Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Sotatercept for the Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).

Annotation of transposable elements in the transcriptome of the Neotropical brown stink bug Euschistus heros and its chromosomal distribution.

Transposable elements (TEs) are DNA sequences capable of moving within the genome. Their distribution is very dynamic among organisms, and despite advances, there are still gaps in the understanding of the diversity and evolution of TEs in many insect species. In the case of Euschistus heros, considered the main stink bug in the soybean crop in Brazil, little is known about the participation of these elements. Therefore, the objective of the current work was to identify the different groups of transposable elements present in the E. heros transcriptome, evidencing their chromosomal distribution. Through RNA-Seq and de novo assembly, 60,009 transcripts were obtained, which were annotated locally via Blastn against specific databases. Of the 367 transcripts identified as TEs, 202 belong to Class II, with emphasis on the TIR order. Among Class I elements or retrotransposons, most were characterized as LINE. Phylogenetic analyses were performed with the protein domains, evidencing differences between Tc1-mariner sequences, which may be related to possible horizontal transfer events. The transposable elements that stood out in the transcriptome were selected for fluorescent in situ hybridization. DNA transposon probes hAT, Helitron, and Tc1-mariner showed mostly scattered signals, with the presence of some blocks. Retrotransposon probes Copia, Gypsy, Jockey, and RTE showed a more pulverized hybridization pattern, with the presence of small interstitial and/or terminal blocks. Studies like this one, integrating functional genomics and molecular cytogenetic tools, are essential to expanding knowledge about transcriptionally active mobile elements, and their behavior in the chromosomes.

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.

BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Transposable elements in the transcriptome of the velvetbean caterpillar Anticarsia gemmatalis Hübner, 1818 (Lepidoptera: Erebidae).

Transposable elements (TEs) are DNA sequences that possess the ability to move from one genomic location to another. These sequences contribute to a significant fraction of the genomes of most eukaryotes and can impact their architecture and regulation. In this paper, we present the first data related to the identification and characterization of TEs present in the transcriptome of Anticarsia gemmatalis. Approximately, 835 transcripts showed significant similarity to TEs and (or) characteristic domains. Retrotransposons accounted for 71.2% (595 sequences) of the identified elements, while DNA transposons were less abundant, with 240 annotations (28.8%). TEs were classified into 30 superfamilies, with SINE3/5S and Gypsy being the most abundant. Based on the sequences of TEs found in the transcriptome, we were able to locate conserved regions in the chromosomes of this species. The analysis of differential expression of TEs in susceptible and resistant strains, challenged and not challenged with Bacillus thuringiensis (Bt) from in silico analysis, indicated that exposure to Bt can regulate the transcription of mobile genetic elements in the velvetbean caterpillar. Thus, these data contribute significantly to the knowledge of the structure and composition of these elements in the genome of this species, and suggest the role of stress on their expression.

Unusual Forms of Pulmonary Hypertension.

There are several forms of pulmonary hypertension that can be considered unusual not solely due to their prevalence but also due to their geographic distribution. The aim of this review is to highlight some of these forms, most of them classified within group 5 of the current pulmonary hypertension classification. This review also discusses on schistosomiasis-associated pulmonary hypertension, a prevalent form of pulmonary hypertension mostly limited to developing countries.

Transcriptional Analysis of Microsatellites in Velvetbean Caterpillar Anticarsia gemmatalis Hübner, 1818.

Brazil is the largest producer of soybeans in the world. The vast extent of soybean plantations across the Brazilian territory exposes this crop to attack by several insects, including the velvetbean caterpillar, Anticarsia gemmatalis. One of the alternatives used to control this insect are the toxins produced by Bacillus thuringiensis (Bt). However, in some cases, resistance to these toxins has been reported in the laboratory. Despite the ecological and economic impact of the velvetbean caterpillar, there are few studies on the genetic structure of this species, especially with regard to microsatellites. In this paper, we carried out a comparative transcriptional analysis of microsatellites in resistant (RES) and susceptible (SUS) strains of A. gemmatalis challenged and not challenged with Bt toxins. According to the number of sequences analyzed in each group, a 7.9% simple sequence repeat (SSR) rate was identified for the SUS library, and 7.4% for SUSBt. For the RES group, this value was 8.5% and for the RESBt 7.7%. Most of the fragments found showed a shorter repeat pattern, located in mono- and trinucleotide motifs. Among the 128 types of SSR motifs, it was possible to notice a large amount of adenine and thymine in relation to guanine and cytosine, which was also seen in chromosomes after staining with base-specific fluorochromes DAPI/CMA3, highlighting DAPI-positive regions. Although the participation of microsatellites in the resistance mechanism of A. gemmatalis to Bt is not clear, the results obtained in this work contribute to a better understanding of the repetitive DNA found in transcribed regions of a non-model organism.

