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Background: This study aimed to determine the parameters for worsening oxygenation in non-severe coronavirus disease 2019 (COVID-19) pneumonia. Methods: This retrospective cohort study included cases of confirmed COVID-19 pneumonia in a public hospital in South Korea. The worsening oxygenation group was defined as that with SpO2 ≤94% or received oxygen or mechanical ventilation (MV) throughout the clinical course versus the non-worsening oxygenation group that did not experience any respiratory event. Parameters were compared, and the extent of viral pneumonia from an initial chest computed tomography (CT) was calculated using artificial intelligence (AI) and measured visually by a radiologist. Results: We included 136 patients, with 32 (23.5%) patients in the worsening oxygenation group; of whom, two needed MV and one died. Initial vital signs and duration of symptoms showed no difference between the two groups; however, univariate logistic regression analysis revealed that a variety of parameters on admission were associated with an increased risk of a desaturation event. A subset of patients was studied to eliminate potential bias, that ferritin ≥280 μg/L (p=0.029), lactate dehydrogenase ≥240 U/L (p=0.029), pneumonia volume (p=0.021), and extent (p=0.030) by AI, and visual severity scores (p=0.042) were the predictive parameters for worsening oxygenation in a sex-, age-, and comorbid illness-matched case-control study using propensity score (n=52). Conclusion: Our study suggests that initial CT evaluated by AI or visual severity scoring as well as serum markers of inflammation on admission are significantly associated with worsening oxygenation in this COVID-19 pneumonia cohort.

Randomized trials of pulmonary vasodilators in pulmonary hypertension due to left heart disease (Group 2) and lung disease (Group 3) have demonstrated potential for harm. Yet these therapies are commonly used in practice. Little is known of the effects of treatment outside of clinical trials. We aimed to establish outcomes of vasodilator treatment for Groups 2/3 pulmonary hypertension in real-world practice. We conducted a retrospective cohort study of 132,552 Medicare-eligible Veterans with incident Groups 2/3 pulmonary hypertension between 2006 and 2016, and a secondary nested case–control study. Our primary outcome was a composite of death by any cause or selected acute organ failures. In our cohort analysis, we calculated adjusted risks of time to our outcome using Cox proportional hazards models with facility-specific random effects. In our case–control analysis, we used logistic mixed-effects models to estimate the effect of any past, recent, and cumulative exposure on our outcome. From our cohort study, 3249 (2.5%) Veterans were exposed to pulmonary vasodilators. Exposure to vasodilators was associated with increased risk of our primary outcome, in both Group 3 (HR: 1.58 (95% CI: 1.37–1.82)) and Group 2 (HR: 1.26 (95% CI: 1.12–1.41)) pulmonary hypertension patients. The case–control study determined odds of our outcome increased by 11% per year of exposure (OR: 1.11 (95% CI: 1.07–1.16)). Treating Groups 2/3 pulmonary hypertension with vasodilators in clinical practice is associated with increased risk of harm. This extension of trial findings to a real-world setting offers further evidence to limit use of vasodilators in Groups 2/3 pulmonary hypertension outside of clinical trials.

The proliferation and migration of pulmonary artery endothelial cells are the pathological basis of pulmonary vascular remodeling with pulmonary hypertension. Recent studies have shown that circular RNA (circRNA) regulates biological processes in various vascular diseases, including pulmonary arterial hypertension. It has been reported that circRNA regulates the vascular endothelial cells’ function. Therefore, circRNA may have crucial roles in human pulmonary artery endothelial cells (hPAECs) proliferation, migration, and tube formation in pulmonary arterial hypertension. In this study, we aimed to discover the role and mechanism of circular RNA HIPK3 (circHIPK3) in the proliferation and migration of pulmonary hypertension hPAECs. First, we used platelet-derived growth factor—stimulated hPAECs as a cellular model of pulmonary arterial hypertension. The results showed that platelet-derived growth factor promoted hPAECs proliferation, migration, and tube formation. Notably, platelet-derived growth factor upregulated the expression of circHIPK3 in hPAECs and regulated their proliferation, migration, and angiogenesis. Mechanistically, we confirmed miR-328-3p was copiously pulled down by circHIPK3 in hPAECs. Luciferase reporter and RNA immunoprecipitation assays further indicated the cytoplasmic interactions between circHIPK3 and miR-328-3p. Subsequently, we found that circHIPK3 might increase the expression of STAT3 by sponging miR-328-3p. Collectively, our results demonstrated that the circHIPK3-miR-328-3p-STAT3 axis contributed to the pathogenesis of pulmonary arterial hypertension by stimulating hPAECs proliferation, migration, and angiogenesis. The circHIPK3 has an accelerated role in pulmonary arterial hypertension development, implicating the potential values of circHIPK3 in pulmonary arterial hypertension therapy.

Previous studies suggest that prone positioning (PP) can increase PaOThis prospective observational cohort study was performed in two teaching hospitals. Non-intubated moderate to severe ARDS patients were included and were placed in PP with NIV or with HFNC. The efficacy in improving oxygenation with four support methods-HFNC, HFNC+PP, NIV, NIV+PP-were evaluated by blood gas analysis. The primary outcome was the rate of intubation.Between January 2018 and April 2019, 20 ARDS patients were enrolled. The main causes of ARDS were pneumonia due to influenza (9 cases, 45%) and other viruses (2 cases, 10%). Ten cases were moderate ARDS and 10 cases were severe. Eleven patients avoided intubation (success group), and 9 patients were intubated (failure group). All 7 patients with a PaOEarly application of PP with HFNC, especially in patients with moderate ARDS and baseline SpOChiCTR, ChiCTR1900023564. Registered 1 June 2019 (retrospectively registered).

Introduction While cigarette use has decreased, adolescents' overall use of tobacco (e.g. e-cigarettes, cigars, and hookah) has increased. The purpose of this qualitative study is to highlight the decision-making process of adolescents to use certain products over others and why certain tobacco products appeal to them. Methods Twenty-five participants were recruited from a larger study surveying adolescents' perceptions and tobacco use (772 high school students). The participants were involved in one-on-one semi-structured phone interviews on the appeal of different tobacco products. Interviews were recorded, transcribed verbatim, and analyzed by identifying relevant codes and themes. Results Participants for this study had a mean age of 16.4 (SD=1.2) years; over half (14/25) were female. Three major themes emerged from the interviews: 1) social context and circumstances to use, including using and sharing with peers, and reducing boredom; 2) importance of flavors, smell, taste, smoke tricks, and accessibility of products; and 3) misperceptions and misinformation of product risks. Conclusions The findings that emerged showed why participants favored certain tobacco products, especially e-cigarettes, over others. The results support areas for future research and practice, and inform how interventions can better address the appeal of different tobacco products to ultimately prevent adolescent use.

Introduction The aim of this study was to determine trends in receiving quit advice from healthcare professionals among current smokers in South Africa, pre- and post-adoption of Article 14 guidelines of the WHO FCTC in 2010, and to determine the association between quit advice, e-cigarette use and quit attempt. Methods This study was a secondary data analysis involving 2206 ever-smokers aged ≥16 years who participated in the South African Social Attitude Surveys conducted in 2007, 2010 and 2017. Data included participants' sociodemographics, tobacco, and/or e-cigarette use (for years 2010 and 2017 only), exposure to others' smoking at home and/or work or public places, quit advice, and quit attempts. Analyses included chi-squared test and logistic regression. Results The mean cigarettes smoked per day, the proportions of smokers offered quit advice, planning to quit and who made a quit attempt did not change significantly between 2007 and 2017 (p=0.67, p=0.70, p=0.09 and p=0.40, respectively). However, there was a marginally significant increase in e-cigarette uptake between 2010 and 2017 (p=0.05). In a bivariate analysis, quit advice was significantly associated with making a quit attempt across all survey years. In the final multivariable-adjusted regression model, having received a quit advice (OR=1.967; 95% CI: 1.255-3.083) compared to not, and being Colored/mixed race (OR=0.467; 95% CI: 0.298-0.732) compared to self-identifying as Black African, remained independently associated with making a quit attempt. Conclusions Except for marginally increased e-cigarette use, there was no significant change in smoking or quitting behavior in South Africa post-adoption of Article 14 guidelines. The study findings highlight the importance of quit advice in promoting quitting behavior and suggest the need to scale it up in South Africa.

