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Background Individuals with COPD have increased sensitivity to traffic-related air pollution (TRAP) such as diesel exhaust (DE), but little is known about the acute effects of TRAP on exercise responses in COPD. Research question Does pre-exercise exposure to TRAP (DE300, PM2.5=300 μg/m3) have greater adverse effects on exercise endurance, exertional dyspnea, and cardiorespiratory responses to exercise in participants with mild-to-moderate COPD compared to former smokers with normal spirometry and healthy controls? Study design and Methods In this double-blind, randomized, placebo-controlled, crossover study, 11 healthy never-smokers, 9 ex-smokers without COPD and 9 ex-smokers with COPD were separately exposed to filtered air (FA) and DE300 for 2 hours separated by a minimum of 4 weeks. Participants performed symptom limited constant load cycling tests within 2.5 hours of exposure with detailed cardiorespiratory and exertional symptom measurements. Results There was a significant negative effect of TRAP on exercise endurance time in healthy controls (DE300 vs. FA: 10.2±8.2 vs. 12.9±9.5 min, respectively; p=0.03), but not in ex-smokers without COPD (10.1±6.9 vs. 12.2±8.0 min; respectively, p=0.57) or ex-smokers with COPD (9.8±6.4 vs. 8.4±6.6 min, respectively, p=0.31). Furthermore, significant increases in inspiratory duty cycle and absolute end-expiratory and end-inspiratory lung volumes were observed, and dyspnea ratings were elevated at select submaximal measurement times only in healthy controls. Interpretation Contrary to our hypothesis, it was the healthy controls rather than the ex-smokers with and without COPD that were negatively impacted by TRAP during exercise.

Background Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. Research Question Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? Study Design and Methods This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. Results A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). Interpretation Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT02147015; URL: www.clinicaltrials.gov

Background Chronic obstructive pulmonary disease (COPD) medications reduce exacerbations and improve quality of life. Despite this, some individuals do not receive medications recommended by practise guidelines. Research question How common is non-receipt of recommended medications among people with COPD and what are factors associated with non-receipt? Study design and methods We conducted a population cohort study in Ontario, Canada, a province with universal health care insurance and medication coverage for those aged 65 and older. Health administrative data were used to identify people 66 years of age or older with physician-diagnosed COPD as of 2018 and group them into lower or higher risk for future COPD exacerbation groups. Proportions of patients in each group who did not receive medications recommended by COPD guidelines were determined. Generalized estimating equation modelling was used to determine associations between patient and physician factors and non-receipt of recommended medications. Results About 54% and 88% of people with COPD receoved sufficient recommended medications in the low and high risk of exacerbation groups, respectively. Longer duration of COPD, higher comorbidity, dementia, and older physician age were associated with non-receipt of recommended medications in both groups. People who had a co-diagnosis of asthma and who received care by a pulmonologist and spirometry were more likely to receive recommended medication . Interpretation COPD medications appear underused by the COPD population and various factors are associated with sub-optimal receipt. Targeting these factors would help improve the care and health of people with COPD.

Background Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) has not been not well studied. VV-ECMO can be discontinued when patients tolerate noninjurious mechanical ventilation (MV) during a sweep gas-off trial (SGOT). However, predictors of safe liberation are unknown. Research Question Can safe liberation from VV-ECMO be predicted at the bedside? Study Design and Methods Two observational studies of adults weaned from VV-ECMO for severe ARDS at Toronto General Hospital were conducted. MV settings, respiratory mechanics, and clinical variables were analyzed to predict safe liberation from VV-ECMO, defined a priori as avoida7ce of ECMO recannulation, increased MV support, need for rescue therapy, or hemodynamic instability developed within 48 h following decannulation. Results During both studies, 83 patients were weaned from VV-ECMO, 21 (25%) of whom did not meet the criteria for safe liberation. In the retrospective study, higher tidal volume per predicted body weight (OR, 1.58; 95% CI, 1.05-2.40; P = .03) and heart rate (OR, 1.07; 95% CI, 1.022-1.15; P = .01) at the end of SGOT were significantly associated with increased odds of unsafe liberation when adjusted for age (OR, 1.02; 95% CI, 0.95-1.09; P = .63) and sequential organ failure assessment score (OR, 1.16; 95% CI, 0.86-1.56; P = .34). Change in ventilatory ratio had an imprecise association (OR, 2.7; 95% CI, 0.94-7.95; P = .06) with unsafe liberation when adjusted for age (OR, 1.03; 95% CI, 0.96-1.10; P = .42), sequential organ failure assessment score (OR, 1.11; 95% CI, 0.81-1.51; P = .52), and heart rate (OR, 1.07; 95% CI, 1.01-1.13; P = .02). In the prospective study, patients who had unsafe liberation from VV-ECMO also had significantly higher inspiratory efforts (esophageal pressure swings, 9 [7-13] vs 18 [7-25] cm H2O; P = .03) and worse outcomes (longer MV duration, ICU and hospital length of stay). Interpretation Patients with higher tidal volume, heart rate, ventilatory ratio, and esophageal pressures swings during SGOT were less likely to achieve safe liberation from VV-ECMO.

Background Cryobiopsy enables specialists to perform high-quality, large, entirely circumferential biopsies; therefore, it may improve the diagnostic yield of peripheral pulmonary lesions (PPLs), as has been previously observed with regard to endobronchial tumors and interstitial lung diseases. Research Question How do the diagnostic accuracy and safety change by cryobiopsy when performed alongside conventional biopsy for PPLs? Study Design and Methods Consecutive patients who underwent cryobiopsy in addition to conventional biopsies for PPL diagnosis at our institution between June 2017 and May 2018 were reviewed retrospectively. The target location was estimated and sampling was performed using conventional devices (i.e., forceps, brush, and/or aspiration needle), and cryobiopsy was performed at the same location. Diagnostic outcomes and cryobiopsy safety when performed in addition to conventional sampling methods were analyzed in this observational study. Results In total, 257 patients were analyzed, and the overall diagnostic yield was 89.9%. Among them, 22 lesions were diagnosable by cryobiopsy exclusively, which improved the rate of diagnosis by 8.6%. Advantages of the use of cryobiopsy were the most apparent when lesions were adjacent to areas assessed via radial endobronchial ultrasound (69.4% vs. 84.3%). Multivariable analysis identified bronchus sign (positive/negative, P=0.001), lobe (other lobes/right upper lobe + left upper segment, P=0.028), and visibility on X-ray (visible/invisible, P=0.047) as factors that significantly affected diagnostic yield. On the other hand, three instances of severe hemorrhage (1.2%), and two of pneumothorax (0.8%) occurred. Although most complications were minor, two patients required hospitalization due to cerebral infarction and lung abscess. Interpretation Cryobiopsy improves the diagnostic yield of PPLs when combined with other conventional sampling methods; however, caution is required due to the possibility of complications.

