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Inhibitors of voltage-gated sodium channels (Nav) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent NaV channel blocker and an activator of small-conductance Ca2+-activated K+ channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED50 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD50/ED50) of 6–9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects NaV and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Nav channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

Background and Purpose The KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses. Experimental Approach We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2 H-1,4-benzothiazin-3(4 H)-one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T-cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4-dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease ( IBD). Key Results NS6180 inhibited cloned human KCa3.1 channels ( IC50 = 9 n M) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15-20 n M). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-γ production, while exerting smaller effects on IL-4 and TNF-α and no effect on IL-17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg−1 b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg−1 q.d.). Conclusions and Implications NS6180 represents a novel class of KCa3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation. [ABSTRACT FROM AUTHOR]

Command and control is the management infrastructure for any large, complex,dynamic resource system (Harris, C.J. and White, I., 1987. Advances in command,control and communication systems. London: Peregrinus). Traditional militarycommand and control is increasingly challenged by a host of modern problems,namely, environmental complexity, dynamism, new technology and competitionthat is able to exploit the weaknesses of an organisational paradigm that has beendominant since the industrial revolution. The conceptual response to thesechallenges is a new type of command and control organisation called NetworkEnabled Capability (NEC). Although developed independently, NEC exhibitsa high degree of overlap with concepts derived from sociotechnical systemstheory, a fact that this paper aims to explore more fully. Uniquely, whatsociotechnical theory brings to NEC research is a successful 50 year legacy in theapplication of open systems principles to commercial organisations. This trackrecord is something that NEC research currently lacks. The paper reviews thetwin concepts of NEC and sociotechnical systems theory, the underlyingmotivation behind the adoption of open systems thinking, a review of classicsociotechnical studies and the current state of the art. It is argued that 'classic'sociotechnical systems theory has much to offer 'new' command and controlparadigms. The principles of sociotechnical systems theory align it exceptionallywell with the challenges of modern organisational design. It is also reflectiveof a wider paradigm shift in ergonomics theory away from 'industrial age' modesof thought to systems-based 'information age' thinking. [ABSTRACT FROM AUTHOR]

This study measured the influence of the flavonoid quercetin on immune changes and incidence rates of upper respiratory tract infections in ultramarathoners competing in the 160-km Western States Endurance Run. Sixty-three runners were randomized to quercetin and placebo groups, and under double-blinded methods ingested 1000 mg/day quercetin for 3 wks before, during, and 2 wks after the race. Thirty-nine of the 63 subjects (n = 18 for quercetin, n = 21 for placebo) finished the race and provided blood and saliva samples the morning before the race and 15 - 30 min postrace. Upper respiratory tract infections were assessed during the week before and the 2-wk period after the race using an illness symptom checklist. Race times did not differ significantly between quercetin and placebo groups. Significant pre- to postrace decreases were measured for natural killer cells (43%), granulocyte respiratory burst activity (55%), and salivary IgA output (48%), and increases for neutrophil (288%) and monocyte (211%) cell counts, with no significant group differences. Postrace illness rates did not differ between groups. In conclusion, quercetin supplementation for 3 wks before and 2 wks after the Western States Endurance Run had no effect on illness rates, perturbations in leukocyte subset counts, or decreases in granulocyte respiratory burst activity and salivary IgA. [ABSTRACT FROM AUTHOR]

The objective of this paper is to illustrate the interconnections between the different phases (or tools) within the cognitive work analysis framework; the benefits of extending an analysis across each of the five phases are highlighted through these interconnections. The paper uses a command and control micro-world example to describe how each of the five phases can be used to describe the constraints within the micro-world domain from a different perspective. Based upon the social organisation and cooperation analysis, design requirements are extracted in order to develop role specific customisable interfaces for use within the micro-world. The interfaces have been specifically developed to communicate real time reconfiguration of the network through each of the individual interfaces; the reallocations of functions or roles are communicated to the actors through changes to the interface. [ABSTRACT FROM AUTHOR]

The concept of situation awareness (SA) is frequently described in the literature. Theoretically, it remains predominantly an individual construct and the majority of the models presented describe SA from an individual perspective. In comparison, team SA has received less attention. SA in complex, collaborative environments thus remains a challenge for the human factors community, both in relation to the development of theoretical perspectives and of valid measures and to the development of guidelines for system, training and procedure design. This article presents a review and critique of what is currently known about SA and team SA, including a comparison of the most prominent individual and team models presented in the literature. In conclusion, it is argued that recently proposed systems level distributed SA approaches are the most suited to describing and assessing SA in real world, collaborative environments. [ABSTRACT FROM AUTHOR]

Rationale: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies.Objectives: To investigate the prognosis of CTEPH in a national setting during recent years.Methods: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records.Measurements and Main Results: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%.Conclusions: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition. [ABSTRACT FROM AUTHOR]

