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Background: Pulmonary hypertension associated with left heart disease (PH-LHD) prevalence ranges significantly across studies with limited real-world evidence., Objectives: To investigate the prevalence and prognostic influence of PH-LHD in a nationwide sample., Methods: Using the 2018 US Nationwide Inpatient Sample we calculated the prevalence of PH across heart failure (HF), cardiomyopathies, aortic, and mitral valve disease. We used logistic regression to assess the impact of PH on LHD and to find significant contributors to in-hospital mortality in the PH-LHD population., Results: Among 6,270,625 hospitalizations with LHD, 801,535 (12.8 %) had a secondary PH diagnosis. PH-LHD prevalence was 17.2 % in HF with preserved ejection fraction (HFpEF), 11.8 % in HF with reduced ejection fraction (HFrEF), 16.8 % in dilated cardiomyopathy, 12.6 % in hypertrophic cardiomyopathy, 18.7 % in mitral regurgitation, 28.5 % in mitral stenosis, 13.5 % in aortic stenosis, and 13.9 % in aortic regurgitation. PH was associated with increased in-hospital mortality in HFpEF (OR 1.23; 95%CI 1.17-1.28), hypertrophic cardiomyopathy (1.42; 1.06-1.89), mitral regurgitation (1.17; 1.07-1.28), and aortic stenosis (1.14; 1.04-1.26), but not in HFrEF (1.04; 0.99-1.10), or dilated cardiomyopathy (1.13; 0.99-1.29). Among PH-LHD, in-hospital mortality was associated with age, atrial fibrillation/flutter, cancer, and acute cardiac (acute right HF, myocardial infarction, ventricular arrhythmia), or extra-cardiac (stroke, sepsis, pneumonia, acute renal failure, venous thromboembolism) diagnoses., Conclusion: In a nationwide inpatient analysis the prevalence of PH-LHD was lower than previously reported indicating reduced recognition of this disease in real world clinical practice. The diagnosis of PH-LHD was associated with worse fatality rates across all forms of LHD, except for HFrEF., Competing Interests: Declaration of competing interest LH received lecture/consultant fees from MSD and Actelion, outside the submitted work. SVB has served in unpaid trial activities for Abbott, Edwards Lifesciences, and University of Göttingen (IIT); and has served on an advisory or Speakers Bureau for Abbott Cardiovascular, Bioventrix, Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, and Neochord. PL has received institutional fees and research grants from Abbott Vascular, Edwards Lifesciences, and ReCor, honoraria from Edwards Lifesciences, Abbott Medical, Innoventric, ReCor, Boehringer Ingelheim, Daiichi Sankyo and has stock options with Innoventric. SR reports grants or contracts from Actelion, AstraZeneca, Bayer, Janssen, and Novartis; consulting fees from Abbott, Acceleron, Actelion, Bayer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; payment or honoraria from Actelion, Bayer, BMS, Ferrer, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor. SVK reports institutional grants and personal lecture/advisory fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; institutional grants from Inari Medical; and personal lecture/advisory fees from MSD and Bristol Myers Squibb/Pfizer. GG has received speaker or consulting fees from ELPEN Pharmaceuticals, Galenica, GlaxoSmithKline, and Janssen Pharmaceutical Companies of Johnson & Johnson and MSD, outside the submitted work. The rest of the authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The number of adults with congenital heart defects (ACHDs) is steadily increasing and is about 360,000 in Germany. Congenital heart defect (CHD) is often associated with pulmonary hypertension (PH), which sometimes develops early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists, redevelops in older age, and is associated with significant morbidity and mortality. The revised European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is treated only relatively superficially in this context. After the first part commenting on a broad range of topics like definition, epidemiology, classification, diagnostics, genetics, risk stratification and follow-up, and gender aspects, the second part focuses on supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management [shunt lesion, left ventricular (LV) disease, univentricular hearts], interventions, intensive care, ACHD follow-up, and future perspective. In the present article, therefore, this topic is commented on from the perspective of congenital cardiology. By examining these aspects in detail, this article aims to fill the gaps in the existing guidelines and provide a more thorough understanding from the perspective of congenital cardiology., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-167/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series. H.K. received sponsorship and honoraria from Janssen/Jonson & Johnson, and Bristol Myers Squibb, and participated in the steering board of COMPERA International. G.P.D. has received honoraria and consulting fees from Janssen Pharmaceuticals. I.D. serves as an unpaid board member for Treasurer of the German Society for Pediatric Cardiology and Congenital Heart Disease. S.A. serves as board member for European Society of Cardiology, and Deutsche Herzstiftung. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. C.A.E. is co-inventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). E.G. has received research grants outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; research grants to the institution outside the submitted work from Acceleron, Actelion, Bayer, MSD, Janssen, Liquidia, United Therapeutics, OMT; consultancy fees outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; Speaker honoraria outside the submitted work from Actelion, Bayer/MSD, GSK, AOP, Janssen, phev, OMT, GEBRO, Ferrer, GWT; participation in AdBoards from MSD and Ferrer; unpaid borard member for A DUE Steering committee and patient organization phev. M.H. received consulting fees, honoraria, and travel support from Janssen. S.M. received Research Grant from German Center for Lung Research (DZL). A.U. received consulting fees from Medtronic. U.H. serves as an unpaid board member for Deutsche Gesellschaft für Kinderkardiologie und Angeborene Herzfehler, and Deutsche Gesellschaft für Kinder- und Jugendmedizin. C.A. received lecture and consulting fees from Janssen. The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The number of adults with congenital heart defects (ACHDs) is steadily increasing and is about 360,000 in Germany. Congenital heart defect (CHD) is often associated with pulmonary hypertension (PH), which sometimes develops early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists, redevelops in older age, and is associated with significant morbidity and lethality. The revised European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is treated only relatively superficially in this context. In the present article, part I, therefore, this topic is commented on in detail from the perspective of congenital cardiology with a special focus on definition, epidemiology, classification, diagnostics, genetics, risk stratification and follow-up and gender aspects of PH in ACHDs. This paper consists of two parts. Part II will provide comments on the topics of supportive therapy, special situations like pregnancy, contraception, and non-cardiac surgery, targeted pharmacotherapy, organ transplantation, special management like shunt lesion, left ventricular disease, and univentricular hearts, interventions, intensive care, ACHDs follow-up and future perspective on PH in ACHDs. By examining these aspects in detail, this article aims to fill the gaps in the existing guidelines and provide a more thorough understanding from the perspective of congenital cardiology., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-148/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series. H.K. received sponsorship and honoraria from Janssen/Jonson&Johnson, and Bristol Myers Squibb, and participated in the steering board of COMPERA International. G.P.D. has received honoraria and consulting fees from Janssen Pharmaceuticals. I.D. serves as an unpaid board member for Treasurer of the German Society for Pediatric Cardiology and Congenital Heart Disease. S.A. serves as board member for European Society of Cardiology, and Deutsche Herzstiftung. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. C.A.E. is co-inventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). E.G. has received research grants outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; research grants to the institution outside the submitted work from Acceleron, Actelion, Bayer, MSD, Janssen, Liquidia, United Therapeutics, OMT; consultancy fees outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; Speaker honoraria outside the submitted work from Actelion, Bayer/MSD, GSK, AOP, Janssen, phev, OMT, GEBRO, Ferrer, GWT; participation in AdBoards from MSD and Ferrer; unpaid board member for A DUE Steering committee and patient organisation phev. M.H. received consulting fees, honoraria, and travel support from Janssen. S.M. received Research Grant from German Center for Lung Research (DZL). A.U. received consulting fees from Medtronic. U.H. serves as an unpaid board member for Deutsche Gesellschaft für Kinderkardiologie und Angeborene Herzfehler, and Deutsche Gesellschaft für Kinder- und Jugendmedizin. C.A. received lecture and consulting fees from Janssen. The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The number of adults with congenital heart defects (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary hypertension (PH), which may develop early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart disease" is addressed only relatively superficial in these guidelines. Therefore, in the present article, this topic is commented in detail from the perspective of congenital cardiology., Competing Interests: Harald Kaemmerer: Unabhängig von diesem Manuskript Sponsorship and honoraria Janssen/Johnson & Johnson; Bristol Myers Squibb. Steering Board COMPERA International.Gerhard Paul Diller: Advisory consultancy work for Janssen/Johnson & Johnson.Ingo Dähnert: Proctortätigkeit für Occlutech und Medtronic, Studien für Janssen und Novartis, Advisory Board