Background Thoracentesis and tube thoracostomy are common procedures with bleeding risks, but existing guidelines may be overly conservative. We reviewed the evidence on the safety of thoracentesis and tube thoracostomy in patients with uncorrected coagulopathy. Research Question Is it safe to perform thoracentesis and tube thoracostomy in patients with uncorrected coagulopathy? Study Design and Methods This systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. PubMed and Embase were searched from inception through December 31, 2019. Included studies involved patients with uncorrected coagulopathy because of disease (eg, thrombocytopenia, liver cirrhosis, kidney failure) or drugs (eg, antiplatelets, anticoagulants). Relevant outcomes were major bleeding and mortality. Results Eighteen studies (5,134 procedures) were included. Using random-effects meta-analysis, the pooled major bleeding and mortality rate was 0 (95% CI, 0%-1%). No publication bias was found. Excluding six studies that were in abstract form, meta-analysis of the remaining 12 full articles showed that the pooled major bleeding and mortality rate also was 0 (95% CI, 0%-2%). Subgroup analysis performed for patients with uncorrected coagulopathy resulting from disease or drugs showed similar results. Interpretation Among patients with uncorrected coagulopathy who underwent thoracentesis or tube thoracostomy, major bleeding and mortality complications were uncommon. Our results suggest that in appropriately selected patients, thoracentesis or tube thoracostomy can be performed safely. Trial Registry PROSPERO; No.: CRD42020152226; URL: www.crd.york.ac.uk/prospero/

Oral corticosteroid (OCS) use in severe asthma remains all too common despite advances in asthma treatment. Use of OCS is associated with significant toxicity that can have a lasting adverse impact on a patient's overall health. Monoclonal antibodies have been developed that reduce both the rate of occurrence of OCS-treated exacerbations and the OCS requirements in patients with oral corticosteroid-dependent asthma. This article describes strategies to prevent and best manage endocrine complications associated with OCS use and provides guidance on OCS dose management after the introduction of steroid-sparing therapies. (1) We identify OCS-dependent patients and assess for comorbidities including bone health, glycemic control, and adrenal function; (2) we begin attempts at OCS dose optimization before or soon after introducing a steroid-sparing biologic therapy; (3) we taper OCS, using explicit criteria for asthma control; (4) we assess hypothalamic-pituitary-adrenal axis integrity once a physiologic dose of OCS is achieved to guide further the rate of OCS taper; and (5) we manage corticosteroid-related comorbidities as detailed in this article.

Background The COVID-19 pandemic resulted in unprecedented adjustments to ICU organization and care processes globally. Research Questions Did hospital emergency responses to the COVID-19 pandemic differ depending on hospital setting? Which strategies worked well to mitigate strain as perceived by intensivists? Study Design and Methods Between August and November 2020, we carried out semistructured interviews of intensivists from tertiary and community hospitals across six regions in the United States that experienced early or large surges of COVID-19 patients, or both. We identified themes of hospital emergency responses using the four S framework of acute surge planning: space, staff, stuff, system. Results Thirty-three intensivists from seven tertiary and six community hospitals participated. Clinicians across both settings believed that canceling elective surgeries was helpful to increase ICU capabilities and that hospitals should establish clearly defined thresholds at which surgeries are limited during future surge events. ICU staff was the most limited resource; staff shortages were improved by the use of tiered staffing models, just-in-time training for non-ICU clinicians, designated treatment teams, and deployment of trainees. Personal protective equipment (PPE) shortages and reuse were widespread, causing substantial distress among clinicians; hands-on PPE training was helpful to reduce clinicians’ anxiety. Transparency and involvement of frontline clinicians as stakeholders were important components of effective emergency responses and helped to maintain trust among staff. Interpretation We identified several strategies potentially to mitigate strain as perceived by intensivists working in both tertiary and community hospital settings. Our study also demonstrated the importance of trust and transparency between frontline staff and hospital leadership as key components of effective emergency responses during public health crises.

Background Malignant pleural effusions (MPEs) often cause symptoms, and guidelines recommend early definitive intervention. However, observational data suggest that systemic anticancer treatment (SACT) may control MPE because of certain pharmacologically sensitive tumors. Research Question Is SACT associated with higher rates of MPE resolution in people with pharmacologically sensitive tumors? Study Design and Methods This was a retrospective analysis of prospectively collected data from an observational cohort study of people diagnosed with MPE from lung, breast, ovarian, and hematologic malignancy between May 11, 2008, and August 6, 2017. MPE resolution (defined as radiologic resolution with removal of drain or catheter and cessation of interventions) was compared in pharmacologically sensitive (high-grade lymphoma, small cell or target-mutation-positive lung cancer, and hormone-receptor-positive breast or ovarian cancer) and nonsensitive (remainder of cohort) tumors, with and without SACT. Secondary outcomes included time to resolution, 3-month resolution rates, and total pleural interventions. Results Of 280 patients, 127 had sensitive and 153 had nonsensitive tumors. One hundred seventy-one received SACT, and 109 did not. More patients with sensitive tumors achieved MPE resolution than those with nonsensitive tumors (53/127 [41.7%] vs 42/153 [27.5%]; P = .01), and this occurred predominantly after receipt of SACT. However, hematologic malignancies were overrepresented in the sensitive group, with high rates of SACT use and MPE resolution. After adjustment for this and other confounders, no relationship was found among pharmacologic sensitivity, SACT, and MPE resolution (adjusted OR, 1.4; 95% CI, 0.5-4.1). The strongest predictor of MPE resolution was administration of chemical pleurodesis (adjusted OR, 6.2; 95% CI, 3.3-11.7). In sensitive tumors, MPE resolution occurred without chemical pleurodesis in 14 or 52 patients (26.9%; 95% CI, 15.6%-41.1%) after SACT and in 5 of 22 patients (22.7%; 95% CI, 8.2%-47.2%) without SACT. Interpretation In this observational study, SACT was not associated independently with MPE resolution in pharmacologically sensitive tumors. Randomized trials are required, but with current data, patients with symptomatic MPE should receive early definitive pleural intervention regardless of underlying tumor or intended treatment.

Mediastinal lymph node staging in the setting of known or suspected lung cancer is supported by multiple professional societies as standard for high-quality care, yet proper mediastinal staging often is lacking. Neglecting pathologic lymph node sampling can understage or overstage the patient and lead to inappropriate treatment. Although some cases of nodal disease are radiographically obvious, others are not as apparent, and both situations require pathologic proof to allow for appropriate treatment selection. This article discusses the nuances of mediastinal staging and emphasizes the usefulness of a multidisciplinary approach and dialog to address lung cancer staging and treatment. We summarize the relevant guidelines and literature and provide a case scenario to illustrate the approach to mediastinal staging from our viewpoints as a thoracic surgeon and pulmonologist.

