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Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.KEY QUESTION: Expand our understanding of the genetic basis for mitral valve prolapse (MVP). Uncover relevant pathways and target genes for MVP pathophysiology. Leverage genetic data for MVP risk prediction.KEY FINDING: Sixteen genetic loci were significantly associated with MVP, including 13 novel loci. Interesting target genes at these loci included LTBP2, TGFB2, ALKP3, BAG3, RBM20, and SPTBN1. A risk score including clinical factors and a polygenic risk score, performed best at predicting MVP, with an area under the receiver operating characteristics curve of 0.677.TAKE-HOME MESSAGE: Mitral valve prolapse has a polygenic basis: many genetic variants cumulatively influence pre-disposition for disease. Disease risk may be modulated via changes to transforming growth factor-β signalling, the cytoskeleton, as well as cardiomyopathy pathways. Polygenic risk scores could enhance the MVP risk prediction.

In July 2007 an intense summer storm resulted in significant activation of the sediment system in the Thinhope Burn, UK. Catchment- and reach-scale morphodynamic modelling is used to investigate the geomorphic work undertaken by Thinhope Burn; comparing this with the more subdued responses shown by its neighbours. Total sediment efflux for Thinhope Burn over the 10 yr period 1998-2007 was 18, 801 m3 four times that of the larger Knar Burn catchment and fifty-four times that of the smaller Glendue Burn catchment. For a discharge of 60 m3s-1, equivalent to the July 2007 Thinhope flood, sediment efflux was 575 m3, 76 m3, and 67 m3 for Thinhope, Glendue and Knar Burns respectively. It is clear that Thinhope Burn undertook significantly more geomorphic work compared to its neighbours. Analysis of the population of shear stress for reach-scale simulations on Thinhope Burn highlighted that the final three simulations (flood peaks of 60, 90, 236 m3s-1) all produced very similar distributions, with no marked increase in the modal shear stress (∼250 Nm-2). This possibly suggests that flows >60 m3s-1 are not able to exert significantly greater energy on the channel boundary, indicating that flows in the region of 60 m3s-1 attain ‘peak’ geomorphic work. It is argued that factors such as strength resistance of the key sediment sources (e.g. paleoberms perched on terraces), structural resistance to flood waves imposed by valley form resistance, location sensitivity and transmission resistance, may all offer explanations for increased geomorphic effectiveness compared with its neighbours. With the expectation of greater rainfall totals in the winter and more extreme summer events in upland areas of the UK, it is clear that attention needs to focus upon the implications of this upon the morphological stability of these areas not least to aid future sustainable flood risk management.

Upland river systems in the UK are predicted to be prone to the effects of increased flood magnitudes and frequency, driven by climate change. It is clear from recent events that some headwater catchments can be very sensitive to large floods, activating the full sediment system, with implications for flood risk management further down the catchment. We provide a 15-year record of detailed morphological change on a 500-m reach of upland gravel-bed river, focusing upon the geomorphic response to an extreme event in 2007, and the recovery in the decade following. Through novel application of 2D hydrodynamic modelling we evaluate the different energy states of pre- and post-flood morphologies of the river reach, exploring how energy state adjusts with recovery following the event. Following the 2007 flood, morphological adjustments resulted in changes to the shear stress population over the reach, most likely as a direct result of morphological changes, and resulting in higher shear stresses. Although the proportion of shear stresses in excess of those experienced using the pre-flood DEM varied over the recovery period, they remained substantially in excess of those experienced pre-2007, suggesting that there is still potential for enhanced bedload transport and morphological adjustment within the reach. Although volumetric change calculated from DEM differencing does indicate a reduction in erosion and deposition volumes in the decade following the flood, we argue that the system still has not recovered to the pre-flood situation. We further argue that Thinhope Burn, and other similarly impacted catchments in upland environments, may not recover under the wet climatic phase currently being experienced. Hence systems like Thinhope Burn will continue to deliver large volumes of sediment further down river catchments, providing new challenges for flood risk management into the future.

Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro., The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.

Post-glacial evolution of upland floodplains has been influenced by temporal changes in vegetation, sediment supply and hydrological regime. Channel-floodplain morphodynamics over the Holocene were conditioned by glacial deposits, lateral interaction with slope processes and fluvial sediment reworking, changes in flow and sediment supply regimes driven by climatic change, and more recently direct and indirect anthropogenic activities, e.g. deforestation, floodplain land use and channel modification. Current drives towards river re-naturalisation, often use floodplain topography as a guide to appraise such a planform state, however reconstruction of former channel state is often restricted to surface features visible on historic maps and aerial photographs. This research focuses upon the floodplain of the upper Swindale Beck, Lake District, UK, that was recently restored to a planform design based on the recent meander pattern visible in the floodplain topography. We investigate the potential of Ground Penetrating Radar (GPR) to reconstruct past channel pattern and evolution, and present findings from 40 intersecting GPR survey lines with a total length of over 3.2 km, covering >51000 m2. A centre frequency of 100 MHz allowed reliable imaging of the stratigraphy above the glacial diamict and was supported by 19 soil cores for ground truthing. An outcrop of an andesitic sill just downstream the study site provides a local base level and several alluvial fans constrain the floodplain laterally but also provide sediment to the system. Upstream of the site Younger Dryas glaciation extended into Swindale and the deposited moraines present a source of sediment to Swindale Beck.Analysis of GPR data revealed several stratigraphic units, including gravel/ cobble plains, small multi-channel systems, several levels of larger channels incised in diamict or fluvial deposits, layered channel fill and floodplain deposits. These were interpreted as braided systems, dynamic wandering planform and single-thread meandering systems with spatial transitions conditioned by tributaries and valley slope. GIS analysis of valley slope, channel gradient and local valley floor aspect allowed the interpretation of individual evolutionary stages of river and floodplain development at Swindale and provides links to processes in the wider environment such as the influence of alluvial fans and bedrock outcrops. Such information can be particularly valuable for restoration projects to aid design of channel dimensions, planform configuration, channel gradient, substrate characteristics and connection with tributaries. While restoration generally aims to resemble a more natural reference state, specific targets may seek to improve a particular set of functionalities (e.g. ecological, flood and sediment management, recreational) which should be resilient to the consequences of ongoing climatic changes and should be achieved sustainably (e.g. locally sourced gravel). Here, GPR-based floodplain analysis provides a non-invasive approach to understand possible evolutionary trajectories and to appraise a wider range of restoration options and sustainable resources.

Background: Mutations in tafazzin ( TAZ ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. Methods: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca 2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca 2+ handling and contractility. Results: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell–derived cardiomyocytes had increased diastolic Ca 2+ and decreased Ca 2+ transient amplitude. BTHS-induced pluripotent stem cell–derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca 2+ /calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca 2+ leak through RYR2. Inhibition of this reactive oxygen species–CaMKII–RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca 2+ handling in BTHS-induced pluripotent stem cell–derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca 2+ and decreased Ca 2+ transient amplitude. These abnormalities were ameliorated by Ca 2+ /calmodulin-dependent protein kinase II or reactive oxygen species inhibition. Conclusions: This study identified a molecular pathway that links TAZ mutation with abnormal Ca 2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.