für Actelion/Janssen.Christina A. Eichstaedt: C. A. E. ist Miterfinderin des europäischen Patents (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. CAE hat von msd Vortragshonorare erhalten, unabhängig von dieser Arbeit.Andreas Eicken: Keine Interessenkonflikte.Annika Freiberger: Keine Interessenkonflikte.Sebastian Freilinger: Keine Interessenkonflikte.Ralf Geiger: Keine Interessenkonflikte.Matthias Gorenflo: Advisory Board für Janssen.Ekkehard Grünig: E. G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.Alfred Hager: Unabhängig von diesem Manuskript erhielt A. H. Reisekostenerstattungen von Actelion, Pfizer, GlaxoSmithKline, Lilly und OMT; Rednergelder von Encysive, Pfizer, Actelion, Medtronic, Schiller, GlaxoSmithKline, OMT, AOP Orphan und Janssen; Autorenvergütungen von Actelion; Beraterhonorare von Actelion, Bayer, Ethypharm und GlaxoSmithKline; er hält Aktien von Merck Inc., Merck KGaA, Johnson & Johnson, Pfizer und Abbott.Michael Huntgeburth: Honorare Advisory-Board Janssen-Cilag, Johnson & Johnson.Ann-Sophie Kaemmerer-Suleiman: Keine Interessenkonflikte.Rainer Kozlik-Feldmann: Teaching-Kurse für Occlutech, Proktortätigkeit für Abbott (Amplatzer).Astrid E. Lammers: CEC chair and advisory consultancy work for Janssen/Johnson & Johnson.Nicole Nagdyman: Keine Interessenkonflikte.Sebastian Michel: Keine Interessenkonflikte.Kai Helge Schmidt: Vortragshonorare von Janssen, MSD und Abbott.Anselm Uebing: Keine Interessenkonflikte.Fabian von Scheidt: Keine Interessenkonflikte.Christian Apitz: Honorare für Vortragstätigkeit und Advisory Board für Janssen., (Thieme. All rights reserved.)

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b ( Pde1b ), a Ca 2+ /calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Background: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media., Purpose: To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH., Study Type: This is a prospective cohort sub-study., Population: Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers., Field Strength/sequence: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST)., Assessment: Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDP PREFUL ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDP DCE ). Furthermore, QDP PREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups., Statistical Tests: t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%., Results: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDP PREFUL was significantly correlated with QDP DCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDP PREFUL  = 33.9 ± 17.2%)., Data Conclusion: PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 1., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The number of adults with congenital heart disease (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary arterial hypertension (PAH), which may develop early in untreated CHD. Despite timely treatment of CHD, PAH often persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is addressed only relatively superficially in these guidelines. Therefore, this article addresses the perspective of congenital cardiology in greater depth., Competing Interests: Harald Kaemmerer: Unabhängig von diesem Manuskript Sponsorship and honoraria Janssen/Johnson & Johnson; Bristol Myers Squibb. Steering Board COMPERA International.Gerhard Paul Diller: Advisory consultancy work for Janssen/Johnson & Johnson.Ingo Dähnert: Proctortätigkeit für Occlutech und Medtronic, Studien für Janssen und Novartis, Advisory Board für Actelion/Janssen.Christina A. Eichstaedt: C.A.E. ist Miterfinderin des europäischen Patents (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. CAE hat von msd Vortragshonorare erhalten, unabhängig von dieser Arbeit.Andreas Eicken: keine Interessenkonflikte.Annika Freiberger: keine Interessenkonflikte.Sebastian Freilinger: keine Interessenkonflikte.Ralf Geiger: keine Interessenkonflikte.Matthias Gorenflo: Advisory Board für Janssen.Ekkehard Grünig: E.G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.Alfred Hager: Unabhängig von diesem Manuskript erhielt A.H. Reisekostenerstattungen von Actelion, Pfizer, GlaxoSmithKline, Lilly und OMT; Rednergelder von Encysive, Pfizer, Actelion, Medtronic, Schiller, GlaxoSmithKline, OMT, AOP Orphan und Janssen; Autorenvergütungen von Actelion; Beraterhonorare von Actelion, Bayer, Ethypharm und GlaxoSmithKline; er hält Aktien von Gilead, Merck Inc., Merck KGaA, Johnson &Johnson, Pfizer, Abbvie und Takeda.Ulrike Herberg: keine Interessenkonflikte.Michael Huntgeburth: Honorare Advisory-Board Janssen-Cilag, Johnson & Johnson.Ann-Sophie Kaemmerer: keine Interessenkonflikte.Rainer Kozlik-Feldmann: Teaching Kurse für Occlutech, Proktortätigkeit für Abbott (Amplatzer).Astrid E. Lammers: CEC chair and advisory consultancy work for Janssen/Johnson & Johnson.Nicole Nagdyman: keine Interessenkonflikte.Sebastian Michel: keine Interessenkonflikte.Kai Helge Schmidt: Vortragshonorare von Janssen, MSD und Abbott.Anselm Uebing: keine Interessenkonflikte.Fabian von Scheidt: keine Interessenkonflikte.Christian Apitz: Honorare Janssen., (Thieme. All rights reserved.)

