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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. [ABSTRACT FROM AUTHOR]

Organizational Culture Matters: Culture is a key driver of organizational performance and underpins strategy. As previously discussed, if the strategy is the plants and the garden plan for a garden, the culture is the soil. Without a healthy culture, nothing will grow, irrespective of how well planned the garden or how beautiful the individual flowers. Using the case of establishing the culture in an institute at the Cleveland Clinic, the article examines an approach to establishing and maintaining an organizational culture. Anchors for this process are a situational assessment of the current culture as a new leader steps in and mindfulness by the leader of how members of the institute should experience the organization. Critical success factors include open communication and establishing psychological safety as well as modeling integrity. Fundamentally, when cultures are grounded in the seven classical virtues-trust, compassion, courage, justice, wisdom, temperance, and hope-they are best positioned to unleash the discretionary effort of its members. When people expend discretionary effort, they do the right thing when nobody is watching and the performance drivers are internal motivation and alignment with mission rather than external drivers to seek reward (carrots) or to avoid punishment (sticks). [ABSTRACT FROM AUTHOR]

In normal airways, hyaluronan (HA) matrices are primarily located within the airway submucosa, pulmonary vasculature walls, and, to a lesser extent, the alveoli. Following pulmonary injury, elevated levels of HA matrices accumulate in these regions, and in respiratory secretions, correlating with the extent of injury. Animal models have provided important insight into the role of HA in the onset of pulmonary injury and repair, generally indicating that the induction of HA synthesis is an early event typically preceding fibrosis. The HA that accumulates in inflamed airways is of a high molecular weight (>1600 kDa) but can be broken down into smaller fragments (<150 kDa) by inflammatory and disease-related mechanisms that have profound effects on HA pathobiology. During inflammation in the airways, HA is often covalently modified with heavy chains from inter-alpha-inhibitor via the enzyme tumor-necrosis-factor-stimulated-gene-6 (TSG-6) and this modification promotes the interaction of leukocytes with HA matrices at sites of inflammation. The clearance of HA and its return to normal levels is essential for the proper resolution of inflammation. These data portray HA matrices as an important component of normal airway physiology and illustrate its integral roles during tissue injury and repair among a variety of respiratory diseases. [ABSTRACT FROM AUTHOR]

Background: Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration. Methods: This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 – 2011 in the Severe Asthma Research Program. Results: The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women. Conclusions: Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma. [ABSTRACT FROM AUTHOR]

The article offers clinical information on nitric oxide (NO) in different pulmonary diseases. The authors reveal that the upregulation of NO by inflammatory cytokines can be monitored in exhaled air. They claim that in asthmatic patients, fraction of exhaled NO (FeNO) denotes eosinophilic-mediated inflammatory pathways moderately well in central or peripheral airway sites. Meanwhile, FeNO can be normal in chronic obstructive pulmonary disease (COPD).

Abstract: Exhaled breath testing is becoming an increasingly important non-invasive diagnostic method that can be used in the evaluation of health and disease states in the lung and beyond. Potential advantages of breath tests over other conventional medical tests include their non-invasive nature, low cost, and safety. To advance in this area further, however, there has to be a close collaboration between technical experts and engineers who have devices looking for clinical application(s), the medical experts who have the clinical problems looking for a test/biomarker that can be helpful in diagnosis or monitoring, and industry/commercial experts who can build and commercialize the final product. [Copyright &y& Elsevier]