The Holderness coastline of Eastern England is the fastest eroding coastline in Europe. The coast is characterised by ‘soft sediment’ tills, which make it distinctly susceptible to cliff retreat, in turn, these pose a socio-economic threat to local communities. The controls and future projections of the rates and patterns of retreat rely upon robust monitoring and process-based understanding of the geomorphological processes. Herein, we report on a 12-month monitoring study (June 2019 to May 2020) along a 220 m stretch of the Holderness coastline (Withernsea), whereby the spatial and temporal patterns of failure were captured using terrestrial LiDAR. Failure footprint, volumetric change and total eroded volume of the cliffs were estimated and compared against local hydrodynamic and meteorological records. The results reveal that >36% of individual failure events occurred solely in the upper portions (upper 75% vertical height) of the cliff, with a further >38% over the central section of the cliff face, with

Description, Cell reprogramming is at the origin of valve calcification., Cell plasticity plays a key role in embryos by maintaining the differentiation potential of progenitors. Whether postnatal somatic cells revert to an embryonic-like naïve state regaining plasticity and redifferentiate into a cell type leading to a disease remains intriguing. Using genetic lineage tracing and single-cell RNA sequencing, we reveal that Oct4 is induced by nuclear factor κB (NFκB) at embyronic day 9.5 in a subset of mouse endocardial cells originating from the anterior heart forming field at the onset of endocardial-to-mesenchymal transition. These cells acquired a chondro-osteogenic fate. OCT4 in adult valvular aortic cells leads to calcification of mouse and human valves. These calcifying cells originate from the Oct4 embryonic lineage. Genetic deletion of Pou5f1 (Pit-Oct-Unc, OCT4) in the endocardial cell lineage prevents aortic stenosis and calcification of ApoE−/− mouse valve. We established previously unidentified self-cell reprogramming NFκB- and OCT4-mediated inflammatory pathway triggering a dose-dependent mechanism of valve calcification.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To evaluate the effects of subcutaneous omalizumab versus placebo for asthma in adults and children.

RationaleGiven its rising prevalence in both the adult and pediatric populations, obesity has become an increasingly important risk factor in the development of atrial fibrillation. However, a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned downstream of multiple obesity-related pathways, and prior work has shown a pathologic role for SGK1 signaling in ventricular remodeling and arrhythmias.ObjectiveTo determine the mechanistic basis of obesity associated atrial fibrillation and explore the therapeutic potential of targeting SGK1 in this context.Methods and ResultsWe utilized a mouse model of diet induced obesity to determine the atrial electrophysiologic effects of obesity using electrophysiologic studies, optical mapping, and biochemical analyses. In C57BL/6J mice fed a high fat diet, there was upregulation of SGK1 signaling along with an increase in AF inducibility determined at electrophysiology (EP) study. These changes were associated with an increase in fibrotic and inflammatory signaling. Transgenic mice expressing a cardiac specific dominant negative SGK1 (SGK1 DN) were protected from obesity-related AF as well as the fibrotic and inflammatory consequences of AF. Finally, optical mapping demonstrated a shorter action potential duration and patch clamp revealed effects onINa, with a decreased peak current as well as a depolarizing shift in activation/inactivation properties in atrial myocytes.ConclusionsDiet induced obesity leads to increased cardiac SGK1 signaling as well as an increase in AF inducibility in obese mice. Genetic SGK1 inhibition reduced AF inducibility, and this effect may be mediated by effects on inflammation, fibrosis, and cellular electrophysiology.

BACKGROUND: Mutations in tafazzin (TAZ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. METHODS: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) and cardiac specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca(2+) handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca(2+) handling and contractility. RESULTS: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared to WT, BTHS iPSC-CMs had increased diastolic Ca(2+) and decreased Ca(2+) transient amplitude. BTHS iPSC-CMs had higher levels of mitochondrial and cellular ROS than WT, which activated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Activated CaMKII phosphorylated the cardiac ryanodine receptor (RYR2) on serine 2814, increasing Ca(2+) leak through RYR2. Inhibition of this ROS-CaMKII-RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca(2+) handling in BTHS iPSC-CMs and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca(2+) and decreased Ca(2+) transient amplitude. These abnormalities were ameliorated by CaMKII or ROS inhibition. CONCLUSIONS: This study identified a molecular pathway that links TAZ mutation to abnormal Ca(2+) handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial ROS production.

Natural flood management (NFM) promotes the sustainable enhancement of natural fluvial processes to reduce flooding (SEPA, 2015; Wilkinson et al., 2019), and is increasingly popular for use by community groups, contractors and governments (Kay et al., 2019). Reintroduction of wood to a river channel is a popular form of NFM often achieved through seeding natural logjams, or with an emphasis on engineering through installing woody dams (WDs). WDs are currently installed or being installed in catchments in an effort to reduce flood risk, through hydrograph attenuation, increase biodiversity and improve geomorphic heterogeneity (Wenzel et al., 2014; Burgess-Gamble et al., 2017; Grabowski et al., 2019). A further objective is to emulate the effect of natural wood found in river channels by partially, or completely, blocking the channel to accelerate the recruitment of natural wood as part of the natural wood cycle (Addy & Wilkinson, 2016).There is a growing body of evidence supporting the benefits of NFM, however, the hydrogeomorphic effects of WDs are less well understood (Dadson et al., 2017). There is little scientific underpinning concerning the long-term impact of these features upon hydrogeomorphology at reach and catchment-scales. Very few numerically based studies consider the influence of sediment transport on WDs, and how changes in local bed morphology influence their effectiveness. Most NFM research to date has focused upon modelling the effectiveness of local NFM measures in small catchments (2) (Dadson et al., 2017), with less work evident at larger spatial and temporal scales (Kay et al., 2019; Wilkinson et al., 2019).There is a need for a verified tool that is able to represent WDs accounting for geomorphic processes and interactions between the dams and morphodynamics, different design specifications of dams, and changing efficacy due to geomorphic evolution. We present the new CAESAR-Lisflood (Coulthard et al., 2013) “Working with Natural Processes” toolkit, capable of representing WDs across a digital experimental environment. Global sensitivity testing was conducted using the Morris method (Morris, 1991) to assess the sensitivity of five aspects of the toolkit, and their potentially influences on geomorphology and flood risk reduction.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3–8.7; P Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.

