Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Monocyte NLRP3 inflammasome and interleukin-1ß activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

Chronic pain in female breast cancer survivors - prevalence, characteristics and contributing factors: a cross-sectional pilot study.

BACKGROUND: While the global incidence of breast cancer is increasing, there is also an increase in the numbers of breast cancer survivors and in survival duration, as early detection programs are implemented, and treatments are optimized. Breast cancer survivors in several countries commonly struggle with a range of symptoms (fatigue, insomnia, depression) with 25-80% of survivors suffering from chronic pain. There is a paucity of literature reporting on breast cancer survivors in South Africa. In this pilot study we aimed to determine the prevalence of chronic pain in female breast cancer survivors attending the breast oncology clinic. METHODS: A cross-sectional survey was conducted of all breast cancer survivors attending the Groote Schuur Hospital Breast Unit during one month in 2019. 44 female breast cancer survivors (median age 60.5y) completed a sociodemographic questionnaire, the Brief Pain Inventory, Pain Catastrophizing Scale and measures for neuropathic pain (DN4), health related quality of life (HRQoL; EQ-5d-3 L), physical activity (IPAQ), depression and anxiety (PHQ4), and screening questions to evaluate sleep, happiness and perceived discrimination in the language of their choice. RESULTS: The prevalence of chronic pain (pain on most days for more than three months) was 59% (95%CI 44-72), a significantly higher number than the 18,3% prevalence of chronic pain reported by South African adults. 39% of the women were classified as having neuropathic pain. The median pain severity score was 3.75 (IQR = 2.75-5) and the median pain interference with function score was 4 (IQR = 2.9-5.4). The women were experiencing pain in a median of 2 different body sites (IQR = 1-3). The women with pain were more likely to be unemployed or receiving a disability grant, had significantly worse HRQoL, and significantly worse scores for risk of depression and anxiety. CONCLUSION: The results of this pilot study suggest that chronic pain may be a significant burden for South African breast cancer survivors. Routine screening for chronic pain in breast cancer survivors is recommended with a larger study indicated to explore this issue further.

Financial Advisers' and Key Informants' Perspectives on the Australian Industry-Led Moratorium on Genetic Tests in Life Insurance.

INTRODUCTION: Genetic discrimination (GD) in the context of life insurance is a perennial concern in Australia and internationally. To address such concerns in Australia, an industry self-regulated Moratorium on Genetic Tests in Life Insurance was introduced in 2019 to restrict life insurers from using genetic test results in underwriting for policies under certain limits. Financial advisers (FAs) are sometimes engaged by clients to provide financial advice and assist them to apply for life insurance. They are therefore well-placed to comment on GD and the operation of the Moratorium. Despite this, the financial advising sector in Australia has yet to be studied empirically with regards to GD and the Moratorium. This study aims to capture this perspective by reporting on interviews with the financial advising sector. METHODS: Ten semi-structured qualitative interviews were conducted with FAs and key informants and were analysed using thematic analysis. CONCLUSION(S): Participants' level of awareness and understanding of the Moratorium varied. Participants reported mixed views on the Moratorium's effectiveness, how it operates in practice, and perceived industry compliance. Participants also provided reflections on Australia's current approach to regulating GD, with most participants supporting the concept of industry self-regulation but identifying a need for this to be supplemented with external oversight and meaningful recourse mechanisms for consumers. Our results suggest that there is scope to increase FAs' awareness of GD, and that further research, consultation, and policy consideration are required to identify an optimal regulatory response to GD in Australia.

Effect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis.

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)-1ß and IL-8 in sputum, accompanied by decreased Pseudomonas burden and restoration of secretory leukoprotease inhibitor levels. Once treated with ETI, all airway inflammatory markers studied in PWCF had reduced to levels found in matched non-CF bronchiectasis controls. In PWCF with advanced disease, ETI resulted in decreased plasma concentrations of IL-6, C-reactive protein and soluble TNF receptor one as well as normalisation of levels of the acute phase protein, alpha-1 antitrypsin. These data clarify the immunomodulatory effects of ETI and underscore its role as a disease modifier.

Tracheostomy insertion in COVID-19: insertion practice and factors leading to unplanned tube exchange.