Introduction: Evidence for use of pulmonary arterial hypertension targeted-therapies in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is limited. In MERIT-1, the endothelin receptor antagonist macitentan improved hemodynamic and functional parameters versus placebo in patients with inoperable CTEPH over a 24-week double-blind (DB) period. Its open-label (OL) extension study (MERIT-2) provides long-term safety/efficacy data., Methods: MERIT-2 (NCT02060721) was a multicenter, single-arm, OL, phase 2 extension study of MERIT-1. Patients completing MERIT-1 were eligible to receive 10 mg macitentan once-daily in MERIT-2. Safety and efficacy (6-min walk distance [6MWD] and change in World Health Organization functional class [WHO FC]) were assessed in all patients in MERIT-2 regardless of treatment received in DB (All patients MERIT-2 OL macitentan 10 mg group) and the subgroup of patients receiving DB macitentan in MERIT-1 (Long-term [DB/OL] macitentan 10 mg subgroup)., Results: Of the 80 patients randomized in MERIT-1, 76 entered MERIT-2 (All patients MERIT-2 OL macitentan 10 mg group): 40 who received DB macitentan (DB-macitentan patients) and 36 DB placebo (DB-placebo patients). Median (interquartile range) macitentan exposure in the All patients MERIT-2 OL macitentan 10 mg group was 45.5 (26.0, 66.1) months. During the OL period, treatment-emergent adverse events (AE) were reported in 72 (94.7%) patients; most frequent were worsening of pulmonary hypertension (19.7%), decreased hemoglobin (18.4%) and upper respiratory tract infection (15.8%). Fourteen (18.4%) patients died; none were assessed as macitentan-related. At Month 6 post-OL baseline, mean (standard deviation) change in 6MWD was - 0.4 m (43.62) for DB-macitentan patients and 10.7 m (45.63) for DB-placebo patients; the majority had unchanged (83.3%) or improved (12.5%) WHO FC. Safety/efficacy analyses were consistent in the Long-term (DB/OL) macitentan 10 mg subgroup., Conclusion: These analyses provide long-term safety/efficacy data in patients with inoperable CTEPH treated with macitentan. No unexpected safety findings occurred; reported AEs were consistent with the known safety profile of macitentan. At 6 months post-OL baseline, DB-placebo patients modestly improved 6MWD; DB-macitentan patients maintained improvements observed in MERIT-1. WHO FC was largely unchanged., Trial Registration: ClinicalTrials.gov Identifiers: NCT02021292; NCT02060721., (© 2024. The Author(s).)

Chronic thromboembolic pulmonary hypertension is a complication of pulmonary embolism and a treatable cause of pulmonary hypertension. The pathology is a unique combination of mechanical obstruction due to failure of clot resolution, and a variable degree of microvascular disease, that both contribute to pulmonary vascular resistance. Accordingly, multiple treatments have been developed to target the disease components. However, accurate diagnosis is often delayed. Evaluation includes high-quality imaging modalities, necessary for disease confirmation and for appropriate treatment planning. All patients with chronic thromboembolic pulmonary disease, and especially those with pulmonary hypertension, should be referred to expert centres for multidisciplinary team decision on treatment. The first decision remains assessment of operability, and the best improvement in symptoms and survival is achieved by the mechanical therapies, pulmonary endarterectomy and balloon pulmonary angioplasty. With the advances in multimodal therapies, excellent outcomes can be achieved with 3-year survival of >90%., Competing Interests: Conflict of interest: N.H. Kim reports consultancy fees from Bayer, Janssen, Merck, United Therapeutics and Pulnovo, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen and Merck, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Merck and United Therapeutics, and leadership roles with International CTEPH Association and CTEPH.com. A.M. D'Armini reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AOP Health and MSD, and participation on a data safety monitoring board or advisory board with AOP Health. M. Delcroix reports consultancy fees from Actelion/Janssen/J&J, Acceleron/MSD, Gossamer and Ferrer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion/Janssen/J&J, Acceleron/MSD and Ferrer. X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, and consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD. M. Jevnikar reports payment or honoraria for lectures, presentations, manuscript writing or educational events and support for attending meetings from Janssen and MSD. M.M. Madani reports royalties or licences from Wexler Surgical, consultancy fees from Bayer/MSD and Actelion/Janssen/J&J, and participation on a data safety monitoring board or advisory board with International CTEPH Association. H. Matsubara reports grants from Nippon Shinyaku, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Kaneka Medix, Mochida, MSD, Nippon Shinyaku, Nipro and AOP Orphan, payment for expert testimony from MSD, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Mochida and MSD, and a leadership role with International CTEPH Association. M. Palazzini reports consultancy fees, payment or honoraria for lectures, presentations, manuscript writing or educational events, and support for attending meetings from Janssen. C.B. Wiedenroth reports consultancy fees from J&J, OrphaCare and MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from J&J, AOP-Health, Bayer, Inari, MSD and Pfizer, and a leadership role with International CTEPH Association. G. Simonneau has no potential conflicts of interest to disclose. D.P. Jenkins reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, and and a leadership role with International CTEPH Association., (Copyright ©The authors 2024.)

Background: The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context., Methods: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019., Results: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm -5 . During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention ( P <0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants ( P =0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention., Conclusions: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02656238., Competing Interests: M.D. reports research grants from Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD outside the submitted work, and all paid to her institution. She was holder of a Janssen chair for pulmonary hypertension at the KU Leuven. J.P.Z. reports research grants from MSD and consultant fees from Ferrer, Gossamer, Janssen outside submitted work. S.G. reports speaker fees or consultant honoraria from Actelion/Janssen, Bayer AG, MSD, and Pfizer. D.P.J. reports speaker fees and consultancy fees from Janssen outside this submitted work. D.G.K. reports speaker fees, consultancy fees, or funding to attend meetings from Acceleron, Altavant, Ferrer, Janssen, Gossamer, MSD and United Therapeutics and research support from Ferrer and Janssen, all outside of the submitted work. N.H.K. reports receiving speaker fees from Bayer and Janssen; consultancy fees from Bayer, Janssen, Merck, Polarean, Pulnovo, and United Therapeutics; and research support from Altavant and Gossamer Bio. All disclosed fees and support are outside the submitted work. M.M.M. reports consultancy fees and royalties from Wexler Surgical and consultancy fees from Actelion/Janssen and Johnson & Johnson. H.M. reports research grants from Nippon Shinyaku; speaker and consultant fees from Bayer, Janssen, and MSD; speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Nipro, all outside of the submitted work. J.S.O.A. reports personal fees from Bayer and MSD. R.S.K. reports having received speaker fees from AOP Health, Actelion/Janssen, and MSD, all outside of the submitted work. GS reports receiving advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. C.B.W. reports speaker fees or consultant honoraria from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer. E.M. reports receiving consultancy or speaker fees from Actelion/Janssen, Bayer, and MSD. I.M.L. has relationships with drug companies including AOP Health, Actelion/Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis, and Sanofi; in addition to being investigator in trials involving these companies, relationships include consultancy services, research grants, and membership of scientific advisory boards. The other authors report no conflicts.