Background Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospital admissions, disease-related morbidity and mortality. COPD is a heterogeneous disease with distinct inflammatory phenotypes, including eosinophilia, which may drive acute exacerbations in a subgroup of patients. Monoclonal antibodies targeting interleukin 5 (IL-5) or its receptor (IL-5R) have a role in the care of people with severe eosinophilic asthma, and may similarly provide therapeutic benefit for people with COPD of eosinophilic phenotype. Objectives To assess the efficacy and safety of monoclonal antibody therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) compared with placebo in the treatment of adults with COPD. Search methods We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, clinical trials registries, manufacturers' websites, and reference lists of included studies. Our most recent search was 23 September 2020. Selection criteria We included randomised controlled trials comparing anti-IL-5 therapy with placebo in adults with COPD. Data collection and analysis Two review authors independently extracted data and analysed outcomes using a random-effects model.The primary outcomes were exacerbations requiring antibiotics or oral steroids, hospitalisations due to exacerbation of COPD, serious adverse events, and quality of life. We used standard methods expected by Cochrane. We used the GRADE approach to assess the certainty of the evidence. Main results Six studies involving a total of 5542 participants met our inclusion criteria. Three studies used mepolizumab (1530 participants), and three used benralizumab (4012 participants). The studies were on people with COPD, which was similarly defined with a documented history of COPD for at least one year. We deemed the risk of bias to be generally low, with all studies contributing data of robust methodology. Mepolizumab 100 mg reduces the rate of moderate or severe exacerbations by 19% in those with an eosinophil count of at least 150/μL (rate ratio (RR) 0.81, 95% confidence interval (CI) 0.71 to 0.93; participants = 911; studies = 2, high-certainty evidence). When participants with lower eosinophils are included, mepolizumab 100 mg probably reduces the exacerbation rate by 8% (RR 0.92, 95% CI 0.82 to 1.03; participants = 1285; studies = 2, moderate-certainty evidence). Mepolizumab 300 mg probably reduces the rate of exacerbations by 14% in participants all of whom had raised eosinophils (RR 0.86, 95% CI 0.70 to 1.06; participants = 451; studies = 1, moderate-certainty evidence); the evidence was uncertain for a single small study of mepolizumab 750 mg. In participants with high eosinophils, mepolizumab probably reduces the rate of hospitalisation by 10% (100 mg, RR 0.90, 95% CI 0.65 to 1.24; participants = 911; studies = 2, moderate-certainty evidence) and 17% (300 mg, RR 0.83, 95% CI 0.51 to 1.35; participants = 451; studies = 1, moderate-certainty evidence). Mepolizumab 100 mg increases the time to first moderate or severe exacerbation compared to the placebo group, in people with the eosinophilic phenotype (hazard ratio (HR) 0.78, 95% CI 0.66 to 0.92; participants = 981; studies 2, high-certainty evidence). When participants with lower eosinophils were included this difference was smaller and less certain (HR 0.87, 95% CI 0.75 to 1.0; participants = 1285; studies 2, moderate-certainty evidence). Mepolizumab 300 mg probably increases the time to first moderate or severe exacerbation in participants who all had eosinophilic phenotype (HR 0.77, 95% CI 0.60 to 0.99; participants = 451; studies = 1, moderate-certainty evidence). Benralizumab 100 mg reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high-certainty evidence). Benralizumab 10 mg probably reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.68, 95% CI 0.49 to 0.94; participants = 765; studies = 1, moderate-certainty evidence). There was probably little or no difference between the intervention and placebo for quality of life measures. Where there were differences the mean difference fell below the pre-specified minimum clinically significant difference. Treatment with mepolizumab and benralizumab appeared to be safe. All pooled analyses showed that there was probably little or no difference in serious adverse events, adverse events, or side effects between the use of a monoclonal antibody therapy compared to placebo. Authors' conclusions We found that mepolizumab and benralizumab probably reduce the rate of moderate and severe exacerbations in the highly selected group of people who have both COPD and higher levels of blood eosinophils. This highlights the importance of disease phenotyping in COPD, and may play a role in the personalised treatment strategy in disease management. Further research is needed to elucidate the role of monoclonal antibodies in the management of COPD in clinical practice. In particular, it is not clear whether there is a threshold blood eosinophil level above which these drugs may be effective. Studies including cost effectiveness analysis may be beneficial given the high cost of these therapies, to support use if appropriate.

Structure-from-Motion (SfM) photogrammetry is rapidly becoming a key tool for morphological characterisation and change detection of the earth surface. This paper demonstrates the use of Terrestrial Structure-from-Motion (TSfM) photogrammetry to acquire morphology and roughness data at the reach-scale in an upland gravel-bed river. We quantify 1) spatially-distributed error in TSfM derived Digital Elevation Models (DEMs) and 2) identify differences in roughness populations acquired from TSfM photogrammetry versus TLS. We identify an association between local topographic variation and error in the TSfM DEM. On flatter surfaces (e.g. bar and terrace surfaces), the difference between the TSfM and TLS DEMs are generally less than ±0.1 m. However, in areas of high topographic variability (>0.4 m) such as berm or terrace edges, differences between the TSfM and TLS DEMs can be up to ±1 m. Our results suggest that grain roughness estimates from the TSfM point cloud generate values twice those derived from the TLS point cloud on coarse berm areas, and up to four-fold those derived from the TLS point cloud over finer gravel bar surfaces. This finding has implications when using SfM data to derive roughness metrics for hydrodynamic modelling. Despite the use of standard filtering procedures, noise pertains in the SfM DEM and the time required for its reduction might partially outweigh the survey efficiency using SfM. Therefore, caution is needed when SfM surveys are employed for the assessment of surface roughness at a reach-scale.

Rationale: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. Objective: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing. Methods and Results: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker’s suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P Conclusions: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.

Rationale: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are a readily available, robustly reproducible, and physiologically appropriate human cell source for cardiac disease modeling, drug discovery, and toxicity screenings in vitro. However, unlike adult myocardial cells in vivo, hPSC-CMs cultured in vitro maintain an immature metabolic phenotype, where majority of ATP is produced through aerobic glycolysis instead of oxidative phosphorylation in the mitochondria. Little is known about the underlying signaling pathways controlling hPSC-CMs’ metabolic and functional maturation. Objective: To define the molecular pathways controlling cardiomyocytes’ metabolic pathway selections and improve cardiomyocyte metabolic and functional maturation. Methods and Results: We cultured hPSC-CMs in different media compositions including glucose-containing media, glucose-containing media supplemented with fatty acids, and glucose-free media with fatty acids as the primary carbon source. We found that cardiomyocytes cultured in the presence of glucose used primarily aerobic glycolysis and aberrantly upregulated HIF1α (hypoxia-inducible factor 1α) and its downstream target lactate dehydrogenase A. Conversely, glucose deprivation promoted oxidative phosphorylation and repressed HIF1α. Small molecule inhibition of HIF1α or lactate dehydrogenase A resulted in a switch from aerobic glycolysis to oxidative phosphorylation. Likewise, siRNA inhibition of HIF1α stimulated oxidative phosphorylation while inhibiting aerobic glycolysis. This metabolic shift was accompanied by an increase in mitochondrial content and cellular ATP levels. Furthermore, functional gene expressions, sarcomere length, and contractility were improved by HIF1α/lactate dehydrogenase A inhibition. Conclusions: We show that under standard culture conditions, the HIF1α-lactate dehydrogenase A axis is aberrantly upregulated in hPSC-CMs, preventing their metabolic maturation. Chemical or siRNA inhibition of this pathway results in an appropriate metabolic shift from aerobic glycolysis to oxidative phosphorylation. This in turn improves metabolic and functional maturation of hPSC-CMs. These findings provide key insight into molecular control of hPSC-CMs’ metabolism and may be used to generate more physiologically mature cardiomyocytes for drug screening, disease modeling, and therapeutic purposes.

