Definition of diaphragmatic sleep disordered breathing and clinical meaning in Duchenne muscular dystrophy.

BACKGROUND: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD. METHODS: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI. RESULTS: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05). CONCLUSIONS: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned.

The impact of immunity on the risk of coronary artery disease: insights from a multiomics study.

BACKGROUND: Immune inflammation is intricately associated with coronary artery disease (CAD) progression, necessitating the pursuit of more efficacious therapeutic strategies. This study aimed to uncover potential therapeutic targets for CAD and myocardial infarction (MI) by elucidating the causal connection between regulatory immune-related genes (RIRGs) and these disorders. METHODOLOGY: We performed summary data-based Mendelian randomization analysis to assess the therapeutic targets linked to expression quantitative trait loci and methylation quantitative trait loci of RIRGs in relation to CAD and MI. Independent validation cohorts and datasets from coronary artery and left ventricular heart tissue were analyzed. To strengthen causal inference, colocalization analysis and PhenoScanner phenotype scans were employed. RESULTS: Utilizing multiomics integration, we pinpointed EIF2B2, FCHO1, and DDT as CAD risk genes. Notably, EIF2B2 and FCHO1 displayed significant associations with MI. High EIF2B2 expression, regulated by cg16144293, heightened CAD and MI risk at rs175438. In contrast, enhanced FCHO1 expression, modulated by cg18329931, reduced CAD and MI risk at rs13382133. DDT upregulation influenced by cg11060661 and cg09664220 was associated with decreased CAD risk at rs5760120. Colocalization analysis firmly established these relationships. CONCLUSION: EIF2B2, FCHO1, and DDT represent risk loci for CAD progression within RIRGs. Our identification of these genes enhances understanding of CAD pathogenesis and directs future drug development efforts.

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study.

INTRODUCTION: Observational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function. METHODS: We obtained genetic instruments for forced expiratory volume in 1 s (FEV1: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation. RESULTS: FEV1 and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV1 and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV10.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation. CONCLUSION: Higher lung function likely protect against CAD and stroke.

State of the art review: from the seaside to the bedside: insights from comparative diving physiology into respiratory, sleep and critical care.

Anatomical and physiological adaptations of animals to extreme environments provide insight into basic physiological principles and potential therapies for human disease. In that regard, the diving physiology of marine mammals and seabirds is especially relevant to pulmonary and cardiovascular function, and to the pathology and potential treatment of patients with hypoxaemia and/or ischaemia. This review highlights past and recent progress in the field of comparative diving physiology with emphasis on its potential relevance to human medicine.

Growth differentiation factor-15 as a biomarker of strength and recovery in survivors of acute respiratory failure.

Muscle mitochondrial dysfunction is implicated in intensive care unit-acquired weakness, but there is no serum biomarker of muscle mitochondrial function for critical illness survivors. Higher serum growth differentiation factor-15 (GDF-15) is a biomarker of inherited mitochondrial myopathy disease and is associated with mortality in several age-related diseases. Among 142 older (age ≥ 65 years) survivors of acute respiratory failure, we found that higher serum GDF-15 measured during the week prior to hospital discharge was cross-sectionally associated with weaker diaphragm, limb and hand-grip strength, and longitudinally associated with lower rates of functional recovery over 6 months, independent of age, sex, pre-existing disability, comorbidity, frailty, Acute Physiology and Chronic Health Evaluation II scores and concurrent interleukin-6 levels.

Environmental exposures and systemic hypertension are risk factors for decline in lung function.

BACKGROUND: Chronic lung disease is a leading contributor to the global disease burden; however, beyond tobacco smoke, we do not fully understand what risk factors contribute to lung function decline in low-income and middle-income countries. METHODS: We collected sociodemographic and clinical data in a randomly selected, age-stratified, sex-stratified and site-stratified population-based sample of 3048 adults aged ≥35 years from four resource-poor settings in Peru. We assessed baseline and annual pre-bronchodilator and post-bronchodilator lung function over 3 years. We used linear mixed-effects models to assess biological, socioeconomic and environmental risk factors associated with accelerated lung function decline. RESULTS: Mean±SD enrolment age was 55.4±12.5 years, 49.2% were male and mean follow-up time was 2.36 (SD 0.61) years. Mean annual pre-bronchodilator FEV1 decline was 30.3 mL/year (95% CI 28.6 to 32.0) and pre-bronchodilator FVC decline was 32.2 mL/year (30.0 to 34.4). Using multivariable linear mixed-effects regression, we found that urban living, high-altitude dwelling and having hypertension accounted for 25.9% (95% CI 15.7% to 36.1%), 21.3% (11.1% to 31.5%) and 15.7% (3.7% to 26.9%) of the overall mean annual decline in pre-bronchodilator FEV1/height2, respectively. Corresponding estimates for pre-bronchodilator FVC/height2 were 42.1% (95% CI% 29.8% to 54.4%), 36.0% (23.7% to 48.2%) and 15.8% (2.6% to 28.9%) of the overall mean annual decline, respectively. CONCLUSION: Urbanisation, living at high altitude and hypertension were associated with accelerated lung function decline in a population with low daily smoking prevalence.

Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants.

RATIONALE: Asthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting ß-agonists. OBJECTIVES: In search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements. METHODS: Forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy - Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns. MEASUREMENTS AND MAIN RESULTS: In the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the 17q21 locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma. CONCLUSIONS: Our method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the 17q21 locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach.

The prevalence extent of Complementary and Alternative Medicine (CAM) use among Saudis.

Introduction: There is worldwide interest in the use of CAM. Studying CAM in Saudi population is important as it will reflect the influence of psychosocial, cultural and religious factors on health beliefs and behaviors. The objective of this study was to present an updated review on the use of CAM practices in Saudi Arabia including commonly used types, common conditions for which it has been used and who uses CAM. Methods: This review used data from national surveys conducted in Saudi Arabia and published between 2000 and 2015. The literature search was performed considering standards adopted such as Moose guidelines for observational studies. Two authors independently reviewed each article. The search yielded 73 articles, and a total of 36 articles were included. Further careful data extraction was carried out by two independents reviewers. Results: Most of the reviewed studies were cross-sectional in design and were published between 2014 and 2015, and mostly in Riyadh region. Substantial difference in the findings for the patterns of CAM use was revealed. The most commonly employed practice was of spiritual type such as prayer and reciting Quran alone or on water. Other types include herbs (8-76%), honey (14-73%) and dietary products (6-82%). Cupping (Alhijamah) was least used (4-45%). Acupuncture was more practiced among professionals. Conclusion: The utilization of CAM is widely practiced in Saudi Arabia. There is need for efforts to promote research in the field of CAM to address each practice individually. Population surveys should be encouraged supported by mass media to raise knowledge and awareness about the practice of different CAM modalities. The national center of CAM should play a major role in these efforts.

Review of the British Thoracic Society Winter Meeting 2014, 3-5 December, London, UK.

The British Thoracic Society Winter Meeting 2014 is reviewed in this article. This annual scientific meeting attracted its largest number of delegates ever and over 3 days in December up-to-date respiratory research was presented and current thinking in respiratory science and clinical academia was discussed. This article reviews a number of symposia and selected abstract presentations from the meeting.

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

RATIONALE: The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs. OBJECTIVES: To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro. METHODS: In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined. MEASUREMENTS AND MAIN RESULTS: Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-ß (TGF-ß) responses in C2C12 cells, suggesting increased sensitivity to TGF-ß in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle. CONCLUSIONS: GDF-15 may increase sensitivity to TGF-ß signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

Fractionated stereotactic radiotherapy plus bevacizumab after response to bevacizumab plus irinotecan as a rescue treatment for high-grade gliomas.

AIM: To evaluate the possibility of implementing a new scheme of rescue treatment after relapse or progression of high-grade glioma (HGG) treated at the first-line with bevacizumab and irinotecan (BVZ+CPT11), evaluating the response and toxicity of associating BVZ and fractionated stereotactic radiotherapy (BVZ+FSRT). MATERIALS AND METHODS: We retrospectively analysed data from 59 patients with relapse of HGG. Nine patients with HGG relapse after treatment using the Stupp protocol that were treated with BVZ+CPT11 for progression between July 2007 and August 2012, after which the response was assessed according to the Revised Assessment in Neuro-Oncology (RANO) criteria. BVZ was administered at a dose of 10 mg/kg and FSRT up to a prescribed dose of 30 Gy, 500 cGy per fraction, three days a week. The median follow-up was 38 months. RESULTS: The treatment was well-tolerated by all patients. The response after nuclear magnetic resonance imaging (MRI) at 3-6 months was progression in two patients, stable disease in four, and three patients had a partial response. The median overall survival (OS) from diagnosis until death or the last control was 36.8 months. The median progression-free survival (PFS) was 10.8 months. The results from tumour sub-group analysis indicated that the PFS was not statistically significant although it seemed that it was higher in grade-III. The OS was higher in grade-III gliomas. CONCLUSIONS: The combination of BVZ+FSRT as a second-line HGG relapse rescue treatment is well-tolerated and seems to offer promising results. We believe that multi-centre prospective studies are needed to determine the long-term efficacy and toxicity of this therapeutic approach.