Background: Tracheostomy insertion in patients with coronavirus disease 2019 (COVID-19) presents unique challenges. Patients frequently have high ventilatory requirements, and as an aerosol generating procedure, tracheostomy insertion creates the potential for staff transmission. Problems with tracheostomies contribute to morbidity and mortality, and tracheostomy changes may increase risks of staff transmission. We sought to quantify the incidence of clinically necessitated tracheostomy changes, establish the indications for change and investigate the incidence of staff transmission. Methods: We conducted a single institution, retrospective, observational cohort study of all intensive care unit (ICU) patients with COVID-19 who had a tracheostomy between March 2020 and April 2021. The institution is a large tertiary referral centre in Ireland. Results: Forty-three patients had a tracheostomy during the study period. All were a Shiley™ Flexible Adult Taperguard or Shiley™ XLT Tracheostomy. 14 patients (33%) required a tracheostomy change, with the majority (57%) involving a change from a standard size to an extended length tracheostomy. Persistent leak was the most common indication for change (71.6%). Other indications included patient-ventilator dyssynchrony, persistent cough and accidental decannulation. No staff transmission of COVID-19 occurred during this study. Conclusions: The incidence of tracheostomy change was 33%, highlighting the importance of selecting the right tracheostomy for each patient. We discuss how key characteristics of tracheostomies such as type, size, length and inner diameter may impact flow, resistance and work of breathing, leading to unplanned tracheostomy change. No staff transmission occurred arising from tracheostomy insertion, adding to increasing evidence that tracheostomy insertion in COVID-19 appears safe with adherence to guidelines describing the correct use of personal protective equipment.

Global series: Complex regional pain syndrome: abstracts from the International Association for the Study of Pain complex regional pain syndrome SIG virtual symposia 2021.

The aim of this IASP complex regional pain syndrome (CRPS) SIG Global Series 2021 was to bring together clinicians including those from developing countries to better understand the clinical presentation of complex regional pain syndrome in countries with less well-published patient populations. The purpose was to learn from each other about the range of treatments, successful outcomes, and challenges experienced. These meeting proceedings comprise abstracts from nine countries that span 4 continents and are summaries of online presentations delivered by speakers representing these countries over the course of 2 symposia. The symposia were attended by a global audience of approximately 360 people. Patients with CRPS were described and treated by clinicians from countries across Asia (Pakistan, Jordan, South Korea, Taiwan, and Singapore), South America (Brazil and Peru), Africa (South Africa), and Europe (Norway). This reflects that CRPS exists across borders, ethnicities, and cultures. These proceedings provide a broader perspective within the international pain community about how we can better understand and treat CRPS across the globe.

Estimating the Effect of Tafamidis on Cardiovascular-Related Hospitalization in NYHA Class III Patients with Transthyretin Amyloid Cardiomyopathy in the Presence of Death.

BACKGROUND: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo. Given the greater mortality rate with placebo, this analysis assessed the impact of the confounding effect of death on the frequency of CV-related hospitalization in ATTR-ACT. METHODS: In ATTR-ACT, patients with ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. Post hoc analyses first defined and compared the effect of tafamidis treatment in the subset of NYHA class III patients from each treatment arm alive at month 30. The impact of a potential survivor bias was then adjusted for using principal stratification, estimating the frequency of CV-related hospitalization in NYHA class III patients who would have survived regardless of assigned treatment group (defined as the survivor average causal effect [SACE]). RESULTS: In the subset of NYHA class III patients alive at month 30, tafamidis reduced the relative risk of CV-related hospitalization versus placebo (relative risk: 0.95 [95% CI: 0.55-1.65]). In the principal stratification analyses of those patients who would survive to 30 months regardless of treatment, tafamidis treatment was associated with a 24% lower risk of CV-related hospitalization (relative risk: 0.76 [95% CI: 0.45-1.24]). Similarly, there was a larger reduction in CV-related hospitalization frequency with tafamidis in NYHA class I or II patients in the SACE than was initially observed in ATTR-ACT. CONCLUSIONS: Initial data from ATTR-ACT likely underestimated the effect of tafamidis on CV-related hospitalizations due to the confounding effect of death. When SACE was used to adjust for survivor bias, there was a 24% reduction in the frequency of CV-related hospitalization in NYHA class III patients treated with tafamidis.

Integrating geographic ranges across temporal scales.

Geographic ranges are a fundamental unit of biogeography and macroecology. Increasingly, paleontologists and ecologists alike are reconstructing geographic ranges of species from fossils, in order to understand the long-term processes governing biogeographic and macroevolutionary patterns. As these reconstructions have become increasingly common, uncertainty has arisen over the equivalency of paleo-ranges and modern ranges. Here, we argue geographic ranges are time-averaged at all temporal scales, and reflect the biotic and abiotic processes operating across the equivalent range of time and space scales. This conceptual framework integrates the study of geographic ranges reconstructed using modern and ancient data, and highlights the potential for ranges to illuminate processes responsible for diversity patterns over intervals spanning days to tens of millions of years of Earth history.

Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease.

In the lung, glycosaminoglycans (GAGs) are dispersed in the extracellular matrix (ECM) occupying the interstitial space between the capillary endothelium and the alveolar epithelium, in the sub-epithelial tissue and in airway secretions. In addition to playing key structural roles, GAGs contribute to a number of physiologic processes ranging from cell differentiation, cell adhesion and wound healing. Cytokine and chemokine-GAG interactions are also involved in presentation of inflammatory molecules to respective receptors leading to immune cell migration and airway infiltration. More recently, pathophysiological roles of GAGs have been described. This review aims to discuss the biological roles and molecular interactions of GAGs, and their impact in the pathology of chronic airway diseases, such as cystic fibrosis and chronic obstructive pulmonary disease. Moreover, the role of GAGs in respiratory disease has been heightened by the current COVID-19 pandemic. This review underlines the essential need for continued research aimed at exploring the contribution of GAGs in the development of inflammation, to provide a better understanding of their biological impact, as well as leads in the development of new therapeutic agents.

Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with Obstructive Lung Disease.

Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma membrane plays a central role in adhesion and subsequent transmigration to underlying tissues. This study aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation therapy abrogates this effect. Plasma and blood neutrophils were donated by healthy controls (n = 20), AATD (n = 30), and AATD patients after AAT augmentation therapy (n = 6). Neutrophil membrane protein expression was investigated using liquid chromatography-tandem mass spectrometry. The effect of once-weekly intravenous AAT augmentation therapy was assessed by calcium fluorometric, µ-calpain, and cell adhesion assays. Decreased neutrophil plasma membrane cholesterol content (P = 0.03), yet increased abundance of integrin α-M (fold change 1.91), integrin α-L (fold change 3.76), and cytoskeletal adaptor proteins including talin-1 (fold change 4.04) were detected on AATD neutrophil plasma membrane fractions. The described inflammatory induced structural changes were a result of a more than twofold increased cytosolic calcium concentration (P = 0.02), leading to significant calcium-dependent µ-calpain activity (3.5-fold change; P = 0.005), resulting in proteolysis of the membrane cholesterol trafficking protein caveolin-1. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased caveolin-1 and membrane cholesterol content (111.8 ± 15.5 vs. 64.18 ± 7.8 µg/2 × 107 cells before and after treatment, respectively; P = 0.02), with concurrent decreased neutrophil integrin expression and adhesion. Results demonstrate an auxiliary benefit of AAT augmentation therapy, evident by a decrease in circulating inflammation and controlled neutrophil adhesion.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.

A narrative literature review of the impact of conscientious objection by health professionals on women's access to abortion worldwide 2013-2021.

Conscientious objection to provide abortion has been enshrined in laws and policies globally. Insufficient attention has been paid to the direct and indirect ways in which conscientious objection compromises women's access to a lawful abortion. Using a systematic search strategy, this narrative literature review synthesises the literature exploring conscientious objection's impact on women's access to abortion in a range of countries. This narrative literature review builds on an extensive literature review published by Chavkin et al. (2013. Conscientious objection and refusal to provide reproductive healthcare: A white paper examining prevalence, health consequences, and policy responses. International Journal of Gynecology & Obstetrics, 123, S41-S56. https://doi.org/10.1016/S0020-7292(13)60002-8). Searches were undertaken on the Medline (Ovid), Global Health, CINAHL, Scopus and Science Direct databases. Thirty six papers were included for thematic analysis. Conscientious objection to abortion was found to impact women's access to abortion at three main levels: the practitioner level, the healthcare system level and the sociocultural environment level. Conscientious objection was found to impact access directly through attempts by health professionals to restrict access, and indirectly by exacerbating pre-existing barriers to access. Further research is required to better quantify the extent to which this impacts women and whether interventions are effective in reducing the barriers that conscientious objection creates and exacerbates.

Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1ß secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers. Methods: Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1ß secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1ß secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1ß secretion. Conclusions: P2X7R expression is regulated by intracellular Cl- levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R-induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.