Pulmonary hypertension associated with left heart disease (PH-LHD) corresponds to group two of pulmonary hypertension according to clinical classification. Haemodynamically, this group includes isolated post-capillary pulmonary hypertension (IpcPH) and combined post- and pre-capillary pulmonary hypertension (CpcPH). PH-LHD is defined by an mPAP > 20 mmHg and a PAWP > 15 mmHg, pulmonary vascular resistance (PVR) with a cut-off value of 2 Wood Units (WU) is used to differentiate between IpcPH and CpcPH. A PVR greater than 5 WU indicates a dominant precapillary component. PH-LHD is the most common form of pulmonary hypertension, the leading cause being left heart failure with preserved (HFpEF) or reduced ejection fraction (HFmrEF, HFrEF), valvular heart disease and, less commonly, congenital heart disease. The presence of pulmonary hypertension is associated with increased symptom burden and poorer outcome across the spectrum of left heart disease. Differentiating between group 1 pulmonary hypertension with cardiac comorbidities and PH-LHD, especially due to HFpEF, is a particular challenge. Therapeutically, no general recommendation for the use of PDE5 inhibitors in HFpEF-associated CpcPH can be made at this time. There is currently no reliable rationale for the use of PAH drugs in IpcPH, nor is therapy with endothelin receptor antagonists or prostacyclin analogues recommended for all forms of PH-LHD., Competing Interests: A.S.: Vortragshonorare im Zusammenhang hiermit: Actelion, Abbott, Edwards, MSD, Forschungsgrands: Abbott.S.S.: Vortragshonorare und Reiseunterstützung von MSD und Johnson & Johnson.A.Y.: Reports personal fees from MSD outside the submitted work.A.J.R.: Vortragshonorare von AstraZeneca und Bayer sowie Reisekostenunterstützung von Johnson & Johnson und Servier, alles ohne Zusammengang mit dem vorliegenden Manuskript.E.P.-J.: Reisekostenunterstützung OMT, Actelion, Boehringer-Ingelheim sowie Honorar von Actelion.K.H.S.: Vortragshonorare von Janssen, MSD und Abbott.Die weiteren Autoren haben keine Interessenkonflikte angegeben., (Thieme. All rights reserved.)

Oxidative stress can damage DNA and thereby contribute to genome instability. To avoid an imbalance or overaccumulation of reactive oxygen species (ROS), cells are equipped with antioxidant enzymes that scavenge excess ROS. Cells lacking the RecQ-family DNA helicase Sgs1, which contributes to homology-dependent DNA break repair and chromosome stability, are known to accumulate ROS, but the origin and consequences of this oxidative stress phenotype are not fully understood. Here, we show that the sgs1 mutant exhibits elevated mitochondrial superoxide, increased mitochondrial mass, and accumulation of recombinogenic DNA lesions that can be suppressed by antioxidants. Increased mitochondrial mass in the sgs1Δ mutant is accompanied by increased mitochondrial branching, which was also inducible in wildtype cells by replication stress. Superoxide dismutase Sod2 genetically interacts with Sgs1 in the suppression of nuclear chromosomal rearrangements under paraquat (PQ)-induced oxidative stress. PQ-induced chromosome rearrangements in the absence of Sod2 are promoted by Rad51 recombinase and the polymerase subunit Pol32. Finally, the dependence of chromosomal rearrangements on the Rev1/Pol ζ mutasome suggests that under oxidative stress successful DNA synthesis during DNA break repair depends on translesion DNA synthesis., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: Right ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe., Methods: Echocardiographic and laboratory examinations were performed at baseline (PE diagnosis), 6 days and 6 months. Echocardiographic parameters were classified into categories representing RV size, RV free wall/tricuspid annulus motion, RV pressure overload and right atrial (RA)/central venous pressure., Results: RV dysfunction based on any abnormal echocardiographic parameter was present in 84% of patients at baseline. RV dilatation was the most frequently abnormal finding (40.6%), followed by increased RA/central venous pressure (34.6%), RV pressure overload (32.1%), and reduced RV free wall/tricuspid annulus motion (20.9%). As early as day 6, RV size remained normal or improved in 260 patients (64.7%), RV free wall/tricuspid annulus motion in 301 (74.9%), RV pressure overload in 297 (73.9%), and RA/central venous pressure in 254 (63.2%). At day 180, the frequencies slightly increased. The median NT-proBNP level decreased from 1448 pg/ml at baseline to 256.5 on day 6 and 127 on day 180., Conclusion: In the majority of patients with acute intermediate-risk PE switched early to a direct oral anticoagulant, echocardiographic parameters of RV function normalised within 6 days and remained normal throughout the first 6 months. Almost one in four patients, however, continued to have evidence of RV dysfunction over the long term., (© 2022. The Author(s).)