A cluster of lung injury cases associated with home humidifier use: an epidemiological investigation.

BACKGROUND: In April 2011 a tertiary hospital in Seoul, Korea reported several cases of severe respiratory distress of unknown origin in young adults. METHODS: To find the route of transmission, causative agent and patient risk factors of the outbreak, an investigation of the epidemic was initiated. Clinicopathological conferences led to the suspicion that the cases related to an inhalation injury. An age- and sex-matched case-control study was therefore performed to examine the inhalation exposure of the patients to various agents. RESULTS: Of the 28 confirmed cases, 18 agreed to participate. A total of 121 age- and sex-matched controls with pulmonary, allergic or obstetric disease were selected. All patients and controls completed questionnaires with questions about exposure to various inhalants. The crude ORs for patient exposure to indoor mould, humidifier use, humidifier detergent use and insecticide use were 4.4 (95% CI 1.5 to 13.1), 13.7 (95% CI 1.8 to 106.3), 47.3 (95% CI 6.1 to 369.7) and 3.9 (95% CI 1.3 to 11.7), respectively. However, when considered concurrently, indoor mould and insecticide use lost statistical significance. Moreover, humidifier use was ruled out as the cause because of a lack of biological plausibility and the weak strength of the association. This suggested that humidifier disinfectant was the cause of the outbreak. This information led the Korean government to order the removal of humidifier detergents from the market. In the years following the ban, no additional cases were detected. CONCLUSIONS: Epidemiological evidence strongly suggests that the lung injury outbreak was caused by humidifier detergent use at home.

The exposome: a new paradigm to study the impact of environment on health.

Environmental factors, here taken to include pollutants, lifestyle factors and behaviours, can play an important role in serious, chronic pathologies with large societal and economic costs, including respiratory disease. However, measurement of the environmental component in epidemiological studies has traditionally relied on much more uncertain and incomplete assessments than measurement of the genome. The 'exposome' has therefore been proposed as a new paradigm to encompass the totality of human environmental (meaning all non-genetic) exposures from conception onwards, complementing the genome. Evidently, there are large challenges in developing the exposome concept into a workable approach for epidemiological research. These include: (1) the accurate and reliable measurement of many exposures in the external environment, (2) the measurement of a wide range of biological responses in the internal environment, and (3) addressing the dynamic, life course nature of the exposome. New tools and technologies that can be applied to address these challenges include exposure biomarker technologies, geographical mapping and remote sensing technologies, smartphone applications and personal exposure sensors, and high-throughput molecular 'omics' techniques. Prospective, population-based cohort studies have recently started to implement these methods using the exposome framework. The exposome thus offers a new and exciting paradigm for improvement and integration of currently scattered and uncertain data on the environmental component in disease aetiology. This should lead to a better understanding of the role of environmental risk factors in respiratory disease and other chronic pathologies, and ultimately to better primary prevention strategies.

Improving care for patients with idiopathic pulmonary fibrosis (IPF) in the UK: a round table discussion.

This article is the result of a round table discussion held at BMA House. Its purpose is to outline the challenges facing both patients and doctors in managing idiopathic pulmonary fibrosis. A number of recommendations for service development and research have been identified.

A practical approach to uveitis screening in children with juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA)-associated uveitis typically presents as a silent chronic anterior uveitis and can lead to blindness. Adherence to current screening guidelines is hampered by complex protocols which rely on the knowledge of specific JIA characteristics. The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to simplify screening to enable local eye care professionals (ECPs), who carry the main burden, to screen children with JIA appropriately and with confidence. METHODS: A consensus meeting took place in January 2023 in Barcelona, Spain, with an expert panel of 10 paediatric rheumatologists and 5 ophthalmologists with expertise in paediatric uveitis. A summary of the current evidence for JIA screening was presented. A nominal group technique was used to reach consensus. RESULTS: The need for a practical but safe approach that allows early uveitis detection was identified by the panel. Three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening taking into account the patient's age at the onset of JIA to determine the screening interval until adulthood. CONCLUSION: By removing the need for the knowledge of JIA categories, antinuclear antibody positivity or treatment status, the recommendations can be more easily implemented by local ECP, where limited information is available. It would improve the standard of care on the local level significantly. The proposed protocol is less tailored to the individual than the 'gold standard' ones it references and does not aim to substitute those where they are being used with confidence.