Detection ofClostridioides difficileinfection by assessment of exhaled breath volatile organic compounds.

Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired infective diarrhea. Current methods for diagnosing CDI have limitations; enzyme immunoassays for toxin have low sensitivity andClostridioides difficilepolymerase chain reaction cannot differentiate infection from colonization. An ideal diagnostic test that incorporates microbial factors, host factors, and host-microbe interaction might characterize true infection. Assessing volatile organic compounds (VOCs) in exhaled breath may be a useful test for identifying CDI. To identify a wide selection of VOCs in exhaled breath, we used thermal desorption-gas chromatography-mass spectrometry to study breath samples from 17 patients with CDI. Age- and sex-matched patients with diarrhea and negativeC.difficiletesting (no CDI) were used as controls. Of the 65 VOCs tested, 9 were used to build a quadratic discriminant model that showed a final cross-validated accuracy of 74%, a sensitivity of 71%, a specificity of 76%, and a receiver operating characteristic area under the curve of 0.72. If these findings are proven by larger studies, breath VOC analysis may be a helpful adjunctive diagnostic test for CDI.

Exhaled Breath Analysis Using Selected Ion Flow Tube Mass Spectrometry and Disease Severity in Heart Failure.

Exhaled breath volatile organic compounds (VOCs) are elevated in heart failure (HF). The ability of VOCs to predict long term cardiovascular mortality and morbidity has not been independently verified. In 55 patients admitted with acute decompensated heart failure (ADHF), we measured exhaled breath acetone and pentane levels upon admission and after 48 h of diuresis. In a separate cohort of 51 cardiac patients undergoing cardiopulmonary exercise testing (CPET), we measured exhaled breath acetone and pentane levels before and at peak exercise. In the ADHF cohort, admission acetone levels correlated with lower left ventricular ejection fraction (LVEF, r = -0.297, p = 0.035). Greater weight loss with diuretic therapy correlated with a greater reduction in both acetone levels (r = -0.398, p = 0.003) and pentane levels (r = -0.309, p = 0.021). In patients with above-median weight loss (≥4.5 kg), patients demonstrated significantly greater percentage reduction in acetone (59% reduction vs. 7% increase, p < 0.001) and pentane (23% reduction vs. 2% reduction, p = 0.008). In the CPET cohort, admission acetone and pentane levels correlated with higher VE/VCO2 (r = 0.39, p = 0.005), (r = 0.035, p = 0.014). However, there were no significant correlations between baseline or peak exercise acetone and pentane levels and peak VO2. In longitudinal follow-up with a median duration of 33 months, patients with elevated exhaled acetone and pentane levels experienced higher composite adverse events of death, ventricular assist device implantation, or orthotopic heart transplantation. In patients admitted with ADHF, higher exhaled breath acetone levels are associated with lower LVEF and poorer outcomes, and greater reductions in exhaled breath acetone and pentane tracked with greater weight loss. Exhaled acetone and pentane may be novel biomarkers in heart failure worthy of future investigation.

Impact of Esophageal Pressure Measurement on Pulmonary Hypertension Diagnosis in Patients With Obesity.

BACKGROUND: Elevated intrathoracic pressure could affect pulmonary vascular pressure measurements and influence pulmonary hypertension (PH) diagnosis and classification. Esophageal pressure (Pes) measurement adjusts for the increase in intrathoracic pressure, better reflecting the pulmonary hemodynamics in patients with obesity. RESEARCH QUESTION: In individuals with obesity, what is the impact of adjusting pulmonary hemodynamic determinations for Pes on PH diagnosis and classification? Can Pes be estimated by positional or respiratory hemodynamic changes? STUDY DESIGN AND METHODS: In this prospective cohort study, we included patients with obesity who underwent right heart catheterization and demonstrated elevated pulmonary artery wedge pressure (PAWP; ≥ 12 mm Hg). After placement of an esophageal balloon, we performed pressure determination using an air-filled transducer connected to a regular hemodynamic monitor. We measured pulmonary pressures changes when sitting and the variations during the respiratory cycle. RESULTS: We included 53 patients (mean ± SD age, 59 ± 12 years; mean ± SD BMI, 44.4 ± 10.2 kg/m2). Supine end-expiratory pressures revealed a mean pulmonary artery pressure of > 20 mm Hg in all patients and a PAWP of >15 mm Hg in most patients (n = 50). The Pes adjustment led to a significant decrease in percentage of patients with postcapillary PH (from 60% to 8%) and combined precapillary and postcapillary PH (from 34% to 11%), at the expense of an increase in percentage of patients with no PH (0% to 23%), isolated precapillary PH (2% to 25%), and undifferentiated PH (4% to 34%). INTERPRETATION: Adjusting pulmonary hemodynamics for Pes in patients with obesity leads to a pronounced reduction in the number of patients who receive a diagnosis of postcapillary PH. Measuring Pes should be considered in patients with obesity, particularly those with elevated PAWP.