Keywords: European Heart Rhythm Association, Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society, Cognitive, Arrythmias, Dementia Table of Contents Introduction 1400 Evidence review 1400 Relationships with industry and other conflicts 1400a Decline of cognitive function: terminology and epidemiology 1400a Terminology: cognitive decline, mild cognitive impairment, and dementia 1400a Epidemiology of dementia 1400a Methods for assessment of cognitive function 1400b Role of imaging 1400c Atrial fibrillation and cognitive function 1400c Atrial fibrillation, overt stroke, and cognitive function 1400c Atrial fibrillation, silent stroke, and cognitive function 1400e Atrial fibrillation and cognitive function in the absence of stroke 1400g Assessment of cognitive function in atrial fibrillation patients in clinical practice 1400g Prevention of cognitive dysfunction in atrial fibrillation patients 1400h Other arrhythmias and cognitive dysfunction 1400j Cognitive dysfunction in patients with regular supraventricular tachycardias 1400j Cognitive impairment after cardiac arrest 1400j Cardiac implantable electronic devices and cognitive dysfunction 1400k Catheter ablation 1400k Implications for electrophysiological procedures and cognitive function 1400l Current knowledge gaps, future directions, and areas for research 1400m Recommendations 1400m Introduction This expert consensus statement of the European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) summarizes the consensus of the international writing group and is based on a thorough review of the medical literature regarding cognitive function in arrhythmias. The document is intended to describe the impact of different types of arrhythmias on cognitive function, to highlight possible risk markers for cognitive decline and to formulate implications for clinical practice regarding follow-up methods, prevention and treatment strategies. Our objective is to raise awareness of cognitive function among physicians treating patients with arrhythmias and to provide them with practical proposals that may lead to improvement of patient care in this regard. This document reviews terminology and the epidemiology of cognitive dysfunction, methods for assessment of cognitive function and the role of imaging. Recent studies have suggested possible associations between cognitive decline and atrial fibrillation (AF). We review the reported literature on AF and cognitive function, including the scenarios of AF with overt stroke, silent stroke, or no stroke, and then make recommendations for assessment of cognitive function and prevention of cognitive decline in patients with AF in clinical practice. The document also reviews the association of other arrhythmias and cognitive dysfunction, including settings such as post-cardiac arrest, cardiac implantable devices, such as implantable cardioverter-defibrillators (ICDs) and pacemakers, or ablation procedures. Implications for electrophysiological procedures and cognitive function are discussed. Long QT syndrome and cognitive function is not addressed in the document. For quick reference, sub-chapters are followed by a short section on consensus recommendations. The document concludes with a summary of consensus statements, current knowledge gaps, and future directions of research. Evidence review Members of the Task Force were asked to perform a detailed literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes for which data exist. Patient-specific modifiers, co-morbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered, as are frequency of follow-up and cost-effectiveness. In controversial areas, or with regard to issues without evidence other than usual clinical practice, a consensus was achieved by agreement of the expert panel after thorough deliberations. This document was prepared by the Task Force with representation from EHRA, HRS, APHRS, and LAHRS. The document was peer-reviewed by official external reviewers representing EHRA, HRS, APHRS, and LAHRS. Consensus statements are evidence-based and derived primarily from published data or determined through consensus opinion if data are not available. Current systems of ranking level of evidence are becoming complicated in a way that their practical utility might be compromised.1 In contrast to guidelines, we opted for an easier and user-friendly system of ranking using ‘coloured hearts’ that should allow physicians to easily assess the current status of the evidence and consequent guidance (Table ​Table11). This EHRA grading of consensus statements does not have separate definitions of the level of evidence. This categorization, used for consensus statements, must not be considered as directly similar to that used for official society guideline recommendations, which apply a classification (Class I–III) and level of evidence (A, B, and C) to recommendations used in official guidelines. Table 1 Scientific rationale of recommendations*

Objectives This study sought to characterize the experience in a cohort of patients prescribed a wearable cardioverter-defibrillator (WCD) over a 2-year interval at 2 academic medical centers. Background The WCD is available for patients felt to be at high risk of sudden cardiac death. However, there is a lack of randomized data to guide its use and prescribing patterns vary. Methods We retrospectively reviewed indications and therapies of all WCD prescriptions over a 2-year period from 2 large academic medical centers. Data on compliance and treatment events of patients wearing the WCD were reviewed. Results Among the 147 patients prescribed a WCD, 80% were male with an age of 59 ± 14 years. The WCD was prescribed for the following reasons: primary prevention in the setting of a left ventricular ejection fraction ≤35% (53%), secondary prevention when an implantable cardioverter-defibrillator was not implanted (16%), implantable cardioverter-defibrillator explantation (23%), and other high-risk scenarios for arrhythmic sudden death (9%). The median wear duration was 50 days (interquartile range [IQR]: 25 to 85 days) with a median of 21.0 h of wear per day (IQR: 15.0 to 22.8 h). High-voltage treatment was delivered in 3 separate patients, 2 of whom died. The third patient received 3 WCD shocks without restoration of a perfusing rhythm and ultimately was resuscitated by emergency responders. No patients received inappropriate therapies. Conclusions Events requiring therapy were rare and no lives were directly saved by the WCD. Future efforts are needed to improve identification of patients most likely to benefit from a WCD.

Optogenetics is a powerful research approach that allows localized optical modulation of selected cells within an animal via the expression of genetically encoded photo-excitable ion channels. Commonly used optogenetic techniques rely on the expression of microbial opsin variants, which have many excellent features but suffer from various degrees of blue spectral overlap and limited channel conductance. Here, we expand the optogenetics toolbox in the form of a tunable, high-conductance vertebrate cation channel, zTrpa1b, coupled with photo-activated channel ligands, such as optovin and 4g6. Our results demonstrate that zTrpa1b/ligand pairing offers high light sensitivity, millisecond-scale response latency in vivo, as well as adjustable channel off latency. Exogenous in vivo expression of zTrpa1b in sensory neurons allowed subcellular photo-activation, enabling light-dependent motor control. zTrpa1b/ligand was also suitable for cardiomyocyte pacing, as shown in experiments performed on zebrafish hearts in vivo as well as in human stem cell-derived cardiomyocytes in vitro. Therefore, zTrpa1b/optovin represents a novel tool for flexible, high-conductance optogenetics.

