Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial.

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FiO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

Importance of timely metadata curation to the global surveillance of genetic diversity.

Genetic diversity within species represents a fundamental yet underappreciated level of biodiversity. Because genetic diversity can indicate species resilience to changing climate, its measurement is relevant to many national and global conservation policy targets. Many studies produce large amounts of genome-scale genetic diversity data for wild populations, but most (87%) do not include the associated spatial and temporal metadata necessary for them to be reused in monitoring programs or for acknowledging the sovereignty of nations or Indigenous peoples. We undertook a distributed datathon to quantify the availability of these missing metadata and to test the hypothesis that their availability decays with time. We also worked to remediate missing metadata by extracting them from associated published papers, online repositories, and direct communication with authors. Starting with 848 candidate genomic data sets (reduced representation and whole genome) from the International Nucleotide Sequence Database Collaboration, we determined that 561 contained mostly samples from wild populations. We successfully restored spatiotemporal metadata for 78% of these 561 data sets (n = 440 data sets with data on 45,105 individuals from 762 species in 17 phyla). Examining papers and online repositories was much more fruitful than contacting 351 authors, who replied to our email requests 45% of the time. Overall, 23% of our email queries to authors unearthed useful metadata. The probability of retrieving spatiotemporal metadata declined significantly as age of the data set increased. There was a 13.5% yearly decrease in metadata associated with published papers or online repositories and up to a 22% yearly decrease in metadata that were only available from authors. This rapid decay in metadata availability, mirrored in studies of other types of biological data, should motivate swift updates to data-sharing policies and researcher practices to ensure that the valuable context provided by metadata is not lost to conservation science forever.

Importancia de la curación oportuna de metadatos para la vigilancia mundial de la diversidad genética Resumen La diversidad genética intraespecífica representa un nivel fundamental, pero a la vez subvalorado de la biodiversidad. La diversidad genética puede indicar la resiliencia de una especie ante el clima cambiante, por lo que su medición es relevante para muchos objetivos de la política de conservación mundial y nacional. Muchos estudios producen una gran cantidad de datos sobre la diversidad a nivel genético de las poblaciones silvestres, aunque la mayoría (87%) no incluye los metadatos espaciales y temporales asociados para que sean reutilizados en los programas de monitoreo o para reconocer la soberanía de las naciones o los pueblos indígenas. Realizamos un "datatón" distribuido para cuantificar la disponibilidad de estos metadatos faltantes y para probar la hipótesis que supone que esta disponibilidad se deteriora con el tiempo. También trabajamos para reparar los metadatos faltantes al extraerlos de los artículos asociados publicados, los repositorios en línea y la comunicación directa con los autores. Iniciamos con 838 candidatos de conjuntos de datos genómicos (representación reducida y genoma completo) tomados de la colaboración internacional para la base de datos de secuencias de nucleótidos y determinamos que 561 incluían en su mayoría muestras tomadas de poblaciones silvestres. Restauramos con éxito los metadatos espaciotemporales en el 78% de estos 561 conjuntos de datos (n = 440 conjuntos de datos con información sobre 45,105 individuos de 762 especies en 17 filos). El análisis de los artículos y los repositorios virtuales fue mucho más productivo que contactar a los 351 autores, quienes tuvieron un 45% de respuesta a nuestros correos. En general, el 23% de nuestras consultas descubrieron metadatos útiles. La probabilidad de recuperar metadatos espaciotemporales declinó de manera significativa conforme incrementó la antigüedad del conjunto de datos. Hubo una disminución anual del 13.5% en los metadatos asociados con los artículos publicados y los repositorios virtuales y hasta una disminución anual del 22% en los metadatos que sólo estaban disponibles mediante la comunicación con los autores. Este rápido deterioro en la disponibilidad de los metadatos, duplicado en estudios de otros tipos de datos biológicos, debería motivar la pronta actualización de las políticas del intercambio de datos y las prácticas de los investigadores para asegurar que en las ciencias de la conservación no se pierda para siempre el contexto valioso proporcionado por los metadatos.

Ventilatory failure in chronic neuromuscular disease.