Transcriptional profiling analysis of susceptible and resistant strains of Anticarsia gemmatalis and their response to Bacillus thuringiensis.

Anticarsia gemmatalis is one of the main defoliators of soybean in Brazil. Bacillus thuringiensis (Bt) transgenic crops are used for their management. In this paper we used RNA-seq to explore the response of A. gemmatalis to Bt HD73, as well as to detect transcriptional differences after Bt infection between resistant and susceptible strains. A total of 3853 and 6224 differentially expressed genes (DGEs) were identified in susceptible and resistant larvae after Bt exposure, respectively. We identified 2143 DEGs between susceptible and resistant larvae and 1991 between susceptible and resistant larvae Bt exposed. Immunity-related genes, Bt toxins receptors, proteases, genes involved in metabolic processes, transporters, cuticle proteins and mobile elements have been identified. qRT-PCR data demonstrated upregulation of five genes in susceptible strain after Bt exposure. These results provide insights to understand the molecular and cellular mechanisms of response to Bt that could be used in strategies to control agricultural pests.

A strategy for designing of customized electromechanical actuators of blood pumps.

Congestive heart failure is a pathology of global incidence that affects millions of people worldwide. When the heart weakens and fails to pump blood at physiological rates commensurate with the requirements of tissues, two main alternatives are cardiac transplant and ventricular assist devices (VADs). This article presents the design strategy for development of a customized VAD electromagnetic actuator. Electromagnetic actuator is a brushless direct current motor customized to drive the pump impeller by permanent magnets located in rotor-stator coupling. In this case, ceramic pivot bearings support the VAD impeller. Electronic circuitry controls rotation switching current in stator coils. The proposed methodology consisted of analytical numerical design, tridimensional computational modeling, numerical simulations using Maxwell software, actuator prototyping, and validation in the dynamometer. The axial flow actuator was chosen by its size and high power density compared to the radial flow type. First step consisted of estimating the required torque to drive the pump. Torque was estimated at 2100 rpm and mean current of 0.5 A. Numerical analysis using finite element method mapped vectors and fields to build stator coils and actuator assemblage. After tests in the dynamometer, experimental results were compared with numerical simulation and validated the proposed model. In conclusion, the proposed methodology for designing of VAD electromechanical actuator was considered satisfactory in terms of data consistency, feasibility, and reliability.

Clinical relevance of pulmonary vasculature involvement in sickle cell disease.

Pulmonary complications are frequent in patients with sickle cell disease (SCD), but few studies have described lung pathology in SCD. We studied the lung tissue of 30 deceased SCD patients (1994-2012). Demographics, genotype, clinical characteristics, cause of death and associated conditions are presented. We quantified the presence of pulmonary arterial changes, thrombosis and venous thickening. Alveolar capillary abnormalities were demonstrated using CD34 expression and confocal microscopy. Autopsy and echocardiography reports were reviewed to classify heart abnormalities. Tissue expression of markers of endothelial activation (vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and vascular endothelial growth factor) was quantified in pulmonary vessels. Median age was 33 years; genotype was SS in 19, SC in 7 and Sß in 4, and there were 18 males. Hypertensive arterial changes were present in 76% of the patients, recent thrombosis in 80% and old thrombosis in 43%. Venous thickening was present in 23% and pulmonary capillary haemangiomatosis foci in 87%. Ten percent of the patients presented right ventricular hypertrophy. There was no increased expression of endothelial activation markers when compared to controls. SCD affects the whole pulmonary vascular tree and reflects the multiple burden on lung vasculature imposed by the disease upon time.

Haemodynamic definitions and updated clinical classification of pulmonary hypertension.

Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management.Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup "pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers", due to the specific prognostic and management of these patients, and a subgroup "PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement", due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.

The global view.