Introduction To inform policy making under the proposed The Control of Tobacco and Electronic Delivery Systems Bill, we compared annual costs of using e-cigarettes versus cigarettes, and estimated revenue from e-cigarette taxation. Methods We extracted e-cigarette retail prices from 231 South African e-cigarette vendor websites. We compared annual costs associated with daily cigarette smoking (self-reports from daily smokers in the 2018 South African Social Attitudes Survey, SASAS) versus daily e-cigarette use (based on cumulative costs of consumables plus device costs). We estimated revenue from excise tax if e-cigarettes were taxed at 75% (the rate proposed by the government) and 37.5% (half of the government's proposal as a hypothetical scenario) of the cigarette excise rate. We applied the different rates to e-cigarette consumption in 2018 SASAS and projected for 2021. Results Mean annual cost associated with daily use was ZAR 6693 (US$460.32, based on an exchange rate of about 69 US$ to 1000 ZAR) for manufactured cigarettes; for e-cigarettes, this ranged from ZAR 8574.69/year (with price minimizing strategies) to ZAR 19780.83/year (retail products exclusively). Expected revenue from e-cigarette excise tax at 75% of the cigarette tax rate was up to ZAR 2.20 billion (95% CI: 0.96-3.44). If taxed at 37.5% of the cigarette tax rate - half of the government's proposed rate - the projected revenue was up to ZAR 1.10 billion (95% CI: 0.48-1.72). Of the projected revenue from e-cigarette excise tax at 75% of the cigarette rate, the portion attributable to hardware (device and batteries) was 61% (ZAR 1.35 billion), while the portion attributable to e-liquid was 39% (ZAR 0.86 billion). Conclusions Calculated daily costs were higher for e-cigarettes than cigarettes. We recommend an e-cigarette excise tax. The government's proposed tax rate may reduce youth e-cigarette access, while allowing adult smokers wishing to switch exclusively to e-cigarettes to reduce their tobacco-related harm.

Introduction The contribution made by e-cigarettes to smoking cessation continues to be controversial. Reports suggest that teenagers are becoming increasingly addicted to e-cigarettes and that e-cigarette use in adolescents is associated with subsequent cigarette smoking. Methods Systematic searches of eleven databases were conducted (January 2015 to June 2020). Systematic reviews, randomized controlled trials (RCTs) and cohort studies comparing e-cigarettes with placebo e-cigarettes, nicotine replacement therapy (NRT) or no e-cigarette use were included. The two primary outcomes were smoking cessation among smokers and smoking initiation among non-smoking teenagers. The secondary outcome was adverse events. Data were synthesized using risk ratio (RR) or adjusted odds ratio (AOR) with 95% confidence interval (CI). Results Six systematic reviews, 5 RCTs and 24 cohort studies were identified. For smoking cessation, findings from 4 systematic reviews indicated that e-cigarettes contributed to cessation while one found the opposite. Meta-analysis of 5 RCTs suggested that e-cigarettes were superior to NRT or placebo for smoking cessation (RR=1.55; 95% CI: 1.00–2.40; I 2 =57.6%; low certainty; 5 trials, n=4025). Evidence from 9 cohort studies showed that e-cigarette use was not associated with cessation (AOR=1.16; 95% CI: 0.88–1.54; I 2 =69.0%; n=22220). Subgroup analysis suggested that intensive e-cigarette use may be associated with cessation. In terms of smoking initiation, adolescents who ever used e-cigarettes had a greater risk for smoking initiation than non-users (AOR=2.91; 95% CI: 2.61–3.23; I 2 =61.0%; 15 trials, n=68943), the findings were consistent with one included systematic review. No serious adverse events were reported in the included studies. Conclusions Low certainty evidence suggests that e-cigarettes appear to be potentially effective for smoking cessation. The use of e-cigarettes in adolescents may be associated with smoking initiation. No serious adverse events were reported.

Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis, so early detection and treatment are very important. Sensitive and non-invasive markers for PAH are urgently required. This study was performed to identify sensitive markers of the clinical severity and prognosis of PAH. Patients diagnosed with PAH (n = 30) and control participants (n = 15) were enrolled in this observational study. Major EPC and MSC markers (including CD34, CD133, VEGFR2, CD90, PDGFRα, and NGFR) in peripheral blood mononuclear cells (PBMNCs) were assessed by flow cytometry. Associations of these markers with hemodynamic parameters (e.g. mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index) were assessed. Patients with PAH were followed up for 12 months to assess the incidence of major adverse events, defined as death or lung transplantation. Levels of circulating EPC and MSC markers in PBMNCs were higher in patients with PAH than in control participants. Among the studied markers, nerve growth factor receptor (NGFR) was significantly positively correlated with hemodynamic parameters. During the 12-month follow-up period, major-event-free survival was significantly higher in patients with PAH who had relatively low frequencies of NGFR positive cells than patients who had higher frequencies. These results suggested that the presence of circulating NGFR positive cells among PBMNCs may be a novel biomarker for the severity and prognosis of PAH.

Pulmonary arterial hypertension is a chronic, progressive, and life-threatening disease in children with diverse causes of pulmonary arterial hypertension. The most severe cases of pulmonary arterial hypertension require aggressive treatments with systemic administration of continuous prostacyclin therapy, including treprostinil and epoprostenol. The successful use of continuous subcutaneous treprostinil therapy eliminates the need for an indwelling central venous catheter and its associated risks. However, pain at the subcutaneous infusion site, an expected side effect of this therapy, is often a deterrent to its widespread use. Effective subcutaneous treprostinil site maintenance and pain management is essential to achieve success with this therapy, but strategies surrounding site maintenance and pain control vary significantly between pediatric pulmonary hypertension treatment centers. In an attempt to standardize practice, a survey on the use of subcutaneous treprostinil and site maintenance and pain management strategies, as well as its perceived effectiveness, was disseminated to 13 pediatric pulmonary hypertension centers of the Pediatric Pulmonary Hypertension Network. Responses to the survey were collected and analyzed and were developed into a set of formalized strategies to facilitate knowledge sharing and standardization of practice.

Background and objectives Mortality of patients with pulmonary tuberculosis (TB) admitted to emergency departments is high. This study was aimed at analysing the risk factors associated with early mortality and designing a risk score based on simple parameters. Methods This prospective case-control study enrolled patients admitted to the emergency department of a referral TB hospital. Clinical, radiological, biochemical and microbiological risk factors associated with death were compared among patients dying within one week from admission (cases) and those surviving (controls). Results Forty-nine of 250 patients (19.6%) experienced early mortality. Multiple logistic regression analysis showed that oxygen saturation (SaO2) ≤90%, severe malnutrition, tachypnoea, tachycardia, hypotension, advanced disease at chest radiography, severe anaemia, hyponatremia, hypoproteinemia and hypercapnia were independently and significantly associated with early mortality. A clinical scoring system was further designed to stratify the risk of death by selecting five simple parameters (SpO2 ≤ 90%, tachypnoea, hypotension, advanced disease at chest radiography and tachycardia). This model predicted early mortality with a positive predictive value of 94.88% and a negative predictive value of 19.90%. Conclusions The scoring system based on simple parameters may help to refer severely ill patients early to a higher level to reduce mortality, improve success rates, minimise the need for pulmonary rehabilitation and prevent post-treatment sequelae.