Background: Previous studies have demonstrated the safety of pulmonary endarterectomy (PEA) across body mass index (BMI) strata. However, long-term survival and patient-reported outcome measures by BMI strata remain unknown. We examined the impact of preoperative BMI on long-term survival, QOL, and functional outcomes for patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Retrospective review of 2,004 patients from the UK National Cohort between 2007 and 2021 undergoing PEA for CTEPH (mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance >160 dynes). Patients were stratified into BMI<20, 20 to 29, 30 to 39, 40 to 49, and 50+. All-cause mortality was the primary outcome measure. Secondary outcome measures were 3- to 6-month postoperative hemodynamics, 6-minute walk distance (6MWD), New York Heart Association (NYHA) class, and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) scores., Results: Hemodynamics and 6MWD at 3 to 6 months were similar across BMI strata. Patients with BMI 50+ reported the highest incidence of postoperative NYHA III/IV limitation (53.3%, p < 0.001) and the highest residual symptom burden by CAMPHOR (p < 0.001). Five-year survival was lowest in patients with BMI 50+ (70.2%) and BMI<20 (73.4%), while highest in BMI 30 to 39 (88.2%, p = 0.008). Ten-year Kaplan-Meier estimates predicted the lowest survival in BMI 50+ and BMI<20., Conclusions: PEA remains safe and effective for all patients regardless of BMI. Despite similar hemodynamic outcomes, patients with BMI 50+ are at the greatest risk of long-term all-cause mortality, and patients with BMI 50+ experience residual symptomatic limitation., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a consequence of unresolved organized thromboembolic obstruction of the pulmonary arteries, which can cause pulmonary hypertension and right ventricular failure. Owing to its subtle signs, determining its exact incidence and prevalence is challenging. Furthermore, CTEPH may also present without any prior venous thromboembolic history, contributing to underdiagnosis and undertreatment. Diagnosis requires a high degree of suspicion and is ruled out by a normal ventilation/perfusion ratio scintigraphy. Additional imaging by computed tomography and/or conventional angiography, as well as right heart catheterization, are required to confirm CTEPH and formulate treatment plans. Pulmonary thromboendarterectomy is the treatment of choice for eligible patients and can be potentially curative. Pulmonary thromboendarterectomy has a low mortality rate of 1% to 2% at expert centers and offers excellent long-term survival. Furthermore, recent advances in the techniques allow distal endarterectomy with comparable outcomes. Alternative treatment options are available for those who may not be operable or have prohibitive risks, providing some benefit. However, CTEPH is a progressive disease with low long-term survival rates if left untreated. Given excellent short- and long-term outcomes of surgery, as well as the benefits seen with other treatment modalities in noncandidate patients, it is crucial that precapillary pulmonary hypertension and CTEPH are ruled out in any patient with dyspnea of unexplained etiology. These patients should be referred to expert centers where accurate operability assessment and appropriate treatment strategies can be offered by a multidisciplinary team., Competing Interests: Disclosures Michael Madani reports a relationship with Wexler Surgical that includes: consulting or advisory and with Janssen Pharmaceuticals Inc that includes: consulting or advisory. David Jenkins reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Marc de Perrot reports a relationship with Merck & Co Inc that includes: consulting or advisory; with Bristol-Myers Squibb Co that includes: consulting or advisory; with AstraZeneca Canada Inc that includes: consulting or advisory; and with Roche that includes: consulting or advisory. Christoph Wiedenroth reports a relationship with Bayer Corporation that includes: consulting or advisory; with Inari Medical Inc that includes: consulting or advisory; with Merck Sharp & Dohme Corp that includes: consulting or advisory; with Johnson & Johnson that includes: consulting or advisory; and with Pfizer Inc that includes: consulting or advisory. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As the UK's Chartered Institute of Ergonomics and Human Factors (CIEHF) celebrates its 75th anniversary, it is worth reflecting on our discipline's contribution, current state, and critical future endeavours. We present the perspectives of 18 EHF professionals who were asked to respond to five questions regarding the impact of EHF, contemporary challenges, and future directions. Co-authors were in agreement that EHF's impact has been only limited to date and that critical issues require resolution, such as increasing the number of suitably qualified practitioners, resolving the research-practice gap, and increasing awareness of EHF and its benefits. Frequently discussed future directions include advanced emerging technologies such as artificial intelligence, the development of new EHF methods, and enhancing the quality and reach of education and training. The majority felt there will be a need for EHF in 75 years; however, many noted that our methods will need to adapt to meet new needs. Practitioner statement: This article provides the perspectives of 18 Ergonomics and Human Factors (EHF) professionals on the impact of EHF, contemporary challenges and critical future directions, and changes that are necessary to ensure EHF remains relevant in future. As such, it provides important guidance on future EHF research and practice.

Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding the process by which a PN transforms into an MPNST would be facilitated by the availability of genetically engineered mouse (GEM) models that accurately replicate the PN-MPNST progression seen in humans with NF1. Unfortunately, GEM models with Nf1 ablation do not fully recapitulate this process. This led us to develop P0-GGFβ3 mice, a GEM model in which overexpression of the Schwann cell mitogen neuregulin-1 (NRG1) in Schwann cells results in the development of PNs that progress to become MPNSTs with high frequency. However, to determine whether tumorigenesis and neoplastic progression in P0-GGFβ3 mice accurately model the processes seen in NF1 patients, we had to first prove that the pathology of P0-GGFβ3 peripheral nerve sheath tumors recapitulates the pathology of their human counterparts. Here, we describe the specialized methodologies used to accurately diagnose and grade peripheral nervous system neoplasms in GEM models, using P0-GGFβ3 and P0-GGFβ3;Trp53 +/- mice as an example. We describe the histologic, immunohistochemical, and histochemical methods used to diagnose PNs and MPNSTs, how to distinguish these neoplasms from other tumor types that mimic their pathology, and how to grade these neoplasms. We discuss the establishment of early-passage cultures from GEM MPNSTs, how to characterize these cultures using immunocytochemistry, and how to verify their tumorigenicity by establishing allografts. Collectively, these techniques characterize the pathology of PNs and MPNSTs that arise in GEM models and critically compare the pathology of these murine tumors to their human counterparts.

