Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

Enterovirus D68 disease burden and epidemiology in hospital-admitted influenza-like illness, Valencia region of Spain, 2014-2020 influenza seasons.

Enterovirus D68 (EV-D68) is an emerging agent for which data on the susceptible adult population is scarce. We performed a 6-year analysis of respiratory samples from influenza-like illness (ILI) admitted during 2014-2020 in 4-10 hospitals in the Valencia Region, Spain. EV-D68 was identified in 68 (3.1%) among 2210 Enterovirus (EV)/Rhinovirus (HRV) positive samples. Phylogeny of 59 VP1 sequences showed isolates from 2014 clustering in B2 (6/12), B1 (5/12), and A2/D1 (1/12) subclades; those from 2015 (n = 1) and 2016 (n = 1) in B3 and A2/D1, respectively; and isolates from 2018 in A2/D3 (42/45), and B3 (3/45). B1 and B2 viruses were mainly detected in children (80% and 67%, respectively); B3 were equally distributed between children and adults; whereas A2/D1 and A2/D3 were observed only in adults. B3 viruses showed up to 16 amino acid changes at predicted antigenic sites. In conclusion, two EV-D68 epidemics linked to ILI hospitalized cases occurred in the Valencia Region in 2014 and 2018, with three fatal outcomes and one ICU admission. A2/D3 strains from 2018 were associated with severe respiratory infection in adults. Because of the significant impact of non-polio enteroviruses in ILI and the potential neurotropism, year-round surveillance in respiratory samples should be pursued.

Pulmonary vascular disease in chronic lung diseases: cause or comorbidity?

PURPOSE OF REVIEW: To provide timely and relevant insights into the complex relationship between pulmonary vascular disease (PVD) and chronic lung disease (CLD), focusing on the causative and consequential dynamics between these conditions. RECENT FINDINGS: There are shared pathogenic mechanisms between pulmonary arterial hypertension (PAH) and group 3 pulmonary hypertension, including altered expression of mediators and growth factors implicated in both conditions. Factors such as hypoxia, hypoxemia, and hypercapnia also contribute to pulmonary vascular remodelling and endothelial dysfunction. However, the role of hypoxia as the sole driver of pulmonary hypertension in CLD is being reconsidered, particularly in chronic obstructive pulmonary disease (COPD), with evidence suggesting a potential role for cigarette smoke products in initiating pulmonary vascular impairment. On the other hand, interstitial lung disease (ILD) encompasses a group of heterogeneous lung disorders characterized by inflammation and fibrosis of the interstitium, leading to impaired gas exchange and progressive respiratory decline, which could also play a role as a cause of pulmonary hypertension. SUMMARY: Understanding the intricate interplay between the pulmonary vascular compartment and the parenchymal and airway compartments in respiratory disease is crucial for developing effective diagnostic and therapeutic strategies for patients with PVD and CLD, with implications for both clinical practice and research.

Guiding Principles for Evaluating Vaccines in Joint Health Technology Assessment in the European Union: Preparing for the EU's Regulation on HTA for Vaccines.

OBJECTIVES: The appraisal of vaccines in the European Union (EU) currently involves many different decision-making bodies and processes. The objective of this study was to help inform the development of standardized methodology and vaccine-specific processes for use in the EU Regulation on health technology assessment (HTA). METHODS: Literature reviews and expert consultation were conducted to identify current practices and gaps related to vaccine appraisals and to develop guiding principles for the joint clinical assessment of vaccines. RESULTS: We found that significant variation exists across the EU Member States in the decision-making processes when clinically evaluating vaccines. Three guiding principles consisting of 13 recommendations were developed to help inform the development of decision-making frameworks for the joint clinical assessment of vaccines in the EU: (1) Support the creation of appropriate terminology and measurements for clinical appraisals of vaccines; (2) Develop inclusive, timely, and transparent vaccine appraisal processes to support stronger evidence generation for vaccine decision-making and appraisal; and (3) Improve the collection and interoperability of real-world data, including robust surveillance, to foster evidence generation and support the standardization of vaccine clinical appraisals. CONCLUSIONS: Given the significance of vaccines for public health, there is an urgency to develop standardized and vaccine-specific methodologies and processes for use in the EU joint HTA framework. The proposed guiding principles could support the effective implementation of the EU Regulation on HTA for vaccines and have the potential to ensure consistent, transparent, and timely access to new vaccines in the EU.

Ralinepag Phase II Open-Label Extension Study in Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. METHODS: Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. RESULTS: In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (P = 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm5 and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (P = 0.05). CONCLUSION: Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements.

