Riociguat real-world use in patients with chronic thromboembolic pulmonary hypertension: A retrospective, observational cohort study in France.

BACKGROUND: Riociguat is the first approved treatment for inoperable and persistent/recurrent post-surgery chronic thromboembolic pulmonary hypertension (CTEPH). The RetrospectIve Adempas® stuDy (RiAD) aimed to describe the real-world utilization of riociguat in France. METHODS: In this retrospective multicentric study in patients initiating riociguat, dosing regimen, co-treatments and clinical characteristics were collected over a 2-year follow-up period. RESULTS: A total of 173 patients (mean age, 71.4 years; female, 63.0%; NYHA II-III, 80.3%) were included from January 2015 to December 2016 in 18 centers. All patients were diagnosed with CTEPH (75.7% inoperable and 20.8% with persistent/recurrent pulmonary hypertension [pH] after surgery) with mean (SD) right atrial pressure 7.6 (4.2) mmHg, mean pulmonary artery pressure 43.0 (11.4) mmHg and mean cardiac output 4.1 (1.1) L/min. Before riociguat initiation, 32.4% of patients previously received at least one pH-specific therapy. At initiation, 93.1% of patients were receiving anticoagulants and 83.2% were not receiving pH-specific co-treatments. Riociguat was initiated at 1 mg three times daily (t.i.d.) in 85.5% of patients and 82.1% were receiving 2.5 mg dose t.i.d. at 24 months. The maximal daily dose of 7.5 mg was never exceeded. At 24 months, the estimated rate of patients still taking riociguat was 78.8% with an estimated mean (SD) time on treatment of 20.1 (0.5) months per patient. No new safety signals were recorded. CONCLUSIONS: The results of this real-world study show that riociguat is used in France in accordance with its therapeutic indication in patients with inoperable or persistent/recurrent post-operative CTEPH and confirm its long-term safety.

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: An observational study based on the French national hospital discharge database (PMSI).

INTRODUCTION: Since 2014, Balloon Pulmonary Angioplasty (BPA) has become an emerging and complementary strategy for chronic thromboembolic hypertension (CTEPH) patients who are not suitable for pulmonary endarterectomy (PEA) or who have recurrent symptoms after the PEA procedure. OBJECTIVE: To assess the hospital cost of BPA sessions and management in CTEPH patients. METHODS: An observational retrospective cohort study of CTEPH-adults hospitalized for a BPA between January 1st, 2014 and June 30th, 2016 was conducted in the 2 centres performing BPA in France (Paris Sud and Grenoble) using the French national hospital discharge database (PMSI-MCO). Patients were followed until 6 months or death, whichever occurred first. Follow-up stays were classified as stays with BPA sessions, for BPA management or for CTEPH management based on a pre-defined algorithm and a medical review using type of diagnosis (ICD-10), delay from last BPA procedure stay and length of stay. Hospital costs (including medical transports) were estimated from National Health Insurance perspective using published official French tariffs from 2014 to 2016 and expressed in 2017 Euros. RESULTS: A total of 191 patients were analysed; mainly male (53%), with a mean age of 64,3 years. The first BPA session was performed 1.1 years in median (IQR 0.3-2.92) after the first PH hospitalisation. A mean of 3 stays with BPA sessions per patient were reported with a mean length of stay of 8 days for the first stay and 6 days for successive stays. The total hospital cost attributable to BPA was € 4,057,825 corresponding to €8,764±3,435 per stay and €21,245±12,843 per patient. Results were sensitive to age classes, density of commune of residence and some comorbidities. CONCLUSIONS: The study generated robust real-world data to assess the hospital cost of BPA sessions and management in CTEPH patients within its first years of implementation in France.

Detection of the nuclear poly(ADP-ribose)-metabolizing enzymes and activities in response to DNA damage.

Poly(ADP-ribosyl)ation is a posttranslational modification of proteins in higher eukaryotes mediated by poly(ADP-ribose) polymerases (PARPs) that is involved in many physiological processes such as DNA repair, transcription, cell division, and cell death. Biochemical studies together with PARP-1- or PARP-2-deficient cellular and animal models have revealed the redundant but also complementary functions of the two enzymes in the surveillance and maintenance of genome integrity. Poly(ADP-ribose) is degraded by the endo- and exo-glycosidase activities of poly(ADP-ribose) glycohydrolase (PARG). In this chapter, biochemical and immunofluorescence methods are described for detecting and assaying PARPs and PARG.

The expanding field of poly(ADP-ribosyl)ation reactions. 'Protein Modifications: Beyond the Usual Suspects' Review Series.

Poly(ADP-ribosyl)ation is a post-translational modification of proteins that is mediated by poly(ADP-ribose) polymerases (PARPs). Although the existence and nature of the nucleic acid-like molecule poly(ADP-ribose) (PAR) has been known for 40 years, understanding its biological functions--originally thought to be only the regulation of chromatin superstructure when DNA is broken--is still the subject of intense research. Here, we review the mechanisms controlling the biosynthesis of this complex macromolecule and some of its main biological functions, with an emphasis on the most recent advances and hypotheses that have developed in this rapidly growing field.

The macroPARP genes Parp-9 and Parp-14 are developmentally and differentially regulated in mouse tissues.

The macroPARPs Parp-9 and Parp-14 are macro domain containing poly(ADP-ribose) polymerases involved in transcriptional regulation in response to immunoregulatory cytokines. Their genes reside in the same locus (16B3), and the Parp-9 gene lies head-to-head and shares its promoter with the gene encoding its partner, Bbap. Here, we provide a detailed analysis of Parp-9, Parp-14, and Bbap expression during mouse development and adulthood. Parp-9 is developmentally regulated, and prominently expressed in the thymus and specific regions of the brain and gut. In adults, highest expression is maintained in the thymus and intestine. Parp-14 is more weakly expressed, mainly in the thymus during development and in adulthood. In addition, we show that Bbap is essentially coexpressed with Parp-9 during development and in adult mouse. However, the different levels of their transcripts detected in the developing brain and gut suggest that Bbap and Parp-9 display both common and independent tissue-specific regulations.