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Objective: Obstructive sleep apnea (OSA) has been associated with structural and functional brain changes and cognitive impairment in sleep clinic samples. Persons with traumatic brain injury (TBI) are at increased risk of OSA compared to community samples, and many experience chronic cognitive disability. However, the impact of OSA on cognitive outcome after TBI is unknown. The purpose of this study was to examine the relationship between polysomnographic sleep parameters on neuropsychological performance 2 years following TBI. We hypothesized that oxygen desaturation, sleep fragmentation, and sleep depth would predict neuropsychological performance. Method: Participants ( N  = 123) were persons with moderate-to-severe TBI who underwent Type 1 Polysomnography during acute neurorehabilitation. At 2 years post-TBI, participants completed telephone-based neuropsychological testing (the Brief Test of Adult Cognition by Telephone). General linear models were fit to investigate the relationship between sleep parameters and neuropsychological performance, controlling for demographics and posttraumatic amnesia. Results: When controlling for demographics, injury characteristics, and other sleep parameters, greater percent of Stage 1 sleep time predicted poorer cognitive performance (Overall BTACT composite, p  = 0.0078, η p 2 = 6.6%; Verbal Memory composite, p  = 0.0407, η p 2 = 3.9%; Executive Function composite, p  = 0.0215, η p 2 = 4.9%). Oxygen desaturation, cortical arousals, Stage 3 sleep, and the obstructive apnea-hypopnea index were not significantly associated with cognitive outcome. Conclusions: Reduced sleep depth was associated with cognitive outcome in persons with TBI; these findings require replication. Future research should examine whether improving sleep (e.g. increasing deep sleep) during acute recovery can improve cognitive recovery following TBI.

Background and Objectives: The Emergency Medical Treatment and Labor Act (EMTALA) is intended to prevent inadequate, delayed, or denied treatment of emergent conditions by emergency departments (EDs). EMTALA requirements pertain to patients of all ages presenting to dedicated EDs regardless of whether facilities have dedicated pediatric specialty services. This study aims to describe EMTALA-related civil monetary penalty (CMP) settlements involving minors., Methods: Descriptions of all EMTALA-related CMPs occurring between 2002 and 2023 were obtained from the Office of the Inspector General web site and reviewed for involvement of minors (<18 years of age) using keywords in settlement summaries. Characteristics of settlements involving minors were described and compared with settlements not involving minors., Results: Of 260 EMTALA-related CMPs, 38 (14.6%) involved minors. Most involved failure to provide a medical screening exam (MSE) (86.8%) and/or stabilizing treatment (52.6%). Seven (18.4%) involved pregnant minors. Eleven (28.9%) involved ED staff directing a patient (or guardian) to another facility, typically by private vehicle, and another involved 2 patients referred to on-campus outpatient clinics without an MSE., Conclusions: One in 7 CMPs related to EMTALA violations involved minors, and 1 in 5 of these minors was pregnant. One-third of CMPs involving minors included ED staff directing patients to proceed to another facility or on-campus clinic without MSE or stabilization. Findings suggest a need for providers to understand EMTALA-specific requirements for appropriate MSE, stabilization, and transfer, and for EDs at hospitals with limited pediatric services to implement policies for the evaluation of minors and protocols for transfer when indicated., (Copyright © 2024 by the American Academy of Pediatrics.)