Bloom syndrome helicase (BLM) is a RecQ-family helicase implicated in a variety of cellular processes, including DNA replication, DNA repair, and telomere maintenance. Mutations in human BLM cause Bloom syndrome (BS), an autosomal recessive disorder that leads to myriad negative health impacts including a predisposition to cancer. BS-causing mutations in BLM often negatively impact BLM ATPase and helicase activity. While BLM mutations that cause BS have been well characterized both in vitro and in vivo, there are other less studied BLM mutations that exist in the human population that do not lead to BS. Two of these non-BS mutations, encoding BLM P868L and BLM G1120R, when homozygous, increase sister chromatid exchanges in human cells. To characterize these naturally occurring BLM mutant proteins in vitro, we purified the BLM catalytic core (BLMcore, residues 636-1298) with either the P868L or G1120R substitution. We also purified a BLMcore K869A K870A mutant protein, which alters a lysine-rich loop proximal to the P868 residue. We found that BLMcore P868L and G1120R proteins were both able to hydrolyze ATP, bind diverse DNA substrates, and unwind G-quadruplex and duplex DNA structures. Molecular dynamics simulations suggest that the P868L substitution weakens the DNA interaction with the winged-helix domain of BLM and alters the orientation of one lobe of the ATPase domain. Because BLMcore P868L and G1120R retain helicase function in vitro, it is likely that the increased genome instability is caused by specific impacts of the mutant proteins in vivo. Interestingly, we found that BLMcore K869A K870A has diminished ATPase activity, weakened binding to duplex DNA structures, and less robust helicase activity compared to wild-type BLMcore. Thus, the lysine-rich loop may have an important role in ATPase activity and specific binding and DNA unwinding functions in BLM., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Cueny et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The genome must be monitored to ensure its duplication is completed accurately to prevent genome instability. In Saccharomyces cerevisiae, the 5' to 3' DNA helicase Rrm3, a member of the conserved PIF1 family, facilitates replication fork progression through an unknown mechanism. Disruption of Rrm3 helicase activity leads to increased replication fork pausing throughout the yeast genome. Here, we show that Rrm3 contributes to replication stress tolerance in the absence of the fork reversal activity of Rad5, defined by its HIRAN domain and DNA helicase activity, but not in the absence of Rad5's ubiquitin ligase activity. The Rrm3 and Rad5 helicase activities also interact in the prevention of recombinogenic DNA lesions, and DNA lesions that accumulate in their absence need to be salvaged by a Rad59-dependent recombination pathway. Disruption of the structure-specific endonuclease Mus81 leads to accumulation of recombinogenic DNA lesions and chromosomal rearrangements in the absence of Rrm3, but not Rad5. Thus, at least two mechanisms exist to overcome fork stalling at replication barriers, defined by Rad5-mediated fork reversal and Mus81-mediated cleavage, and contribute to the maintenance of chromosome stability in the absence of Rrm3., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice., Methods: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice., Results: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors., Conclusions: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities., Methods: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities., Results: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities., Conclusions: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients., Methods: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension)., Findings: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries)., Interpretation: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration., Funding: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK., Competing Interests: Declaration of interests MMH received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, and Pfizer. KD has received research funding from Janssen Pharmaceuticals, National Institute of Health Research (NIHR), UK and The Wellcome Trust, UK. RAL has received honoraria and research grants from Janssen Pharmaceuticals. KMO has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. DH has received travel compensation from Shire. DP has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. EG has received fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. GS has received honoraria for lectures or consultancy for Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. CDV has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. HG reports personal fees from