Background e-Cigarette or vaping-induced lung injury (EVALI) causes a spectrum of CT lung injury patterns. Relative frequencies and associations with vaping behavior are unknown. Research Question What are the frequencies of imaging findings and CT patterns in EVALI and what is the relationship to vaping behavior? Study Design and Methods CT scans of 160 subjects with EVALI from 15 institutions were retrospectively reviewed. CT findings and patterns were defined and agreed on via consensus. The parenchymal organizing pneumonia (OP) pattern was defined as regional or diffuse ground-glass opacity (GGO) ± consolidation without centrilobular nodules (CNs). An airway-centered OP pattern was defined as diffuse CNs with little or no GGO, whereas a mixed OP pattern was a combination of the two. Other patterns included diffuse alveolar damage (DAD), acute eosinophilic-like pneumonia, and pulmonary hemorrhage. Cases were classified as atypical if they did not fit into a pattern. Imaging findings, pattern frequencies, and injury severity were correlated with substance vaped (marijuana derives [tetrahydrocannabinol] [THC] only, nicotine derivates only, and both), vaping frequency, regional geography, and state recreational THC legality. One-way analysis of variance, χ2 test, and multivariable analyses were used for statistical analysis. Results A total of 160 patients (79.4% men) with a mean age of 28.2 years (range, 15-68 years) with EVALI underwent CT scan. Seventy-seven (48.1%), 15 (9.4%), and 68 (42.5%) patients admitted to vaping THC, nicotine, or both, respectively. Common findings included diffuse or lower lobe GGO with subpleural (78.1%), lobular (59.4%), or peribronchovascular (PBV) sparing (40%). Septal thickening (50.6%), lymphadenopathy (63.1%), and CNs (36.3%) were common. PBV sparing was associated with younger age (P = .02). Of 160 subjects, 156 (97.5%) had one of six defined patterns. Parenchymal, airway-centered, and mixed OP patterns were seen in 89 (55.6%), 14 (8.8%), and 32 (20%) patients, respectively. Acute eosinophilic-like pneumonia (six of 160, 3.8%), DAD (nine of 160, 5.6%), pulmonary hemorrhage (six of 160, 3.8%), and atypical (four of 160, 2.5%) patterns were less common. Increased vaping frequency was associated with more severe injury (P = .008). Multivariable analysis showed a negative association between vaping for > 6 months and DAD pattern (P = .03). Two subjects (1.25%) with DAD pattern died. There was no relation between pattern and injury severity, geographic location, and state legality of recreational use of THC. Interpretation EVALI typically causes an OP pattern but exists on a spectrum of acute lung injury. Vaping habits do not correlate with CT patterns except for negative correlation between vaping > 6 months and DAD pattern. PBV sparing, not previously described in acute lung injury, is a common finding.

Background The short- and long-term prognosis of Takotsubo syndrome (TTS) presenting with right ventricular (RV) involvement remains poorly understood. Research Question What is the incidence and clinical outcome of RV involvement in TTS? Study Design and Methods This study analyzed 839 consecutive patients with TTS (758 female subjects and 81 male subjects) in a multicenter registry. RV involvement was defined as wall motion abnormality of the RV free wall, with or without apical involvement. The median long-term follow-up was 2.1 years (interquartile range, 0.3-4.5 years). The primary outcome was in-hospital and out-of-hospital all-cause mortality. The secondary end point was a composite of in-hospital death, thromboembolic events, cardiogenic shock, pulmonary edema, and malignant arrhythmias. Results The incidence of RV involvement in TTS was 11% (n = 93). More often patients with RV involvement were male compared with patients without RV involvement (P = .02). There was a slight difference in the left ventricular ejection fraction measured in patients with RV involvement vs those patients with isolated left ventricular TTS (38 ± 10% vs 40 ± 10%; P = .03). No major differences in terms of comorbidities were observed between groups except regarding a history of cancer, which was significantly more prevalent in patients with TTS presenting with RV involvement (P = .03). Physical stressors were more prevalent in the RV group (P Interpretation RV involvement defines a high-risk cohort of patients with TTS. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT04361994 ; URL: www.clinicaltrials.gov .

Background Ultrasound may be useful to assess the structure, activity, and function of the abdominal muscles in patients who are mechanically ventilated. Research Question Does measurement of abdominal muscle thickening on ultrasound in patients who are mechanically ventilated provide clinically relevant information about abdominal muscle function and weaning outcomes? Study Design and Methods This study consisted of two parts, a physiological study conducted in healthy subjects and a prospective observational study in patients who were mechanically ventilated. Abdominal muscle thickness and thickening fraction were measured during cough and expiratory efforts in 20 healthy subjects, and prior to and during a spontaneous breathing trial in 57 patients being ventilated. Results In healthy subjects, internal oblique and rectus abdominis thickening fraction correlated with pressure generated during expiratory efforts (P Interpretation Abdominal muscle thickening on ultrasound was correlated to the airway pressure generated by expiratory efforts. In patients who were mechanically ventilated, abdominal muscle ultrasound measurements are feasible and moderately reproducible. Among patients who passed a spontaneous breathing trial, reduced abdominal muscle thickening during cough was associated with a high risk of liberation failure. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT03567564; URL: www.clinicaltrials.gov

Background The current nodal classification is unsatisfactory in distinguishing the prognostically heterogeneous N1 or N2 non-small cell lung cancer (NSCLC). Research Question Is the combination of the current N category and the number of metastatic lymph nodes (N-#number) or the combination of the current N category and the ratio of the number of positive to resected lymph nodes (N-#ratio) better than the current N category alone? Study Design and Methods We identified 2,162 patients with N1 or N2 NSCLC from the Surveillance, Epidemiology, and End Results database (2004-2016). We classified these patients into three N-#number categories (N-#number-1, N-#number-2a, N-#number-2b) and three N-#ratio categories (N-#ratio-1, N-#ratio-2a, N-#ratio-2b). Lung cancer-specific survival (LCSS) were compared using the Kaplan-Meier method. The prognostic significance of the new nodal classifications was validated across each tumor size category (≤3 cm, 3-5 cm, 5-7cm, >7 cm). Cox proportional hazards regression was used to evaluate the association between each nodal classification and LCSS. Results The survival curves showed clear differences between each pair of N-#number and N-#ratio categories. A significant tendency toward the deterioration of LCSS from N-#number-1 to N-#number-2b was observed in all tumor size categories. However, the differences between each pair of N-#ratio categories were significant only in tumors from 3 to 7 cm. Although all three nodal classifications were independent prognostic indicators, the N-#number classification provided more accurate prognostic stratifications compared with the N-#ratio classification and the current nodal classification. Interpretation The N-#number classification followed by the N-#ratio classification might be better prognostic determinants than the current nodal classification in prognostically heterogeneous N1 or N2 NSCLC.