Predictors of survival in portopulmonary hypertension: a 20-year experience.

BACKGROUND AND OBJECTIVES: Portopulmonary hypertension (PoPH) is a rare complication of portal hypertension associated with poor survival. Scarce data is available on predictors of survival in PoPH with conflicting results. We sought to characterize the outcomes and variables associated with survival in a large cohort of patients with PoPH in an American population of patients. STUDY DESIGN AND METHODS: We identified PoPH patients from the Cleveland Clinic Pulmonary Hypertension Registry between 1998 and 2019. We collected prespecified data, particularly focusing on hepatic and cardiopulmonary assessments and tested their effect on long-term survival. RESULTS: Eighty patients with PoPH with a mean ± SD age of 54 ± 10 years, (54% females) were included in the analysis. The median Model for End-Stage Liver Disease with sodium (MELD-Na) score was 13.0 (10.0-18.0) at PoPH diagnosis. World Health Association functional class III-IV was noted in 57%. Mean pulmonary arterial pressure was 47 ± 10 mmHg and pulmonary vascular resistance 6.0 ± 2.8 Woods units. A total of 63 (78.5%) patients were started on pulmonary arterial hypertension (PAH)-specific treatment during the first 6 months of diagnosis. Survival rates at 1-, 3- and 5-year were 77, 52 and 34%, respectively. Cardiopulmonary hemodynamics as well as PAH-specific treatment did not affect survival. In the multivariable model, MELD-Na, resting heart rate and the presence of hepatic encephalopathy were independent predictors of survival. CONCLUSION: PoPH patients have poor 5-year survival which is strongly associated to the severity of underlying liver disease and not to the hemodynamic severity of PoPH; therefore efforts should be focused in facilitating liver transplantation for these patients.

Surge capacity and capability of intensive care units across a large healthcare system: An operational blueprint for regional integration.

OBJECTIVE: Many hospitals were unprepared for the surge of patients associated with the spread of coronavirus disease 2019 (COVID-19) pandemic. We describe the processes to develop and implement a surge plan framework for resource allocation, staffing, and standardized management in response to the COVID-19 pandemic across a large integrated regional healthcare system. SETTING: A large academic medical center in the Cleveland metropolitan area, with a network of 10 regional hospitals throughout Northeastern Ohio with a daily capacity of more than 500 intensive care unit (ICU) beds. RESULTS: At the beginning of the pandemic, an equitable delivery of healthcare services across the healthcare system was developed. This distribution of resources was implemented with the potential needs and resources of the individual ICUs in mind, and epidemiologic predictions of virus transmissibility. We describe the processes to develop and implement a surge plan framework for resource allocation, staffing, and standardized management in response to the COVID-19 pandemic across a large integrated regional healthcare system. We also describe an additional level of surge capacity, which is available to well-integrated institutions called "extension of capacity." This refers to the ability to immediately have access to the beds and resources within a hospital system with minimal administrative burden. CONCLUSIONS: Large integrated hospital systems may have an advantage over individual hospitals because they can shift supplies among regional partners, which may lead to faster mobilization of resources, rather than depending on local and national governments. The pandemic response of our healthcare system highlights these benefits.

Cutaneous iontophoresis of vasoactive medications in patients with scleroderma-associated pulmonary arterial hypertension.

BACKGROUND: It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). METHODS: We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naïve PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). RESULTS: The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naïve + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). CONCLUSIONS: Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

The breath print represents a novel biomarker of malnutrition in pulmonary arterial hypertension: A proof of concept study.