Current evidence on the effect of highly effective CFTR modulation on interleukin-8 in cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is a genetically inherited disease, with mortality and morbidity associated with respiratory disease. The inflammatory response in CF is characterized by excessive neutrophil influx to the airways, mainly due to the increased local production and retention of interleukin-8 (IL-8), a potent neutrophil chemoattractant. AREAS COVERED: We discuss how the chemokine IL-8 dominates the inflammatory profile of the airways in CF lung disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein resulting from specific CFTR mutations. This review covers current evidence on the impact of CFTR impairment on levels of IL-8 and outlines the influence of effective CFTR modulation on inflammation in CF with a focus on cytokine production. Review of the literature was carried out using the PUBMED database, Google Scholar, and The Cochrane Library databases, using several appropriate generic terms. EXPERT OPINION: Therapeutic interventions specifically targeting the defective CFTR protein have improved the outlook for CF. Accumulating studies on the effect of highly effective CFTR modulation on inflammation indicate an impact on IL-8 levels. Further studies are required to increase our knowledge of early onset innate inflammatory dysregulation and on anti-inflammatory mechanisms of CFTR modulators.

C3d Elicits Neutrophil Degranulation and Decreases Endothelial Cell Migration, with Implications for Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. The current study investigated the impact of C3d on circulating neutrophils. Blood was collected from AATD (n = 88) or non-AATD COPD patients (n = 10) and healthy controls (HC) (n = 40). Neutrophils were challenged with C3d, and degranulation was assessed by Western blotting, ELISA, or fluorescence resonance energy transfer (FRET) substrate assays. Ex vivo, C3d levels were increased in plasma (p < 0.0001) and on neutrophil plasma membranes (p = 0.038) in AATD compared to HC. C3d binding to CR3 receptors triggered primary (p = 0.01), secondary (p = 0.004), and tertiary (p = 0.018) granule release and increased CXCL8 secretion (p = 0.02). Ex vivo plasma levels of bactericidal-permeability-increasing-protein (p = 0.02), myeloperoxidase (p < 0.0001), and lactoferrin (p < 0.0001) were significantly increased in AATD patients. In endothelial cell scratch wound assays, C3d significantly decreased cell migration (p < 0.0001), an effect potentiated by neutrophil degranulated proteins (p < 0.0001). In summary, AATD patients had increased C3d in plasma and on neutrophil membranes and, together with neutrophil-released granule enzymes, reduced endothelial cell migration and wound healing, with potential implications for AATD-related vasculitis.

"I haven't had to bare my soul but now I kind of have to": describing how voluntary assisted dying conscientious objectors anticipated approaching conversations with patients in Victoria, Australia.

BACKGROUND: Dealing with end of life is challenging for patients and health professionals alike. The situation becomes even more challenging when a patient requests a legally permitted medical service that a health professional is unable to provide due to a conflict of conscience. Such a scenario arises when Victorian health professionals, with a conscientious objection (CO) to voluntary assisted dying (VAD), are presented with patients who request VAD or merely ask about VAD. The Voluntary Assisted Dying Act 2017 (Vic) recognizes the inherent conflict of conscience that may arise for some health professionals when asked to provide VAD and responds by affording broad protection to conscientious objectors who wish to refuse to take part in the VAD process. METHODS: Seventeen semi-structured qualitative interviews were conducted with Victorian health professionals with a self-identified CO to VAD in the lead-up to the implementation of VAD in Victoria. Interviews explored how participants anticipated they would manage their CO in practice. Interviews were transcribed verbatim and analyzed thematically. RESULTS: Our results reveal that the way in which health professionals claimed they would approach CO conversations is variable and was dependant on the strength of their opposition to VAD. We categorized conscientious objectors according to their approach as either dissuasive non-referrers, passive non-referrers, facilitators or negotiators. Our study also explores the perceived difficulties of exercising one's CO as identified by our participants. CONCLUSION: The broad protection offered by the Voluntary Assisted Dying Act 2017 (Vic) encourages a range of behaviors from conscientious objectors, due to the minimal obligations imposed. In order to assist conscientious objectors, more policy, institutional guidance, and education needs to be available to conscientious objectors explicitly addressing how to effectively manage one's CO. Such guidance is imperative to ensuring that their moral integrity is preserved and that they are exercising their CO appropriately.

Effects of non-invasive respiratory support on gas exchange and outcomes in COVID-19 outside the ICU.

Non-invasive respiratory support (NRS) outside of the ICU has played an important role in the management of COVID-19 pneumonia. There is little data to guide selection of NRS modality. We present outcomes of NRS outside the ICU and discuss the effects of NRS on gas exchange with implications for management.