Actelion, AstraZeneca, Bayer, Bristol Myers Squib, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. OD has or has had a consultancy relationship or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, Bristol Myers Squib, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GlaxoSmithKline, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm, and Sinoxa in the area of potential treatments of scleroderma and its complications including PAH; and reports a patent mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143). JSRG has received fees for lectures or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer, and United Therapeutics. MD reports research grants from Actelion/J&J; speaker and consultant fees from Bayer, MSD, Acceleron, AOP, Daiichi Sankyo, outside of the submitted work; and being a holder of the Janssen Chair for Pulmonary Hypertension at the Katholieke Universiteit Leuven, Leuven, Belgium. D-HP has received lecture fees from Janssen Pharmaceuticals. HAG has received honorariums for consultations or speaking at conferences from Bayer HealthCare, Actelion, Pfizer, Janssen, Merck/MSD, and Gossamer; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion, Merck/MSD, Janssen, and Gossamer; and has received public grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Institute, State Government of Hessen, and the German Ministry for Education and Research. RE has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, and United Therapeutics. HKa has received honoraria for lectures or consultancy from Actelion, Bristol Myers Squibb, and Janssen. H-JK has received fees from Actelion, Anamed, AstraZeneca, Berlin Chemie/Menarini, Boehringer Ingelheim, Chiesi, Daiichi-Sankyo, Dräger, Fisher & Paykel Healthcare, GlaxoSmithKline, Heinen + Löwenstein, Lilly, MSD, Novartis, Pfizer, Weinmann, Philips Healthcare, Pulmonx, ResMed, Roche, Sanofi-Genzyme, Sapio Life, Weinmann. DS received fees for lectures, consulting, or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. JB received grants from Actelion, Boehringer Ingelheim and Roche; and honoraria from Bayer, Biogen, Boehringer-Ingelheim, Galapagos, Novartis, Roche, and Sanofi/Genzyme. KM has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and Sanofi-Aventis. TJL has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD, Pfizer, and United Therapeutics. HW received fees for lectures or consultations from Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. H-JS has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, and MSD. MHe has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. DD declares honoraria for lectures or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. IT has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. AV-N reports receiving fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. SU reports personal fees from Actelion, Janssen, MSD, and Orpha-Swiss outside of the submitted work. HKl has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, and United Therapeutics. MC reports honoraria for lectures from Boehringer Ingelheim Pharma and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. SE has received honoraria for lectures or consultations from Actelion, MSD, Bayer, Acceleron, Gilead, AstraZeneca, Pulmox, Boston Scientific, and Boehringer Ingelheim. K-HS has received fees for lectures and educational events from Abbott, Janssen, and MSD. AJS has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Wellcome Trust, and NIHR; has undertaken consultancy work and received honoraria for lectures from Janssen Pharmaceuticals; and has undertaken consultancy work for General Electric. AART is supported by a British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281) and has received research grants to their institution from Janssen Pharmaceuticals and GlaxoSmithKline. CAE has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen and MSD. SR has received fees for lectures or consultations from Abbott, Acceleron, Actelion, Bayer, Bristol Myers Squib, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; and research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis. RC has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen, and MSD. DGK has received honoraria for lectures or consultations from Acceleron, Actelion, Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, and MSD; and research grants to institution from Actelion, GlaxoSmithKline and Janssen Pharmaceuticals. MHa has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen, and Novartis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria., Methods and Results: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI., Conclusion: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care., Competing Interests: Conflict of interest: A.C.M. was supported by a research grant from the German Academic