Pulmonary artery sarcoma (PAS) is a rare and devastating disease. The diagnosis is often delayed, and optimal treatment remains unclear. The aim of this study is to report our experience in the surgical management of this disease. Between 2000 and 2018, 17 patients underwent operations for PAS at our center. The medical records were retrospectively reviewed to evaluate the clinical characteristics, operative findings, the postoperative outcomes, and the long-term results. The mean age at operation was 46.0 ± 12.4 years (range, 26–79 years), and eight (47.1%) patients were male. Six patients underwent tumor resection alone, whereas the other 11 patients received pulmonary endarterectomy (PEA). There were two perioperative deaths. Follow-up was completed for all patients with a mean duration of 23.5 ± 17.6 months (1–52 months). For all 17 patients, the median postoperative survival was 36 months, and estimated cumulative survival rates at 1, 2, 3, and 4 years were 60.0%, 51.4%, 42.9%, and 21.4%, respectively. The mean survival was 37.0 months after PEA and 14.6 months after tumor resection only ( p = 0.046). Patients who had no pulmonary hypertension (PH) postoperatively were associated with improved median survival (48 vs. 5 months, p = 0.023). In conclusion, PAS is often mistaken for chronic pulmonary thromboembolism. The prognosis of this very infrequent disease remains poor. Early detection is essential for prompt and best surgical approach, superior to tumor resection alone, and PEA surgery with PH relieved can provide better chance of survival.

Introduction Invasive mechanical ventilation (IMV) is associated with several complications. Placement of a long-term airway (tracheostomy) is also associated with short and long-term risks for patients. Nevertheless, tracheostomies are placed to help reduce the duration of IMV, facilitate weaning and eventually undergo successful decannulation. Methods We performed a narrative review by searching PubMed, Embase and Medline databases to identify relevant citations using the search terms (with synonyms and closely related words) “non-invasive ventilation”, “tracheostomy” and “weaning”. We identified 13 publications comprising retrospective or prospective studies in which non-invasive ventilation (NIV) was one of the strategies used during weaning from IMV and/or tracheostomy decannulation. Results In some studies, patients with tracheostomies represented a subgroup of patients on IMV. Most of the studies involved patients with underlying cardiopulmonary comorbidities and conditions, and primarily involved specialized weaning centres. Not all studies provided data on decannulation, although those which did, report high success rates for weaning and decannulation when using NIV as an adjunct to weaning patient off ventilatory support. However, a significant percentage of patients still needed home NIV after discharge. Conclusions The review supports a potential role for NIV in weaning patients with a tracheostomy either off the ventilator and/or with its decannulation. Additional research is needed to develop weaning protocols and better characterize the role of NIV during weaning.

Male patients with pulmonary hypertension have poor survival than their female counterparts. Poor right ventricular function in men may be one of the major determinants of poor prognosis. This study aimed to investigate the difference in hemodynamics during exercise between men and women by exercise echocardiography. Consecutive patients with pulmonary hypertension who underwent right heart catheterization were enrolled, and survival was analyzed. In patients who underwent exercise echocardiography, the change in tricuspid regurgitation pressure gradient during exercise was calculated at multiple stages (low-, moderate-, and high-load exercise), and the mortality was also recorded. In a total of 93 patients, although there were no differences in pulmonary artery pressure and vascular resistance between sexes, male patients showed poor survival. In patients with exercise echocardiography, change in tricuspid regurgitation pressure gradient at low-load (25 W) exercise was significantly lower in men, although that at maximum-load exercise was not different between men and women. In the Kaplan–Meier analysis, in a median follow-up duration of 1760 days, male patients and those with lower change in tricuspid regurgitation pressure gradient at low-load exercise showed poorer survival ( P = 0.002 and 0.026, respectively). In the Cox proportional hazards analysis, the change in tricuspid regurgitation pressure gradient at low-load exercise was independently associated with poor survival after adjustment for age and sex. In conclusion, a lower change in tricuspid regurgitation pressure gradient at low-load exercise was observed in male patients and was a prognostic marker, which may be associated, at least in part, with poorer prognosis in male patients with pulmonary hypertension.

Background A positive D-dimer test has high sensitivity but relatively poor specificity for the diagnosis of pulmonary embolism, causing difficulty for clinicians unskilled in pulmonary embolism diagnosis in determining whether a patient with a positive D-dimer test needs to undergo computed tomographic pulmonary angiography. Objectives We sought to develop a new clinical decision-making rule based on a positive D-dimer result to predict the probability of pulmonary embolism and to guide clinicians in making decisions regarding the need for computed tomographic pulmonary angiography. Methods We conducted a prospective, multicenter study in three hospitals in China. A total of 3014 inpatients with positive D-dimer results were included. In the derivation group, we built a multivariate logistic regression model and deduced a regression equation from which our score was derived. Finally, we validated the score in an independent cohort. Results Our score included nine variables (points): chest pain (1.4), chest tightness (2.3), shortness of breath (3.6), hemoptysis (3.4), heart rate ≥100 beats/min (3.6), blood gas analysis (2.9), electrocardiogram presenting a typical S1Q3T3 pattern (4.1), electrocardiogram findings (2.4), and ultrasonic cardiogram findings (3.7). The sensitivities and specificities were 100% and 86.94%, respectively, in the derivation group and 100% and 90.82%, respectively, in the validation group. Additionally, the observed and predicted proportions of patients who underwent computed tomographic pulmonary angiography were 16.82% and 10.76%, respectively, in the derivation group and 18.72% and 11.40%, respectively, in the validation group. Conclusions The new score can categorize inpatients with a positive D-dimer test as pulmonary embolism-likely or pulmonary embolism-unlikely, thus reducing unnecessary computed tomographic pulmonary angiography examinations.

Luca Richeldi,1 Alessio Piraino,2 Francesco Macagno,1 Gianluigi Micarelli,2 Eleonora Ingrassia2 1Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A, Gemelli, Rome; 2Chiesi Italia S.p.a., Parma, ItalyCorrespondence: Gianluigi MicarelliChiesi Italia S.p.a., Via Giacomo Chiesi 1, Parma 43122, ItalyTel +39 345 6350692Fax +39 0521 279592Email g.micarelli@chiesi.comBackground: The fixed triple combination Beclometasone dipropionate/Formoterol fumarate/Glycopyrronium (BDP/FF/G, Trimbow®), an extrafine formulation in a unique pressurized metered dose inhaler, is indicated for the maintenance treatment in adult patients with moderate to severe COPD, not adequately treated by ICS/LABA or LABA/LAMA. Besides the evidence from three randomized controlled trials, the impact of fixed triple therapy has not been extensively evaluated in a real-world population of COPD patients. TRITRIAL (TRIple Therapy in Real life: Impact on Adherence and HeaLth status) is a non-interventional study to assess the effect of BDP/FF/G in a real world setting in Italy.Design: TRITRIAL is a 12-month, multicenter, cohort, prospective, longitudinal observational study. Two follow-up visits will be performed at 6 and 12 months, respectively. The study includes the collection of anamnestic clinical and functional data before the start of BDP/FF/G. The study is built for digital conduction, from signature of the informed consent on a dedicated web platform, to the collection of questionnaires and clinical data on the eCRF.Population: A total of 800 patients with COPD ranging from Global Initiative for Obstructive Lung Disease (GOLD) stages 2 to 4, receiving therapy with BDP/FF/G according to the Summary of Product Characteristics and local clinical practice, will be recruited. All concomitant therapies will be permitted for the duration of the study.Evaluations: The primary endpoint is the change of CAT score at 12 months versus baseline. Secondary endpoints are adherence, health-related quality of life, sleep quality, disease-related outcomes (lung function and COPD exacerbations), device usability, economic resources consumption, and safety.Conclusion: TRITRIAL study is expected to give relevant information about effectiveness of BDP/FF/G fixed triple therapy in a real-life setting of patients with COPD, where adherence, usability of inhalers and patient’s preference of the device are crucial factors for the success of the therapy.Keywords: COPD, symptoms, health status, adherence, LAMA, LABA, ICS