PURPOSE OF REVIEW: To understand the global distribution of different forms of pulmonary hypertension. RECENT FINDINGS: Different registries have explored the epidemiological characteristics of pulmonary hypertension. Interestingly, there is a clear difference in the prevalence of different forms of pulmonary hypertension in developed regions in comparison with less developed countries. This finding suggests not only that extrapolation of data should be avoided but also that the known prevalence of pulmonary hypertension might be underestimated. SUMMARY: Pulmonary hypertension might be more prevalent than what is currently believed. Specific forms of pulmonary hypertension distributed worldwide might characterize an unrecognized burden that still have to be properly approached. This highlights the heterogeneity of pulmonary hypertension around the world. It is clear that more epidemiological data are still needed as well as studies addressing management alternatives in these specific regions.

Pulmonary Embolism and Gas Exchange.

Acute pulmonary embolism (PE) impairs hemodynamics, gas exchange, and lung mechanical capacity. Considering PE pathophysiology, most attention has been paid to hemodynamic impairment. However, the most prevalent symptoms in PE patients come from gas exchange alterations, which have not been in the spotlight for many years. Pulmonary physiology and consequent gas exchange impairment play a pivotal role in the high risk of death from PE. In this review, we will look at the pathophysiology of PE, from the vascular occlusion to the resultant heterogeneity in pulmonary perfusion and gas exchange impairment, discussing in detail its causes and consequences.

Functional annotation and distribution overview of RNA families in 27 Streptococcus agalactiae genomes.

BACKGROUND: Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a Gram-positive bacterium that colonizes the gastrointestinal and genitourinary tract of humans. This bacterium has also been isolated from various animals, such as fish and cattle. Non-coding RNAs (ncRNAs) can act as regulators of gene expression in bacteria, such as Streptococcus pneumoniae and Streptococcus pyogenes. However, little is known about the genomic distribution of ncRNAs and RNA families in S. agalactiae. RESULTS: Comparative genome analysis of 27 S. agalactiae strains showed more than 5 thousand genomic regions identified and classified as Core, Exclusive, and Shared genome sequences. We identified 27 to 89 RNA families per genome distributed over these regions, from these, 25 were in Core regions while Shared and Exclusive regions showed variations amongst strains. We propose that the amount and type of ncRNA present in each genome can provide a pattern to contribute in the identification of the clonal types. CONCLUSIONS: The identification of RNA families provides an insight over ncRNAs, sRNAs and ribozymes function, that can be further explored as targets for antibiotic development or studied in gene regulation of cellular processes. RNA families could be considered as markers to determine infection capabilities of different strains. Lastly, pan-genome analysis of GBS including the full range of functional transcripts provides a broader approach in the understanding of this pathogen.

Estimation of Stroke Volume and Stroke Volume Changes by Electrical Impedance Tomography.

BACKGROUND: Electrical impedance tomography (EIT) is a noninvasive imaging method that identifies changes in air and blood volume based on thoracic impedance changes. Recently, there has been growing interest in EIT to measure stroke volume (SV). The objectives of this study are as follows: (1) to evaluate the ability of systolic impedance variations (ΔZsys) to track changes in SV in relation to a baseline condition; (2) to assess the relationship of ΔZsys and SV in experimental subjects; and (3) to identify the influence of body dimensions on the relationship between ΔZsys and SV. METHODS: Twelve Agroceres pigs were instrumented with transpulmonary thermodilution catheter and EIT and were mechanically ventilated in a random order using different settings of tidal volume (VT) and positive end-expiratory pressure (PEEP): VT 10 mL·kg and PEEP 10 cm H2O, VT 10 mL·kg and PEEP 5 cm H2O, VT 6 mL·kg and PEEP 10 cm H2O, and VT 6 mL·kg and PEEP 5 cm H2O. After baseline data collection, subjects were submitted to hemorrhagic shock and successive fluid challenges. RESULTS: A total of 204 paired measurements of SV and ΔZsys were obtained. The 4-quadrant plot showed acceptable trending ability with a concordance rate of 91.2%. Changes in ΔZsys after fluid challenges presented an area under the curve of 0.83 (95% confidence interval, 0.74-0.92) to evaluate SV changes. Conversely, the linear association between ΔZsys and SV was poor, with R from linear mixed model of 0.35. Adding information on body dimensions improved the linear association between ΔZsys and SV up to R from linear mixed model of 0.85. CONCLUSIONS: EIT showed good trending ability and is a promising hemodynamic monitoring tool. Measurements of absolute SV require that body dimensions be taken into account.

RV Fractional Area Change and TAPSE as Predictors of Severe Right Ventricular Dysfunction in Pulmonary Hypertension: A CMR Study.