BACKGROUND: The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. METHODS: We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnoses and nutrition status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), control, and control with malnutrition (Control-Mal), based on the malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. RESULTS: A total of 74 patients met inclusion criteria (PAH: 52; PAH-Mal: 10; control: 10; Control-Mal: 2). Levels of 1-octene (PAH-Mal, 5.1 ± 1.2; PAH, 12.5 ± 11.2; P = 0.005) and ammonia (PAH-Mal, 14.6 ± 15.8; PAH, 56.2 ± 64.2; P = 0.013) were reduced in PAH-Mal compared with PAH. The combination of 1-octene (P = 0.010) and 3-methylhexane (P = 0.045) distinguished malnutrition in PAH (receiver operating characteristic area under the curve: 0.8549). CONCLUSIONS: This proof of concept study provides the first evidence that the breath print is altered in malnutrition. Larger prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting.

Diagnosis of Clostridioides difficile infection by analysis of volatile organic compounds in breath, plasma, and stool: A cross-sectional proof-of-concept study.

Clostridioides difficile infection (CDI) is an important infectious cause of antibiotic-associated diarrhea, with significant morbidity and mortality. Current diagnostic algorithms are based on identifying toxin by enzyme immunoassay (EIA) and toxin gene by real-time polymerase chain reaction (PCR) in patients with diarrhea. EIA's sensitivity is poor, and PCR, although highly sensitive and specific, cannot differentiate infection from colonization. An ideal test that incorporates microbial factors, host factors, and host-microbe interaction might characterize true infection, and assess prognosis and recurrence. The study of volatile organic compounds (VOCs) has the potential to be an ideal diagnostic test. The presence of VOCs accounts for the characteristic odor of stool in CDI but their presence in breath and plasma has not been studied yet. A cross-sectional proof-of-concept study analyzing VOCs using selected ion flow tube mass spectrometry (SIFT-MS) was done on breath, stool, and plasma of patients with clinical features and positive PCR for CDI (cases) and compared with patients with clinical features but a negative PCR (control). Our results showed that VOC patterns in breath, stool, and plasma, had good accuracy [area under the receiver operating characteristic curve (ROC) 93%, 86%, and 91%, respectively] for identifying patients with CDI.

Optimal Tricuspid Regurgitation Velocity to Screen for Pulmonary Hypertension in Tertiary Referral Centers.

BACKGROUND: A mean pulmonary artery pressure >20 mm Hg now defines pulmonary hypertension. We hypothesize that echocardiographic thresholds must be adjusted. RESEARCH QUESTION: Should tricuspid regurgitation velocity thresholds to screen for pulmonary hypertension be revised, given the new hemodynamic definition? STUDY DESIGN AND METHODS: This multicenter retrospective study included 1,608 patients who underwent both echocardiography and right heart catherization within 4 weeks. The discovery cohort consisted of 1,081 individuals; the validation cohort included 527. Screening criteria for pulmonary hypertension were derived with the use of receiver operating characteristic analysis and the Youden index, assuming equal cost for false-positive and -negative classification. A lower threshold was calculated with the use of a predefined sensitivity: 95%. RESULTS: In the discovery cohort, echocardiographic tricuspid regurgitation velocity had a good discrimination for pulmonary hypertension: area under the curve, 88.4 (95% CI, 85.3-91.5). A 3.4-m/s threshold provided a 78% sensitivity, 87% specificity, and 6.13 positive likelihood ratio to detect pulmonary hypertension; 2.7 m/s had a 95% sensitivity and 0.12 negative likelihood ratio to exclude pulmonary hypertension. In the validation cohort, the discovery threshold of 2.7 m/s provided sensitivity and negative likelihood ratios of 80% and 0.31, respectively. Right cardiac size improved detection of pulmonary hypertension in the lower tricuspid regurgitation velocity groups. INTERPRETATION: Our data support a lower tricuspid regurgitation velocity of approximately 2.7 m/s for screening pulmonary hypertension, with a high sensitivity in tertiary referral centers. Right heart chamber measurements improve the diagnostic yield of echocardiography.

Causes and Circumstances of Death in Portopulmonary Hypertension.