Fine sediment infiltration into gravel interstices is known to be detrimental to incubating salmonid embryos. Infiltration into spawning riffles can show large spatial variations at the scale of a morphological unit and over time, with significant implications for embryo survival. Furthermore some process-based infiltration studies, and incubation-to-emergence models assume that fines are delivered to redds via suspension rather than bedload. This process-based twelve-month study examined spatial patterns of predominantly sand infiltration into gravels in an upland trout stream, using infiltration baskets. An assessment of Rouse numbers for infiltrated sand indicated that it was transported predominantly as bedload at flow peaks. Clear temporal and spatial patterns existed; with highest rates of infiltration strongly associated with higher discharges (r2 = 0.7, p

We performed deep level transient spectroscopy (DLTS), in capacitance, constant-capacitance and current mode, on 5 MeV proton irradiated 4H-SiC p+-i-n diodes. The study has revealed the presence of several majority and minority traps, ranging in the 0.4-1.6 eV below the conduction band edge and in the 0.4-1.5 eV above the valence band edge. We present a comparison of the results obtained with the three modes and discuss the nature of the detected traps, in the light of previous results found in the literature. At last, the impact of the irradiation on the minority carrier lifetime is evaluated by electrical measurements.

Background: The objective of this study is to evaluate the incidence of non-AIDS defining malignancies (NADMs) among people living with HIV/AIDS (PLWHA) in British Columbia, focusing on clinical correlates, highly active antiretroviral therapy (HAART) use, and survival, in order to elucidate mechanisms for NADM development. Methods: A retrospective population based analysis was carried out for individuals with HIV/AIDS that began their treatment between 1996 and 2008. Results: There were 145 (2.95%) NADMs and 123 (2.50%) AIDS defining malignancies (ADMs) identified in 4918 PLWHA in the study population. NADMs were represented by a range of cancer types including, most commonly, lung cancer, followed by anal, breast, head/neck, prostate, liver, rectal, and renal cancers. PLWHA had a SIR of 2.05 (CI:1.73, 2.41) for the development of NADMs compared to individuals without an HIV/AIDS diagnosis in the general population. Independent factors significantly associated with a NADM were: male gender, older age, lower CD4 cell counts, previous NADM, absence of HAART (non-HAART versus HAART) and treatment during the early-HAART era (before 2000 versus after 2000). Conclusions: NADMs represent an important source of morbidity for PLWHA. Use of HAART with its associated improvement in immune-restoration, and tailored targeted cancer screening interventions, may be beneficial and improve outcomes in this unique patient population.

We gathered data from counselor educators to study their experiences with emotionally charged exchanges while teaching multicultural counseling. We then used descriptive phenomenology and an ecological systems framework to reveal the emotions counselor educators experienced and the outcomes of the exchanges. We discuss the implications of our findings for counselor preparation programs and educators.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the efficacy and safety of monoclonal antibody therapies targeting IL‐5 signalling (anti‐IL‐5 or anti‐IL‐5Rα) compared with placebo in the treatment of adults with COPD.

Long-term data quantifying the response of fluvial systems to geomorphically effective events are rare, limiting our ability to validate conceptual models of geomorphic evolution. Here we present geomorphic change data for a 200 m reach of the Thinhope Burn a small (12 km2) tributary to the South Tyne, Cumbria, UK, monitored since 2003. In July 2007 a severe flood resulted in a peak discharge of 60 m3s-1, and boundary shear stress maxima of 533 Nm-2; capable of mobilising metre-size boulders. The Thinhope Burn catchment showed ‘responsive’ behaviour to the event causing; full activation the valley floor and slopes, a peat slide in the headwaters, and delivery ~3077 m3 of gravel to the study reach. Ten years on, there appears to be limited evidence of recovery to the valley floor, possibly due to the effects of several wet winters. The channel and floodplain surface appear unconsolidated and vegetation-free, and as a consequence remains highly mobile during floods. Some climate change predictions for the UK uplands indicate wetter winters, that could push sensitive upland catchments closer towards ‘tipping-point’, where thresholds are crossed within the fluvial system resulting in significant morphological changes to the river channel and it’s floodplain, and producing very high bedload transport volumes. A new regime of wetter winters may also halt recovery of upland rivers where the sediment system has already been fully activated by previous floods. We conclude that a better understanding of relative catchment sensitivity and the potential implications of climate-change induced increases in flows upon those catchments is needed to plan for the potential impacts of enhanced sediment loads upon flood risk.