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., Competing Interests: Declaration of interests H-AG has received fees for serving as a board member for AbbVie, Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer. GS has received consultancy fees, lecture fees and travel support from Actelion Pharmaceuticals, Bayer, Merck, GlaxoSmithKline, and Pfizer; and grant support and fees for serving on a steering committee from Actelion Pharmaceuticals and Bayer. AMD’A has received fees for organising Masters-level courses, lecture fees and writing assistance from Bayer and Merck; and fees for serving on steering committees from Actelion Pharmaceuticals. PF has received fees for serving on an adjudication committee for Actelion Pharmaceuticals. LSH has received consultancy fees from Endotronix; fees for serving on steering committees from Actelion Pharmaceuticals, Bristol-Myers Squibb, and BTG plc; lecture fees, fees for serving on advisory boards, and travel support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, and Merck; grant support from Bayer; and departmental funding from Actelion Pharmaceuticals. XJ has received fees for serving on an adjudication committee for Actelion Pharmaceuticals; grant support from Actelion Pharmaceuticals and GlaxoSmithKline; and personal fees from Actelion Pharmaceuticals, GlaxoSmithKline, and Merck. DPJ has received fees for serving on a steering committee for Actelion Pharmaceuticals and lecture fees from Bayer. Z-CJ has received consultancy fees, lecture fees and fees for serving on a steering committee from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Lee's Pharmaceuticals, and Pfizer; fees for serving on an adjudication committee from Actelion Pharmaceuticals; and grant support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Pfizer, The National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), and The National Key Research and Development Program of China (No. 2016YFC0901502). MMM has received fees for serving on an adjudication committee for Actelion Pharmaceuticals and consultancy fees from Bayer. NM is an employee of Actelion Pharmaceuticals. EM has received consultancy fees from Actelion Pharmaceuticals, Bayer, Merck, and GlaxoSmithKline; lecture fees from Actelion Pharmaceuticals, Bayer, Merck, Pfizer, and GlaxoSmithKline; and fees for serving on a steering committee for Actelion Pharmaceuticals. KP and DR are employees of and hold stock in Actelion Pharmaceuticals. NHK has received consultancy fees from Actelion Pharmaceuticals, Arena, Bayer, Merck, and SteadyMed; lecture fees from Actelion Pharmaceuticals and Bayer; fees for serving on a steering committee for Actelion Pharmaceuticals; and grant support from Bellerophon, Eiger, Gilead, Lung Biotechnology, and Sonivie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The ability of monkeys and rats to carry out spatial working memory tasks has been shown to depend on the persistent firing of pyramidal cells in the prefrontal cortex (PFC), arising from recurrent excitatory connections on dendritic spines. These spines express hyperpolarization-activated cyclic nucleotide-gated (HCN) channels whose open state is increased by cAMP signaling, and which markedly alter PFC network connectivity and neuronal firing. In traditional neural circuits, activation of these non-selective cation channels leads to neuronal depolarization and increased firing rate. Paradoxically, cAMP activation of HCN channels in PFC pyramidal cells reduces working memory-related neuronal firing. This suggests that activation of HCN channels may hyperpolarize rather than depolarize these neurons. The current study tested the hypothesis that Na + influx through HCN channels activates Slack Na + -activated K + (K Na ) channels to hyperpolarize the membrane. We have found that HCN and Slack K Na channels co-immunoprecipitate in cortical extracts and that, by immunoelectron microscopy, they colocalize at postsynaptic spines of PFC pyramidal neurons. A specific blocker of HCN channels, ZD7288, reduces K Na current in pyramidal cells that express both HCN and Slack channels, but has no effect on K Na currents in an HEK cell line expressing Slack without HCN channels, indicating that blockade of HCN channels in neurons reduces K + current indirectly by lowering Na + influx. Activation of HCN channels by cAMP in a cell line expressing a Ca 2+ reporter results in elevation of cytoplasmic Ca 2+ , but the effect of cAMP is reversed if the HCN channels are co-expressed with Slack channels. Finally, we used a novel pharmacological blocker of Slack channels to show that inhibition of Slack in rat PFC improves working memory performance, an effect previously demonstrated for blockers of HCN channels. Our results suggest that the regulation of working memory by HCN channels in PFC pyramidal neurons is mediated by an HCN-Slack channel complex that links activation HCN channels to suppression of neuronal excitability., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pulmonary endarterectomy (PEA) is the guideline-recommended treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, some patients develop severe cardiopulmonary compromise before surgery, intraoperatively, or early postoperatively. This may result from advanced CTEPH, reperfusion pulmonary edema, massive endobronchial bleeding, or right ventricular (RV) failure secondary to residual pulmonary hypertension. Conventional cardiorespiratory support is ineffective when these complications are severe. Since 2005, we used extracorporeal membrane oxygenation (ECMO) as a rescue therapy for this group. We review our experience with ECMO support in these patients., Methods: This study was a retrospective analysis of patients who received perioperative ECMO for PEA from a single national center from August 2005 to July 2022. Data were prospectively collected., Results: One hundred and ten patients (4.7%) had extreme cardiorespiratory compromise requiring perioperative ECMO. Nine were established on ECMO before PEA. Of those who received ECMO postoperatively, 39 were for refractory reperfusion lung injury, 20 for RV failure, 31 for endobronchial bleeding, and the remaining 11 were for "other" reasons, such as cardiopulmonary resuscitation following late tamponade and aspiration pneumonitis. Sixty-two (56.4%) were successfully weaned from ECMO. Fifty-seven patients left the hospital alive, giving a salvage rate of 51.8%. Distal disease (Jamieson Type III) and significant residual pulmonary hypertension were also predictors of mortality on ECMO support. Overall, 5- and 10-year survival in patients who were discharged alive following ECMO support was 73.9% (SE: 6.1%) and 58.2% (SE: 9.5%), respectively., Conclusions: Perioperative ECMO support has an appropriate role as rescue therapy for this group. Over 50% survived to hospital discharge. These patients had satisfactory longer-term survival., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH), provided lesions are proximal enough in the pulmonary vasculature to be surgically accessible and the patient is well enough to benefit from the operation in the longer term. It is a major cardiothoracic operation, requiring specialized techniques and instruments developed over several decades to access and dissect out the intra-arterial fibrotic material. While in-hospital operative mortality is low (<5%), particularly in high-volume centers, careful perioperative management in the operating theater and intensive care is mandatory to balance ventricular performance, fluid balance, ventilation, and coagulation to avoid or treat complications. Reperfusion pulmonary edema, airway hemorrhage, and right ventricular failure are the most problematic complications, often requiring the use of extracorporeal membrane oxygenation to bridge to recovery. Successful PEA has been shown to improve both morbidity and mortality in large registries, with survival >70% at 10 years. For patients not suitable for PEA or with residual PH after PEA, balloon pulmonary angioplasty and/or PH medical therapy may prove beneficial. Here, we describe the indications for PEA, specific surgical and perioperative strategies, postoperative monitoring and management, and approaches for managing residual PH in the long term., Competing Interests: D.P.J. reports Honoraria and consulting fees from Actelion J&J; membership of CTEPH executive board. J.P.-Z. receipts grants from MSD and Actelion J&J; membership of advisory board for Actelion J&J and Ferrer., (Thieme. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of multimodal therapeutic options in CTEPH to improve long-term outcomes for patients., Competing Interests: Declaration of interests MD reports research grants from Janssen; and speaker and consultancy fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD, outside of the submitted work and all paid to her institution. She is holder of a Janssen Chair for Pulmonary Hypertension at the KU Leuven. MdP reports speaker fees and consultancy honoraria from AstraZeneca and BMS; speaker fees from Bayer; and consultancy honoraria from Merck and Roche. XJ reports research grants from Janssen, MSD, and Bayer HealthCare; and speaker fees from Janssen and MSD, outside of the submitted work. DPJ reports speaker and consultancy fees from Janssen, outside of the submitted work. IML has relationships with drug companies, including AOP-Health, Actelion-Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis and Sanofi; in addition to being an investigator in trials involving these companies, relationships include consultancy service, research grants, and membership of scientific advisory boards. HM reports research grants from Nippon Shinyaku; speaker and consultancy fees from Bayer, Janssen, and MSD; and speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Niprol, outside of the submitted work. LJM participated in an advisory board on CTEPH imaging for Janssen. GS has received advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. CBW reports speaker fees from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer; and consultancy honoraria from Actelion/Janssen and MSD. NHK has received speaker fees from Bayer and Janssen; consultancy fees from Bayer, Janssen, Merck, Polarean, Pulnovo, and United Therapeutics; and research support from Altavant and Gossamer Bio, outside of the submitted work. RQ declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are derived from Schwann cells or their precursors. In patients with the tumor susceptibility syndrome neurofibromatosis type 1 (NF1), MPNSTs are the most common malignancy and the leading cause of death. These rare and aggressive soft-tissue sarcomas offer a stark future, with 5-year disease-free survival rates of 34-60%. Treatment options for individuals with MPNSTs are disappointingly limited, with disfiguring surgery being the foremost treatment option. Many once-promising therapies such as tipifarnib, an inhibitor of Ras signaling, have failed clinically. Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients. In recent years, functional genomic screening methods combined with genetic profiling of cancer cell lines have proven useful for identifying essential cytoplasmic signaling pathways and the development of target-specific therapies. In the case of rare tumor types, a variation of this approach known as cross-species comparative oncogenomics is increasingly being used to identify novel therapeutic targets. In cross-species comparative oncogenomics, genetic profiling and functional genomics are performed in genetically engineered mouse (GEM) models and the results are then validated in the rare human specimens and cell lines that are available. This paper describes how to identify candidate driver gene mutations in human and mouse MPNST cells using whole exome sequencing (WES). We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.