Carbon monoxide (CO) and nitric oxide (NO) are endogenous vasoregulatory molecules whose role in heart failure is not fully known. Exhaled CO and NO measurement provide novel noninvasive assessment of their endogenous production. We compared exhaled CO and NO in 24 patients with advanced ischemic and nonischemic cardiomyopathy and in 13 control subjects without known cardiac disease at rest and at 1 and 5 minutes after exercise testing. Exhaled CO was lower in patients with cardiomyopathy at rest (1.66 ± 0.2 vs 1.80 ± 0.5 ppm, p = 0.02) and 1 minute after exercise (1.35 ± 0.2 vs 1.81 ± 0.5 ppm, p = 0.009), with a similar trend at 5 minutes after exercise (1.45 ± 0.3 vs 1.81 ± 0.5 ppm, p = 0.14). Exhaled CO decreased in patients with cardiomyopathy after exercise (p <0.001 and p = 0.02 at rest vs 1 and 5 minutes after exercise, respectively) but was maintained in controls. Exhaled NO did not differ between patients with cardiomyopathy and controls at rest (9.48 ± 1.4 vs 9.68 ± 1.5 ppb, p = NS) and after exercise (1 minute: 10.91 ± 1.8 vs 9.19 ± 1.2 ppb; 5 minutes: 10.52 ± 1.5 vs 8.90 ± 1.2 ppb, p = NS). Exhaled NO increased after exercise in patients with cardiomyopathy (p = 0.01 and p = 0.04 rest vs exercise at 1 and 5 minutes, respectively), but was maintained in controls. Exhaled CO and NO were not correlated with peak oxygen consumption in patients with cardiomyopathy. The differential responses in exhaled CO and NO at rest or with exercise between patients with cardiomyopathy and normal controls may point to dysregulation in endogenous CO and NO production. [Copyright &y& Elsevier]

In chronic beryllium disease (CBD), a granulomatous lung disease characterized by hypersensitivity to beryllium salts (BE), BE challenge of bronchoalveolar lavage cells induces IFNγ. Although nitric oxide (NO) is elevated in CBD airways, the effects of NO on CBD IFNγ responses are unknown. Here we report that BE-stimulated IFNγ production in CBD lavage cells was markedly reduced (74%) by the NO generator DETA NONOate. Investigation of IFNγ-stimulatory cytokine involvement indicated that lavage cell IL-18 was significantly increased (fourfold) by BE and reduced (64%) by DETA NONOate but IL-12 was undetectable. IL-18 production was caspase-1-dependent but caspase 1 inhibition reduced IFNγ only partially (43%). Specific antibody depletion of lavage cell IL-18 yielded marginal reduction (19%) of IFNγ. Data are the first to show that: (1) BE stimulates IL-18 as well as IFNγ in CBD; (2) BE cytokine responses are NO-sensitive; and (3) NO down-regulation of IFNγ involves other sites in addition to IL-18. [Copyright &y& Elsevier]

Investigates how nitric oxide (NO) participates in inflammatory airway events in asthma. Measurement of NO and NO chemical reaction products prior to, during and 48 hours after bronchoscopic antigen challenge; Harmful effects of NO through formation of peroxynitrite.

Pulmonary hypertension is associated with adverse cardiac outcomes and death in the general population. Bolignano and colleagues studied the prevalence of higher estimated pulmonary artery systolic pressure (⩾35 mm Hg) assessed using echocardiogram among patients with stage 1-4 chronic kidney disease. They further examined the associations of higher pulmonary pressures with a composite cardiovascular outcome. These findings suggest the potential role of pulmonary arterial systolic pressure as a risk marker in those with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Alveolar hemorrhage (AH) is a clinical syndrome with diverse etiologies both immune and nonimmune. The defining pathological feature of AH is the presence or absence of pulmonary capillaritis. The antineutrophil cytoplasmic antibody (ANCA) related vasculitis and systemic lupus erythematosus are the commonest causes of immune AH with pulmonary capillaritis, whereas Goodpasture's syndrome and idiopathic pulmonary hemosiderosis are common causes of immune AH without pulmonary capillaritis. The major nonimmune causes of AH are primarily drug induced, or due to hematological malignancy and disorders of coagulation. Clinical features of AH include: dyspnea, fever, hemotypsis, bilateral crackles and pallor. Hypoxemia and bilateral diffuse airspace disease on the chest radiograph with relative sparing of the bases and apices which most often clears within 48 hours after its onset further characterize this syndrome. The major clinical implications of this syndrome are its potential to cause respiratory failure in severe cases and its sequelae of pulmonary fibrosis with associated morbidity and disability. In addition, AH may be the initial manifestation of a systemic immune disorder which can be managed optimally if recognized early. The diagnosis of AH is confirmed by bronchoalveolar lavage by demonstrating a progressively bloody return on successive aliquots of instilled saline or hemosiderin laden macrophages in the bronchoalveolar lavage fluid. The open lung biopsy remains the gold standard for the diagnosis of AH but is reserved for inapparent cases in whom corticosteroids and immunosuppressive therapy may be life saving. Serologic testing and examination of the urine sediment are useful adjuncts to the diagnosis. The treatment of AH is primarily supportive while an attempt is made to determine its etiology and initiate specific therapy. Glucocorticoids and cyclophosphamide are the cornerstones of therapy in immune AH with adjunctive plasmapheresis in... [ABSTRACT FROM AUTHOR]