BACKGROUND: Cough both protects and clears the airway. Cough has three phases: breathing in (inspiration), closure of the glottis, and a forced expiratory effort. Chronic cough has a negative, far‐reaching impact on quality of life. Few effective medical treatments for individuals with unexplained (idiopathic/refractory) chronic cough (UCC) are known. For this group, current guidelines advocate the use of gabapentin. Speech and language therapy (SLT) has been considered as a non‐pharmacological option for managing UCC without the risks and side effects associated with pharmacological agents, and this review considers the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of SLT in this context. OBJECTIVES: To evaluate the effectiveness of speech and language therapy for treatment of people with unexplained (idiopathic/refractory) chronic cough. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, trials registries, and reference lists of included studies. Our most recent search was 8 February 2019. SELECTION CRITERIA: We included RCTs in which participants had a diagnosis of UCC having undergone a full diagnostic workup to exclude an underlying cause, as per published guidelines or local protocols, and where the intervention included speech and language therapy techniques for UCC. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 94 records. Two clinical trials, represented in 10 study reports, met our predefined inclusion criteria. Two review authors independently assessed risk of bias for each study and extracted outcome data. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs) or geometric mean differences. We used standard methods recommended by Cochrane. Our primary outcomes were health‐related quality of life (HRQoL) and serious adverse events (SAEs). MAIN RESULTS: We found two studies involving 162 adults that met our inclusion criteria. Neither of the two studies included children. The duration of treatment and length of sessions varied between studies from four sessions delivered weekly, to four sessions over two months. Similarly, length of sessions varied slightly from one 60‐minute session and three 45‐minute sessions to four 30‐minute sessions. The control interventions were healthy lifestyle advice in both studies. One study contributed HRQoL data, using the Leicester Cough Questionnaire (LCQ), and we judged the quality of the evidence to be low using the GRADE approach. Data were reported as between‐group difference from baseline to four weeks (MD 1.53, 95% confidence interval (CI) 0.21 to 2.85; participants = 71), revealing a statistically significant benefit for people receiving a physiotherapy and speech and language therapy intervention (PSALTI) versus control. However, the difference between PSALTI and control was not observed between week four and three months. The same study provided information on SAEs, and there were no SAEs in either the PSALTI or control arms. Using the GRADE approach we judged the quality of evidence for this outcome to be low. Data were also available for our prespecified secondary outcomes. In each case data were provided by only one study, therefore there were no opportunities for aggregation; we judged the quality of this evidence to be low for each outcome. A significant difference favouring therapy was demonstrated for: objective cough counts (ratio for mean coughs per hour on treatment was 59% (95% CI 37% to 95%) relative to control; participants = 71); symptom score (MD 9.80, 95% CI 4.50 to 15.10; participants = 87); and clinical improvement as defined by trialists (OR 48.13, 95% CI 13.53 to 171.25; participants = 87). There was no significant difference between therapy and control regarding subjective measures of cough (MD on visual analogue scale of cough severity: −9.72, 95% CI −20.80 to 1.36; participants = 71) and cough reflex sensitivity (capsaicin concentration to induce five coughs: 1.11 (95% CI 0.80 to 1.54; participants = 49) times higher on treatment than on control). One study reported data on adverse events, and there were no adverse events reported in either the therapy or control arms of the study. AUTHORS' CONCLUSIONS: The paucity of data in this review highlights the need for more controlled trial data examining the efficacy of SLT interventions in the management of UCC. Although a large number of studies were found in the initial search as per protocol, we could include only two studies in the review. In addition, this review highlights that endpoints vary between published studies. The improvements in HRQoL (LCQ) and reduction in 24‐hour cough frequency seen with the PSALTI intervention were statistically significant but short‐lived, with the between‐group difference lasting up to four weeks only. Further studies are required to replicate these findings and to investigate the effects of SLT interventions over time. It is clear that SLT interventions vary between studies. Further research is needed to understand which aspects of SLT interventions are most effective in reducing cough (both objective cough frequency and subjective measures of cough) and improving HRQoL. We consider these endpoints to be clinically important. It is also important for future studies to report information on adverse events. Because of the paucity of data, we can draw no robust conclusions regarding the efficacy of SLT interventions for improving outcomes in unexplained chronic cough. Our review identifies the need for further high‐quality research, with comparable endpoints to inform robust conclusions.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objective of this systematic review is to explore the benefits of second‐line chemotherapy in patients with resistant (a relapse within three months of first treatment) or relapsed (a relapse after three months of first treatment) SCLC.

Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i -GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1 , a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P =4.36×10 -10 ), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1 A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

Objectives: The role of sotalol is well established for the maintenance of sinus rhythm after successful conversion of atrial fibrillation (AF). However, its role in pharmacologic conversion of AF is poorly defined. The purpose of this study is to compare the efficacy of sotalol to that of other antiarrhythmic agents for AF conversion. Methods: Standard methods of meta-analysis were employed. Full-text publications of clinical trials in English that compared the efficacy of sotalol to that of other antiarrhythmics or placebo/no treatment were eligible for inclusion. Results: A systematic review revealed 10 eligible publications. Sotalol was superior to placebo and/or no antiarrhythmic therapy in AF conversion, with a relative success of 24 (95% CI 4.7-119, p < 0.001). Sotalol was not significantly different from class IA antiarrhythmic drugs. Similarly, sotalol was not different from class IC antiarrhythmic drugs or amiodarone in terms of conversion efficacy. In one study, sotalol was less effective than high-dose ibutilide (2 mg), with a relative success of 0.248 (95% CI 0.128-0.481, p < 0.001). Ibutilide caused more proarrhythmia. Conclusions: Sotalol is as effective as class IA and class IC antiarrhythmic agents, and it is also as effective as amiodarone for pharmacologic conversion of AF. Only ibutilide at a high dose showed a greater conversion rate of AF.

Rationale: More than 25 million individuals have heart failure worldwide, with ≈4000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft rejection remain major limitations with only ≈2500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure. Objective: The objective of this study is to translate previous work to human scale and clinically relevant cells for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human induced pluripotent stem cell–derived cardiomyocytes. Methods and Results: To provide a clinically relevant tissue scaffold, we translated perfusion-decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiomyocytes derived from nontransgenic human induced pluripotent stem cells and generated tissues of increasing 3-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole-heart scaffolds with human induced pluripotent stem cell–derived cardiomyocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue and showed electrical conductivity, left ventricular pressure development, and metabolic function. Conclusions: Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human induced pluripotent stem cell–derived cardiomyocytes and enable the bioengineering of functional human myocardial-like tissue of multiple complexities.

Background— The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results— We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44–4.92, P Conclusions— In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

To better understand the thermal stability of dislocation loops formed by long-term neutron irradiation in reactor pressure vessel (RPV) steels, in-situ scanning transmission electron microscopy (STEM) observation was performed for a surveillance test specimen of a European pressurized water reactor (PWR). The surveillance test specimen was neutron irradiated to a fluence of 8.2 × 1023 neutrons•m−2. A membrane sample from the surveillance test specimen was annealed at 673 K and 723 K for 30 min using a heating holder, and the same area was in-situ observed under STEM. After annealing, dislocation loops with Burgers vectors of ½ 〈111〉 and 〈100〉 were quantitatively examined. When annealing temperature increased from 673 K to 723 K, the number of dislocation loops decreases, whereas the size of them becomes larger. Correspondingly, the proportion of 〈100〉 dislocation loops changes from 27% to 45%. The ratio of 〈100〉 to ½ 〈111〉 loops increases with annealing temperature rising. The evolution process of dislocation loops during annealing at 723 K was in-situ observed and analyzed to shed light on the transformation mechanism of dislocation loops going from ½ 〈111〉 to 〈100〉. It is the first time to directly observe that two ½ 〈111〉 dislocation loops collide with each other and coalesce to form a 〈100〉 dislocation loop. Moreover, small ½ 〈111〉 dislocation loops could be absorbed by large 〈100〉 dislocation loops, whereas the Burgers vector of 〈100〉 loops remained unchanged. Dislocation decoration occurs during annealing due to the interaction between dislocations and loops. The dislocations decorated by loops are pretty stable during the continuous annealing process, which is well explained by molecular dynamics simulation.

Nonsyndromic Mitral valve prolapse (MVP) is a common degenerative valvular heart disease with severe health consequences, including arrhythmia, heart failure and sudden death. MVP is characterized by excess extracellular matrix secretion and cellular disorganization which leads to bulky valves that are unable to co-apt properly during ventricular systole. However, the triggering mechanisms of this process are mostly unknown. Using pathway enrichment tools applied to GWAS we show that genes at risk loci are involved in biological functions relevant to cell adhesion and migration during cardiac development and in response to shear stress. Through genetic, in silico and in vivo experiments we demonstrates the presence of several genes involved in gene regulation, including GLIS1, a transcription factor that regulates Hedgehog signaling. Our findings define genetic, molecular and cellular mechanisms underlying non-syndromic MVP and implicate disrupted endothelial to mesenchymal transition and cell migration as a potential common cause to this disease.