Patients with neuromuscular diseases (NMD) can present to the neurologist with symptoms and signs of respiratory failure, either acutely or as an insidious process in the outpatient setting. Since the advent of non-invasive ventilation, the outcomes of patients with ventilatory failure due to NMD have dramatically improved. However, the natural history of different NMDs requires a nuanced approach to respiratory investigation and management. Respiratory failure dictates the prognosis of many NMDs and timing the most appropriate investigation and referral to ventilation services is crucial in optimising care.

Digital Extended Specimens: Enabling an Extensible Network of Biodiversity Data Records as Integrated Digital Objects on the Internet.

The early twenty-first century has witnessed massive expansions in availability and accessibility of digital data in virtually all domains of the biodiversity sciences. Led by an array of asynchronous digitization activities spanning ecological, environmental, climatological, and biological collections data, these initiatives have resulted in a plethora of mostly disconnected and siloed data, leaving to researchers the tedious and time-consuming manual task of finding and connecting them in usable ways, integrating them into coherent data sets, and making them interoperable. The focus to date has been on elevating analog and physical records to digital replicas in local databases prior to elevating them to ever-growing aggregations of essentially disconnected discipline-specific information. In the present article, we propose a new interconnected network of digital objects on the Internet-the Digital Extended Specimen (DES) network-that transcends existing aggregator technology, augments the DES with third-party data through machine algorithms, and provides a platform for more efficient research and robust interdisciplinary discovery.

Bridging the Research Gap between Live Collections in Zoos and Preserved Collections in Natural History Museums.

Zoos and natural history museums are both collections-based institutions with important missions in biodiversity research and education. Animals in zoos are a repository and living record of the world's biodiversity, whereas natural history museums are a permanent historical record of snapshots of biodiversity in time. Surprisingly, despite significant overlap in institutional missions, formal partnerships between these institution types are infrequent. Life history information, pedigrees, and medical records maintained at zoos should be seen as complementary to historical records of morphology, genetics, and distribution kept at museums. Through examining both institution types, we synthesize the benefits and challenges of cross-institutional exchanges and propose actions to increase the dialog between zoos and museums. With a growing recognition of the importance of collections to the advancement of scientific research and discovery, a transformational impact could be made with long-term investments in connecting the institutions that are caretakers of living and preserved animals.

Do We Have a Trust Problem? Exploring Undergraduate Student Views on the Tentativeness and Trustworthiness of Science.

Science includes the fundamental attributes of durability and uncertainty; hence, we teach about the "tentative yet durable" nature of science. Public discourse can be different, where one hears both confidence about "settled science" and doubts about "just theories." The latter observation gives rise to the possibility that emphasis on learning the tentative nature of science offers some people the actionable option of declining to accept canonical science. Our paper reports the findings from initial and replication exploratory studies involving about 500 preservice, elementary/middle school teacher education students at a large Midwestern public university. Using a survey method that included opportunities for student comments, the study tested hypotheses about confidence in the veracity, durability, tentativeness, and trustworthiness of science. We found that most students embrace noncontroversial science as correct, and that almost all embraced the tentative nature of science regardless of what they thought about controversial topics. However, when asked about the trustworthiness of science, many students were not willing to say that they trust scientific knowledge. Even students strongly supportive of science, including controversial science, responded similarly. And why did they say that science is not trustworthy? The explanation echoed by many students was that scientific knowledge is tentative. Our paper concludes with implications for instruction and research. Our findings suggest that it would be prudent for science educators to increase instructional focus on the relationship between data and evidence that leads to the durability of scientific knowledge. Future research needs to thoroughly investigate the public interpretation of what we teach about the nature and characteristics of science, and for the implications it might have on how scientific knowledge is or is not incorporated in the development and implementation of public policy.

Prognostic accuracy of emergency department triage tools for adults with suspected COVID-19: the PRIEST observational cohort study.