Metabolic syndrome is characterized by insulin resistance/hyperinsulinemia, atherogenic dyslipidemia (elevated triglycerides, low HDL), and hyperglycemia. The high prevalence of metabolic syndrome in pulmonary hypertension leads to the hypothesis that metabolic syndrome may play a contributing role in pulmonary hypertension and heart failure with preserved ejection fraction pathogenesis. We present a 62-year-old woman with morbid obesity, mild pre-capillary pulmonary hypertension, and metabolic syndrome. Her metabolic syndrome was treated with a medically-supervised ketogenic diet delivered by a telehealth healthcare team via a continuous remote care platform. Following one year of treatment, metabolic syndrome was reversed, leading to successful weight loss concurrent with hemodynamic improvement. This case highlights the feasibility of using a nutritional strategy to treat pulmonary hypertension associated with obesity and metabolic syndrome, common contributors to group 2 and 3 pulmonary hypertension. We bring this case and technique to the pulmonary hypertension community to share a tool in our therapeutic toolkit and highlight the importance of nutritional advice extending beyond telling a patient they should lose weight to invoking a rational strategy. We argue that strategic nutritional intervention through reversal of her metabolic syndrome using a medically-supervised ketogenic diet is a safe and effective treatment strategy in metabolic syndrome-associated pulmonary hypertension.

For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic material, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of DNA sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expression of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condition is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circulation of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immunology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

Recent studies suggest that pregnancy may not be absolutely contraindicated in women with moderate pulmonary hypertension. We aimed to evaluate the long-term outcomes of pregnant women with pulmonary hypertension diagnosed by echocardiography in our clinical department. Pregnant women with pulmonary hypertension, diagnosed by a pulmonary systolic arterial pressure > 30 mmHg via echocardiography, who were admitted in our department for termination of pregnancy or delivery between 2004 and 2016 were included in this retrospective cohort study. Demographic characteristics, clinical histories, perinatal outcomes, and follow-up outcomes after discharge were reported. The primary outcome was survival of the pregnant women after discharge. A total of 88 pregnant women with pulmonary hypertension were included in this cohort study. The women were categorized into severe and moderate pulmonary hypertension groups according to their pulmonary systolic arterial pressure at admission. Women with severe pulmonary hypertension were significantly more likely to have deteriorated cardiac function and higher incidence of neonatal complications during the perinatal periods (p 90% for women with moderate pulmonary hypertension within the follow-up period. Multivariate Cox regression analyses showed that poor cardiac function before pregnancy, irregular antenatal care, and hyperuricemia were independent mortality risk factors for women with pulmonary hypertension after discharge. In conclusion, the long-term survival of pregnant women with moderate pulmonary hypertension diagnosed by echocardiography was considered acceptable in this cohort. Our findings suggest that pregnancy might not be absolutely contraindicated in women with moderate pulmonary hypertension.

Background: Pleurodesis fails in 10%-40% of patients with recurrent malignant pleural effusions malignant pleural effusion and dyspnea. This study aimed to assess the values of pleural elastance (PEL) after the aspiration of 500 mL of pleural fluid and their relation to the pleurodesis outcome, and to compare the pleurodesis outcome with the chemical characteristics of pleural fluid. Methods: A prospective study was conducted in Kasr El-Aini Hospital, Cairo University, during the period from March 2019 to January 2020. The study population consisted of 40 patients with malignant pleural effusion. The measurement of PEL after the aspiration of 500 mL of fluid was done with “PEL 0.5” (cm H2O/L), and the characteristics of the pleural fluid were chemically and cytologically analyzed. Pleurodesis was done and the patients were evaluated one month later. The PEL values were compared with pleurodesis outcomes. Results: After 4-week of follow-up, the success rate of pleurodesis was 65%. The PEL 0.5 was significantly higher in failed pleurodesis than it was in successful pleurodesis. A cutoff point of PEL 0.5 >14.5 cm H2O/L was associated with pleurodesis failure with a sensitivity and specificity of 93% and 100%, respectively. The patients with failed pleurodesis had significantly lower pH levels in fluid than those in the successful group (p

Purpose HRCT is the preferred imaging technique to evaluate Interstitial-Lung-Disease. Optimal Low-Dose-Computed-Tomography protocol for monitoring ILD with lowest radiation dose and optimal diagnostic accuracy and image quality unknown. Methods 28 Patients underwent HRCT. Image reconstructions with varying combinations of tube current (50mA, 20mA, 15 mA, 10mA) and image-thickness/increment (1/1mm, 2/2mm, 3/2.4mm, 5/4mm) were simulated from raw data. 448 CTs evaluated by 2 readers on image quality and ILD-specific features (ground glass opacification (ggo), honeycombing (hc), reticulation (ret)). Results Reduced dose settings with 20 mA did not show any significant difference to standard dose settings for all parameters in reader 1, while results were significantly altered in reader 2. Slice thickness did not significantly influence rating of typical ILD features like ggo, hc, ret or total disease extent. The correct differentiation between UIP and NSIP could be made on all dose settings and with all slice thickness. It was even found, that an increased slice thickness can compensate for the noise associated image quality degradation. Overall, for ggo detection a combination of 20 mA and 3 or 5 mm slice thickness was not different to the original evaluation. Conclusions Assessment of ILD specific CT features down to 20 mA and a slice thickness of 3 or 5 mm is feasible.

Background: Particulate matter 10 (PM10; airborne particles

Background: Lung inflammation plays a vital role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the characteristics of the inflammatory process remain unclear. There is growing interest in the role of granzyme B (GzmB) because CD8+ T cells can induce apoptosis of target cells by releasing GzmB, which in turn may cause tissue injury and remodeling. However, GzmB is also expressed by regulatory cells, which are able to suppress CD8+ T cell. The role of GzmB+ cells needs to be defined in COPD. Methods: GzmB+ and CD8+ cells on alveolar wall of surgically resected lungs of microscopically classified 12 nonsmoking control, 12 panlobular emphysema (PLE) and 30 centrilobular emphysema (CLE) subjects were localized by immunohistochemical method. Positively stained cells on alveolar wall were counted and length of corresponding alveolar wall was measured. The results were expressed as mean number of positively stained cells per mm of alveolar wall in each subject. Results: The number of GzmB+ and CD8+ cells on alveolar wall of CLE was greater than that of control or PLE subjects (p

Ozone is known to cause bronchial inflammation and airway hyper-responsiveness via oxidative injury and inflammation. While other ambient air pollutants such as particulate matter (PM) and nitrogen dioxide showed decreasing trends in mean annual concentrations, ozone concentrations have not declined recently in most countries across the world. Short-term exposure to high concentrations of ozone has been associated with increased mortality and cardiovascular and respiratory morbidity in many regions of the world. However, the long-term effects of ozone have been less investigated than the short-term exposure due to the difficulty in modeling ozone exposure and linking between individual exposures and health outcome data. A recently developed model of ozone exposure enabled the investigation of long-term ozone effects on health outcomes. Recent findings suggested that long-term exposure to ozone was associated with an increased risk of cardiovascular and respiratory mortality. Longitudinal studies using large cohorts also revealed that long-term exposure to ozone was associated with a greater decline in lung function and the progression of emphysema. The development of long-term standards for ozone as well as PM should be considered to protect the respiratory health of the general population and people with chronic respiratory diseases.