Background Atrial fibrillation (AF) is the most common clinical arrhythmia, although the pathophysiology remains poorly understood. Population-based genetic studies have identified a susceptibility locus for AF at the gene ZFHX3. Hypothesis We hypothesized that a cardiac-restricted knockout of the transcription factor ZFHX3 in a mammalian model organism would perturb normal cardiac development and function, and illuminate the role of ZFHX3 in AF. Methods and results We generated a murine cardiac-restricted knockdown of ZFHX3 using cre-lox recombination. Knockdown was confirmed by organ specific genotyping. Among knockdown mice, increased inducibility of atrial arrhythmias was observed at in vivo electrophysiology testing at 3 months of age (% arrhythmia induction maneuvers 10 vs 0, p Conclusion We have uncovered a role for ZFHX3 in the left-right patterning of cardiac atria. Disruption of this developmental process predisposes to atrial cardiomyopathy, affects atrial electrophysiology properties, changes which may increase the susceptibility to AF.

Background: The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer-term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost-effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions.Objectives: To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis.Search methods: We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies.Selection criteria: We included RCTs reported as full-text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high-resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method.Data collection and analysis: Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs).Main results: Four randomised trials were eligible for inclusion in this systematic review - two studies with 83 adults comparing fluoroquinolones with β-lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations - one of our primary outcomes. Included studies reported no serious adverse events - another of our primary outcomes - and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β-lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low-quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low-quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low-quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low-quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low-quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information.Authors' conclusions: Limited low-quality evidence favours short-term oral fluoroquinolones over beta-lactam antibiotics for patients hospitalised with exacerbations. Very low-quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head-to-head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short-term or long-term therapy. More research on this topic is needed.

Background: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation of the smaller airways and associated with a mortality rate greater than twice that of the general population. Antibiotics serve as front-line therapy for managing bacterial load, but their use is weighed against the development of antibiotic resistance. Dual antibiotic therapy has the potential to suppress infection from multiple strains of bacteria, leading to more successful treatment of exacerbations, reduced symptoms, and improved quality of life. Further evidence is required on the efficacy of dual antibiotics in terms of management of exacerbations and extent of antibiotic resistance.Objectives: To evaluate the effects of dual antibiotics in the treatment of adults and children with bronchiectasis.Search methods: We identified studies from the Cochrane Airways Group Specialised Register (CAGR), which includes the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine (AMED), and PsycINFO, as well as studies obtained by handsearching of journals/abstracts. We also searched the following trial registries: US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. We imposed no restriction on language of publication. We conducted our search in October 2017.Section criteria: We searched for randomised controlled trials comparing dual antibiotics versus a single antibiotic for short-term (< 4 weeks) or long-term management of bronchiectasis diagnosed in adults and/or children by bronchography, plain film chest radiography, or high-resolution computed tomography. Primary outcomes included exacerbations, length of hospitalisation, and serious adverse events. Secondary outcomes were response rates, emergence of resistance to antibiotics, systemic markers of infection, sputum volume and purulence, measures of lung function, adverse events/effects, deaths, exercise capacity, and health-related quality of life. We did not apply outcome measures as selection criteria.Data collection and analysis: Two review authors independently screened the titles and abstracts of 287 records, along with the full text of seven reports. Two studies met review inclusion criteria. Two review authors independently extracted outcome data and assessed risk of bias. We extracted data from only one study and conducted GRADE assessments for the following outcomes: successful treatment of exacerbation; response rates; and serious adverse events.Main results: Two randomised trials assessed the effectiveness of oral plus inhaled dual therapy versus oral monotherapy in a total of 118 adults with a mean age of 62.8 years. One multi-centre trial compared inhaled tobramycin plus oral ciprofloxacin versus ciprofloxacin alone, and one single-centre trial compared nebulised gentamicin plus systemic antibiotics versus a systemic antibiotic alone. Published papers did not report study funding sources.Effect estimates from one small study with 53 adults showed no evidence of treatment benefit with oral plus inhaled dual therapy for the following primary outcomes at the end of the study: successful management of exacerbation - cure at day 42 (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.22 to 2.01; 53 participants; one study; very low-quality evidence); number of participants with Pseudomonas aeruginosa eradication at day 21 (OR 2.33, 95% CI 0.66 to 8.24; 53 participants; one study; very low-quality evidence); and serious adverse events (OR 0.48, 95% CI 0.08 to 2.87; 53 participants; one study; very low-quality evidence). Similarly, researchers provided no evidence of treatment benefit for the following secondary outcomes: clinical response rates - relapse at day 42 (OR 0.57, 95% CI 0.12 to 2.69; 53 participants; one study; very low-quality evidence); microbiological response rate at day 21 - eradicated (OR 2.40, 95% CI 0.67 to 8.65; 53 participants; one study; very low-quality evidence); and adverse events - incidence of wheeze (OR 5.75, 95% CI 1.55 to 21.33). Data show no evidence of benefit in terms of sputum volume, lung function, or antibiotic resistance. Outcomes from a second small study with 65 adults, available only as an abstract, were not included in the quantitative data synthesis. The included studies did not report our other primary outcomes: duration; frequency; and time to next exacerbation; nor our secondary outcomes: systemic markers of infection; exercise capacity; and quality of life. We did not identify any trials that included children.Authors' conclusions: A small number of studies in adults have generated high-quality evidence that is insufficient to inform robust conclusions, and studies in children have provided no evidence. We identified only one dual-therapy combination of oral and inhaled antibiotics. Results from this single trial of 53 adults that we were able to include in the quantitative synthesis showed no evidence of treatment benefit with oral plus inhaled dual therapy in terms of successful treatment of exacerbations, serious adverse events, sputum volume, lung function, and antibiotic resistance. Further high-quality research is required to determine the efficacy and safety of other combinations of dual antibiotics for both adults and children with bronchiectasis, particularly in terms of antibiotic resistance.

Background: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r 2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=−4.74, P =1.52×10 −14 ) and QRS intervals (rs6599251, QRS β=−0.73; P =1.2×10 −4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r 2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03). Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction.

