Multicentre sleep-stage scoring agreement in the Sleep Revolution project.

Determining sleep stages accurately is an important part of the diagnostic process for numerous sleep disorders. However, as the sleep stage scoring is done manually following visual scoring rules there can be considerable variation in the sleep staging between different scorers. Thus, this study aimed to comprehensively evaluate the inter-rater agreement in sleep staging. A total of 50 polysomnography recordings were manually scored by 10 independent scorers from seven different sleep centres. We used the 10 scorings to calculate a majority score by taking the sleep stage that was the most scored stage for each epoch. The overall agreement for sleep staging was κ = 0.71 and the mean agreement with the majority score was 0.86. The scorers were in perfect agreement in 48% of all scored epochs. The agreement was highest in rapid eye movement sleep (κ = 0.86) and lowest in N1 sleep (κ = 0.41). The agreement with the majority scoring varied between the scorers from 81% to 91%, with large variations between the scorers in sleep stage-specific agreements. Scorers from the same sleep centres had the highest pairwise agreements at κ = 0.79, κ = 0.85, and κ = 0.78, while the lowest pairwise agreement between the scorers was κ = 0.58. We also found a moderate negative correlation between sleep staging agreement and the apnea-hypopnea index, as well as the rate of sleep stage transitions. In conclusion, although the overall agreement was high, several areas of low agreement were also found, mainly between non-rapid eye movement stages.

Investigating psychological mechanisms linking pain severity to depression symptoms in women cancer survivors at a cancer center with a rural catchment area.

PURPOSE: Women cancer survivors, especially those in rural areas, with high levels of depression may be acutely susceptible to pain due to the ways they think, feel, and behave. The current study seeks to elucidate the relationship between symptoms of depression and pain severity in women cancer survivors, by examining the putative mediators involved in this relationship, specifically their self-efficacy for managing their health, how overwhelmed they were from life's responsibilities, and relational burden. METHODS: Self-report data were collected from 183 cancer survivors of breast, cervical, ovarian, or endometrial/uterine cancer, who were between 6 months and 3 years post-active therapy. RESULTS: Women cancer survivors with higher (vs. lower) symptoms of depression had more severe pain. Individual mediation analyses revealed that survivors with higher levels of depression felt more overwhelmed by life's responsibilities and had lower self-efficacy about managing their health, which was associated with greater pain severity. When all mediators were simultaneously entered into the same model, feeling overwhelmed by life's responsibilities significantly mediated the link between survivors' symptoms of depression and their pain severity. CONCLUSIONS: The relationship between symptoms of depression and pain severity in women cancer survivors may be attributed in part to their self-efficacy and feeling overwhelmed by life's responsibilities. Early and frequent assessment of psychosocial factors involved in pain severity for women cancer survivors may be important for managing their pain throughout the phases of cancer survivorship.

Pulmonary Vascular Responses to Chronic Intermittent Hypoxia in a Guinea Pig Model of Obstructive Sleep Apnea.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

How to recognise a Behçet's ulcer from other types of oral ulceration? Defining Behçet's ulceration by an International Delphi Consultation.

OBJECTIVES: To define the clinical characteristics of oral ulceration (OU) in Behçet's disease (BD), to allow differentiation from other causes of OU, including aphthous ulcers, by an International Delphi consultation. To develop a clinical guideline on how to recognise BD ulcers. METHODS: Round 1. 40 clinical images of OU in BD, recurrent aphthous stomatitis (RAS), inflammatory bowel disease (IBD) and mucous membrane pemphigoid (MMP) were shown. Participants answered, independently, which images would be consistent with a BD ulcer. Round 2. The results from marking independently were shown. The panel remarked the questions through iteration process. The images not agreed to be a possible BD ulcer were discarded. Round 3. 10 clinical descriptors that may define BD ulcers were suggested. Participants ranked the level of importance for each descriptor on each image presented. Round 4. Participants re-ranked their level of agreement for each descriptor through iteration process. Whether the clinical pictures would be different from RAS was also explored. A final agreement was reached. RESULTS: This study has shown clear differentiation between BD, IBD and MMP ulcers when defining them by phenotype through clinical images only. On the other hand, no differentiation between RAS and BD ulcers was found. The most important clinical descriptors that define BD ulcers have been agreed. CONCLUSIONS: New clinical guidance for Health Care Professionals (HCP) on how to recognise a BD ulcer has been proposed. This should elucidate an earlier diagnosis, quicker access to treatment and control of the disease enhancing patient's quality of life.

Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions.

Disruption of protein folding in the endoplasmic reticulum (ER) causes unfolded proteins to accumulate, triggering the unfolded protein response (UPR). UPR outputs in turn decrease ER unfolded proteins to close a negative feedback loop. However, because it is infeasible to directly measure the concentration of unfolded proteins in vivo, cells are generically described as experiencing "ER stress" whenever the UPR is active. Because ER redox potential is optimized for oxidative protein folding, we reasoned that measureable redox changes should accompany unfolded protein accumulation. To test this concept, we employed fluorescent protein reporters to dynamically measure ER redox status and UPR activity in single cells. Using these tools, we show that diverse stressors, both experimental and physiological, compromise ER protein oxidation when UPR-imposed homeostatic control is lost. Using genetic analysis we uncovered redox heterogeneities in isogenic cell populations, and revealed functional interlinks between ER protein folding, modification, and quality control systems.

Associations between context and affect within the daily lives of cancer caregivers.

PURPOSE: This study used ecological momentary assessment (EMA) to test the association between activity, location, and social company contexts with cancer caregivers' in-the-moment affect to identify precisely when and where to deliver psychological interventions for caregivers. METHODS: Current cancer caregivers (N = 25) received 8 EMA prompts per day for 7 consecutive days. At each prompt, caregivers reported their current positive affect and negative affect, as well as what they were doing, where they were located, and who they were with. Multilevel logistic regressions tested the associations between caregivers' contexts with their own person-mean-centered state (concurrent momentary level) and trait (overall weekly average) positive or negative affect. RESULTS: Caregivers reported lower state negative affect, as well as higher state positive affect, when socializing (ps < .001), when at a public location (ps < .03), and when around their friends, family, spouse/partner, or care recipient (i.e., person with cancer, ps < .02), relative to when not endorsing the context. Caregivers also reported lower state negative affect when eating/drinking or engaging in leisure (ps < .01; but no parallel effects for state positive affect). Caregivers reported higher state negative affect while working, when at their workplace, or when around work colleagues (ps < .001) and lower state positive affect when at home or alone (ps < .03). CONCLUSIONS: Results suggest the pertinence of a behavioral activation framework to mitigate the emotional strain of caregiving. Interventions that facilitate caregivers' ability to socialize with a range of friends and family, including their loved one with cancer, outside of the home may have the strongest positive emotional impact.

Late Holocene anthropogenic landscape change in northwestern Europe impacted insect biodiversity as much as climate change did after the last Ice Age.

Since the last Ice Age (ca 115 000-11 700 years ago), the geographical ranges of most plants and animals have shifted, expanded or contracted. Understanding the timing, geographical patterns and drivers of past changes in insect communities is essential for evaluating the biodiversity implications of future climate changes, yet our knowledge of long-term patterns is limited. We applied a network modelling approach to the recent fossil record of northwestern European beetles to investigate how their taxonomic and trait composition changed during the past 16 000 years. We found two major changes in beetle faunas 4000-3500 and 10 000-9500 years ago, coinciding with periods of human population growth in the Late Holocene and climate warming in the Early Holocene. Our results demonstrate that humans have affected insect biodiversity since at least the introduction of agropastoralism, with landscape-scale effects that can be observed at sites away from areas of direct human impact.

Layers, broiler chickens and their F1 cross develop distinctly different caecal microbial communities when hatched and reared together.