Introduction Males have a higher prevalence of waterpipe tobacco smoking (WTS) than females in most Eastern Mediterranean Region (EMR) countries, with a smaller gender gap than that of cigarette smoking. The objective of this study was to determine gender differences among university students with respect to WTS initiation, smoking behavior, tobacco flavors, and expenditure on WTS, in four EMR countries. Methods A cross-sectional online survey was conducted based on convenient samples of ever waterpipe smokers among university students in four EMR countries (Egypt, Jordan, Occupied Palestinian Territories, and the United Arab Emirates) in 2016. The total samples included 2470 participants. Study participants were invited through flyers, university portals, emails and Facebook, followed by emails with links to the internet survey. Results Females (80.4%) were more likely than males (66.4%, p

INTRODUCTION Few studies to date have characterized daily exclusive e-cigarette users, device characteristics, and use behaviors. This study describes daily e-cigarette user characteristics, and assesses the association between user behaviors and demographics. METHODS From 2015–2017, 100 daily exclusive e-cigarette users and 50 nonusers were recruited in Maryland, USA. Sociodemographic characteristics, health status, e-cigarette/tobacco use behaviors, device characteristics, and reasons for e-cigarette use were collected by interview. Chi-squared tests (categorical variables), Student’s t-test (continuous variables), and linear regressions were used to assess relationships between variables. RESULTS Most daily exclusive e-cigarette users were men, White, former smokers, used MODs/tanks, and vaped on average 365 puffs/day (SD: 720). A third of users first vaped within 5 minutes of waking in the morning, and 56% vaped throughout the day. E-liquid consumption ranged from 5–240 mL/week (median: 32.5), with nicotine concentration 0–24 mg/mL (median: 3). E-cigarette users were more likely to report wheezing/whistling and hypertension than controls, although the finding was not statistically significant after adjustment. Less than half planned to quit vaping. CONCLUSIONS Daily e-cigarette users between 2015–2017 most commonly vaped MOD/tank devices. Being male and of lower education was associated with higher usage. Daily users with no intention to quit may be at risk for increased exposure to emissions from e-cigarettes that include inorganic (metals) and organic (e.g. acrolein, formaldehyde) compounds with known toxic effects, particularly to the lung. Further research is needed to characterize the long-term health effects of daily e-cigarette use

Introduction The Tobacco Control Scale (TCS) was designed for advocacy purposes but has also been used as a research tool. In the present study, we characterized TCS use, its limitations and strengths, and critically assessed its use as a research instrument. Methods We conducted an extensive search of the biomedical databases PubMed and Web of Science for the keyword 'tobacco control scale' in all fields. The search was limited to studies published in the period March 2006 to December 2019. Out of 69 hits, 32 studies met the inclusion criteria. Two reviewers independently extracted information from each publication regarding their general characteristics, publication and research aspects, and the characteristics of the use of the TCS. Results We found that researchers have used the TCS as a tool to monitor tobacco control policies mainly in cross-sectional observational studies with ecological and multilevel designs directed to advocacy and the promotion of further research. Different outcomes, such as smoking prevalence and quit ratios, have been associated with tobacco control policy scores. The main reported limitations of the TCS were a low variance across countries and a failure to express enforcement and to incorporate the most recent legislation. Conclusions The TCS has been commonly used to assess differences in outcomes according to tobacco control policies. However, there are still areas for improvement in its use in research regarding the lack of comparability of TCS scores across time. The lessons that have been learned should be used to adapt and expand the TCS overseas.

Rationale: Use of noninvasive ventilation (NIV) has increased in intensive care units, but sleep during NIV has received little attention. The authors surmised that due to frequent air leaks and mask discomfort, patients receiving NIV would manifest poorer sleep quality than those receiving invasive mechanical ventilation (INV). Methods: A prospective observational study on patients receiving NIV or INV for respiratory failure in a medical intensive care unit or coronary care unit. Patients were monitored by polysomnography for 24 hours with simultaneous collection of data on ventilator and environmental parameters. Results: Eight subjects in each group were studied. Mean total sleep time was 7.29 +1.78 hours (range: 0.57–13.82) in the NIV versus 11.74 +0.65 hours (8.95–15.19) in the INV group (p=0.034). Sleep efficiency was lower in NIV than INV group (30.4% versus 53.3%, respectively; p=0.013). The NIV group had lighter sleep than the INV group (mean % of Stage 1: 36.9% versus 17.2% of total sleep time, respectively; p=0.000), whereas no significant differences were found for other stages. Median total arousal and awakening indexes were higher in the NIV group (16.8/hour versus 4.4/hour and 5.3/hour versus 2.1/hour, respectively; p=0.005), as well as spontaneous arousals and awakenings (p=0.006 and p=0.005, respectively). Sedation was provided mostly by intermittent bolus in the NIV group whereas often by infusion in the INV group. Conclusion: Compared to INV, NIV in critically ill patients was associated with poorer quality and quantity of sleep. Future studies should determine whether adjustments in ventilator settings, mask type or fit, or use of sedation/analgaesia can improve sleep in patients receiving NIV.

Introduction While electronic cigarette (EC) use is rapidly increasing among asthmatic adolescents, little is known about the links between EC use and depression or suicidality. We assessed associated factors for depression and suicidality in asthmatic adolescents with experience of EC use. Methods We analyzed the data from the 11th to 13th Korea Youth Risk Behavior Web-based Surveys, which were completed from 2015 to 2017. Data were obtained from a stratified, multistage, clustered sample. Students supplied 'yes or no' answers to questions about previous asthma diagnosis by a doctor. Associated factors for depression and suicidality were evaluated by logistic regression models after controlling for potential confounding factors. We targeted 203336 adolescents, and 195847 completed the survey. Results The proportion of asthma among the respondents was 8.9%. The rate of experience of EC use was higher among asthmatic respondents than non-asthmatic respondents (10.3% vs 8.6%). Asthmatic respondents with experience of EC use had a much higher proportion of negative mental health states including depression and suicidality than subjects without EC experience. In our adjusted models, perception of stress was most strongly associated with depression (adjusted odds ratio, AOR=4.79; 95% CI: 4.12-5.58), and perception of unhappiness was most strongly associated with suicidal ideation (AOR=5.24; 95% CI: 4.51-6.09) and suicide attempt (AOR=4.37; 95% CI: 3.36-5.69). Conclusions Many Korean asthmatic adolescents with experience of EC use report relatively high depression and suicidal behaviors. A multidisciplinary approach, including psychological help, may be required to prevent suicide among this population, especially those who report associated factors.

Introduction Smoking status based solely on self-reporting is unreliable and might be inaccurate, particularly among women. This study investigated the association between urinary cotinine-verified smoking status and hyperuricemia in a nationwide Korean population. Methods This study included 5,329 participants aged ≥19 years with information on smoking status, urine cotinine levels and serum uric acid. We determined smoking status according to self-reports and urinary cotinine levels. Multivariate linear regression analysis was used to measure the association between smoking exposure and serum uric acid levels. The effects of smoking on hyperuricemia were evaluated by multivariate logistic regression analysis. Results Biochemically-verified active and passive smokers comprised 22% (38.7% of men and 8.8% of women) and 12.3% (11.9% of men and 12.6% of women) of the study population, respectively. While reclassification rate of active smokers was 1.4% in men, 31.8% of cotinine-verified female active smokers were self-reported never smokers. Higher uric acid levels were observed with increased tobacco exposure among women (P trend = 0.007) but not among men. After adjusting for confounders, the risk of hyperuricemia increased with tobacco exposure only in women (P trend = 0.016). Conclusions Cotinine-verified smoking status was associated with increased serum uric acid and hyperuricemia in a dose-response manner only in women. This study might provide evidence to support the importance of smoking cessation in women with gout and further studies are necessary to elucidate the underlying mechanism of the observed association.