International audience; Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P \textless 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P \textless 0.0001). Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

Background: Bronchiectasis is a chronic inflammatory disease characterised by a recurrent cycle of respiratory bacterial infections associated with cough, sputum production and impaired quality of life. Antibiotics are the main therapeutic option for managing bronchiectasis exacerbations. Evidence suggests that inhaled antibiotics may be associated with more effective eradication of infective organisms and a lower risk of developing antibiotic resistance when compared with orally administered antibiotics. However, it is currently unclear whether antibiotics are more effective when administered orally or by inhalation.Objectives: To determine the comparative efficacy and safety of oral versus inhaled antibiotics in the treatment of adults and children with bronchiectasis.Search methods: We identified studies through searches of the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Information Specialist for the group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched ClinicalTrials.gov and the WHO trials portal. We searched all databases in March 2018 and imposed no restrictions on language of publication.Selection criteria: We planned to include studies which compared oral antibiotics with inhaled antibiotics. We would have considered short-term use (less than four weeks) for treating acute exacerbations separately from longer-term use as a prophylactic (4 weeks or more). We would have considered both intraclass and interclass comparisons. We planned to exclude studies if the participants received continuous or high-dose antibiotics immediately before the start of the trial, or if they have received a diagnosis of cystic fibrosis (CF), sarcoidosis, active allergic bronchopulmonary aspergillosis or active non-tuberculous Mycobacterial infection.Data collection and analysis: Two review authors independently applied study inclusion criteria to the searches and we planned for two authors to independently extract data, assess risk of bias and assess overall quality of the evidence using GRADE criteria. We also planned to obtain missing data from the authors where possible and to report results with 95% confidence intervals (CIs).Main results: We identified 313 unique records through database searches and a further 21 records from trial registers. We excluded 307 on the basis of title and abstract alone and a further 27 after examining full-text reports. No studies were identified for inclusion in the review.Authors' conclusions: There is currently no evidence indicating whether orally administered antibiotics are more beneficial compared to inhaled antibiotics. The recent ERS bronchiectasis guidelines provide a practical approach to the use of long-term antibiotics. New research is needed comparing inhaled versus oral antibiotic therapies for bronchiectasis patients with a history of frequent exacerbations, to establish which approach is the most effective in terms of exacerbation prevention, quality of life, treatment burden, and antibiotic resistance.

Background: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.Objectives: To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.Search methods: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.Selection criteria: We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.Data collection and analysis: Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.Main results: We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.Authors' conclusions: Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.

BACKGROUND: Bronchiectasis is a long term respiratory condition with an increasing rate of diagnosis. It is associated with persistent symptoms, repeated infective exacerbations, and reduced quality of life, imposing a burden on individuals and healthcare systems. The main aims of therapeutic management are to reduce exacerbations and improve quality of life. Self‐management interventions are potentially important for empowering people with bronchiectasis to manage their condition more effectively and to seek care in a timely manner. Self‐management interventions are beneficial in the management of other airways diseases such as asthma and COPD (chronic obstructive pulmonary disease) and have been identified as a research priority for bronchiectasis. OBJECTIVES: To assess the efficacy, cost‐effectiveness and adverse effects of self‐management interventions for adults and children with non‐cystic fibrosis bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Specialised Register of trials, clinical trials registers, reference lists of included studies and review articles, and relevant manufacturers’ websites up to 13 December 2017. SELECTION CRITERIA: We included all randomised controlled trials of any duration that included adults or children with a diagnosis of non‐cystic fibrosis bronchiectasis assessing self‐management interventions delivered in any form. Self‐management interventions included at least two of the following elements: patient education, airway clearance techniques, adherence to medication, exercise (including pulmonary rehabilitation) and action plans. DATA COLLECTION AND ANALYSIS: Two review authors independently screened searches, extracted study characteristics and outcome data and assessed risk of bias for each included study. Primary outcomes were, health‐related quality of life, exacerbation frequency and serious adverse events. Secondary outcomes were the number of participants admitted to hospital on at least one occasion, lung function, symptoms, self‐efficacy and economic costs. We used a random effects model for analyses and standard Cochrane methods throughout. MAIN RESULTS: Two studies with a total of 84 participants were included: a 12‐month RCT of early rehabilitation in adults of mean age 72 years conducted in two centres in England (UK) and a six‐month proof‐of‐concept RCT of an expert patient programme (EPP) in adults of mean age 60 years in a single regional respiratory centre in Northern Ireland (UK). The EPP was delivered in group format once a week for eight weeks using standardised EPP materials plus disease‐specific education including airway clearance techniques, dealing with symptoms, exacerbations, health promotion and available support. We did not find any studies that included children. Data aggregation was not possible and findings are reported narratively in the review. For the primary outcomes, both studies reported health‐related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ), but there was no clear evidence of benefit. In one study, the mean SGRQ total scores were not significantly different at 6 weeks', 3 months' and 12 months' follow‐up (12 months mean difference (MD) ‐10.27, 95% confidence interval (CI) ‐45.15 to 24.61). In the second study there were no significant differences in SGRQ. Total scores were not significantly different between groups (six months, MD 3.20, 95% CI ‐6.64 to 13.04). We judged the evidence for this outcome as low or very low. Neither of the included studies reported data on exacerbations requiring antibiotics. For serious adverse events, one study reported more deaths in the intervention group compared to the control group, (intervention: 4 of 8, control: 2 of 12), though interpretation is limited by the low event rate and the small number of participants in each group. For our secondary outcomes, there was no evidence of benefit in terms of frequency of hospital admissions or FEV1 L, based on very low‐quality evidence. One study reported self‐efficacy using the Chronic Disease Self‐Efficacy scale, which comprises 10 components. All scales showed significant benefit from the intervention but effects were only sustained to study endpoint on the Managing Depression scale. Further details are reported in the main review. Based on overall study quality, we judged this evidence as low quality. Neither study reported data on respiratory symptoms, economic costs or adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether self‐management interventions benefit people with bronchiectasis. In the absence of high‐quality evidence it is advisable that practitioners adhere to current international guidelines that advocate self‐management for people with bronchiectasis. Future studies should aim to clearly define and justify the specific nature of self‐management, measure clinically important outcomes and include children as well as adults.

Induced pluripotent stem cells (iPSCs) offer an unprece-dented opportunity to study human physiology and disease at the cellular level. They also have the potential to be leveraged in the practice of precision medicine, for example, personalized drug testing. This statement comprehensively describes the provenance of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and strategies through which to promote their wider use for biomedical applications. Human iPSCs exhibit properties that render them uniquely qualified as model systems for studying human diseases: they are of human origin, which means they carry human genomes; they are pluripotent, which means that in principle, they can be differentiated into any of the human body’s somatic cell types; and they are stem cells, which means they can be expanded from a single cell into millions or even billions of cell progeny. iPSCs offer the opportunity to study cells that are genetically matched to individual patients, and genome-editing tools allow introduction or correction of genetic variants. Initial progress has been made in using iPSCs to better understand cardiomyopathies, rhythm disorders, valvular and vascular disorders, and metabolic risk factors for ischemic heart disease. This promising work is still in its infancy. Similarly, iPSCs are only just starting to be used to identify the optimal medications to be used in patients from whom the cells were derived. This statement is intended to (1) summarize the state of the science with respect to the use of iPSCs for modeling of cardiovascular traits and disorders and for therapeutic screening; (2) identify opportunities and challenges in the use of iPSCs for disease modeling and precision medicine; and (3) outline strategies that will facilitate the use of iPSCs for biomedical applications. This statement is not intended to address the use of stem cells as regenerative therapy, such as transplantation into the body to treat ischemic heart disease or heart failure.