Pulmonary arterial hypertension is a rare disease caused by elevated pressure in the blood vessels connecting the heart to the lungs. A previous phase 2 study found that ralinepag significanlty reduced pulmonary vascular resistance (the force or resistance that blood encounters as it flows through the blood vessels in the lungs) compared with placebo. This clinical study of 45 patients investigated whether ralinepag was safe and effective for long-term use to treat people with pulmonary arterial hypertension. All participants received ralinepag twice daily until a new once daily pill was available later in the study. The primary endpoints were long-term safety and tolerability, and secondary endpoints included exercise capacity, impact on daily life (functional class), clinical worsening, and hemodynamic measures (metrics to measure how well the heart is working). The study found that ralinepag had a manageable side effect profile, with a decrease in side effects for patients who continued taking ralinepag over time. Moreover, the study showed that ralinepag improved the ability to exercise, maintained functional measures, and helped to reduce pressure in the blood vessels connecting the heart to the lungs over a 24-month period for participants with pulmonary arterial hypertension.

Imaging of chronic thromboembolic pulmonary hypertension before, during and after balloon pulmonary angioplasty.

Balloon pulmonary angioplasty (BPA) has recently been elevated as a class I recommendation for the treatment of inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH). Proper patient selection, procedural safety, and post-procedural evaluation are crucial in the management of these patients, with imaging work-up playing a pivotal role. Understanding the diagnostic and therapeutic imaging algorithms of CTEPH, the imaging features of patients amenable to BPA, all imaging findings observed during and immediately after the procedure and the changes observed during the follow-up is crucial for all interventional radiologists involved in the care of patients with CTEPH. This article illustrates the imaging work-up of patients with CTEPH amenable to BPA, the imaging findings observed before, during and after BPA, and provides a detailed description of all imaging modalities available for CTEPH evaluation.

Real world evidence for public health decision-making on vaccination policies: perspectives from an expert roundtable.

INTRODUCTION: Influenza causes significant morbidity and mortality, but influenza vaccine uptake remains below most countries' targets. Vaccine policy recommendations vary, as do procedures for reviewing and appraising the evidence. AREAS COVERED: During a series of roundtable discussions, we reviewed procedures and methodologies used by health ministries in four European countries to inform vaccine recommendations. We review the type of evidence currently recommended by each health ministry and the range of approaches toward considering randomized controlled trials (RCTs) and real-world evidence (RWE) studies when setting influenza vaccine recommendations. EXPERT OPINION: Influenza vaccine recommendations should be based on data from both RCTs and RWE studies of efficacy, effectiveness, and safety. Such data should be considered alongside health-economic, cost-effectiveness, and budgetary factors. Although RCT data are more robust and less prone to bias, well-designed RWE studies permit timely evaluation of vaccine benefits, effectiveness comparisons over multiple seasons in large populations, and detection of rare adverse events, under real-world conditions. Given the variability of vaccine effectiveness due to influenza virus mutations and increasing diversification of influenza vaccines, we argue that consideration of both RWE and RCT evidence is the best approach to more nuanced and timely updates of influenza vaccine recommendations.

Relative Effectiveness of the MF59®-Adjuvanted Influenza Vaccine Versus High-Dose and Non-Adjuvanted Influenza Vaccines in Preventing Cardiorespiratory Hospitalizations During the 2019-2020 US Influenza Season.

BACKGROUND: Adults ≥ 65 years of age have suboptimal influenza vaccination responses compared to younger adults due to age-related immunosenescence. Two vaccines were specifically developed to enhance protection: MF59-adjuvanted trivalent influenza vaccine (aIIV3) and high-dose egg-based trivalent influenza vaccine (HD-IIV3e). METHODS: In a retrospective cohort study conducted using US electronic medical records linked to claims data during the 2019-2020 influenza season, we compared the relative vaccine effectiveness (rVE) of aIIV3 with HD-IIV3e and a standard-dose non-adjuvanted egg-based quadrivalent inactivated influenza vaccine (IIV4e) for the prevention of cardiorespiratory hospitalizations, including influenza hospitalizations. We evaluated outcomes in the "any" diagnosis position and the "admitting" position on the claim. A doubly robust methodology using inverse probability of treatment weighting and logistic regression was used to adjust for covariate imbalance. rVE was calculated as 100 * (1 - ORadjusted). RESULTS: The study included 4,299,594 adults ≥ 65 years of age who received aIIV3, HD-IIV3e, or IIV4e. Overall, aIIV3 was associated with lower proportions of cardiorespiratory hospitalizations with diagnoses in any position compared to HD-IIV3e (rVE = 3.9% [95% CI, 2.7-5.0]) or IIV4e (9.0% [95% CI, 7.7-10.4]). Specifically, aIIV3 was more effective compared with HD-IIV3e and IIV4e in preventing influenza hospitalizations (HD-IIV3e: 9.7% [95% CI, 1.9-17.0]; IIV4e: 25.3% [95% CI, 17.7-32.2]). Consistent trends were observed for admitting diagnoses. CONCLUSION: Relative to both HD-IIV3e and IIV4e, aIIV3 provided improved protection from cardiorespiratory or influenza hospitalizations.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

Cellular Immunity of SARS-CoV-2 in the Borriana COVID-19 Cohort: A Nested Case-Control Study.