Background: It is not evident that the attributable risk of smoking on mortality in Korea has decreased. We investigated the impact of smoking on all-cause mortality and estimated the attributable risk of smoking in Korean adults. Methods: Those aged ≥20 years with smoking history in the Korean National Health and Nutrition Examination Surveys (KNHANES) 2007-2015 were enrolled. We categorized the participants into three groups as follows: never smoker

Resumen: Introducción: No se ha aclarado suficientemente el papel de la disfunción diafragmática estimada mediante ecografía como predictora del fracaso de la extubación. Métodos: Realizamos una revisión sistemática y metaanálisis de estudios observacionales que incluyeron pacientes intubados sometidos a ventilación mecánica (VM), a los que se realizó una ecografía diafragmática uni- o bilateral para evaluar la disfunción diafragmática antes de la extubación. Se efectuó una búsqueda en las bases de datos Pubmed y Embase entre el primero de enero de 2010 y el 30 de junio de 2019, utilizando los términos diaphragm ultrasound, diaphragm ultrasonography, weaning y extubation. Definimos fracaso del destete como la necesidad de reintubación y soporte con VMI o fracaso de la prueba de respiración espontánea (PRE). Se utilizaron como medidas ecográficas para predecir el fracaso del destete en pacientes intubados sometidos a VM la excursión diafragmática (ED), la fracción de engrosamiento diafragmático (FEG), el tiempo hasta la amplitud del pico inspiratorio del diafragma (TAPI dia), puntuación de ultrasonido pulmonar modificada (PUPm) y el índice de tiempo de excursión diafragmática (ITED). Secundariamente, evaluamos su utilidad para predecir la muerte por cualquier causa, la duración de la estancia hospitalaria y la necesidad de ventilación no invasiva (VMNI) o de oxigenoterapia de alto flujo tras el destete. Para la agregación de datos se utilizó un modelo de efectos aleatorios, la odds ratio (OR) y sus intervalos de confianza (IC) del 95%. La heterogeneidad de los estudios originales se evaluó mediante el estadístico I2. En todos los análisis, los niveles de significación fueron bilaterales y se consideraron significativos los valores de p

Background Adiponectin is a polypeptide hormone related to obesity, and a known modulator of pulmonary vascular remodeling. Association between plasma adiponectin levels and pulmonary hypertension (PH) has not been studied in African Americans (AAs) who are disproportionately affected by obesity. The relationship between adiponectin and heart failure (HF) and mortality, outcomes associated with PH, is unclear. Methods We performed cross-sectional and longitudinal analysis to examine if there is an association between plasma adiponectin and PH and associated clinical outcomes, in participants of Jackson Heart Study (JHS). JHS is a prospective observational cohort study of heart disease in AAs from Jackson, Mississippi. Results Of the 3161 participants included in the study, mean age (SD) was 56.38 (12.61) years, 1028 were men (32.5%), and mean (SD) BMI was 31.42 (7.05) kg/m 2 . Median (IQR) adiponectin was 4516.82 (2799.32–7065.85) ng/mL. After adjusting for potential confounders including BMI, higher adiponectin levels were associated with increased odds of PH (adjusted odds ratio per log increment in adiponectin, (1.81; 95% CI, 1.41–2.32). High adiponectin levels were also associated with associated HF admissions (adjusted hazard ratio [HR] per log increment in adiponectin, 1.63, 95% CI, 1.24–2.14) and mortality (adjusted HR per log increment in adiponectin, 1.20; 95% CI 1.02–1.41). Conclusions Elevated plasma adiponectin levels are associated with PH, HF admissions and mortality risk in AAs. High adiponectin levels may help identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies

Enhanced vasoconstriction is increasingly identified as an important contributor to the development of pulmonary hypertension. Chronic hypoxia results in enhanced Rho kinase mediated Ca 2+ sensitization contributing to pressure-dependent pulmonary arterial tone as well as augmented vasoconstriction to endothelin-1 and depolarizing stimuli. We sought to investigate the interaction between these vasoconstrictor stimuli in isolated, pressurized, pulmonary arteries. We used the K + ionophore, valinomycin, to clamp membrane potential (V m ) to investigate the role of membrane depolarization in endothelin-1 and pressure-dependent constriction, and endothelin-1 receptor inhibitors to determine whether membrane depolarization or stretch signal through endothelin-1 receptors. Clamping V m prevented pressure-dependent tone, but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia. Furthermore, endothelin-1 receptor inhibition had no effect on either pressure-dependent tone or vasoconstriction to KCl. As Src kinases contribute to both pressure-dependent tone and enhanced endothelin-1 vasoconstriction following chronic hypoxia, we further investigated their role in depolarization-induced vasoconstriction. Inhibition of Src kinases attenuated enhanced vasoconstriction to KCl. We conclude that membrane depolarization contributes to pressure-dependent tone but not enhanced vasoconstriction to ET-1, and that Src kinases serve as upstream mediators facilitating enhanced Rho kinase-dependent vasoconstriction following chronic hypoxia.

Pulmonary arterial compliance is a measure of the pulsatile afterload of the right ventricle. Lower pulmonary arterial compliance is associated with reduced right ventricular function and worse prognosis in pulmonary hypertension. The effect of pulmonary vasodilators on pulmonary arterial compliance has not been evaluated in detail in pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In this post hoc analysis of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the PATENT and CHEST studies, we evaluated the change in pulmonary arterial compliance with riociguat versus placebo. Association of pulmonary arterial compliance with clinical outcomes was assessed using Kaplan–Meier and Cox proportional hazards analyses. Compared with placebo, riociguat significantly improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline was associated with survival and clinical worsening-free survival in pulmonary arterial hypertension but only with clinical worsening-free survival in chronic thromboembolic pulmonary hypertension. In patients with pulmonary arterial hypertension, pulmonary arterial compliance at follow-up ≥1.6 mL/mmHg was associated with better outcomes than pulmonary arterial compliance

A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINT® technology offers a substantial advantage over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation administration to patients with pulmonary arterial hypertension via nebulized Tyvaso® inhalation solution. LTI-101 was a phase 1, placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate treprostinil exposure from LIQ861 inhalation. Subjects ( n = 57) were randomly assigned in a 3:1 ratio to receive a single dose of either LIQ861 ( n = 43) or placebo ( n = 14); 56 subjects completed all protocol-defined assessments. Following single-dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the pharmacokinetics profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently reported treatment-emergent adverse events related to study drug administration were coughing and throat irritation, which are common to dry-powder formulations. Treatment-related treatment-emergent adverse events were reported more frequently at higher dose levels; however, all were assessed as mild in severity. We conclude that the pharmacokinetics profile of treprostinil using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of inhaled, nebulized treprostinil (Tyvaso®). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with pulmonary arterial hypertension was initiated.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs). To explore the potential mechanism of miR-193-3p in pulmonary arterial hypertension, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and p21-activated protein kinase 4 (PAK4) in the lung samples of PAH patients and paired healthy samples from the healthy subjects in PHA cells and rats were detected by quantitative reverse transcriptase-PCR. Morphological changes in lung tissues were determined using hematoxylin and eosin staining. Right ventricular systolic pressure (RVSP) and ratio of right ventricle to left ventricle plus septum (RV/LV p S) were measured. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, and migration were detected by 3-(4, 5-Dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) flow cytometry, and wound-healing assays, respectively. The protein expressions of PAK4, proliferating cell nuclear antigen (PCNA), P21, p-AKT, and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in pulmonary arterial hypertension, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia condition promoted cell proliferation, migration, and inhibited apoptosis accompanied with increased expressions of PCNA and p-AKT/AKT and decreased expression of P21 in PASMCs. MiR-193-3p overexpression attenuated the effects of hypoxia on PASMCs via downregulating PAK4. Monocrotaline treatment increased p-AKT/AKT and decreased P21 expression and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT, and increased P21 levels via downregulating PAK4 in monocrotaline-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregulating PAK4.