Describes a patient with pulmonary infection with actinomyces that presented as a plasma cell granuloma. Symptoms; Dominance of plasma cells; Denial of fever and chills; Treatment with multiple courses of oral and intravenous antibiotics with no improvement in symptoms or radiographic findings.

The authors comment on the article "Treatment of Sarcoidosis-Associated Pulmonary Hypertension: A Two Center Experience," by C. F. Barnett and colleagues. The authors found some limitations in the study particularly the patients who entered the study not by means of a standardized approach to identify pulmonary hypertension (PH) but by the fact they were treated with pulmonary vasodilators. They indicate a lack of information on which patients to treat with pulmonary vasodilators or what particular therapy is best.

The article comments on the study conducted by Konstantinos Kostikas and colleagues which evaluated the utility of exhaled nitric oxide (FENO) measured by a portable device as a screening tool for asthma in young adults during pollen season. It recommended a cut-off value of less than 19-parts-per-billion FENO for the diagnosis of asthma.

The article discusses the role of nitric oxide (NO) and arginine in the lung. Nitric oxide has played a vital role in lung physiology including airway and vascular smooth muscle relaxation and ventilation perfusion matching. In late 1980, the scientific community has shifted its attention from arginine's traditional role in protein synthesis to its role as a precursor for the production of NO. Furthermore, lung is found to be the major source of NO synthesis inhibitor asymmetric.

Beryllium exposure remains an ongoing occupational health concern for workers worldwide. Since the initial Occupational Safety and Health Administration (OSHA) ruling on a permissible exposure limit (PEL) for beryllium in 1971, our understanding of the risks of beryllium sensitization and chronic beryllium disease (CBD) has evolved substantially. A new OSHA ruling released in early 2017 and implemented in late 2018 reduced the PEL for beryllium, increased requirements for medical screening and monitoring, and may ultimately enhance worker protection. This review highlights advances in our understanding of the pathway from beryllium exposure to sensitization and progression to CBD that guided the development of this OSHA ruling. Screening workers exposed to beryllium and management of CBD will also be discussed. Finally, we will discuss the role of beryllium as a cause of morbidity and mortality among exposed workers in this potentially preventable occupational lung disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension," by T. Pulido, I Adzerikho, R. N. Channick and colleagues in the August 29, 2013 issue.

Comments on the medical search for the selective pulmonary vasodilator that will aid the research and understanding of pulmonary hypertension. Levels of nitric oxide in patients with high blood pressure; Reference to a study by Hossein Ghofrani et al; Administration of hemodynamics and ventilation perfusion; Evidence for the use of sildenafil as a pulmonary vasodilator.

Comments on an article concerning the association between primary pulmonary hypertension and thyroid disease published in the November 1999 issue of the 'Chest' journal. Effect of decreased cholinergic output on pulmonary artery pressure and pulmonary vascular resistance.

An abstract of the article "Heart Rate Recovery in Patients With Pulmonary Arterial Hypertension" by Qamar Iqbal and colleagues is presented.

An abstract of the article "Pulmonary Artery Pressure and Right Ventricular Evaluation After Unilateral Pneumonectomy" by Gustavo Cumbo-Nacheli and colleagues is presented.

