship was not associated with higher rates of BR exacerbations or BR-related hospitalizations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with other causes of BR, 18% for RA, and 28.5% for BCOS. Mortality was statistically higher in patients with BROS and BCOS compared with those with all other etiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS compared with those with idiopathic BR (BSI mean, 7.7 vs 7.1, respectively; P < .05). Patients with BCOS had significantly higher BSI scores (mean, 10.4), Pseudomonas aeruginosa colonization rates (24%), and previous hospitalization rates (58%). CONCLUSIONS: Both the BROS and BCOS groups have an excess of mortality. The mechanisms for this finding may be complex, but these data emphasize that these subgroups require additional study to understand this excess mortality.

Comorbidities and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study.

BACKGROUND: Patients with bronchiectasis often have concurrent comorbidities, but the nature, prevalence, and impact of these comorbidities on disease severity and outcome are poorly understood. We aimed to investigate comorbidities in patients with bronchiectasis and establish their prognostic value on disease severity and mortality rate. METHODS: An international multicentre cohort analysis of outpatients with bronchiectasis from four European centres followed up for 5 years was done for score derivation. Eligible patients were those with bronchiectasis confirmed by high-resolution CT and a compatible clinical history. Comorbidity diagnoses were based on standardised definitions and were obtained from full review of paper and electronic medical records, prescriptions, and investigator definitions. Weibull parametric survival analysis was used to model the prediction of the 5 year mortality rate to construct the Bronchiectasis Aetiology Comorbidity Index (BACI). We tested the BACI as a predictor of outcomes and explored whether the BACI added further prognostic information when used alongside the Bronchiectasis Severity Index (BSI). The BACI was validated in two independent international cohorts from the UK and Serbia. FINDINGS: Between June 1, 2006, and Nov 22, 2013, 1340 patients with bronchiectasis were screened and 986 patients were analysed. Patients had a median of four comorbidities (IQR 2-6; range 0-20). 13 comorbidities independently predicting mortality rate were integrated into the BACI. The overall hazard ratio for death conferred by a one-point increase in the BACI was 1·18 (95% CI 1·14-1·23; p<0·0001). The BACI predicted 5 year mortality rate, hospital admissions, exacerbations, and health-related quality of life across all BSI risk strata (p<0·0001 for mortality and hospital admissions, p=0·03 for exacerbations, p=0·0008 for quality of life). When used in conjunction with the BSI, the combined model was superior to either model alone (p=0·01 for combined vs BACI; p=0·008 for combined vs BSI). INTERPRETATION: Multimorbidity is frequent in bronchiectasis and can negatively affect survival. The BACI complements the BSI in the assessment and prediction of mortality and disease outcomes in patients with bronchiectasis. FUNDING: European Bronchiectasis Network (EMBARC).