Extracellular histones released from injured or dying cells following trauma and other severe insults can act as potent damage-associated molecular patterns. In fact, elevated levels of histones are present in human circulation in hyperinflammatory states such as acute respiratory distress syndrome and sepsis. The molecular mechanisms owing to histone-induced pathologies are at the very beginning of elucidating. However, neutralization of histones with antibodies, histone-binding or histone-degrading proteins, and heparan sulfates have shown promising therapeutic effects in pre-clinical acute respiratory distress syndrome and sepsis models. Various cell types undergoing necrosis and apoptosis or activated neutrophils forming neutrophil extracellular traps have been implicated in excessive release of histones which further augments tissue injury and may culminate in multiple organ failure. At the molecular level, an uncontrolled inflammatory cascade has been considered as the major event; however, histone-activated coagulation and thrombosis represent additional pathologic events reflecting coagulopathy. Furthermore, epigenetic regulation and chemical modifications of circulating histones appear to be critically important in their biological functions as evidenced by increased cytotoxicity associated with citrullinated histone. Herein, we will briefly review the current knowledge on the role of histones in acute respiratory distress syndrome and sepsis, and discuss the future potential of anti-histone therapy for treatment of these life-threatening disorders.

Transmembrane protein 16A was involved in the development of the monocrotaline-induced pulmonary arterial hypertension model through ERK1/2 activation, and it was considered as potential target for pulmonary arterial hypertension treatment. A pulmonary arterial hypertension rat model was established by intraperitoneal administration of monocrotaline. Noninvasive pulsed-wave Doppler and histological analysis was performed, and it revealed proliferation and remodeling of pulmonary arterioles and right ventricle hypertrophy. In addition, transmembrane protein 16A, proliferating cell nuclear antigen—a proliferate marker, P-ERK1/2 increased following monocrotaline treatment. Expression of transmembrane protein 16A in the pulmonary arteries was co-localized with a specific marker of vascular smooth muscle α-actin. Then, a specific inhibitor of transmembrane protein 16A-T16A inh -A01 was administered to pulmonary arterial hypertension rats. It was found to alleviate the remodeling of pulmonary arterioles and right ventricle hypertrophy significantly, and decrease the upregulation of proliferating cell nuclear antigen in monocrotaline-induced pulmonary arteries. In addition, T16A inh -A01 could inhibit the activation of ERK1/2 in pulmonary arterial hypertension model. Transmembrane protein 16A mediated the proliferation and remodeling of pulmonary arterioles in the monocrotaline-induced pulmonary arterial hypertension model. ERK1/2 pathway is one of downstream factors. Long-term use of T16A inh -A01 in vivo could alleviate remodeling and pressure in pulmonary arterial hypertension.

Pulmonary hypertension in interstitial lung diseases is associated with increased mortality and hospitalizations and reduced exercise capacity. Interstitial pneumonia with autoimmune features (IPAF) is a recently described interstitial lung disease. The characteristics of pulmonary hypertension in IPAF patients are unknown. We sought to characterize patients with IPAF based on their echocardiographic probability of pulmonary hypertension and compare patients with and without pulmonary hypertension identified by right heart catheterization. We conducted a retrospective study of patients seen in the interstitial lung disease clinic from 2015 to 2018. Forty-seven patients with IPAF were identified. Patients were classified into low, intermediate and high echocardiographic pulmonary hypertension probabilities. A sub-group analysis of patients with pulmonary hypertension and without pulmonary hypertension (IPAF-PH vs. IPAF-no PH) identified by right heart catheterization was also performed. Linear regression analysis was performed to study the association between 6-min-walk-distance (6MWD) and pulmonary vascular resistance (PVR) while adjusting for age and body mass index. Right ventricular hypertrophy (>5 mm), right ventricular enlargement (>41 mm) and right ventricular systolic dysfunction defined as fractional area change% ≤35 was present in 76%, 24%, and 39% of patients, respectively. Pulmonary hypertension was identified in 12.7% of patients. IPAF-PH patients had higher mean pulmonary artery pressure and lower cardiac output compared to the IPAF-no PH group (34 mmHg vs. 19 mmHg, p = 0.002 and 4.0 vs. 5.7 L/min, p = 0.023, respectively). Lower 6MWD was associated with higher PVR on regression analysis ( p = 0.002). Pulmonologists should be aware that a significant number of IPAF patients may develop pulmonary hypertension. Reduced 6MWD may suggest the presence of pulmonary hypertension in IPAF patients.

Resumen: Uno de los elementos claves en la medicina de la segunda década del siglo XXI es el crecimiento exponencial de la información producida por los pacientes que se debe no solo a la transición hacia la digitalización de las historias clínicas, sino también a la aparición de nuevas fuentes de información y a la capacidad de análisis e interpretación de las ya existentes. Se estima que la cantidad de información médica se duplica cada 2 años, lo que supone que en 2020 existirá 50 veces más información que en 2011. En este contexto, el manejo adecuado de grandes cantidades de datos o big data debe traducirse en nuevas iniciativas que mejoren el diagnóstico, tratamiento y pronóstico de los pacientes en el camino hacia la medicina personalizada.El concepto de personalización o de medicina de precisión cobra especial interés en la patología respiratoria crónica. En los últimos años la investigación en entidades como el asma, la EPOC, el cáncer o el SAHS se ha centrado en la identificación de alteraciones genómicas, moleculares, metabólicas y proteicas (biomarcadores). Su análisis mediante herramientas de análisis de big data permite dejar atrás los modelos centrados en la respuesta media al tratamiento, que a su vez resultan subóptimos para la mayoría, para dar paso a la respuesta individualizada. En este camino se incorpora la medicina de sistemas, que, integrando también datos clínicos y poblacionales, aporta una visión multidimensional de la enfermedad y facilita el establecimiento de asociaciones causales, la mayoría de las cuales solo son apreciables mediante análisis de big data. Abstract: One of the key elements of medicine in the second decade of the 21st century is the exponential growth of patient-produced information, due not only to the transition to the digitization of medical records, but also to the emergence of new sources of information and the capacity for analysis and interpretation of existing ones. The amount of medical information is expected to double every 2 years, which means that there will be 50 times more information available in 2020 than in 2011. In this setting, these large amounts of data or «big data» must be properly managed to implement new initiatives that improve the diagnosis, treatment, and prognosis of patients on the path to personalized medicine.The concept of personalization or precision medicine is of special interest in chronic respiratory disease. In recent years, research in entities such as asthma, COPD, cancer, or SAHS has focused on the identification of genomic, molecular, metabolic, and protein changes (biomarkers). Big data analysis tools can be used to move on from models based on the mean response to treatment, which are suboptimal for most patients, to focus on the individualized response. Part of this journey involves systems medicine, which also integrates clinical and population data to provide a multidimensional view of the disease and help identify causal associations that are usually only evident on big data analysis.