BACKGROUND: The WHO and National Institute for Health and Care Excellence recommend various triage tools to assist decision-making for patients with suspected COVID-19. We aimed to compare the accuracy of triage tools for predicting severe illness in adults presenting to the ED with suspected COVID-19. METHODS: We undertook a mixed prospective and retrospective observational cohort study in 70 EDs across the UK. We collected data from people attending with suspected COVID-19 and used presenting data to determine the results of assessment with the WHO algorithm, National Early Warning Score version 2 (NEWS2), CURB-65, CRB-65, Pandemic Modified Early Warning Score (PMEWS) and the swine flu adult hospital pathway (SFAHP). We used 30-day outcome data (death or receipt of respiratory, cardiovascular or renal support) to determine prognostic accuracy for adverse outcome. RESULTS: We analysed data from 20 891 adults, of whom 4611 (22.1%) died or received organ support (primary outcome), with 2058 (9.9%) receiving organ support and 2553 (12.2%) dying without organ support (secondary outcomes). C-statistics for the primary outcome were: CURB-65 0.75; CRB-65 0.70; PMEWS 0.77; NEWS2 (score) 0.77; NEWS2 (rule) 0.69; SFAHP (6-point rule) 0.70; SFAHP (7-point rule) 0.68; WHO algorithm 0.61. All triage tools showed worse prediction for receipt of organ support and better prediction for death without organ support. At the recommended threshold, PMEWS and the WHO criteria showed good sensitivity (0.97 and 0.95, respectively) at the expense of specificity (0.30 and 0.27, respectively). The NEWS2 score showed similar sensitivity (0.96) and specificity (0.28) when a lower threshold than recommended was used. CONCLUSION: CURB-65, PMEWS and the NEWS2 score provide good but not excellent prediction for adverse outcome in suspected COVID-19, and predicted death without organ support better than receipt of organ support. PMEWS, the WHO criteria and NEWS2 (using a lower threshold than usually recommended) provide good sensitivity at the expense of specificity. TRIAL REGISTRATION NUMBER: ISRCTN56149622.

Post-exertion oxygen saturation as a prognostic factor for adverse outcome in patients attending the emergency department with suspected COVID-19: a substudy of the PRIEST observational cohort study.

BACKGROUND: Measurement of post-exertion oxygen saturation has been proposed to assess illness severity in suspected COVID-19 infection. We aimed to determine the accuracy of post-exertional oxygen saturation for predicting adverse outcome in suspected COVID-19. METHODS: We undertook a substudy of an observational cohort study across 70 emergency departments during the first wave of the COVID-19 pandemic in the UK. We collected data prospectively, using a standardised assessment form, and retrospectively, using hospital records, from patients with suspected COVID-19, and reviewed hospital records at 30 days for adverse outcome (death or receiving organ support). Patients with post-exertion oxygen saturation recorded were selected for this analysis. We constructed receiver-operating characteristic curves, calculated diagnostic parameters, and developed a multivariable model for predicting adverse outcome. RESULTS: We analysed data from 817 patients with post-exertion oxygen saturation recorded after excluding 54 in whom measurement appeared unfeasible. The c-statistic for post-exertion change in oxygen saturation was 0.589 (95% CI 0.465 to 0.713), and the positive and negative likelihood ratios of a 3% or more desaturation were, respectively, 1.78 (1.25 to 2.53) and 0.67 (0.46 to 0.98). Multivariable analysis showed that post-exertion oxygen saturation was not a significant predictor of adverse outcome when baseline clinical assessment was taken into account (p=0.368). Secondary analysis excluding patients in whom post-exertion measurement appeared inappropriate resulted in a c-statistic of 0.699 (0.581 to 0.817), likelihood ratios of 1.98 (1.26 to 3.10) and 0.61 (0.35 to 1.07), and some evidence of additional prognostic value on multivariable analysis (p=0.019). CONCLUSIONS: Post-exertion oxygen saturation provides modest prognostic information in the assessment of selected patients attending the emergency department with suspected COVID-19. TRIAL REGISTRATION NUMBER: ISRCTN Registry (ISRCTN56149622) http://www.isrctn.com/ISRCTN28342533.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Corrigendum: The Extended Specimen Network: A Strategy to Enhance US Biodiversity Collections, Promote Research and Education.