The causes and circumstances surrounding death are poorly studied in patients with portopulmonary hypertension (PoPH). We sought to determine the specific reasons for dying and characteristics surrounding this process in patients with PoPH. METHODS: All deaths of patients with PoPH followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the pulmonary hypertension team between 1996 and 2020. RESULTS: A total of 69 patients with PoPH (age 56.0 ± 8.9 y), with 49% females, were included. Causes of death were available in 52 (75%) patients, of these PoPH either directly or indirectly contributed to death in 13 of 52 (25%) of patients, meanwhile 39 of 52 (75%) of the patients died because of progressive liver disease and its related complications. Decompensated liver disease was the leading cause of death in this cohort 20 of 52 (38%), whereas 19 of 52 (37%) died because of conditions associated with liver disease. About half, 36 of 69 (52%) of patients died in a healthcare environment and 23 of 36 (64%) during a hospitalization at Cleveland Clinic. A total of 59 of 69 (74%) of patients received pulmonary arterial hypertension (PAH)-specific therapies. Six patients died after liver transplantation (in 3 death was related to PAH-related complications). Most of the patients in this cohort of PoPH patients were considered unsuitable for liver transplantation for a variety of reasons. Advanced healthcare directives were available in only 28% of patients. CONCLUSIONS: Most patients with PoPH died because of complications of their liver disease. PAH directly or indirectly contributed to death in a third of them. A quarter of them did not receive PAH-specific therapy before their death.

Is pulmonary vascular resistance index better than pulmonary vascular resistance in predicting outcomes in pulmonary arterial hypertension?

BACKGROUND: In contrast to pulmonary vascular resistance (PVR), PVR index (PVRI) accounts for variations in body habitus. We tested the association of PVRI compared to PVR with clinical outcomes in lean and obese (BMI ≥30 kg/m2) patients with pulmonary arterial hypertension (PAH). METHODS: This retrospective study included adult patients with PAH who underwent right heart catheterization at Cleveland Clinic between February 1992 and November 2019. RESULTS: We included 644 patients (mean age, 53 ± 16 years, and 74 % females). PAH was idiopathic or heritable in 44% of patients. Cardiac output increased (p <0.0001), while PVR decreased (p <0.0001) with increasing body weight. Both PVR and PVRI were associated with markers of disease severity, with more pronounced association for PVRI. Both PVR and PVRI were risk factors for first PAH hospitalization, mortality and mortality or lung transplant in the whole cohort and the group of patients with BMI < 30 kg/m2. However, PVRI (HR (95% CI): 1.06 (1.02 -1.11)), but not PVR (HR (95% CI): 1.03 (0.99-1.07)), was a risk factor for first PAH hospitalization in obese patients. In the obese group, neither PVR nor PVRI were risk factors for mortality. CONCLUSIONS: PVRI appears to have a stronger association than PVR with disease severity markers in PAH; however, both PVR and PVRI were similarly associated with hospitalizations and survival in the overall cohort. We found no strong evidence to recommend a change from PVR to PVRI in the definition of PAH.

Abnormal levels of apolipoprotein A-I in chronic thromboembolic pulmonary hypertension.

Recent studies have shown low high-density lipoprotein cholesterol (HDL-C) and dysregulated lipid metabolism in chronic thromboembolic pulmonary hypertension (CTEPH). Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-C and mediates most of its functions. We hypothesize that ApoA-1 and its oxidative state might be more sensitive biomarkers in CTEPH. Plasma levels of HDL-C, ApoA-I, paraoxonase-1 enzyme activity (PON1), and the oxidized dysfunctional ApoA-I (oxTrp72-ApoA-I) were measured in patients with CTEPH and compared to those in healthy controls. Association with markers of disease severity in CTEPH was assessed. We included a total of 61 patients with CTEPH (age: 61.2 ± 15 years; male 52.5%) and 28 control subjects (age: 60.1 ± 8 years; male 59.3%). When adjusting for age, sex, body mass index, and statin use, ApoA-I was lower in CTEPH compared to controls (CTEPH:125.2 ± 27 mg/dl; control:158.3 ± 29.4 mg/dl; p < 0.001), but HDL-C levels were not statistically different. There were no significant differences in PON and oxTrp72-ApoA-I/ApoA-I ratio. In exploratory analyses, ApoA-I was associated with mean right atrial pressure (rs = -0.32, p = 0.013) and N-terminal pro B-type natriuretic peptide (rs = -0.31, p = 0.038). There were no significant associations between HDL-C, PON1, or oxTrp72-ApoA-I/ApoA-I ratio and markers of disease severity. We conclude that ApoA-I is a more sensitive biomarker than HDL-C in CTEPH, and may be associated with right heart dysfunction.