This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a serious, life-altering condition. Patients who are diagnosed are often of childbearing potential. Given the well-documented risks associated with this condition during pregnancy, as well as risks to the fetus from medications used to treat this disorder, patients should be strongly advised against pregnancy. Despite this, patients still become pregnant, leading to the question of whether care providers are counseling patients and their partners about the risks of pregnancy, methods of contraception, and issues of intimacy on a regular basis. We have conducted a survey of pulmonary hypertension specialist physicians and allied healthcare professionals on their practice patterns related to counseling on intimacy, contraception, and pregnancy prevention. Most respondents indicated they are counseling on these issues to varying degrees, but our survey pointed to several areas where improvements can be made. The most significant barrier to counseling for all respondents was lack of time. Survey respondents reported that a large percentage of the pregnancies seen in their practices were either intentional or due to contraceptive non-compliance. We review specific practical approaches to initiate reproductive health counseling as well as ways to integrate this important aspect of PAH care into regular practice routines and documentation. Protocols regarding pregnancy avoidance and PAH should be developed and become standard procedure.

Inappropriate mechanical ventilation may induce hemodynamic alterations through cardiopulmonary interactions. The aim of this study was to explore the relationship between airway pressure and central venous pressure during the first 72 h of mechanical ventilation and its relevance to patient outcomes. We conducted a retrospective study of the Department of Critical Care Medicine of Peking Union Medical College Hospital and a secondary analysis of the MIMIC-III clinical database. The relationship between the ranges of driving pressure and central venous pressure during the first 72 h and their associations with prognosis were investigated. Data from 2790 patients were analyzed. Wide range of driving airway pressure (odds ratio, 1.0681; 95% CI, 1.0415–1.0953; p

While the prognosis of idiopathic pulmonary arterial hypertension has improved significantly due to newer medications, lung transplantation remains a critical therapeutic option for severe pulmonary arterial hypertension. Hence, it is essential for patients awaiting lung transplantation to avoid complications, including thrombocytopenia, which may affect their surgical outcomes. Herein we present the case of a 21-year-old woman diagnosed with idiopathic pulmonary arterial hypertension at the age of 15. She developed thrombocytopenia while awaiting lung transplantation. Her medication was switched from epoprostenol to treprostinil, suspecting possible drug-induced thrombocytopenia. Furthermore, she was administered thrombopoietin receptor agonists in view of the possibility of idiopathic thrombocytopenic purpura, along with maximum support for right heart failure. Subsequently, her platelet count increased to >70,000/µL, enabling her to successfully undergo bilateral lung transplantation. Post-bilateral lung transplantation, pulmonary arterial hypertension as well as thrombocytopenia appeared to have resolved. In this case, we suspected that thrombocytopenia could have resulted owing to a combination of pulmonary arterial hypertension, right heart failure, drug interactions, and idiopathic thrombocytopenic purpura. Thrombocytopenia is a very critical condition in patients with pulmonary arterial hypertension, especially those awaiting lung transplantation. Several approaches are known to improve intractable thrombocytopenia in patients with pulmonary arterial hypertension.

Large administrative healthcare (including insurance claims) databases are used for various retrospective real-world evidence studies. However, in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, identifying patients retrospectively based on administrative codes remains challenging, as it relies on code combinations (algorithms) and the accuracy for patient identification of most of them is unknown. This study aimed to assess the performance of various algorithms in correctly identifying patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension in administrative databases. A systematic literature review was performed to find publications detailing code-based algorithms used to identify pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients. PheValuator, a diagnostic predictive modelling tool, was applied to three US claims databases, yielding models that estimated the probability of a patient having the disease. These models were used to evaluate the performance characteristics of selected pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension algorithms. With increasing algorithm complexity, average positive predictive value increased (pulmonary arterial hypertension: 13.4-66.0%; chronic thromboembolic pulmonary hypertension: 10.3-75.1%) and average sensitivity decreased (pulmonary arterial hypertension: 61.5-2.7%; chronic thromboembolic pulmonary hypertension: 20.7-0.2%). Specificities and negative predictive values were high (≥97.5%) for all algorithms. Several of the algorithms performed well overall when considering all of these four performance parameters, and all algorithms performed with similar accuracy across the three claims databases studied, even though most were designed for patient identification in a specific database. Therefore, it is the objective of a study that will determine which algorithm may be most suitable; one- or two-component algorithms are most inclusive and three- or four-component algorithms identify most precise pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension populations, respectively.

Background WHO Group 1 pulmonary arterial hypertension is a progressive and potentially fatal disease. Individuals living at higher altitude are exposed to lower barometric pressure and hypobaric hypoxemia. This may result in pulmonary vasoconstriction and contribute to disease progression. We sought to examine the relationship between living at moderately high altitude and pulmonary arterial hypertension characteristics. Methods Forty-two US centers participating in the Pulmonary Hypertension Association Registry enrolled patients who met the definition of WHO Group 1 pulmonary arterial hypertension. We utilized baseline data and patient questionnaire responses. Patients were divided into two groups: moderately high altitude residence (home ≥4000 ft) and low altitude residence (home

This study investigated whether dilated bronchial arteries are associated with reperfusion pulmonary edema in patients with chronic thromboembolic pulmonary hypertension. Results showed that the extent of enlarged bronchial arteries was not associated with the development of reperfusion pulmonary edema, whereas the residual pulmonary hypertension had a significant association.

Acute respiratory distress syndrome in patients with Coronavirus disease 19 is associated with an unusually high incidence of pulmonary embolism and microthrombotic disease, with evidence for reduced fibrinolysis. We describe seven patients requiring invasive ventilation for COVID-19-associated acute respiratory distress syndrome with pulmonary thromboembolic disease, pulmonary hypertension ± severe right ventricular dysfunction on echocardiography, who were treated with alteplase as fibrinolytic therapy. All patients were non-smokers, six (86%) were male and median age was 56.7 (50–64) years. They had failed approaches including therapeutic anticoagulation, prone ventilation ( n = 4), inhaled nitric oxide ( n = 5) and nebulised epoprostenol ( n = 2). The median duration of mechanical ventilation prior to thrombolysis was seven (5–11) days. Systemic alteplase was administered to six patients (50 mg or 90 mg bolus over 120 min) at 16 (10–22) days after symptom onset. All received therapeutic heparin pre- and post-thrombolysis, without intracranial haemorrhage or other major bleeding. Alteplase improved PaO 2 /FiO 2 ratio (from 97.0 (86.3–118.6) to 135.6 (100.7–171.4), p = 0.03) and ventilatory ratio (from 2.76 (2.09–3.49) to 2.36 (1.82–3.05), p = 0.011) at 24 h. Echocardiographic parameters at two (1–3) days ( n = 6) showed right ventricular systolic pressure (RVSP) was 63 (50.3–75) then 57 (49–66) mmHg post-thrombolysis ( p = 0.26), tricuspid annular planar systolic excursion (TAPSE) was unchanged (from 18.3 (11.9–24.5) to 20.5 (15.4–24.2) mm, p = 0.56) and right ventricular fractional area change (from 15.4 (11.1–35.6) to 31.2 (16.4–33.1)%, p = 0.09). At seven (1–13) days after thrombolysis, using dual energy computed tomography imaging ( n = 3), average relative peripheral lung enhancement increased from 12.6 to 21.6% ( p = 0.06). In conclusion, thrombolysis improved PaO 2 /FiO 2 ratio and ventilatory ratio at 24 h as rescue therapy in patients with right ventricular dysfunction due to COVID-19-associated ARDS despite maximum therapy, as part of a multimodal approach, and warrants further study.