[This corrects the article DOI: 10.1093/biosci/biz140.].

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

Intrapleural use of tissue plasminogen activator and DNase in pleural infection.

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

Long-Term Adherence to Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnoea Set Up in a Complete Remote Pathway: A Single-Centre Service Evaluation Project.

Background: Continuous positive airway pressure (CPAP) is the first-line treatment for obstructive sleep apnoea (OSA). Maintaining adherence to CPAP in the long term is a clinical problem, and numerous factors have been identified that impact adherence. Although fully remote diagnostic and CPAP services were frequently utilised during the COVID-19 pandemic for patients with OSA, long-term adherence data have not been published. The aim of this service evaluation project was to describe the long-term adherence to CPAP. We also analysed factors that are associated with it. Methods: two-hundred and eighty patients diagnosed with OSA and set up on CPAP remotely during the first wave of the COVID-19 pandemic as part of routine clinical practice were analysed. Results: One-hundred and seven patients (38%) were fully adherent to CPAP at 24 months, determined by at least 4 h of usage on at least 70% of the days. Of the factors analysed, body mass index, disease severity, driving status and the presence of depression were related to long-term adherence (all p < 0.05). Conclusions: with the likelihood of future pandemics similar to COVID-19, our data provide evidence that fully remote pathways for management of patients with OSA can be designed and be sustainable with good long-term adherence.

Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial.

BACKGROUND: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. METHOD/DESIGN: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. DISCUSSION: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. TRIAL REGISTRATION: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Primary spontaneous pneumothorax: a diffuse disease of the pleura.

Primary spontaneous pneumothorax (PSP) is by definition not associated with any underlying lung disease. However, this does not mean that there is no underlying pathological process. It has become increasingly apparent over recent years that PSP is associated with diffuse and often bilateral abnormalities within the pleura and is not simply a disease caused by ruptured blebs/bullae. The pathological process includes emphysema-like changes, pleural porosity and inflammation. In this review, we summarise the recent advances in our understanding of the pathogenesis of PSP and discuss how this relates to management strategies for patients with PSP.

Evaluation of triage methods used to select patients with suspected pandemic influenza for hospital admission.

OBJECTIVES: Prepandemic projections anticipated huge excess attendances and mortality in an influenza pandemic. A number of tools had been suggested for triaging patients with influenza for inpatient and critical care admission, but none had been validated in these patients. The authors aimed to evaluate three potential triage tools--CURB-65, PMEWS and the Department of Health community assessment tool (CAT)--in patients in the first waves of the 2009 H1N1 pandemic. SETTING: Prospective cohort study in three urban emergency departments (one adult, one paediatric, one mixed) in two cities. PARTICIPANTS: All patients presenting to the three emergency departments fulfilling the national definition of suspected pandemic influenza. OUTCOME MEASURES: 30-day follow-up identified patients who had died or had required advanced respiratory, cardiovascular or renal support. RESULTS: The pandemic was much less severe than expected. A total of 481 patients (347 children) were recruited, of which only five adults fulfilled the outcome criteria for severe illness. The c-statistics for CURB-65, PMEWS and CAT in adults in terms of discriminating between those admitted and discharged were 0.65 (95% CI 0.54 to 0.76), 0.76 (95% CI 0.66 to 0.86) and 0.62 (95% CI 0.51 to 0.72), respectively. In detecting adverse outcome, sensitivities were 20% (95% CI 4% to 62%), 80% (95% CI 38% to 96%) and 60% (95% CI 23% to 88%), and specificities were 94% (95% CI 88% to 97%), 40% (95% CI 32% to 49%) and 81% (95% CI 73% to 87%) for CURB-65, PMEWS and CAT, respectively. CONCLUSIONS: Although limited by a paucity of cases, this research shows that current triage methods for suspected pandemic influenza did not reliably discriminate between patients with good and poor outcomes.