Unilateral stimulation of the hypoglossal nerve may result in clinically valuable patency of the upper airway in well-selected patients for treatment of OSA. The Food and Drug Administration has established stringent criteria for the placement of this medical device. The treatment is a consideration among patients who have been nonadherent or intolerant of positive airway pressure therapy, with moderate to severe OSA, and a BMI of ≤ 32 kg/m2. Some of the insurance providers have lowered BMI guidelines to allow implantation in patients with a BMI of

Children with asthma grow to become adults with asthma. Adolescents are not simply older children and do not automatically transform into independent adults, nor do they become proficient in self-management of their condition overnight. Adolescence is a high-risk time for many people with asthma, with increased risk of asthma-related morbidity and mortality. Children with high-risk asthma attend hospital-based asthma clinics with their parents until they reach young adulthood, and parents usually take on the significant burden of disease management on behalf of their children. Once patients are transferred to adult medical teams, many will continue to have limited knowledge about their asthma, limited understanding of how to manage their symptoms and comorbidities, and limited comprehension of how and why to take their regular medication. Adolescence is a critical time of change during which young people yearn for autonomy. Effective transition gives young people the skills and knowledge necessary to manage their health independently and provides the substrate for autonomous care, the bed rock of long-term conditions. This review focuses on the challenges of adolescent health care and provides guidance on how to take a planned, patient-centered approach to ensure each transition is effective and safe.

Background Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting β2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. Research Question Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? Study Design and Methods We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. Results Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. Interpretation Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Background: Although the burden of bronchiectasis is recognized globally, pediatric data are limited, particularly on trends over the years. Also, no published data exists regarding whether vitamin D deficiency or insufficiency and human T-cell lymphotropic virus type 1 (HTLV-1) infection, both found to be related to severe bronchiectasis in First Nations adults, also are important in children with bronchiectasis. Research Question: Among children with bronchiectasis, (1) have the clinical and BAL profiles changed between two 5-year periods (period 1, 2007-2011; period 2, 2012-2016) and (b) are vitamin D deficiency or insufficiency, HTLV-1 infection, or both associated with radiologic severity of bronchiectasis? Study Design and Methods: We analyzed the data from children with bronchiectasis prospectively enrolled at Royal Darwin Hospital, Australia, at the first diagnosis; that is, no child was included in both periods. Data collected include demographics, BAL, routine investigation bloods, and high-resolution CT scan of the chest evaluated using the Bhalla and modified Bhalla scores. Results: The median age of the 299 children was 2.2 years (interquartile range, 1.5-3.7 years). One hundred sixty-eight (56%) were male and most were First Nations (92%). Overall, bronchiectasis was high over time, particularly among First Nations children. In the later period, numbers of non-First Nations children more than tripled, but did not reach statistical significance. In period 2 compared with period 1, fewer First Nations children demonstrated chronic cough (period 1, 61%; period 2, 47%; P =.03), and were younger, First Nations children were less likely to have received azithromycin (period 1, 42%; period 2, 21%; P

Background The role of portable high-efficiency particulate air (HEPA) filters for supplemental aerosol mitigation during exercise testing is unknown and might be relevant during COVID-19 pandemic. Research Question What is the effect of portable HEPA filtering on aerosol concentration during exercise testing and its efficiency in reducing room clearance time in a clinical exercise testing laboratory? Study Design and Methods Subjects were six healthy volunteers aged 20 to 56 years. In the first experiment, exercise was performed in a small tent with controlled airflow with the use of a stationary cycle, portable HEPA filter with fume hood, and particle counter to document aerosol concentration. Subjects performed a four-stage maximal exercise test that lasted 12 min plus 5 min of pretest quiet breathing and 3 min of active recovery. First, they exercised without mitigation then with portable HEPA filter running. In a separate experiment, room aerosol clearance time was measured in a clinical exercise testing laboratory by filling it with artificially generated aerosols and measuring time to 99.9% aerosol clearance with heating, ventilation, and air conditioning (HVAC) only or HVAC plus portable HEPA filter running. Results In the exercise experiment, particle concentrations reached 1,722 ± 1,484/L vs 96 ± 124/L (P < .04) for all particles (>0.3 μm), 1,339 ± 1,281/L vs 76 ± 104/L (P < .05) for smaller particles (0.3 to 1.0 μm), and 333 ± 209/L vs 17 ± 19/L (P < .01) for larger particles (1.0 to 5.0 μm) at the end of the protocol in a comparison of mitigation vs portable HEPA filter. Use of a portable HEPA filter in a clinical exercise laboratory clearance experiment reduced aerosol clearance time 47% vs HVAC alone. Interpretation The portable HEPA filter reduced the concentration of aerosols generated during exercise testing by 96% ± 2% for all particle sizes and reduced aerosol room clearance time in clinical exercise testing laboratories. Portable HEPA filters therefore might be useful in clinical exercise testing laboratories to reduce the risk of COVID-19 transmission., Graphical Abstract

COPD is a chronic inflammatory and destructive disease characterized by progressive decline in lung function that can accelerate with aging. Preclinical studies suggest that mesenchymal stem cells (MSCs) may provide a therapeutic option for this incurable disease because of their antiinflammatory, reparative, and immunomodulatory properties. To date, clinical trials using MSCs demonstrate safety in patients with COPD. However, because of the notable absence of large, multicenter randomized trials, no efficacy or evidence exists to support the possibility that MSCs can restore lung function in patients with COPD. Unfortunately, the investigational status of cell-based interventions for lung diseases has not hindered the propagation of commercial businesses, exploitation of the public, and explosion of medical tourism to promote unproven and potentially harmful cell-based interventions for COPD in the United States and worldwide. Patients with COPD constitute the largest group of patients with lung disease flocking to these unregulated clinics. This review highlights the numerous questions and concerns that remain before the establishment of cell-based interventions as safe and efficacious treatments for patients with COPD.

Primary prevention and interception of chronic lung disease are essential in the effort to reduce the morbidity and mortality caused by respiratory conditions. In this review, we apply a life course approach that examines exposures across the life span to identify risk factors that are associated with not only chronic lung disease but also an intermediate phenotype between ideal lung health and lung disease, termed "impaired respiratory health." Notably, risk factors such as exposure to tobacco smoke and air pollution, as well as obesity and physical fitness, affect respiratory health across the life course by being associated with both abnormal lung growth and lung function decline. We then discuss the importance of disease interception and identifying those at highest risk of developing chronic lung disease. This work begins with understanding and detecting impaired respiratory health, and we review several promising molecular biomarkers, predictive symptoms, and early imaging findings that may lead to a better understanding of this intermediate phenotype.