Pulmonary endarterectomy (PEA) may not achieve full clearance of vascular obstructions in patients with more distal chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be indicated to treat these residual vascular lesions. We compared whether patients post-PEA (PP) treated by BPA derived similar benefit to those who had inoperable CTEPH (IC), and assessed predictors of BPA response after surgery. We treated 109 patients with BPA-89 with IC and 20 PP. Serial right heart catheterization performed at baseline (immediately before BPA) and 3 months after completing BPA, compared pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) as well as change in WHO functional class and 6-minute walk distance. We also assessed the impact of total thrombus tail length (TTTL) from photographed PEA surgical specimens and PP computed tomography pulmonary angiography (CTPA)-quantified residual disease burden on BPA response. PP and IC groups did not differ significantly in terms of demographics, baseline hemodynamics or procedural characteristics. However, IC derived greater hemodynamic benefit from BPA: ΔPVR (-27.9 ± 20.2% vs. -13.9 ± 23.9%, p  < 0.05) and ΔmPAP (-17.1 ± 14.4% vs. -8.5 ± 18.0%, p  < 0.05). There was a negative correlation between pre-BPA PVR and TTTL ( r  = -0.47, p  < 0.05) which persisted post-BPA. PVR, mPAP, WHO FC and 6MWD were not improved significantly post-BPA in PP patients. BPA response was not related to TTTL terciles or CTPA-quantified residual disease burden. Patients PP experienced inferior response to BPA, despite similar baseline and procedural characteristics to IC. BPA does not abolish the relationship between TTTL and postsurgical PVR in PP patients, suggesting that BPA is less effective in treating residual PH after surgery in an experienced surgical center., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Heart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls., Methods and Results: Consecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41-59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6-14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4-26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain -12.6 ± 3.1% vs -17.2 ± 1.8%, P < .0001; global circumferential strain -16.9 ± 3.1% vs -19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain -15.7 ± 4.5% vs -21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain -13.1 ± 3.0% vs -12.1 ± 3.1%, P = .14; global circumferential strain -17.3 ± 2.9% vs -16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain -15.9 ± 4.9% vs -15.5 ± 4.1%, P = .71) between DCD and DBD HTx., Conclusions: HTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable., Competing Interests: Disclosures Royal Papworth Hospital has received grants from the European Society of Organ Transplantation, The Freemasons Grand Charity, the Masonic Samaritan Fund, the Evelyn Trust, RPH Charity, NHSBT, and the Gledhill Fellowship to fund the early DCD research programme. J.R.W.M. is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension., Methods: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival., Results: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality., Conclusions: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity)., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by chronic organised fibrotic clots, despite adequate anticoagulation. The pulmonary hypertension is also caused by concomitant microvasculopathy which may progress without timely treatment. Timely and accurate diagnosis requires the combination of imaging and haemodynamic assessment. Optimal therapy should be individualised to each case and determined by an experienced multidisciplinary CTEPH team with the ability to offer all current treatment modalities. This report summarises current knowledge and presents key messages from the International CTEPH Conference, Bad Nauheim, Germany, 2021. Sessions were dedicated to 1) disease definition; 2) pathophysiology, including the impact of the hypertrophied bronchial circulation, right ventricle (dys)function, genetics and inflammation; 3) diagnosis, early after acute pulmonary embolism, using computed tomography and perfusion techniques, and supporting the selection of appropriate therapies; 4) surgical treatment, pulmonary endarterectomy for proximal and distal disease, and peri-operative management; 5) percutaneous approach or balloon pulmonary angioplasty, techniques and complications; and 6) medical treatment, including anticoagulation and pulmonary hypertension drugs, and in combination with interventional treatments. Chronic thromboembolic pulmonary disease without pulmonary hypertension is also discussed in terms of its diagnostic and therapeutic aspects., Competing Interests: Conflict of interest: E. Fadel, G. Martinez, G. Simonneau, K. Salaunkey, N. Screaton and P. Brénot have no conflicts of interest to declare. A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012–08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610); his institute received speakers fees from Johnson & Johnson, MSD, Actelion, Bayer and Ferrer in the past 3 years; and he served as a member of the scientific advisory boards of Morphogen-X, Ferrer, Gossamer Bio Services Inc. and Johnson & Johnson. C.B. Wiedenroth has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD and Pfizer. D.P. Jenkins is on the adjudication committees for the SELECT and Maciteph studies (Actelion), and has received fees for lectures on CTEPH from Actelion. E. Mayer has received speaker or consulting fees from Actelion/Janssen, Bayer and MSD. F.A. Klok has received research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Leo Pharma, Actelion, the Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, the Dutch Heart Foundation and the Horizon Europe Program, unrelated to the current work and paid to his institution. H.A. Ghofrani has received grants/research support from Actelion, Janssen, Bayer, Gossamer, Acceleron; honoraria or consultation fees from Actelion, Janssen, Bayer, Gossamer, Acceleron, Pfizer, Novartis and MSD; and participated in a company sponsored speaker's bureau for Actelion, Janssen, Bayer, Gossamer, Pfizer, Novartis and MSD. H. Matsubara has received honoraria for lectures from Janssen Pharmaceutical KK, Bayer Yakuhin Ltd, Nippon Shinyaku Co Ltd, Mochida Pharmaceutical Co. Ltd and Kaneka Medix Corporation. I.M. Lang has a financial interest with Actelion/Janssen, AOP Orphan, Medtronic, Daiichi Sankyo, Neutrolis, United Therapeutics and Ferrer that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. J. Pepke-Zaba has received speaker or consulting fees from Actelion/Janssen, Bayer, MSD and Ferrer, and a research grant from MSD, all outside submitted work. M.C. McInnis reports honoraria from Bayer and Boehringer Ingelheim, unrelated to the current work. M. Delcroix reports research grants from Actelion/Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Daiichi Sankyo, Bayer, Ferrer, Gossamer and MSD, outside the submitted work, and all paid to her institution. She is holder of the Janssen Chair for Pulmonary Hypertension at KU Leuven. M.M. Hoeper reports fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. M.M. Madani is a consultant for Actelion. M. Toshner reports grants and personal fees from Bayer, personal fees from MSD, grants and personal fees from Actelion, and personal fees from GSK within the last 5 years. N.H. Kim has served as consultant for Bayer, Janssen, Merck and United Therapeutics. S. Guth has received speaker fees and/or consultant honoraria from Actelion, Bayer, GSK, MSD and Pfizer. X. Jaïs reports grants from the French Ministry of Health and Bayer Healthcare, during the conduct of the study; grants from Acceleron, Janssen and MSD; personal fees from Janssen and MSD; and non-financial support from Janssen., (Copyright ©The authors 2023.)