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. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary arterial hypertension (PAH) is usually associated with a poor outcome but the prognosis with other forms of PAH is not well-described. Advances in therapy have furthered clouded the disease course. We sought to determine the baseline indicators of prognosis in patients with PAH. We reviewed the records of patients with PAH followed up at our institution to identify those who died within 2 years (reduced survival group; n = 21) and those who survived >5 years (long survival group; n = 60). The groups were compared for prognostic significance of the baseline clinical parameters. The reduced survival group were older (p = 0.001) and more likely to have scleroderma-associated PAH (p = 0.01), have pericardial effusion (p = 0.01), have a shorter 6-minute walk test (6MWT) distance (p = 0.001), to require oxygen during 6MWT (p = 0.02), have a worse World Health Organization functional class (p <0.001), and have greater serum brain natriuretic peptide levels (p = 0.01). Regression analysis showed age, World Health Organization functional class, 6MWT distance, the need for oxygen during the 6MWT, and renal disease to be independently associated with a poor prognosis. In conclusion, age, PAH etiology, World Health Organization functional class, pericardial effusion, 6MWT distance, the need for oxygen during the 6MWT, and brain natriuretic peptide are predictors of prognosis in patients PAH receiving specific therapy and might help identify a group that could benefit from aggressive upfront therapy. [Copyright &y& Elsevier]

Hyaluronan (HA) is a glycosaminoglycan found in the extracellular matrix and ranges from several thousand to millions of daltons in size. HA has importance in various pathological conditions and is known to be elevated in several diseases. Three commonly used, commercially available HA enzyme-linked immunosorbent assay (ELISA)-like assays (from Corgenix, Echelon and R&D) were compared on the basis of accuracy, sample variability and ability to measure a range of HA sizes. The Corgenix HA ELISA-like assay displayed the lowest intra-assay variability [coefficient of variation (CV) = 11.7 ± 3.6%], followed by R&D (CV = 12.3 ± 4.6%) and Echelon (CV = 18.9 ± 9.2%). Interassay variability was also lowest for the Corgenix assay (CV = 6.0%), intermediate for the Echelon assay (9.5%) and highest for the R&D assay (CV = 34.1%). The high interassay variability seen for the R&D assay may have been due to the effect of dilution, since the dilution-independent interassay variability was 15.5%. The concentration of the standard HA was overestimated by the Echelon assay by 85% and underestimated by the R&D and Corgenix assays by 34 and 32%, respectively. The Echelon HA ELISA-like assay was the most effective at measuring all sizes of HA tested (2 MDa and 132, 66 and 6.4 kDa), whereas the Corgenix and R&D assays were unable to detect 6.4 kDa HA. These findings suggest that the Echelon HA ELISA-like assay is better suited for size-sensitive HA measurements but has a relatively high variability. The Corgenix and R&D HA ELISA-like assays have low variability and high accuracy but are not suitable for detecting low-molecular-weight HA. [ABSTRACT FROM PUBLISHER]

Background: The pattern of volatile organic compounds (VOCs) in the exhaled breath of patients with lung cancer may be unique. New sensor systems that detect patterns of VOCs have been developed. One of these sensor systems, a calorimetric sensor array, has 36 spots composed of different chemically sensitive compounds impregnated on a disposable cartridge. The colours of these spots change based on the chemicals with which they come into contact. In this proof of principle study, the ability of this sensor system to detect a pattern of VOCs unique to lung cancer is assessed. Methods: Individuals with lung cancer, those with other lung diseases and healthy controls performed tidal breathing of room air for 12 min while exhaling into a device designed to draw their breath across a calorimetric sensor array. The colour changes that occurred for each individual were converted into a numerical vector. The vectors were analysed statistically, using a random forests technique, to determine whether lung cancer could be predicted from the responses of the sensor. Results: 143 individuals participated in the study: 49 with non-small cell lung cancer, 18 with chronic obstructive pulmonary disease 15 with idiopathic pulmonary fibrosis 20 with pulmonary arterial hypertension 20 with sarcoidosis and 21 controls. A prediction model was developed using observations from 70% of the subjects. This model was able to predict the presence of lung cancer in the remaining 30% of subjects with a sensitivity of 73.3% and a specificity of 72.4% (p = 0.01). Conclusions: The unique chemical signature of the breath of patients with lung cancer can be detected with moderate accuracy by a calorimetric sensor array. [ABSTRACT FROM AUTHOR]