Background Different lung ultrasound (LUS) scanning protocols have been used, and the results in terms of diagnostic accuracy are heterogeneous. Research Questions What is the diagnostic accuracy of the LUS score to predict moderate to severe bronchopulmonary dysplasia (msBPD)? Does scanning of posterior lung fields improve the diagnostic accuracy? Study Design and Methods This was a multicenter prospective, observational study in six centers. Two LUS aeration scores, one involving only anterolateral lung fields and the other adding the posterior fields were obtained at birth, on the third day of life (DOL), on the seventh DOL, on the 14th DOL, and on the 21st DOL. The diagnostic accuracy of both scores to predict msBPD was assessed at each time point. Results Eight hundred thirty-two LUS examinations in 298 infants were included. Both LUS score using anterolateral and posterior fields and LUS score using only anterolateral fields showed a similar moderate diagnostic accuracy to predict msBPD on the third DOL (area under the receiver operating characteristic curve [AUC] 95% CI, 0.68-0.85 vs 0.68-0.85; P = .97), seventh DOL (AUC 95% CI, 0.74-0.85 vs 0.74-0.84; P = .26), and 21st DOL (AUC 95% CI, 0.72-0.86 vs 0.74-0.88; P = .17). The LUS score using anterolateral and posterior fields was slightly more accurate at 14th DOL (AUC 95% CI, 0.69-0.83 vs 0.66-0.80; P = .01). A cutoff of 8 points in the LUS score using only anterolateral fields on the seventh DOL provided a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 70%, 79%, 3.3, and 0.38, respectively, to predict msBPD. Adding gestational age (GA) and sex improved the discriminative value without significant differences compared with a predictive model based on multiple clinical variables: AUC 95% CI, 0.77-0.88 vs 0.80-0.91 (P = .52). Interpretation The LUS score is able to predict msBPD from the third DOL with a moderate diagnostic accuracy. Scanning posterior lung fields slightly improved diagnostic accuracy only at the 14th DOL. Adding GA and sex improves the diagnostic accuracy of the LUS scores. The LUS score is useful to stratify BPD risk early after birth.

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Background Limited convincing evidence is available of the relationship between habitual snoring and cardiovascular diseases (CVDs). Research Question Is habitual snoring associated with total CVD and CVD subtypes in different age groups of Chinese adults? Study Design and Methods The China Kadoorie Biobank study enrolled more than 0.5 million adults aged 30 to 79 years from 10 regions in China. Snoring status and other baseline characteristics were collected from 2004 to 2008, using an interviewer-administered laptop-based questionnaire. The current analysis included 489,583 participants without stroke or coronary heart disease at baseline. Cox proportional hazards models were used to calculate the adjusted hazard ratios (HRs) and 95% CIs of cardiovascular diseases (CVDs) for habitual snoring vs nonhabitual snoring. Results During a median follow-up of 9.6 years, 130,935 participants developed CVDs. Associations between habitual snoring and CVDs varied with age. Among participants aged younger than 50 years at baseline, habitual snoring was associated with an increased risk of total CVD (HR, 1.11; 95% CI, 1.07-1.14) after adjustment for known CVD risk factors, including systolic BP. The corresponding HRs (95% CIs) for ischemic heart disease, ischemic stroke, and hemorrhagic stroke were 1.18 (1.12-1.24), 1.12 (1.05-1.19), and 1.05 (0.92-1.19), respectively. However, such associations in adults aged 50 to 64 years were much weaker, and no statistically significant association was observed among individuals aged ≥65 years. Age-specific risk estimates were generally similar across sex and obesity subgroups. Interpretation Habitual snoring was associated with increased risks of total CVD, ischemic heart disease, ischemic stroke, but not hemorrhagic stroke in Chinese, and these associations were mainly limited to those aged

Background Evidence-based guidelines recommend management strategies for malignant pleural effusions (MPEs) based on life expectancy. Existent risk-prediction rules do not provide precise individualized survival estimates. Research Question Can a newly developed continuous risk-prediction survival model for patients with MPE and known metastatic disease provide precise survival estimates? Study Design and Methods Single-center retrospective cohort study of patients with proven malignancy, pleural effusion, and known metastatic disease undergoing thoracentesis from 2014 through 2017. The outcome was time from thoracentesis to death. Risk factors were identified using Cox proportional hazards models. Effect-measure modification (EMM) was tested using the Mantel-Cox test and was addressed by using disease-specific models (DSMs) or interaction terms. Three DSMs and a combined model using interactions were generated. Discrimination was evaluated using Harrell’s C-statistic. Calibration was assessed by observed-minus-predicted probability graphs at specific time points. Models were validated using patients treated from 2010 through 2013. Using LENT (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance score, neutrophil-to-lymphocyte ratio and tumor type) variables, we generated both discrete (LENT-D) and continuous (LENT-C) models, assessing discrete vs continuous predictors’ performances. Results The development and validation cohort included 562 and 727 patients, respectively. The Mantel-Cox test demonstrated interactions between cancer type and neutrophil to lymphocyte ratio (P Interpretation EMM is present between cancer type and other predictors; thus, DSMs outperformed the models that failed to account for this. Discrete risk-prediction models lacked enough precision to be useful for individual-level predictions.

Background Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous. Research Question Does the OX40 pathway influence the suppressive functions of Treg cells in PS? Study Design and Methods Fifty treatment-naive patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated. Results We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients’ BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4+Foxp3–) and Treg (CD4+Foxp3+) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor β). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions. Interpretation We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

Background Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers. Research Question Are the HAL and HOMER models valid across multiple centers? Study Design and Methods This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. HOMER was used to predict the probability of N0 vs N1 vs N2 or N3 (N2|3) disease, and HAL was used to predict the probability of N2|3 (vs N0 or N1) disease. Model discrimination was assessed using the area under the receiver operating characteristics curve (ROC-AUC), and calibration was assessed using the Brier score, calibration plots, and the Hosmer-Lemeshow test. Results Thirteen centers enrolled 1,799 patients. HAL and HOMER demonstrated good discrimination: HAL ROC-AUC = 0.873 (95%CI, 0.856-0.891) and HOMER ROC-AUC = 0.837 (95%CI, 0.814-0.859) for predicting N1 disease or higher (N1|2|3) and 0.876 (95%CI, 0.855-0.897) for predicting N2|3 disease. Brier scores were 0.117 and 0.349, respectively. Calibration plots demonstrated good calibration for both models. For HAL, the difference between forecast and observed probability of N2|3 disease was +0.012; for HOMER, the difference for N1|2|3 was −0.018 and for N2|3 was +0.002. The Hosmer-Lemeshow test was significant for both models (P = .034 and .002), indicating a small but statistically significant calibration error. Interpretation HAL and HOMER demonstrated good discrimination and calibration in multiple centers. Although calibration error was present, the magnitude of the error is small, such that the models are informative.

Background Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications. Research Question What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV1 Study Design and Methods This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV1 measurements Results There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV1 Interpretation There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV1

We describe a request for CPR without chest compressions from a patient's daughter. Requests for partial codes raise numerous clinical concerns, including lack of evidence-based effectiveness, risk of medical error, and difficulty in communication. These in turn lead to ethical concerns, including a misapplication of respect for patient autonomy, violating the foundational principle of "first do no harm," and inconsistency with the tenets of shared decision-making. Many requests for partial codes are also based on a conflation of cardiopulmonary arrest and pre-arrest emergencies. We argue physicians have no ethical obligation to honor a request for a partial code and that doing so does not violate respect for patient autonomy. Requests for partial codes should be seen as a request for information about CPR and an invitation to conversation. We also report here the move our health system made to only offer evidence-based code status options and reject those with negligible likelihood for therapeutic benefit. This work included limiting options for code status to "Full Code" or "Do Not Attempt Resuscitation," creating an order set for non-arrest emergencies, and sample language to guide physicians in responding to requests for partial codes. To assist other hospitals or health systems considering this move, we provide the content of the order set for non-arrest emergencies and the sample language guide.