Hypercapnia in COPD: Causes, Consequences, and Therapy.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder that may lead to gas exchange abnormalities, including hypercapnia. Chronic hypercapnia is an independent risk factor of mortality in COPD, leading to epithelial dysfunction and impaired lung immunity. Moreover, chronic hypercapnia affects the cardiovascular physiology, increases the risk of cardiovascular morbidity and mortality, and promotes muscle wasting and musculoskeletal abnormalities. Noninvasive ventilation is a widely used technique to remove carbon dioxide, and several studies have investigated its role in COPD. In the present review, we aim to summarize the causes and effects of chronic hypercapnia in COPD. Furthermore, we discuss the use of domiciliary noninvasive ventilation as a treatment option for hypercapnia while highlighting the controversies within the evidence. Finally, we provide some insightful clinical recommendations and draw attention to possible future research areas.

A randomised controlled trial of non-invasive ventilation compared with extracorporeal carbon dioxide removal for acute hypercapnic exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Patients presenting with acute hypercapnic respiratory failure due to exacerbations of chronic obstructive pulmonary disease (AECOPD) are typically managed with non-invasive ventilation (NIV). The impact of low-flow extracorporeal carbon dioxide removal (ECCO2R) on outcome in these patients has not been explored in randomised trials. METHODS: Open-label randomised trial comparing NIV (NIV arm) with ECCO2R (ECCO2R arm) in patients with AECOPD at high risk of NIV failure (pH < 7.30 after ≥ 1 h of NIV). The primary endpoint was time to cessation of NIV. Secondary outcomes included device tolerance and complications, changes in arterial blood gases, hospital survival. RESULTS: Eighteen patients (median age 67.5, IQR (61.5-71) years; median GOLD stage 3 were enrolled (nine in each arm). Time to NIV discontinuation was shorter with ECCO2R (7:00 (6:18-8:30) vs 24:30 (18:15-49:45) h, p = 0.004). Arterial pH was higher with ECCO2R at 4 h post-randomisation (7.35 (7.31-7.37) vs 7.25 (7.21-7.26), p < 0.001). Partial pressure of arterial CO2 (PaCO2) was significantly lower with ECCO2R at 4 h (6.8 (6.2-7.15) vs 8.3 (7.74-9.3) kPa; p = 0.024). Dyspnoea and comfort both rapidly improved with commencement of ECCO2R. There were no severe or life-threatening complications in the study population. There were no episodes of major bleeding or red blood cell transfusion in either group. ICU and hospital length of stay were longer with ECCO2R, and there was no difference in 90-day mortality or functional outcomes at follow-up. INTERPRETATION: There is evidence of benefit associated with ECCO2R with time to improvement in respiratory acidosis, in respiratory physiology and an immediate improvement in patient comfort and dyspnoea with commencement of ECCO2R. In addition, there was minimal clinically significant adverse events associated with ECCO2R use in patients with AECOPD at risk of failing or not tolerating NIV. However, the ICU and hospital lengths of stay were longer in the ECCO2R for similar outcomes. Trial registration The trial is prospectively registered on ClinicalTrials.gov: NCT02086084. Registered on 13th March 2014, https://clinicaltrials.gov/ct2/show/NCT02086084?cond=ecco2r&draw=2&rank=8.

Non-cardiac Manifestations in Adult Patients With Mucopolysaccharidosis.

Mucopolysaccharidoses (MPS) are a heterogeneous group of disorders that results in the absence or deficiency of lysosomal enzymes, leading to an inappropriate storage of glycosaminoglycans (GAGs) in various tissues of the body such as bones, cartilage, heart valves, arteries, upper airways, cornea, teeth, liver and nervous system. Clinical manifestations can become progressively exacerbated with age and affect their quality of life. Developments in advanced supportive treatment options such as enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT) may have improved patients' life span. Adult MPS patients require specialist clinical surveillance long-term. In many cases, in addition to the MPS-related health problems, they may develop age-related complications. Considering the complexity of their clinical manifestations and lack of guidelines on the management of adult MPS disorders, multispecialty and multidisciplinary teams' care is essential to diagnose and treat health problems that are likely to be encountered. This review presents non-cardiac clinical manifestations, their pathophysiology, management and long-term outcomes in adult MPS patients.