Abstract: The airway mucosal epithelium is the first site of virus contact with the host, and the main site of infection and inflammation. Nitric oxide (NO) produced by the airway epithelium is vital to antiviral inflammatory and immune defense in the lung. Multiple mechanisms function coordinately to support high-level basal NO synthesis in healthy airway epithelium and further induction of NO synthesis in the infected airway of normal hosts. Hosts deficient in NO synthesis, such as those patients with cystic fibrosis, have impaired antiviral defense and may benefit from therapies to augment NO levels in the airways. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO–oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Study objectives: To evaluate the diagnostic accuracy and safety of transbronchial needle aspiration (TBNA) in patients receiving mechanical ventilation in the ICU. Methods: Retrospective review of all patients in the medical and surgical ICUs from February 1999 to July 2001 who underwent TBNA while receiving mechanical ventilation. Results: A total of eight histology (19 gauge) and eight cytology (22 gauge) TBNAs were performed on eight patients (four men and four women). TBNA yielded a definitive pathologic diagnosis in five of eight patients (62.5%). Diagnoses were posttransplantation lymphoproliferative disorder, large cell carcinoma, poorly differentiated non-small cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Among patients with negative TBNA results (n = 3), two patients underwent mediastinoscopy. Results of mediastinoscopy were non-small cell carcinoma and inflamed tissue. TBNA led to management changes in five of these patients. Excluding one patient in whom a negative TBNA result could not be further confirmed, TBNA yielded a sensitivity of 83%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 50%. The overall accuracy of the procedure was 75%. There were no complications following any of the TBNAs. Conclusions: In this small group of patients, TBNA was safe and had a high diagnostic accuracy in selected patients receiving mechanical ventilation in the ICU. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). This retrospective study included adult patients with PAH who underwent right heart catheterization at Cleveland Clinic between February 1992 and November 2019. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Early and accurate diagnosis of pancreatic cancer is important. Our aim was to identify potential volatile organic compounds (VOCs) in the bile that can help distinguish pancreatic cancer from chronic pancreatitis.Methods: In this prospective observational study, bile was aspirated from patients undergoing endoscopic retrograde cholangiopancreatography for chronic pancreatitis and pancreatic cancer, and the gaseous headspace was analyzed using mass spectrometry.Results: The study included a discovery cohort of 57 patients (46 pancreatic cancer, 11 chronic pancreatitis) and a validation cohort of 31 patients (19 and 12, respectively). Using logistic regression analysis, the model [0.158 × age + 9.747 × log (ammonia) - 3.994 × log (acetonitrile) + 5.044 × log (trimethylamine) - 30.23] successfully identified patients with pancreatic cancer with a sensitivity of 93.5 % and specificity of 100 % (likelihood ratio 40.9, area under the curve 0.98, 95 % confidence interval 0.95 - 1.00). The diagnostic accuracy of this model was confirmed in the second independent validation cohort.Conclusion: The measurement of VOCs in bile helped to accurately distinguish pancreatic cancer from chronic pancreatitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines include thermodilution cardiac index (TDCI) and mixed venous oxygen saturation (SvO2) as two of the three hemodynamic determinations used in risk assessment of patients with pulmonary arterial hypertension (PAH). SvO2 may be a better measurement than TDCI to assess prognosis in patients with either idiopathic or heritable PAH.Research Question: What is the concordance between TDCI and SvO2 ESC/ERS risk group allocation and their prognostic value in patients with PAH?Study Design and Methods: In this retrospective study, we assessed the correlation between SvO2 and TDCI in patients with idiopathic and heritable PAH. We determined concordance in the ESC/ERS risk group allocation and association with survival, both at baseline and follow-up.Results: A total of 158 patients (mean age, 58 ± 17 years; 72% women) with idiopathic (91%) and heritable (9%) PAH were included. There was moderate association between TDCI and SvO2 (r = 0.50; 95% CI, 0.37-0.62). Weighted kappa revealed a fair agreement between TDCI and SvO2 (κ = 0.30; 95% CI, 0.18-0.42), with concordance in risk group allocation in 49% of patients. During a median follow-up of 45 months (interquartile range, 23-105), 62 patients (39%) died. Using Kaplan-Meier analysis, survival was impacted by the SvO2 (log rank = 0.002) but not by the TDCI risk group allocation (log-rank = 0.51). Using the Cox proportional hazard model, adjusted for age and sex, SvO2 (but not TDCI) was associated with mortality (hazard ratio per 1% change, 0.94; 95% CI, 0.91-0.97; P < .001).Interpretation: When using the cutoffs proposed by the ESC/ERS guidelines, we noted poor concordance in risk score allocation between TDCI and SvO2. In patients with idiopathic or heritable PAH, SvO2 measurements are superior to TDCI in predicting long-term mortality. [ABSTRACT FROM AUTHOR]

Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology. [ABSTRACT FROM AUTHOR]

Rationale: Inhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked. Objectives: We investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response. Findings: We enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86–118) and 114 (87–129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104–170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3–5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively). Conclusions: Both nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature. [ABSTRACT FROM AUTHOR]

Background: Pulmonary edema may complicate the use of pulmonary arterial hypertension (PAH)-targeted therapies. We aimed to determine the proportion of patients who develop pulmonary edema after initiation of parenteral prostacyclin therapy, to identify its risk factors, and to assess its implications for hospital length of stay and mortality.Methods: A retrospective cohort study of patients with PAH at the initiation of parenteral prostacyclin between 1997 and 2015 enrolled in the Cleveland Clinic PAH registry. Pulmonary edema was defined as at least one symptom or clinical sign and radiographic evidence of pulmonary edema. We determined patient characteristics predictive of pulmonary edema as well as the association between pulmonary edema and hospital length of stay (LOS) and 6-month mortality.Results: One hundred and fifty-five patients were included (median age, 51 years; female, 72%; white, 85%; idiopathic, 64%; and connective tissue disease [CTD], 23%). Pulmonary edema developed in 33 of 155 patients (21%). Independent predictors of pulmonary edema were high right atrial pressure (RAP), CTD etiology, and the presence of three or more risk factors for left heart disease (LHD). Pulmonary edema was associated with a 4.5-day increase in hospital LOS (95% CI, 1.4-7.5 days; P < .001) and a 4-fold increase in 6-month mortality (OR, 4.3; 95% CI, 1.28-14.36; P = .031).Conclusions: Pulmonary edema occurred in 21% of patients with PAH initiated on parenteral prostacyclin. Three or more risk factors for LHD, CTD-PAH, and a high baseline RAP were independent predictors of pulmonary edema. Pulmonary edema was associated with a prolonged hospital LOS and increased 6-month mortality. [ABSTRACT FROM AUTHOR]

Background: Serum chloride is an important homeostatic biomarker in left heart failure, with significant prognostic implications. The impact of serum chloride in the long-term survival of patients with pulmonary arterial hypertension (PAH) is unknown. We tested whether serum chloride levels are associated with long-term survival in patients with PAH.Methods: We included patients with idiopathic or heritable PAH who had a basic metabolic panel performed at the time of their diagnostic right heart catheterization. Laboratory results were recorded both at diagnosis and 6-month follow-up.Results: We included 277 patients, mean age 51 ± 18 years and 73% women, of whom 254 had a follow-up electrolyte determination at 6 months. Serum chloride was 102.9 ± 3.9 mM/L at diagnosis. A serum chloride ≤ 100 mM/L was noted in 65 (24%) and 53 (21%) patients at diagnosis and 6 months, respectively. Patients with serum chloride ≤ 100 mM/L at 6 months tracked with increase mortality when adjusted by age, sex, pulmonary vascular resistance, diuretics or prostacyclin analogs usage, and serum creatinine and sodium at 6 months (hazard ratio, 1.83; 95% CI, 1.11-3.00). This group of patients was older, with decreased functional capacity, had worse renal function, took more diuretics, had higher pulmonary artery wedge pressure but lower mean pulmonary artery pressure, transpulmonary gradient, and pulmonary vascular resistance.Conclusions: Serum chloride at 6 months from the PAH diagnosis is a strong and independent predictor of mortality in patients with idiopathic or heritable PAH, even after adjusting serum sodium, renal function, diuretic, and prostacyclin analog usage. [ABSTRACT FROM AUTHOR]