Having a strategic plan is important to reach organizational goals. Equally important is knowing how to develop and execute that plan. Also, such plans evolve and are executed in the context of the organization's culture, which is another critical success element. Using a garden metaphor, the arrangement of the plants in the garden is like the strategy. With a good strategy, the arrangement of the plants will be appealing. But the soil in the garden is the organizational culture. If the soil is fouled, no plants will grow, regardless of how appealing the garden plan. This "How We Do It" paper addresses the issue of developing and executing a strategy and then, in a companion piece, the related process of envisioning and cultivating an organizational culture. The strategic planning discussion invokes a "real-win-worth" paradigm to address the real-world case of assuring uniform, best-in-class ICU outcomes across multiple ICUs in a large academic medical center system.

BACKGROUND: Supervised exercise training improves outcomes in patients with pulmonary arterial hypertension (PAH). The effect of an unsupervised activity intervention has not been tested. RESEARCH QUESTION: Can a text-based mobile health intervention increase step counts in patients with PAH? STUDY DESIGN AND METHODS: We performed a randomized, parallel arm, single-blind clinical trial. We randomized patients to usual care or a text message-based intervention for 12 weeks. The intervention arm received three automated text messages per day with real-time step count updates and encouraging messages rooted in behavioral change theory. Individual step targets increased by 20% every 4 weeks. The primary end point was mean week 12 step counts. Secondary end points included the 6-min walk test, quality of life, right ventricular function, and body composition. RESULTS: Among 42 randomized participants, the change in raw steps between baseline and week 12 was higher in the intervention group (1,409 steps [interquartile range, –32 to 2,220] vs –149 steps [interquartile range, –1,010 to 735]; P = .02), which persisted after adjustment for age, sex, baseline step counts, and functional class (model estimated difference, 1,250 steps; P = .03). The intervention arm took a higher average number of steps on all days between days 9 and 84 (P < .05, all days). There was no difference in week 12 six-minute walk distance. Analysis of secondary end points suggested improvements in the emPHasis-10 score (adjusted change, –4.2; P = .046), a reduction in visceral fat volume (adjusted change, –170 mL; P = .023), and nearly significant improvement in tricuspid annular plane systolic excursion (model estimated difference, 1.2 mm; P = .051). INTERPRETATION: This study demonstrated the feasibility of an automated text message-based intervention to increase physical activity in patients with PAH. Additional studies are warranted to examine the effect of the intervention on clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No. NCT03069716; URL: www.clinicaltrials.gov

Traumatic brain injury (TBI) is a major global health problem and a major contributor to morbidity and mortality following multisystem trauma. Extracranial organ dysfunction is common after severe TBI and significantly impacts clinical care and outcomes following injury. Despite this, extracranial organ dysfunction remains an understudied topic compared with organ dysfunction in other critical care paradigms. In this review, we will: 1) summarize the epidemiology of extracranial multiorgan dysfunction following severe TBI; 2) examine relevant mechanisms that may be involved in the development of multi-organ dysfunction following severe TBI; and 3) discuss clinical management strategies to care for these complex patients.

Nonexpanding lung is a mechanical complication in which part of the lung is unable to expand to the chest wall, preventing apposition of the visceral and parietal pleura. This can result from various visceral pleural disease processes, including malignant pleural effusion and empyema. Nonexpanding lung can be referred to as trapped lung or lung entrapment, both with distinct clinical features and management strategies. Early evaluation of pleural effusions is important to address underlying causes of pleural inflammation and to prevent the progression from lung entrapment to trapped lung. Some patients with trapped lung will not experience symptomatic relief with pleural fluid removal. Therefore, misrecognition of trapped lung can result in patients undergoing unnecessary procedures with significant cost and morbidity. We reviewed the current understanding of nonexpanding lung, which included causes, common presentations, preventative strategies, and recommendations for clinical care.

Background Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined. Research Question Are smoking-related exposures associated with risk of IPF and does interaction between them exist? Study Design and Methods We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data. Results We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95% CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95% CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95% CI, 0.45-1.54) and a ratio of HRs of 1.50 (95% CI, 1.05-2.14). Interpretation Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.

Background Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). Results One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P Interpretation According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

BACKGROUND The use of electronic clinical decision support (CDS) systems for pediatric critical care trials is rare. We sought to describe in detail the use of a CDS tool (Children's Hospital Euglycemia for Kids Spreadsheet [CHECKS]), for the management of hyperglycemia during the 32 multicenter Heart And Lung Failure-Pediatric Insulin Titration trial. RESEARCH QUESTION In critically ill pediatric patients who were treated with CHECKS, how was user compliance associated with outcomes; and what patient and clinician factors might account for the observed differences in CHECKS compliance? STUDY DESIGN AND METHODS During an observational retrospective study of compliance with a CDS tool used during a prospective randomized controlled trial, we compared patients with high and low CHECKS compliance. We investigated the association between compliance and blood glucose metrics. We describe CHECKS and use a computer interface analysis framework (the user, function, representation, and task analysis framework) to categorize user interactions. We discuss implications for future randomized controlled trials. RESULTS Over a 4.5-year period, 658 of 698 children were treated with the CHECKS protocol for ≥24 hours with a median of 119 recommendations per patient. Compliance per patient was high (median, 99.5%), with only 30 patients having low compliance (

Acute illness and hospitalization introduce several risk factors for sleep disruption in children that can negatively affect recovery and healing and potentially compromise long-term cognition and executive function. The hospital setting is not optimized for pediatric sleep promotion, and many of the pharmacologic interventions intended to promote sleep in the hospital actually may have deleterious effects on sleep quality and quantity. To date, evidence to support pharmacologic sleep promotion in the pediatric inpatient setting is sparse. Therefore, nonpharmacologic interventions to optimize sleep-wake patterns are of highest yield in a vulnerable population of patients undergoing active neurocognitive development. In this review, we briefly examine what is known about healthy sleep in children and describe risk factors for sleep disturbances, available sleep measurement tools, and potential interventions for sleep promotion in the pediatric inpatient setting.

Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Study Design and Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov

Background Working in the ICU during the first COVID-19 wave was associated with high levels of mental health disorders. Research Question What are the mental health symptoms in health care providers (HCPs) facing the second wave? Study Design and Methods A cross-sectional study (October 30-December 1, 2020) was conducted in 16 ICUs during the second wave in France. HCPs completed the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised (for post-traumatic stress disorder), and the Maslach Burnout Inventory. Results Of 1,203 HCPs, 845 responded (70%) (66% nursing staff, 32% medical staff, 2% other professionals); 487 (57.6%) had treated more than 10 new patients with COVID-19 in the previous week. Insomnia affected 320 (37.9%), and 7.7% were taking a psychotropic drug daily. Symptoms of anxiety, depression, post-traumatic stress disorder, and burnout were reported in 60.0% (95% CI, 56.6%-63.3%), 36.1% (95% CI, 32.9%-39.5%), 28.4% (95% CI, 25.4%-31.6%), and 45.1% (95% CI, 41.7%-48.5%) of respondents, respectively. Independent predictors of such symptoms included respondent characteristics (sex, profession, experience, personality traits), work organization (ability to rest and to care for family), and self-perceptions (fear of becoming infected or of infecting family and friends, feeling pressure related to the surge, intention to leave the ICU, lassitude, working conditions, feeling they had a high-risk profession, and “missing the clapping”). The number of patients with COVID-19 treated in the first wave or over the last week was not associated with symptoms of mental health disorders. Interpretation The prevalence of symptoms of mental health disorders is high in ICU HCPs managing the second COVID-19 surge. The highest tiers of hospital management urgently need to provide psychological support, peer-support groups, and a communication structure that ensure the well-being of HCPs.