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Objectives: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation., Design: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620)., Setting: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites)., Patients: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization., Interventions: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy., Measurements and Main Results: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments., Conclusions: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination., Competing Interests: Dr. Rein disclosed that she served as a consultant for AbbVie, Blueprint Medicines, Celgene, CTI BioPharma, and Novartis and as a site principal investigator on clinical trials involving ruxolitinib. Dr. Rein reports receiving research funding including salary support from Incyte Corporation for Ruxolitinib in Participants With COVID-19–Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT). Dr. Calero reports receiving grants from Incyte Corporation. Dr. Lodhi reports receiving grants and personal fees from Incyte Corporation and Theravance and nonfinancial support from Incyte Corporation. Drs. Daniel, Schaub, and O’Hayer disclosed they are employees of and own stock in Incyte Corporation. Dr. Hager reports receiving a research grant and salary support from Incyte Corporation for the conduct of the RUXCOVID-DEVENT trial, past salary support from the Embedded Precision in Acute Care Trials (EMPACT) Precision Medicine Network for participation in EMPACT Network and from the Marcus Foundation for the conduct of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial, and other support from the Centers for Disease Control and Prevention (via subcontract with Vanderbilt University Medical Center). Dr. Theodoropoulos received funding from Incyte Corporation for the RUXCOVID-DEVENT trial. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Introduction: Obstructive sleep apnea is an important and common disorder with associated health risks. Assuring successful longitudinal management is vital to patient health and sleep-related quality of life. This paper provides guidance from the American Academy of Sleep Medicine (AASM) regarding the use of polysomnography (PSG) and home sleep apnea tests (HSATs) after a diagnosis of obstructive sleep apnea has been established and, in most cases, treatment implemented., Methods: The AASM commissioned a task force of five sleep medicine experts. A literature search was conducted to identify studies that included adult patients with OSA who underwent follow-up PSG or an HSAT. The task force developed clinical guidance statements based on a review of these studies and expert opinion. The AASM Board of Directors approved the final clinical guidance statements., Clinical Guidance Statements: The AASM supports the following clinical guidance statements on indications for follow-up PSG and HSAT in adult patients with OSA. 1. Follow-up PSG or HSAT is not recommended for routine reassessment of asymptomatic patients with obstructive sleep apnea on PAP therapy, however, follow-up PSG or HSAT can be used to reassess patients with recurrent or persistent symptoms, despite good PAP adherence. 2. Follow-up PSG or HSAT is recommended to assess response to treatment with non-PAP interventions. 3. Follow-up PSG or HSAT may be used if clinically significant weight gain or loss has occurred since diagnosis of OSA or initiation of its treatment. 4. Follow-up PSG may be used for reassessment of sleep-related hypoxemia and/or sleep-related hypoventilation following initiation of treatment for OSA. 5. Follow-up PSG or HSAT may be used in patients being treated for OSA who develop or have a change in cardiovascular disease. 6. Follow-up PSG may be used in patients with unexplained PAP device-generated data. The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options and resources., (© 2021 American Academy of Sleep Medicine.)

Delirium in the intensive care unit (ICU) affects up to 80% of critically ill, mechanically ventilated (MV) adults. Delirium is associated with substantial negative outcomes, including increased hospital complications and long-term effects on cognition and health status in ICU survivors. The purpose of this randomized controlled trial is to test the effectiveness of a Family Automated Voice Reorientation (FAVoR) intervention on delirium among critically ill MV patients. The FAVoR intervention uses scripted audio messages, which are recorded by the patient's family and played at hourly intervals during daytime hours. This ongoing orientation to the ICU environment through recorded messages in a voice familiar to the patient may enable the patient to more accurately interpret the environment and thus reduce risk of delirium. The study's primary aim is to test the effect of the FAVoR intervention on delirium in critically ill MV adults in the ICU. The secondary aims are to explore: (1) if the effect of FAVoR on delirium is mediated by sleep, (2) if selected biobehavioral factors moderate the effects of FAVoR on delirium, and (3) the effects of FAVoR on short-term and long-term outcomes, including cognition and health status. Subjects (n = 178) are randomly assigned to the intervention or control group within 48 h of initial ICU admission and intubation. The intervention group receives FAVoR over a 5-day period, while the control group receives usual care. Delirium-free days, sleep and activity, cognition, patient-reported health status and sleep quality, and data regarding iatrogenic/environmental and biobehavioral factors are collected., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP. Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern. Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology. Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%). Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Background: Mechanically ventilated (MV) patients in the intensive care unit (ICU) often experience disturbed sleep and profound inactivity., Objectives: The aim of this study was to report 5 consecutive days' descriptive analyses on sleep efficiency (SE), total sleep time (TST), daytime activity ratio (DAR), and hourly activity counts among critically ill MV adults from 9 ICUs across 2 hospitals., Methods: A secondary analysis was undertaken from our parent National Institutes of Health-funded randomized controlled trial (NIH R01 NR016702). Subjects included 31 critically ill patients from multiple ICUs. Wrist actigraphy estimated SE and TST. Mean DAR, an indicator of altered sleep-wake cycles, was calculated. Continuous 24-hour activity counts over 5 consecutive days were summarized. Descriptive analyses were used., Results: A total of 31 subjects with complete actigraphy data were included. Mean age was 59.6 (SD, 17.3) years; 41.9% were male; 83.9% were White, and 67.7% were Hispanic/Latino; and the mean APACHE III (Acute Physiology and Chronic Health Evaluation III) severity of illness score was 74.5 (SD, 25.5). The mean nighttime SE and TST over the 5-day ICU period were 83.1% (SD, 16.14%) and 6.6 (SD, 1.3) hours, respectively. The mean DAR over the 5-day ICU period was 66.5% (SD, 19.2%). The DAR surpassed 80% on only 17.5% of subject days. The majority of subjects' activity level was low, falling below 1000 activity counts per hour., Conclusion: Our study revealed poor rest-activity cycle consolidation among critically ill MV patients during the early ICU period. Future interventional studies should promote quality sleep at nighttime and promote mobilization during the daytime., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: OSA is prevalent during a time of critical neural repair after traumatic brain injury (TBI). The diagnostic utility of existing sleep studies is needed to inform clinical management during acute recovery from TBI., Research Question: This study aimed to evaluate the non-inferiority and diagnostic accuracy of a portable level 3 sleep study relative to level 1 polysomnography in hospitalized neurorehabilitation patients with TBI., Study Design and Methods: This is a prospective clinical trial conducted at six TBI Model System study sites between May 2017 and February 2019. Of 896 admissions, 449 were screened and eligible for the trial, with 345 consented. Additional screening left 263 eligible for and completing simultaneous administration of both level 1 and level 3 sleep studies, with final analyses completed on 214 (median age = 42 years; ED Glasgow Coma Scale = 6; time to polysomnography [PSG] = 52 days)., Results: Agreement was moderate to strong (weighted kappa = 0.78, 95% CI, 0.72-0.83) with the misclassification commonly occurring with mild sleep apnea due to underestimation of apnea hypopnea index (AHI). Most of those with moderate to severe sleep apnea were correctly classified (n = 54/72). Non-inferiority was not demonstrated: the minimum tolerable specificity of 0.5 was achieved across all AHI cutoff scores (lower confidence limits [LCL] range, 0.807-0.943), but the minimum tolerable sensitivity of 0.8 was not (LCL range, 0.665-0.764)., Interpretation: Although the non-inferiority of level 3 portable diagnostic testing relative to level 1 was not established, strong agreement was seen across sleep apnea indexes. Most of those with moderate to severe sleep apnea were correctly identified; however, there was risk of misclassification with level 3 sleep studies underestimating disease severity for those with moderate to severe AHI and disease presence for those with mild AHI during early TBI neurorehabilitation., (Published by Elsevier Inc.)