Background: Ex-situ heart perfusion (ESHP) is commonly used for the reanimation and preservation of hearts following donation after circulatory determined death (DCD). The only commercially available existing ESHP device promotes perfusate lactate levels for assessment of heart viability. The reliability of this marker is yet to be confirmed for DCD heart transplantation., Methods: This is a single center, retrospective study examining DCD heart transplants from March 1, 2015 to June 30, 2020. Recipients were divided into 2 groups dependent upon their requirement for or absence of mechanical circulatory support post-transplant. Lactate profiles obtained during ESHP were analyzed. Hearts were procured using the direct procurement and perfusion (DPP) method., Results: Fifty-one DCD heart transplant recipients were studied, of which 20 (39%) were dependent on mechanical circulatory support (MCS) following transplantation, (2% Ventricular Assist Device (VAD), 16% Extra Corporeal Membrane Oxygenation (ECMO) and 21% Intra-aortic balloon pumps (IABP). There was no difference in arterial lactate profiles on ESHP at any time point for those dependent upon MCS support (MCS) and those that were not (no MCS) post-transplant. After 3 hours of ESHP, the arterial lactate was >5mmol/L in 80% upon MCS vs 62% no MCS, p = .30. There was also no difference in ESHP rising arterial lactate concentrations, (15% MCS vs 13% non MCS, p = 1.00)., Conclusion: For DCD hearts transplants retrieved using the DPP technique, lactate profiles do not seem to be a reliable predictor of mechanical circulatory support requirement post-transplant., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Predicted heart mass (PHM) equations may be used in donor-recipient size matching in heart transplantation. We compared PHM and actual heart mass in 25 consecutive DBD heart transplants. There was a moderate positive correlation between actual heart mass and PHM. There was a similar moderate correlation between actual heart mass and donor weight or donor body surface area but not donor height. PHM was lower than actual heart mass for all donor hearts. Bland-Altman analysis showed a systematic bias between PHM and actual heart mass, with a mean difference of 190.9 ± 66.4 g. The utility of PHM equations is likely to be part of a multi-parametric assessment of the relative differences between donor and recipient, so the absolute difference is likely to be unimportant., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The objective was to review national trends in activity and hospital outcomes in older patients having cardiac surgery over a 15-year time period., Methods: Data were collected prospectively and uploaded to the National Institute for Cardiovascular Outcomes Research electronically. Data were validated, cleaned and processed using reproducible algorithms. Mortality was death in hospital after index operation., Results: A total of 227 442 cardiac procedures were recorded in patients aged ≥70 years of which 46 354 were in those aged ≥80 years. Overall patients aged ≥70 years represented 43% of all adult cardiac surgery in the most recent study year. The annual proportion of surgery in patients ≥80 years increased from 4.1% to 10.8% between the first and last study years. There has been a significant linear increase in octogenarian valve [β 67.44, 95% confidence interval (CI) 55.04 to 79.83, P < 0.001] and coronary artery bypass graft surgery (β 32.53, 95% CI 6.16 to 58.90, P = 0.020) patients. In-hospital mortality reduced significantly for patients aged 70-79 years (β -0.17, 95% CI -0.20 to -0.13, P < 0.001) and all patients aged ≥80 (β -0.37, 95% CI -0.45 to -0.30, P < 0.001). The median length of hospital stay was 7 days for 70-79 and 9 days for ≥80 group, compared with 7 days for the whole cohort <70 years., Conclusions: This study represents the largest complete validated national dataset of cardiac surgery in the entire population of older patients. Octogenarians represent 11% of adult patients having cardiac surgery by the end of the study period, a three-fold increase from the start. In-hospital mortality in patients aged ≥80 years halved during study period to only 4% despite high logistic EuroSCORE of 15%. Cardiac surgery in octogenarians places a higher demand on resources, however, with an increased postoperative length of stay., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Pulmonary thromboendarterectomy (PTE) was first introduced to the UK 25 years ago, and the UK national service is provided by a single hospital. The aim of this work is to summarize our experience and review activity and outcomes by era at a high-volume PTE center. During this period the understanding of chronic thromboembolic pulmonary hypertension (CTEPH) increased and drug treatments and balloon angioplasty were developed. We also review our contribution to the better understanding of this surgery and CTEPH., Methods: We retrospectively reviewed all patients undergoing PTE for CTEPH at our center between Jan 1997 and Sept 2019, dividing them into four equal cohorts. Pre-operative characteristics and post-operative outcomes are described by era. A MEDLINE search was performed and original scientific clinical publications from this unit were reviewed. Their contemporary relevance and influence to the evolution of the clinical service are discussed., Results: Over this 23-year period from the commencement of our program, 2,116 consecutive PTE were performed. The mean patient age was 57.8 years (range, 11-89 years). The first 25% of our PTE were performed over 12 years whilst the most recent 25% were performed in less than three years. Over time, the average pre-operative mean pulmonary artery pressure has not changed significantly. The 30-day mortality by era quartile has progressively fallen from 12.3% to 1.9% most recently (P<0.001). Overall, one year survival exceeded 90%. 17 publications influenced our practice development during this period., Conclusions: There was a consistent increase in activity and significant improvement in outcomes between the first and last quartiles of activity studied., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest., (2022 Annals of Cardiothoracic Surgery. All rights reserved.)