BACKGROUND: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (DLCO) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low DLCO has not been explored. RESEARCH QUESTION: Could a DLCO threshold help define an increased risk of death and a different clinical presentation in these patients? STUDY DESIGN AND METHODS: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 +/- 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for DLCO was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality. RESULTS: A DLCO cutoff value of = 60%: 9% vs DLCO < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a DLCO < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a DLCO < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined.

Background Family members of patients admitted to the ICU experience a constellation of sequelae described as postintensive care syndrome-family. The influence that an inter-ICU transfer has on psychological outcomes is unknown. Research Question Is inter-ICU transfer associated with poor psychological outcomes in families of patients with acute respiratory failure? Study Design and Methods Cross-sectional observational study of 82 families of patients admitted to adult ICUs (tertiary hospital). Data included demographics, admission source, and outcomes. Admission source was classified as inter-ICU transfer (n = 39) for patients admitted to the ICU from other hospitals and direct admit (n = 43) for patients admitted from the ED or the operating room of the same hospital. We used quantitative surveys to evaluate psychological distress (Hospital Anxiety and Depression Scale [HADS]) and posttraumatic stress (Post-Traumatic Stress Scale; PTSS) and examined clinical, family, and satisfaction factors associated with psychological outcomes. Results Families of transferred patients travelled longer distances (mean ± SD, 109 ± 106 miles) compared with those of patients directly admitted (mean ± SD, 65 ± 156 miles; P ≤ .0001). Transferred patients predominantly were admitted to the neuro-ICU (64%), had a longer length of stay (direct admits: mean ± SD, 12.7 ± 9.3 days; transferred patients: mean ± SD, 17.6 ± 9.3 days; P Interpretation In this exploratory study, posttraumatic stress measured by the PTSS was higher in the transferred families, but these findings will need to be replicated to infer clinical significance.

Background Hypoxemia is a cardinal feature of fibrotic interstitial lung disease (ILD). The incidence, progression, and prognostic significance of hypoxemia in patients with fibrotic ILD currently is unknown. Research Question What are the epidemiologic features of hypoxemia and its additive prognostic value in a current risk prediction model of fibrotic ILD? Methods We identified 848 patients with fibrotic ILD (258 with idiopathic pulmonary fibrosis [IPF]) in five prospective ILD registries from Australia, Canada, and Switzerland. Cumulative incidence of exertional and resting hypoxemia from the time of diagnosis was estimated at 1-year intervals in patients with baseline 6-min walk tests, adjusted for competing risks of death and lung transplantation. Likelihood ratio tests were used to determine the prognostic significance of exertional and resting hypoxemia for 1-year mortality or transplantation when added to the ILD-GAP model. The cohort was divided into derivation and validation subsets to evaluate performance characteristics of the extended model (the ILD-GAP-O2 model), which included oxygenation status as a predictor. Results The 1-, 2-, and 5-year overall cumulative incidence was 6.1%, 17.3%, and 40.1%, respectively, for exertional hypoxemia and 2.4%, 5.6%, and 16.5%, respectively, for resting hypoxemia, which were significantly higher in patients with IPF compared with patients without IPF (P Interpretation Patients with IPF have higher cumulative incidence of exertional and resting hypoxemia than patients without IPF. The extended ILD-GAP-O2 model provides additional risk stratification for 1-year prognosis in fibrotic ILD.

Background The formulation of expert opinion guidelines has several sources of bias that may adversely affect their quality. To minimize bias, guideline creators must use rigorous methodology. There has been no appraisal of the methodologic quality of basic critical care echocardiography (BCCE) training/education guidelines. Research Question What is the methodologic quality of expert guidelines/recommendations on BCCE training? Study Design and Methods The review was performed by a multidisciplinary team including intensive care specialists, a hospital scientist, a trainee, a nurse sonographer, and a public health expert. Four databases (PubMed, OVID-Embase, Clarivate Analytics Web of Science, and Google Scholar) were searched on July 31, 2020, to identify guidelines on BCCE training/education. Every guideline was assessed subjectively for the degree of detail of the recommendations and assessed objectively by using the AGREE-II critical appraisal tool for clinical practice guidelines to generate a scaled domain score. A score ≥ 75% in every domain was the cut off for guidelines to be used without modifications. Results From 4,288 abstracts screened, 24 guidelines met the inclusion criteria. Very few guidelines made clear recommendations regarding introductory courses: physics (n = 6 [25%]), instrumentation (n = 5 [20.8%]), image acquisition theory (n = 6 [25%]), course curriculum (n = 5 [[20.8%]), pre-course/post-course tests (n = 1 [4.2%]), minimum course duration (n = 6 [25%]), or trainer qualifications (n = 5 [20.8%]). Very few provided clear recommendations for longitudinal competence programs: clinically indicated scans (n = 8 [33.3%]), logbook (n = 14 [58.3%]), image storage (n = 9 [37.5%]), formative assessment (n = 6 [25%]), minimum scan numbers (n = 14 [58.3%]), image acquisition competence (n = 3 [12.5%]), image interpretation competence (n = 2 [8.3%]), and credentialing/certification (n = 3 [12.5%]). Five guidelines (20.8%) attained a scaled overall AGREE-II score ≥ 75%. One guideline (4.2%) attained scores ≥ 75% in every domain. Interpretation The methodologic appraisal of BCCE-training guidelines showed widespread deficiencies in guideline formulation processes. The impact of these deficiencies on the validity of the recommendations requires further evaluation in longitudinal studies.

Background The purpose of this summary is to provide a synopsis of evidence-based and consensus-derived guidance for clinicians to improve individual diagnostic decision-making for hypersensitivity pneumonitis (HP) and decrease diagnostic practice variability. Study Design and Methods Approved panelists developed key questions regarding the diagnosis of HP using the PICO (Population, Intervention, Comparator, and Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. The quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus. Results The systematic review of the literature based on 14 PICO questions resulted in 14 key action statements: 12 evidence-based, graded recommendations, and 2 ungraded consensus-based statements. All evidence was of very low quality. Interpretation Diagnosis of HP should employ a patient-centered approach and include a multidisciplinary assessment that incorporates the environmental and occupational exposure history and CT pattern to establish diagnostic confidence prior to considering BAL and/or lung biopsy. Additional research is needed on the performance characteristics and generalizability of exposure assessment tools and traditional and new diagnostic tests in modifying clinical decision-making for HP, particularly among those with a provisional diagnosis.