Our goal was to determine the cellular immune response (CIR) in a sample of the Borriana COVID-19 cohort (Spain) to identify associated factors and their relationship with infection, reinfection and sequelae. We conducted a nested case-control study using a randomly selected sample of 225 individuals aged 18 and older, including 36 individuals naïve to the SARS-CoV-2 infection and 189 infected patients. We employed flow-cytometry-based immunoassays for intracellular cytokine staining, using Wuhan and BA.2 antigens, and chemiluminescence microparticle immunoassay to detect SARS-CoV-2 antibodies. Logistic regression models were applied. A total of 215 (95.6%) participants exhibited T-cell response (TCR) to at least one antigen. Positive responses of CD4+ and CD8+ T cells were 89.8% and 85.3%, respectively. No difference in CIR was found between naïve and infected patients. Patients who experienced sequelae exhibited a higher CIR than those without. A positive correlation was observed between TCR and anti-spike IgG levels. Factors positively associated with the TCR included blood group A, number of SARS-CoV-2 vaccine doses received, and anti-N IgM; factors inversely related were the time elapsed since the last vaccine dose or infection, and blood group B. These findings contribute valuable insights into the nuanced immune landscape shaped by SARS-CoV-2 infection and vaccination.

Factores de riesgo de síntomas de rinitis alérgica en adolescentes de Castellón, España / Risk factors for symptoms of allergic rhinitis in adolescents in Castellón, Spain

OBJETIVOS: Estimar factores de riesgo de síntomas de rinitis alérgica en adolescentes de Castellón, España. MÉTODOS: Estudio transversal de base poblacional a partir de la fase III del ISAAC (International Study of Asthma and Allergies in Childhood) llevado a cabo en 2002 entre adolescentes de 13 a 14 años. Se utilizó el cuestionario ISAAC para definir los casos de rinitis alérgica. Se estimaron razones de posibilidades (RP) y sus intervalos de confianza de 95 por ciento (IC95 por ciento) mediante modelos de regresión logística. RESULTADOS: La participación fue de 66,8 por ciento (3 995 adolescentes de un total de 5 981). La prevalencia de síntomas de rinoconjuntivitis en los últimos 12 meses fue de 16,5 por ciento, y la prevalencia de alergia nasal alguna vez, de 7,4 por ciento. Con la regresión logística, la rinoconjuntivitis se asoció a la mujer (RP=1,63; IC95 por ciento:1,33-2,00); fumar la madre en casa (RP=1,32; IC95 por ciento:1,08-1,63); historia de sinusitis (RP=2,02; IC95 por ciento:1,51-2,70), y circulación constante de camiones por la calle de residencia (RP=1,58; IC95 por ciento:1,02-2,44). De igual manera, la alergia nasal se asoció con la historia familiar de rinitis alérgica (RP=2,62; IC95 por ciento:1,90-3,63); historia de sinusitis (RP=2,65; IC95 por ciento:1,77-3,96), historia de bronquitis (RP=1,68; IC95 por ciento:1,19-2,36), y clase social, con descensos progresivos al comparar las clases superiores e inferiores. CONCLUSIONES: Diferentes factores de riesgo medioambientales se asociaron con el hecho de sufrir síntomas de alergia nasal; se sugiere la importancia de adecuar medidas preventivas específicas.

OBJECTIVES: To estimate the risk factor for symptoms of allergic rhinitis in adolescents in Castellón, Spain. METHODS: A cross-sectional population based study of Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) conducted in 2002 among adolescents from 13-14 years of age. The ISAAC questionnaire was used to define cases of allergic rhinitis. Logistic regression models were used to estimate odds ratio (OR) and their 95 percent confidence intervals (95 percentCI). RESULTS: Participation was 66.8 percent (3 995 adolescents of the 5 981 total). The prevalence of rhinoconjunctivitis symptoms in the last 12 months was 16.5 percent and the prevalence of nasal allergy at some point was 7.4 percent. Logistic regression showed that rhinoconjunctivitis was associated with being female (OR = 1.63; 95 percentCI: 1.33-2.00); a mother who smokes in the home (OR = 1.32; 95 percentCI: 1.08-1.63); a history of sinusitis (OR = 2.02; 95 percentCI: 1.51-2.70); and living on a street with heavy truck traffic (OR = 1.58; 95 percentCI: 1.02-2.44). Likewise, nasal allergy was associated with a family history of allergic rhinitis (OR = 2.62; 95 percentCI: 1.90-3.63); a history of sinusitis (OR = 2.65; 95 percent CI: 1.77-3.96); a history of bronchitis (OR = 1.68; 95 percentCI: 1.19-2.36); and social class, with a steady decline when comparing higher classes to lower classes. CONCLUSIONS: Various environmental risk factors were associated with the symptoms of nasal allergies, which points to the importance of implementing specific preventive measures.