Study Objectives: The objective of this study was to compare obstructive sleep apnea (OSA), demographic, and traumatic brain injury (TBI) characteristics across the American Academy of Sleep Medicine (AASM) and Centers for Medicare and Medicare (CMS) scoring rules in moderate to severe TBI undergoing inpatient neurorehabilitation., Methods: This is a secondary analysis from a prospective clinical trial of sleep apnea at 6 TBI Model System study sites (n = 248). Scoring was completed by a centralized center using both the AASM and CMS criteria for OSA. Hospitalization and injury characteristics were abstracted from the medical record, and demographics were obtained by interview by trained research assistants using TBI Model System standard procedures., Results: OSA was prevalent using the AASM (66%) and CMS (41.5%) criteria with moderate to strong agreement (weighted κ = 0.64; 95% confidence interval = 0.58-0.70). Significant differences were observed for participants meeting AASM and CMS criteria (concordant group) compared with those meeting criteria for AASM but not CMS (discordant group). At an apnea-hypopnea index ≥ 5 events/h, the discordant group (n = 61) had lower Emergency Department Glasgow Coma Scale Scores consistent with greater injury severity (median, 5 vs 13; P = .0050), younger age (median, 38 vs 58; P < .0001), and lower body mass index (median, 22.1 vs 24.8; P = .0007) compared with the concordant group (n = 103). At an apnea-hypopnea index ≥ 15 events/h, female sex but no other differences were noted, possibly because of the smaller sample size., Conclusions: The underestimation of sleep apnea using CMS criteria is consistent with prior literature; however, this is the first study to report the impact of the criteria in persons with moderate to severe TBI during a critical stage of neural recovery. Management of comorbidities in TBI has become an increasing focus for optimizing TBI outcomes. Given the chronic morbidity after moderate to severe TBI, the impact of CMS policy for OSA diagnosis for persons with chronic disability and young age are considerable., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Comparison of Sleep Apnea Assessment Strategies to Maximize TBI Rehabilitation Participation and Outcome; Identifier: NCT03033901., (© 2020 American Academy of Sleep Medicine.)

Background: Older adults who required mechanical ventilation while in an intensive care unit (ICU) require adequate sleep throughout recovery from critical illness. Poor post-ICU sleep quality may contribute to worsening impairments in physical, cognitive, or psychological status after critical illness, known as post-ICU syndrome. Previous research has evaluated post-ICU sleep with qualitative or mixed methods (eg, interviews, questionnaires). We proposed measurement of sleep with actigraphy. We hypothesized that nighttime sleep is associated with length of stay (LOS)., Objectives: The aims of this study were to describe sleep quality of previously mechanically ventilated older adults recently transferred out of ICU and explore relationships between sleep duration and LOS outcomes., Methods: We enrolled 30 older adults, 65 years and older, within 24 to 48 hours after ICU discharge. We collected actigraphy data on post-ICU sleep duration (total sleep time [TST]) and sleep fragmentation (wake time after sleep onset) over 2 consecutive nights. We explored associations between TST and LOS (in days) outcomes using multivariate regression., Results: Subjects' mean TST was 7.55 ± 2.52 hours, and mean wake time after sleep onset was 2.26 ± 0.17 hours. In exploratory regression analyses, longer ICU LOS (β = 0.543, P < .001) and longer length of mechanical ventilation (β = 0.420, P = .028) were associated with greater post-ICU TST, after adjusting for potential confounding factors. Total sleep time was prospectively associated with total hospital LOS (β = 0.535, P < .001)., Discussion: Older ICU survivors demonstrate greater sleep duration and worse sleep fragmentation. Poor sleep may contribute to longer LOS, secondary to post-ICU syndrome and sequelae. We recommend nursing interventions to promote sleep consolidation throughout transitions of care in the acute post-ICU recovery period.