BACKGROUND: The COVID-19 pandemic has led to unprecedented demand for ICUs, with the need to triage admissions along with the development of ICU triage criteria. However, how these criteria relate to outcomes in patients already admitted to the ICU is unknown, as is the incremental ICU capacity that triage of these patients might create given existing admission practices. RESEARCH QUESTION: What is the short- and long-term survival of low- vs high-priority patients for ICU admission according to current pandemic triage criteria? STUDY DESIGN AND METHODS: This study analyzed prospectively collected registry data (2007-2018) in 23 ICUs in Victoria, Australia, with probabilistic linkage with death registries. After excluding elective surgery, admissions were stratified according to existing ICU triage protocol prioritization as low (age ≥ 85 years, or severe chronic illness, or Sequential Organ Failure Assessment [SOFA] score = 0 or ≥ 12), medium (SOFA score = 8-11) or high (SOFA score = 1-7) priority. The primary outcome was long-term survival. Secondary outcomes were in-hospital mortality, ICU length of stay (LOS) and bed-day usage. RESULTS: This study examined 126,687 ICU admissions. After 5 years of follow-up, 1,093 of 3,296 (33%; 95% CI, 32-34) of "low-priority" patients aged ≥ 85 years or with severe chronic illness and 86 of 332 (26%; 95% CI, 24-28) with a SOFA score ≥ 12 were still alive. Sixty-three of 290 (22%; 95% CI, 17-27) of patients in these groups followed up for 10 years were still alive. Together, low-priority patients accounted for 27% of all ICU bed-days and had lower in-hospital mortality (22%) than the high-priority patients (28%). Among nonsurvivors, low-priority admissions had shorter ICU LOS than medium- or high-priority admissions. INTERPRETATION: Current SOFA score or age or severe comorbidity-based ICU pandemic triage protocols exclude patients with a close to 80% hospital survival, a > 30% five-year survival, and 27% of ICU bed-day use. These findings imply the need for stronger evidence-based ICU triage protocols.

Background The value of the single-breath diffusing capacity of the lungs for carbon monoxide (D lco ) relates to outcomes for patients with COPD. However, little is known about the natural course of D lco over time, intersubject variability, and factors that may influence D lco progression. Research Question What is the natural course of D lco in patients with COPD over time, and which other factors, including sex differences, could influence this progression? Study Design and Methods We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including D lco, was monitored annually over 5 years. A random coefficients model was used to evaluate D lco changes over time. Results The mean (± SE) yearly decline in D lco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant D lco % slope annual decline (4.14%/y). At baseline, women with COPD had lower D lco values (11.37% ± 2.27%; P lco annual decline of 0.89% ± 0.42%/y (P = .039). Interpretation Patients with COPD have an accelerated decline in D lco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in D lco values in women, compared with men, suggests a differential impact of sex in gas exchange function. Trial Registry ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov

Sleep-disordered breathing (SDB) is highly prevalent in adults and leads to significant cardiovascular and neurologic sequelae. Intermittent hypoxia during sleep is a direct consequence of SDB. Administration of nocturnal supplemental oxygen (NSO) has been used as a therapeutic alternative to positive airway pressure (PAP) in SDB. NSO significantly improves oxygen saturation in OSA but is inferior to PAP in terms of reducing apnea severity and may prolong the duration of obstructive apneas. The effect of NSO on daytime sleepiness remains unclear, but NSO may improve physical function-related quality of life in OSA. Its effects on BP reduction remain inconclusive. The effects of NSO vs PAP in OSA with comorbid COPD (overlap syndrome) are unknown. NSO is effective in reducing central sleep apnea related to congestive heart failure; however, its impact on mortality and cardiovascular clinical outcomes are being investigated in an ongoing clinical trial. In conclusion, studies are inconclusive or limited regarding clinical outcomes with oxygen therapy compared with sham or PAP therapy in patients with OSA and overlap syndrome. Oxygen does mitigate central sleep apnea. This review examines the crucial knowledge gaps and suggests future research priorities to clarify the effects of optimal dose and duration of NSO, alone or in combination with PAP, on cardiovascular, sleep, and cognitive outcomes.

Background The COVID-19 pandemic placed considerable strain on critical care resources. How US hospitals responded to this crisis is unknown. Research Question What actions did US hospitals take to prepare for a potential surge in demand for critical care services in the context of the COVID-19 pandemic? Study Design and Methods From September to November 2020, the chief nursing officers of a representative sample of US hospitals were surveyed regarding organizational actions taken to increase or maintain critical care capacity during the COVID-19 pandemic. Weighted proportions of hospitals for each potential action were calculated to create estimates across the entire population of US hospitals, accounting for both the sampling strategy and nonresponse. Also examined was whether the types of actions taken varied according to the cumulative regional incidence of COVID-19 cases. Results Responses were received from 169 of 540 surveyed US hospitals (response rate, 31.3%). Almost all hospitals canceled or postponed elective surgeries (96.7%) and nonsurgical procedures (94.8%). Few hospitals created new medical units in areas not typically dedicated to health care (12.9%), and almost none adopted triage protocols (5.6%) or protocols to connect multiple patients to a single ventilator (4.8%). Actions to increase or preserve ICU staff, including use of ICU telemedicine, were highly variable, without any single dominant strategy. Hospitals experiencing a higher incidence of COVID-19 did not consistently take different actions compared with hospitals facing lower incidence. Interpretation Responses of hospitals to the mass need for critical care services due to the COVID-19 pandemic were highly variable. Most hospitals canceled procedures to preserve ICU capacity and scaled up ICU capacity using existing clinical space and staffing. Future research linking hospital response to patient outcomes can inform planning for additional surges of this pandemic or other events in the future.

Background Visceral pleural invasion (VPI) with PL1 or PL2 increases the T classification from T1 to T2 in non-small cell lung cancers (NSCLCs) ≤ 3 cm. We proposed a modified T classification based on VPI to guide adjuvant therapy. Research Question Is it reasonable to upstage PL1-positive cases from T1 to T2 for NSCLCs ≤ 3 cm? Study Design and Methods In total, 1,055 patients with resected NSCLC were retrospectively included. Tumor sections were restained with hematoxylin and eosin stain and Victoria blue elastic stain for the elastic layer. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Subgroup analysis and a Cox proportional hazards model were used to further determine the impact of VPI on survival. Results The extent of VPI was diagnosed as PL0 in 824 patients, PL1 in 133 patients, and PL2 in 98 patients. The 5-year DFS rates of patients with PL0, PL1, and PL2 were 62.6%, 60.2%, and 28.8% (P Interpretation In NSCLCs ≤ 3 cm, tumors with PL1 should remain defined as T1, not T2. Overtreatment by adjuvant chemotherapy in node-negative NSCLCs ≤ 3 cm might be avoided in PL1 cases.