AIM: To compare the caecal microbiota of layer, broiler, and intermediate F1 layer × broiler cross birds with the hypothesis that significant differences in caecal microbial composition would persist between the three groups when host and environmental interactions were minimized. METHODS AND RESULTS: Caecal contents were characterized using 16S rRNA for males of broiler (n = 12), layer (n = 12) and F1 layer × broiler cross (n = 9) birds that were hatched and reared under the same conditions. The microbial community structure differed significantly between the three groups of birds at phylum, genus and OTU levels, with clear separation of the groups observed. Firmicutes was the phylum most represented across samples; however, the high abundance of Proteobacteria in the layer birds at d28 post-hatch was unexpected, and driven by a higher abundance of E. coli. CONCLUSIONS: The microbiota phylotype between broilers, layers and their F1 cross significantly differed in community structure, diversity and relative abundance in the absence of environmental confounding, which is generally difficult to avoid in microbial studies. SIGNIFICANCE AND IMPACT OF STUDY: The results provide a unique comparison and evidence that there is a strong genetic component driving microbial composition within poultry strains, despite the embryonic development occurring in ovo.

Effects of an internet-delivered insomnia intervention for older adults: A secondary analysis on symptoms of depression and anxiety.

OBJECTIVE: To test whether an Internet-delivered cognitive behavioral therapy for insomnia (CBT-I) program for older adults attenuates symptoms of depression and anxiety. METHODS: Adults aged ≥ 55 with insomnia were randomized to SHUTi-OASIS (Sleep Healthy Using the Internet for Older Adult Sufferers of Insomnia and Sleeplessness; N = 207) or Patient Education (PE; N = 104). Depression and anxiety were assessed (HADS-D and HADS-A, respectively) at baseline, post-assessment, and 6- and 12-month follow-ups. RESULTS: Multilevel modeling of HADS-D showed a condition by time interaction (F[3,779] = 3.23, p = .02): SHUTi-OASIS participants reported lower symptoms than PE at post-assessment. There was no such interaction effect for HADS-A (F[3,779] = 2.12, p = .10). Generalized linear modeling showed no moderation of effects by baseline symptom severity. CONCLUSIONS: Participants randomized to Internet-delivered CBT-I showed stable depression and anxiety across time, while control participants' depressive symptoms briefly increased. CBT-I may help prevent development or worsening of psychological distress among older adults with insomnia. TRIAL REGISTRATION: [Registered at ClinicalTrials.gov; identifier removed for anonymity].

Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress.

Diverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such "ER stress," we employed an ER-targeted, redox-responsive, green fluorescent protein-eroGFP-that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress regimes cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to "reflux" back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in Saccharomyces cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and cochaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.

Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment.

PURPOSE: To develop an agreed upon set of outcomes known as a "core outcome set" (COS) for noninfectious uveitis of the posterior segment (NIU-PS) clinical trials. DESIGN: Mixed-methods study design comprising a systematic review and qualitative study followed by a 2-round Delphi exercise and face-to-face consensus meeting. PARTICIPANTS: Key stakeholders including patients diagnosed with NIU-PS, their caregivers, and healthcare professionals involved in decision-making for patients with NIU-PS, including ophthalmologists, nurse practitioners, and policymakers/commissioners. METHODS: A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a 2-round Delphi exercise of stakeholders rating the importance of outcomes on a 9-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of "include," "exclude," or "for discussion" that were taken to a face-to-face consensus meeting of key stakeholders at which they agreed on the final COS. MAIN OUTCOME MEASURE: Items recommended for inclusion in the COS for NIU-PS. RESULTS: A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting, of which 7 of 15 were agreed on for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, health-related quality of life, treatment side effects, and disease control. CONCLUSIONS: This study builds on international work across the clinical trials community and our qualitative research to construct the world's first COS for NIU-PS. The COS provides a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce noninformative research. Some of the outcomes identified do not yet have internationally agreed upon methods for measurement and should be the subject of future international consensus development.

Broad Diversity of Near-Infrared Single-Photon Emitters in Silicon.

We report the detection of individual emitters in silicon belonging to seven different families of optically active point defects. These fluorescent centers are created by carbon implantation of a commercial silicon-on-insulator wafer usually employed for integrated photonics. Single photon emission is demonstrated over the 1.1-1.55 µm range, spanning the O and C telecom bands. We analyze their photoluminescence spectra, dipolar emissions, and optical relaxation dynamics at 10 K. For a specific family, we show a constant emission intensity at saturation from 10 K to temperatures well above the 77 K liquid nitrogen temperature. Given the advanced control over nanofabrication and integration in silicon, these individual artificial atoms are promising systems to investigate for Si-based quantum technologies.