Disease-specific platelet signaling defects in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with several treatment options. Long-term mortality remains high with great heterogeneity in treatment response. Even though most of the pathology of IPAH is observed in the lung, there is systemic involvement. Platelets from patients with IPAH have characteristic metabolic shifts and defects in activation; therefore, we investigated whether they could be used to identify other disease-specific abnormalities. We used proteomics to investigate protein expression changes in platelets from patients with IPAH compared with healthy controls. Key abnormalities of nitric oxide pathway were tested in platelets from a larger cohort of unique patients with IPAH. Platelets showed abnormalities in the prostacyclin and nitric oxide pathways, which are dysregulated in IPAH and hence targets of therapy. We detected reduced expression of G protein αs and increased expression of the regulatory subunits of the cAMP-dependent protein kinase (PKA) type II isoforms, supporting an overall decrease in the activation of the prostacyclin pathway. We noted reduced levels of the soluble guanylate cyclase (sGC) subunits and increased expression of the phosphodiesterase type 5 A (PDE5A), conditions that affect the response to nitric oxide. Ensuing analysis of 38 unique patients with IPAH demonstrated considerable variation in the levels and specific activity of sGC, a finding with novel implications for personalized therapy. Platelets have some of the characteristic vasoactive signal abnormalities seen in IPAH and may provide comprehensive ex vivo mechanistic information to direct therapeutic decisions.

Strategic Planning for the Chest Clinician.

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.

Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Rationale: Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy.Objectives: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine.Methods: The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines.Measurements and Main Results: There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when 1) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (replacement); 2) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (complementary); or 3) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "sequential").Conclusions: Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Multicenter Study of Temporal Changes and Prognostic Value of a CT Visual Severity Score in Hospitalized Patients With Coronavirus Disease (COVID-19).

BACKGROUND. Chest CT findings have the potential to guide treatment of hospitalized patients with coronavirus disease (COVID-19). OBJECTIVE. The purpose of this study was to assess a CT visual severity score in hospitalized patients with COVID-19, with attention to temporal changes in the score and the role of the score in a model for predicting in-hospital complications. METHODS. This retrospective study included 161 inpatients with COVID-19 from three hospitals in China who underwent serial chest CT scans during hospitalization. CT examinations were evaluated using a visual severity scoring system. The temporal pattern of the CT visual severity score across serial CT examinations during hospitalization was characterized using a generalized spline regression model. A prognostic model to predict major complications, including in-hospital mortality, was created using the CT visual severity score and clinical variables. External model validation was evaluated by two independent radiologists in a cohort of 135 patients from a different hospital. RESULTS. The cohort included 91 survivors with nonsevere disease, 55 survivors with severe disease, and 15 patients who died during hospitalization. Median CT visual lung severity score in the first week of hospitalization was 2.0 in survivors with non-severe disease, 4.0 in survivors with severe disease, and 11.0 in nonsurvivors. CT visual severity score peaked approximately 9 and 12 days after symptom onset in survivors with nonsevere and severe disease, respectively, and progressively decreased in subsequent hospitalization weeks in both groups. In the prognostic model, in-hospital complications were independently associated with a severe CT score (odds ratio [OR], 31.28), moderate CT score (OR, 5.86), age (OR, 1.09 per 1-year increase), and lymphocyte count (OR, 0.03 per 1 × 109/L increase). In the validation cohort, the two readers achieved C-index values of 0.92-0.95, accuracy of 85.2-86.7%, sensitivity of 70.7-75.6%, and specificity of 91.4-91.5% for predicting in-hospital complications. CONCLUSION. A CT visual severity score is associated with clinical disease severity and evolves in a characteristic fashion during hospitalization for COVID-19. A prognostic model based on the CT visual severity score and clinical variables shows strong performance in predicting in-hospital complications. CLINICAL IMPACT. The prognostic model using the CT visual severity score may help identify patients at highest risk of poor outcomes and guide early intervention.

Community-acquired Pneumonia Guideline Recommendations-Impact of a Consensus-based Process versus Systematic Reviews.

BACKGROUND: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews. PURPOSE: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines. METHODS: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline's systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined. RESULTS: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64-1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%). CONCLUSIONS: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action.