BACKGROUND: The right ventricular ejection fraction (RVEF) is a surrogate marker of right ventricular function in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The tricuspid annular plane systolic excursion (TAPSE) measures only the longitudinal component of RV contraction while the right ventricular fractional area change (RVFAC) takes into account both the longitudinal and the transversal components. The aim of our study was to evaluate the relationship between RVEF, RVFAC, and TAPSE according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Fifty-four patients with PAH (n = 15) and CTEPH (n = 39) underwent right heart catheterization and cardiac magnetic resonance (CMR). The ventricular volumes and areas, TAPSE, and eccentricity index were measured. The RVFAC was more strongly correlated with the RVEF (r = 0.81, p < 0.0001) than the TAPSE (r = 0.63, p < 0.0001). RVEF < 35% was better predicted by the RVFAC than the TAPSE (TAPSE: AUC = 0.77 and RVFAC: AUC = 0.91; p = 0.042). In the group with the worse hemodynamic status, the RVFAC correlated much better with the RVEF than the TAPSE. There were no significant differences in the CMR data analyzed between the groups of PAH and CETPH patients. CONCLUSIONS: The RVFAC is a good index to estimate RVEF in PH patients; even better than the TAPSE in patients with more severe hemodynamic profile, possibly for including the transversal component of right ventricular function in its measurement. Furthermore, RVFAC performance was similar in the two PH groups (PAH and CTEPH).

Pulmonary arterial hypertension in Latin America: epidemiological data from local studies.

BACKGROUND: Pulmonary arterial hypertension is a rare, progressive disease with poor prognosis. However, there is limited information available on the characteristics of PAH patients outside of North America and Europe. This is particularly important as researchers have described that there are potential geographical and regional differences which are vital to consider in the design of clinical trials as well as PAH treatment. The aim of this study was to describe the epidemiology of PAH (PH group 1) in Latin America. METHODS: A search of electronic databases for studies published in English, Spanish or Portuguese was conducted specifying publication dates from the 1st of January 1987 until 10th October 2016. Two authors independently assessed papers for inclusion and extracted data. A narrative synthesis of the findings was conducted. RESULTS: The search revealed 22 conference abstracts and articles, and on application of the inclusion criteria, six conference abstracts and articles were included in the final review. Studies/registries were based in Argentina, Brazil and Chile. In contrast to the available literature from developed countries, in Latin America, most patients were diagnosed at younger age; nevertheless, the higher prevalence of idiopathic PAH (IPAH) and the advanced stage of the disease at diagnosis were comparable to the existing literature, as the long term survival, despite the lower availability of targeted therapies. CONCLUSION: This study highlights the regional characteristics in the epidemiology of group 1 PH. The recognition of these differences should be considered when developing clinical guidelines and extrapolating diagnostic and treatment algorithms. Equitable access to health care and therapies are also issues that need to be addressed in Latin America. Information coming from a large prospective registry representing the different populations in Latin America is of critical importance to increase disease awareness in the region and improve diagnosis and management.

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.

Aims: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. Methods and results: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively). Conclusions: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.

Distribution of Divo in Coffea genomes, a poorly described family of angiosperm LTR-Retrotransposons.

Coffea arabica (the Arabica coffee) is an allotetraploid species originating from a recent hybridization between two diploid species: C. canephora and C. eugenioides. Transposable elements can drive structural and functional variation during the process of hybridization and allopolyploid formation in plants. To learn more about the evolution of the C. arabica genome, we characterized and studied a new Copia LTR-Retrotransposon (LTR-RT) family in diploid and allotetraploid Coffea genomes called Divo. It is a complete and relatively compact LTR-RT element (~5 kb), carrying typical Gag and Pol Copia type domains. Reverse Trancriptase (RT) domain-based phylogeny demonstrated that Divo is a new and well-supported family in the Bianca lineage, but strictly restricted to dicotyledonous species. In C. canephora, Divo is expressed and showed a genomic distribution along gene rich and gene poor regions. The copy number, the molecular estimation of insertion time and the analysis at orthologous locations of insertions in diploid and allotetraploid coffee genomes suggest that Divo underwent a different and recent transposition activity in C. arabica and C. canephora when compared to C. eugenioides. The analysis of this novel LTR-RT family represents an important step toward uncovering the genome structure and evolution of C. arabica allotetraploid genome.