Incidence of sight-threatening diabetic retinopathy in an established urban screening programme: An 11-year cohort study.

AIMS: Systematic annual screening to detect sight-threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up-to-date data for policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years. METHODS: All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives). RESULTS: 133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5-6.8), screen positive for retinopathy 3.1% (3.0-3.1), unassessable images 2.6% (2.5-2.7), other significant eye diseases 1.0% (1.0-1.1). 1.6% (1.6-1.7) had sight-threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%-10.6% and 4.4%-4.6% in 2007/09 to 4.4%-6.8% and 2.3%-2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% [9.4-10.2] vs. 6.1% [6.0-6.2]) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9-5.2) of previous non-attenders had sight-threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0-27.4). CONCLUSIONS: In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.

Epidemiology of disease-activity related ophthalmological manifestations in Systemic Lupus Erythematosus: A systematic review.

OBJECTIVE: Ophthalmic complications in Systemic Lupus Erythematosus (SLE) are broad and can occur in up to a third of patients. The British Isles Lupus Assessment Group (BILAG) 2004 Index identifies 13 ocular manifestations of active SLE, as opposed to those related to previous disease activity and/or the consequences of therapy. We conducted a systematic review of published literature to determine the frequency of ophthalmic manifestations of active SLE. METHODS: A systematic literature search of Ovid MEDLINE and EMBASE from their respective inceptions to July 2020 was conducted to identify cohort, case-control and cross-sectional studies. RESULTS: 22 studies meeting eligibility criteria were included. Most studies featured small sample sizes and were judged to have a high risk of methodological bias. The number and quality of studies did not allow us to confidently estimate the incidence of the conditions. No studies reported epidemiological data for orbital inflammation/myositis/proptosis. The prevalence of each of the other ocular manifestations, with the exception of retinal vaso-occlusive disease, was consistently less than 5%. Retinal vasculitis, uveitis and isolated cotton wool spots tended to be associated with more active SLE disease. CONCLUSION: The prevalence of eye disease due to SLE activity is uncommon, but clinicians should be aware that some conditions tend to be associated with more active systemic disease. Further studies to determine the incidence and risk factors for these ophthalmic manifestations are needed.

Feasibility of ecological momentary assessment to study depressive symptoms among cancer caregivers.

OBJECTIVE: Ecological momentary assessment (EMA) may help with the development of more targeted interventions for caregivers' depression, yet the use of this method has been limited among cancer caregivers. This study aimed to demonstrate the feasibility of EMA among cancer caregivers and the use of EMA data to understand affective correlates of caregiver depressive symptoms. METHODS: Caregivers (N = 25) completed a depressive symptom assessment (Patient Health Questionnaire-8) and then received eight EMA survey prompts per day for 7 days. EMA surveys assessed affect on the orthogonal dimensions of valence and arousal. Participants completed feedback surveys regarding the EMA protocol at the conclusion of the week-long study. RESULTS: Of 32 caregivers approached, 25 enrolled and participated (78%), which exceeded the a priori feasibility cutoff of 55%. The prompt completion rate (59%, or 762 of 1,286 issued) did not exceed the a priori cutoff of 65%, although completion was not related to caregivers' age, employment status, physical health quality of life, caregiving stress, or depressive symptoms or the patients' care needs (ps > 0.22). Caregivers' feedback about their study experience was generally positive. Mixed-effects location scale modeling showed caregivers' higher depressive symptoms were related to overall higher reported negative affect and lower positive affect, but not to affective variability. CONCLUSIONS: Findings from this feasibility study refute potential concerns that an EMA design is too burdensome for distressed caregivers. Clinically, findings suggest the potential importance of not only strategies to reduce overall levels of negative affect, but also to increase opportunities for positive affect.

Demetallization of Sewage Sludge Using Low-Cost Ionic Liquids.