Objective: To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions., Design: Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography., Setting: Six TBI Model System Inpatient Rehabilitation Centers., Participants: Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248., Intervention: Not applicable., Main Outcome Measures: Area under the curve (AUC) of screening tools relative to total apnea hypopnea index≥15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47)., Results: The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI≥30 (severe apnea); however, no differences across scales was observed at AHI≥5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden's index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples., Conclusion: This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema. Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management. Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control). Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV 1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV 1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment ( n  = 113) or control ( n  = 59). Mean FEV 1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax. Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Background: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test., Methods: We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results., Findings: The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412)., Interpretation: The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned., Funding: Veracyte., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Older adults in the intensive care unit (ICU) often experience sleep disturbances, which may stem from life-threatening illness, the ICU environment, medications/sedation, or psychological stress. Two complementary endocrinological responses occur as a result of compromised sleep and consequently could exacerbate ICU-acquired weakness: a decrease in anabolic hormones leading to decreased protein synthesis and an increase in catabolic hormones leading to increased protein degradation. Age-associated decreases in anabolic hormones, such as insulin-like growth factor 1, testosterone, and growth hormone, may inhibit protein synthesis. Likewise, age-associated increases in insulin resistance, glucocorticoids, and myostatin can stimulate muscle atrophy and further reduce protein synthesis. Thus, perhaps, sleep promotion in the ICU may attenuate muscle atrophy among critically ill older adults who are at risk for ICU-acquired weakness and subsequent functional decline., Objectives: The aim of this study was to discuss the hypothesized theoretical underpinnings of the relationship between sleep disturbances and ICU-acquired weakness among critically ill older adults., Methods: A search of research literature published from 1970 to 2018 and indexed in MEDLINE, Embase, CINAHL, and Ovid was undertaken, and relevant sources were selected to build an informed discussion., Results: Nurses must be mindful of secondary sleep disturbances that occur throughout the acute phase of critical illness and their probable links to ICU-acquired weakness. Targeted interventions to promote functional outcomes in elderly patients should consider this relationship., Discussion: Improved sleep may have the potential to decrease the severity of muscle atrophy and ICU-acquired weakness. Future research must explore this hypothesis and the underlying mechanisms of the association between sleep disturbances and ICU-acquired weakness in critically ill older adults.

Objectives: Explore the effect of an automated reorientation intervention on ICU delirium in a prospective randomized controlled trial., Background: Delirium is common in ICU patients, and negatively affects outcomes. Few prevention strategies have been tested., Methods: Thirty ICU patients were randomized to 3 groups. Ten received hourly recorded messages in a family member's voice during waking hours over 3 ICU days, 10 received the same messages in a non-family voice, and 10 (control) did not receive any automated reorientation messages. The primary outcome was delirium free days during the intervention period (evaluated by CAM-ICU). Groups were compared by Fisher's Exact Test., Results: The family voice group had more delirium free days than the non-family voice group, and significantly more delirium free days (p = 0.0437) than the control group., Conclusions: Reorientation through automated, scripted messages reduced incidence of delirium. Using identical scripted messages, family voice was more effective than non-family voice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not yet been characterized. Based on existing evidence that RB interferes with mitochondrial electron transport to produce oxidative stress in peripheral tissues, we hypothesized that RB would produce oxidative damage to macromolecules in specific brain regions. Parameters of oxidative DNA damage and repair, lipid peroxidation, and superoxide dismutase (SOD) activity were measured across six mouse brain regions 24 h after administration of a single dose of RB. Lipid peroxidation and oxidative DNA damage were either unchanged or decreased in all brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant with these decreased indices of oxidative macromolecular damage, SOD activity was significantly increased in all brain regions. Oxyguanosine glycosylase activity (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased in three brain regions--cerebellum (CB), caudate/putamen (CP), and cortex (CX)--but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB-enhanced OGG1 catalytic activity in these brain regions was not due to increased OGG1 protein expression, but was a result of enhanced catalytic activity of the enzyme. In conclusion, specific brain regions responded to an acute dose of RB by significantly altering SOD and OGG1 activities to maintain the degree of oxidative DNA damage equal to, or less than, that of normal steady-state levels.