Objectives: The aim of this study was to review the UK national trends in activity and outcome in coronary artery bypass graft (CABG) over a 15-year period (2002-2016)., Methods: Validated data collected (2002-2016) and uploaded to National Institute for Cardiovascular Outcomes Research were used to generate summary data from the National Adult Cardiac Surgery Audit Database for the analysis. Logistic European System of Cardiac Operative Risk Evaluation was used for risk stratification with recalibration applied for governance. Data were analysed by financial year and presented as numerical, categorical, %, mean and standard deviation where appropriate. Mortality was recorded as death in hospital at any time after index CABG operation., Results: A total of 347 626 CABG procedures (282 883 isolated CABG, 61 109 CABG and valve and 4132 redo CABG) were recorded. Over this period annual activity reduced from 66.6% of workload to 41.7%. The mean age for isolated CABG was 65.7 years. The mean log European System of Cardiac Operative Risk Evaluation was 3.1, 5.9 and 23.2 for elective, urgent and emergency isolated CABG, respectively. There was a decline in the observed mortality for all procedures. Overall mortality for isolated CABG surgery is now 1.0% and only 0.6% for elective operations., Conclusions: Quality of care and risk-adjusted mortality rates have consistently improved over the last 15 years despite the increasing risk profile of patients. There have been a consistent decline in overall case volumes and a three-fold increase in elderly cases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is an under-diagnosed complication of acute pulmonary embolism (PE), whereby there is incomplete resolution of pulmonary emboli, which then become organized into obstructive fibrotic material with an associated small vessel vasculopathy. CTEPH is diagnosed by abnormal lung perfusion despite 3-months of oral anticoagulation with persistent pulmonary artery thromboembolic/ fibrotic material confirmed on cross sectional imaging and pulmonary hypertension on right heart catheterization. Without treatment the prognosis is bleak, but there are now three treatment modalities that are effective in treating patients with CTEPH: pulmonary endarterectomy (PEA) surgery, balloon pulmonary angioplasty (BPA) and medical therapy., Areas Covered: We provide a comprehensive review of the literature with particular emphasis on the epidemiology, pathophysiology, diagnosis, and the established and emerging treatments of CTEPH., Expert Opinion: It is important to recognize that CTEPH is complication of an acute PE as there are effective and sometimes curative treatments available. In European and North American practice, PEA surgery remains the cornerstone of therapy in patients with CTEPH and accessible disease without significant comorbidity. For those patients with a disease burden that is inaccessible or fails to justify the risk of major surgery, initiating medical therapy and considering BPA is appropriate. Those with persistent pulmonary hypertension after PEA should also receive medical therapy and be considered for BPA or re-do endarterectomy. The available therapies are not necessarily mutually exclusive, and the treatment decision is often subjective and individualized, based on the local available expertise. Further research is needed to understand the optimal treatment strategy for patients and in particular to identify 'responders' and assess the synergies between these three treatment strategies.

Objectives: Since the turn of the century, cardiac surgery has evolved quite notably. This study sought to investigate the trends in aortic valve surgery activity and subsequent outcomes in the UK by using a mandatory national cardiac surgical clinical database within the context of a comprehensive public healthcare system (National Health Service)., Methods: The UK National Adult Cardiac Surgery Audit database provided data for aortic valve surgery procedures performed between 2002 and 2016, and the data were validated and cleaned using reproducible algorithms. The findings and trends in in activity and outcomes were then analysed by financial year., Results: During the study period, a total of 148 862 procedures were performed, with the number of cases per year peaking in 2014/2015 at 12 483. The mean in-hospital mortality rate for all aortic valve surgery has fallen from 5.6% to 3.4%, despite an increase in patient age and mean logistic EuroSCORE. While the number of isolated aortic valve replacements has remained stable at around 5000 per year, aortic valve replacement and coronary artery bypass graft have increased to over 3200 with transcatheter aortic valve implantation activity continuing to increase., Conclusions: This study demonstrates that despite an increase in patient risk profile, there has been a consistent reduction in in-hospital mortality within all aortic valve surgery procedures performed in the UK over a 15-year period. Increasing catheter-based interventions have not yet resulted in a significant decrease in surgical aortic valve replacements in the UK., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)