Sludge produced from wastewater treatment has little to no value and is typically treated through volume reduction techniques, such as dewatering, thickening, or digestion. However, these methods inherently increase heavy metal concentrations, which makes the sludge unsuitable for land spreading and difficult to dispose of, owing to strict legal requirements/regulations concerning these metals. We addressed this problem, for the first time, by using recyclable low-cost protic ionic liquids to complex these toxic metals through a chemical fractionation process. Sewage sludge samples collected from wastewater plants in the UK were heated with methylimidazolium chloride ([Hmim]Cl, triethylammonium hydrogen sulfate ([TEA][HSO4]) and dimethylbutylammonium hydrogen sulfate ([DMBA][HSO4]) under various operating temperatures, times and solids loadings to separate the sludge from its metal contaminants. Analysis of the residual solid product and metal-rich ionic liquid liquor using inductively coupled plasma-emission spectrometry showed that [Hmim]Cl extracted >90% of CdII, NiII, ZnII, and PbII without altering the phosphorus content, while other toxic metals such as CrIII, CrVI and AsIII were more readily removed (>80%) with [TEA][HSO4]. We test the recyclability of [Hmim]Cl, showing insignificant efficiency losses over 6 cycles and discuss the possibilities of using electrochemical deposition to prevent the buildup of metal in the IL. This approach opens up new avenues for sewage sludge valorization, including potential applications in emulsion fuels or fertilizer development, accessed by techno-economic analysis.

Penile calciphylaxis: A retrospective case-control study.

BACKGROUND: Calciphylaxis is a rare disorder characterized by skin necrosis caused by calcium deposition within vessels, thrombosis, and subsequent tissue ischemia. Penile involvement may rarely occur. OBJECTIVE: To identify risk factors, diagnosis, management, and mortality of patients with penile calciphylaxis. METHODS: A retrospective medical record review was conducted of 16 patients with penile calciphylaxis treated at 2 large urban tertiary care centers between January 2001 and December 2019. A control group of 44 male patients with nonpenile calciphylaxis at the same institution was included. RESULTS: The median survival of patients with penile calciphylaxis was 3.8 months (interquartile range, 27.0 months). Mortality was 50% at 3 months and 62.5% at 6 months for penile calciphylaxis, and 13.6% at 3 months and 29.5% at 6 months for controls (P = .008). Patients with penile calciphylaxis were less likely to be obese (P = .04) but more likely to have hyperparathyroidism (P = .0003) and end-stage renal disease (P = .049). LIMITATIONS: Retrospective study design and small sample size. CONCLUSIONS: This study further defines the disease course of penile calciphylaxis, which has high mortality. Imaging may be used to aid diagnosis. Risk factors include end-stage renal disease, hyperparathyroidism, and normal body mass index.

Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease.

BACKGROUND: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data. METHODS: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic. RESULTS: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone. LIMITATIONS: Selection bias and single-center nature. CONCLUSIONS: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions.

Breath-holding as a novel approach to risk stratification in COVID-19.

BACKGROUND: Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea ('silent hypoxemia') in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). METHODS: Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. RESULTS: The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. CONCLUSIONS: Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension.

Group 3 pulmonary hypertension (PH), which occurs secondary to hypoxia lung diseases, is one of the most common causes of PH worldwide and has a high unmet clinical need. A deeper understanding of the integrative pathological and adaptive molecular mechanisms within this group is required to inform the development of novel drug targets and effective treatments. The production of oxidants is increased in PH Group 3, and their pleiotropic roles include contributing to disease progression by promoting prolonged hypoxic pulmonary vasoconstriction and pathological pulmonary vascular remodeling, but also stimulating adaptation to pathological stress that limits the severity of this disease. Inflammation, which is increasingly being viewed as a key pathological feature of Group 3 PH, is subject to complex regulation by redox mechanisms and is exacerbated by, but also augments oxidative stress. In this review, we investigate aspects of this complex crosstalk between inflammation and oxidative stress in Group 3 PH, focusing on the redox-regulated transcription factor NF-κB and its upstream regulators toll-like receptor 4 and high mobility group box protein 1. Ultimately, we propose that the development of specific therapeutic interventions targeting redox-regulated signaling pathways related to inflammation could be explored as novel treatments for Group 3 PH.