Background: High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Objectives: We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH. Methods: We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort. Results: HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34–57 mg/dl; PAH: 35.3, 29–39 mg/dl; Control: 49, 40–60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity. Conclusions: HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH. [ABSTRACT FROM AUTHOR]

Background: The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. Objectives: We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. Methods: Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. Results: A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54–3.98)) Conclusions: Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective A dilated pulmonary artery ( PA) is a common finding in patients with pulmonary arterial hypertension ( PAH). Little is known on the variations in PA size over time and whether these changes track with disease severity and/or predict long-term survival. Methods We included patients with PAH who had at least two computed tomography ( CT) scans of the chest done on different visits. Both scans matched the use of i.v. contrast. Results Pairs of CT scans were compared in 113 PAH patients. During a median (interquartile range ( IQR)) time difference between scans of 8 (IQR: 3.5-20.0) months, we noted an increase in main PA diameter of 0.5 ± 1.8 mm (mean ± SD) ( P = 0.008). When CT scans were performed >12 months apart ( n = 47), the main PA diameter increased or decreased by >1 mm in 40% and 13% of the patients, respectively. An increase in main PA diameter was associated with lower PA compliance, higher right ventricular ( RV) systolic pressure, worse RV function and a decline in 6-min walk distance. During a median ( IQR) follow-up of 33 (IQR: 4.5-47) months, 53 (46.9%) patients died. The change in PA diameter was a significant predictor of mortality (hazard ratio ( HR) per mm increase: 1.33 (95% CI: 1.11-1.61), P = 0.002) when adjusted for difference in time and slice thickness between CT scans, age, gender, PAH aetiology and pulmonary vascular resistance. Conclusion In PAH patients, an increase in CT-derived main PA diameter over time is associated with progression in pulmonary pressures, RV dysfunction, a decline in functional capacity and higher mortality. [ABSTRACT FROM AUTHOR]

Background The number of cardiac cycles that need to be reviewed by echocardiography before a significant intrapulmonary shunt can be excluded remains unclear. Methods We retrospectively identified patients with cirrhosis who underwent technetium-99 m-labeled macroaggregated albumin scanning. The kinetics of bubble appearance after the injection of agitated saline during transthoracic echocardiograms were assessed in these patients. Results For the 64 eligible patients, the mean ± SD age was 56 ± 9 years. The median (IQR) shunt fraction by radionuclide scanning was 7.7% (2.8%-19.9%). Microbubbles were seen in the left atrium (LA) and left ventricle (LV) at a median (IQR) of 4 (2-5) and 4 (2-5) beats, respectively. The number of heart cycles before microbubbles appeared in the LA or LV was inversely associated with the nuclear scanning shunt fraction ( R = −0.42, P = .001, R = −0.46, P < .001, respectively). If no microbubbles were detected by heart cycle 7, the shunt fraction was uniformly less than 3%. Patients with arterial oxygen <60 mm Hg, compared to ≥60 mm Hg, had earlier appearance of microbubbles in the left heart chambers (2.6 ± 1.9 vs 4.0 ± 2.3 beats, P = .046). Conclusions In patients with advanced cirrhosis suspected of having hepatopulmonary syndrome, a greater shunt fraction during nuclear scanning was associated with more pronounced hypoxemia and a prompt and more intense appearance of microbubbles in the left-sided heart chambers. Patients with a shunt fraction above 3% have microbubbles in the LA or LV at some point during the first seven heart cycles. [ABSTRACT FROM AUTHOR]