Dureza del agua de consumo doméstico y prevalencia de eczema atópico en escolares de Castellón, España / Domestic water hardness and prevalence of atopic eczema in Castellon (Spain) schoolchildren

OBJETIVO: Estudiar la asociación entre la prevalencia de eczema atópico (EA) y la dureza del agua de uso doméstico. MATERIAL Y MÉTODOS: El estudio ISAAC (International Study of Asthma and Allergies in Childhood) estimó la prevalencia de EA en seis localidades de Castellón, España, en escolares de 6-7 y 13-14 años durante 2002. Se establecieron tres zonas de <200 mg/l, 200-250 mg/l, y >300 mg/l según la dureza del agua doméstica de esas localidades. Se empleo regresión logística en el análisis. RESULTADOS: En escolares de 6-7 años, las prevalencias acumuladas de EA en las tres zonas fueron de 28.6, 30.5 y 36.5 por ciento. Entre la zona 1 y la zona 3, la razón de momios ajustada (RMa) fue 1.58 (IC 95 por ciento 1.04-2.39) (prueba de tendencia ajustada p=0.034). La prevalencias de síntomas de EA en el último año fueron de 4.7, 4.5, y 10.4 por ciento, respectivamente. Entre la zona 1 y la zona 3, la (RMa) fue 2.29 (IC95 por ciento 1.19-4.42) (prueba de tendencia ajustada p=0.163). En escolares de 13-14 años no se apreciaron tendencias significativas. CONCLUSIONES: Se sugiere que la dureza del agua podría tener alguna importancia en el desarrollo de la enfermedad en los escolares de 6-7 años.

Water hardness has been associated with atopic eczema (AE) prevalence in two epidemiologic studies carried out on schoolchildren in England and Japan. OBJECTIVE: To estimate the association between the prevalence of AE and domestic water hardness. METHODS: The prevalence of AE was obtained from The International Study of Asthma and Allergies in Childhood, carried out in six towns in the province of Castellón on schoolchildren 6-7 and 13-14 years of age, using a standard questionnaire in 2002. Three zones were defined according to domestic water hardness of the six study localities: <200 mg/l, 200-250 mg/l, and >300 mg/l. A logistic regression analysis was performed. RESULTS: The lifetime prevalence of AE in schoolchildren 6-7 years of age was higher with the increment of water hardness, 28.6, 30.5 and 36.5 percent respectively for each zone; between zone 1 and zone 3, the adjusted odds ratios (ORa) were 1.58 (95 percent Confidence Intervals [CI] 1.04-2.39) (adjusted tendency test p=0.034). Prevalence of symptoms of AE within the past year were 4.7, 4.5, and 10.4 percent, respectively by zone; between zone 1 and zone 3, the ORa was 2.29 (95 percent CI 1.19-4.42) (adjusted tendency test p=0,163). For 13-14 year-old schoolchildren, tendencies to lifetime prevalence of AE at any time or in the past year were not significant. CONCLUSIONS: This study suggests that in 6-7 year-old schoolchildren, water hardness in the area where they live has some relevance to the development of the disease.

Interés actual del óxido nítrico en patología respiratoria / Recent interest of the nitric oxide in respiratory diseases

El óxido nítrico (NO) es una molécula de síntesis endógena que ejerce funciones de señalización intercelular y actúa como mediador del sistema inmunitario. Distintas células del aparato respiratorio poseen la capacidad de sintetizar NO a través de la acción de la óxido nítrico sintasa (NOS), tanto sus isoformas constitutivas como inducible. El NO es un gas que puede ser administrado por vía inhalada. Debido a su gran afinidad con la hemoglobina, el NO inhalado es un potente vasodilatador pulmonar selectivo útil en el tratamiento de situaciones de hipertensión pulmonar. En algunos pacientes con síndrome de distrés respiratorio agudo o con insuficiencia respiratoria causada por cortocircuito intrapulmonar, el NO inhalado puede mejorar la oxigenación arterial. El NO sintetizado endógenamente puede ser medido en el aire exhalado. La concentración de NO exhalado aumenta en procesos inflamatorios de la vía aérea, como el asma o las bronquiectasias, reflejando una mayor actividad de la NOS inducible. El estudio de la biología del NO no sólo ha aumentado el conocimiento de la fisiopatología de las enfermedades respiratorias, sino que ha puesto una aproximación novedosa al tratamiento de algunas enfermedades críticas