Exchange Service (DAAD; 57440918). S.B. reports grants or contracts from Bayer, INARI, Boston Scientific, Medtronic, Bard, SANOFI, and Concept Medical; consulting fees from INARI; payment or honoraria from INARI, Boston Scientific, and Concept Medical; and support for attending meetings and/or travel from Bayer and Daiichi Sankyo. R.E. reports consulting fees from Actelion Germany, Boehringer Ingelheim, Janssen, AstraZeneca, OMT, and LungPacer; payment or honoraria from Janssen, Boehringer Ingelheim, AstraZeneca, OMT, Berlin Chemie, and Novartis; support for attending meetings and/or travel from Janssen, Boehringer Ingelheim, AstraZeneca, OMT, Berlin Chemie, and Novartis; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen, Boehringer Ingelheim, AstraZeneca, and Berlin Chemie. M.F. reports payment or honoraria and support for attending meetings and/or travel from Janssen. F.G. reports grants or contracts from Janssen, Bayer; consulting fees from Bayer & Janssen and AstraZeneca; payment or honoraria from Bayer, Janssen, AstraZeneca, and MSD; payment for expert testimony from Janssen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Janssen. H.-A.G. reports grants or contracts from Actelion/Janssen and Bayer; consulting fees from Actelion/Janssen, Bayer, MSD, Accelleron, MorphogenIX, and Gossamer Bio; payment or honoraria from Actelion/Janssen, Bayer, MSD, and Gossamer Bio; and support for attending meetings and/or travel from Actelion/Janssen, Bayer, and MSD. A.G. reports payment or honoraria from Bayer Vital, Roche, MSD, and Boehringer-Ingelheim; and support for attending meetings and/or travel from Bayer Vital. E.G. reports consulting fees from Actelion, Bayer/MSD, GSK, United Therapeutics, Novartis, REATA, OMT, and Pfizer; payment or honoraria from Actelion, Bayer/MSD, and GSK; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Janssen and Bayer; and leadership or fiduciary role for Actelion/Janssen. M.Ha. reports consulting fees from MSD; payment or honoraria from Actelion, AstraZeneca, Bayer, Berlin Chemie, Janssen-Cilag, and MSD; support for attending meetings and/or travel from Actelion; and participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Actelion, GSK, Janssen-Cilag, and MSD. M.He. reports consulting fees from Actelion, Bayer, Berlin Chemie, BMS, Boehringer Ingelheim, Janssen, MSD, and Pfizer; payment or honoraria from Actelion, AstraZeneca, Bayer, BMS, Berlin Chemie, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MSD, and Pfuter Santis; and support for attending meetings and/or travel from Boehringer Ingelheim and Janssen. L.H. reports payment or honoraria from Actelion and MSD. M.M.H. reports consulting fees from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, and Pfizer; and payment or honoraria from Actelion, Bayer, GSK, Janssen, MSD, and Pfizer. F.A.K. reports grants or contracts from Bayer, BMS, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion. M.L. reports grants or contracts from Thermo Fisher Scientific, payment or honoraria from Actelion/Johnson & Johnson, Bayer, Daiichi Sankyo, MSD, Pfizer, and Georg Thieme Verlag Stuttgart Germany; support for attending meetings and/or travel from Actelion/Johnson & Johnson and Bayer; participation on a Data Safety Monitoring Board or Advisory Board for Thermo Fisher Scientific. H.H.L. reports travel fees for the study by Bayer, Germany, consulting fees, payment or honoraria, and payment for expert testimony from MSD, Germany; and participation on a Data Safety Monitoring Board or Advisory Board for MSD, Germany. E.M. reports payment or honoraria from Actelion/Janssen, MSD, and Bayer; support for attending meetings and/or travel from Actelion/Janssen, MSD, and Bayer; and participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen. H.-J.S. reports payment or honoraria from Janssen/Actelion, Bayer, GSK, and MSD; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen. R.W. reports grants or contracts from Boehringer Ingelheim and Medtronic; and payment or honoraria from Abbott, AstraZeneca, Bayer, BMS, CVRx, Daichii Sankyo, Novartis, Pfizer, Pharmacosmos, Sanofi, Servier, and SOBI. H.W. reports payment or honoraria from Actelion/Janssen, Bayer, Biotest, Boehringer Ingelheim, MSD, Pfizer, and Roche; support for attending meetings and/or travel from Actelion and Boehringer Ingelheim; and participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Boehringer Ingelheim, and MSD. P.S.W. reports study grants from Bayer AG, grants or contracts from Boehringer Ingelheim, DiaSorin, Sanofi-Aventis, AstraZeneca, Bayer Health Care, Bayer Vital, Daiichy Sankyo Europe, and Novartis Pharma; payment or honoraria from Bayer Health Care, Pfizer Pharma, and Bristol Myers Squibb; and other non-financial support from Philips Medical Systems, DiaSorin, and IEM. S.V.K. reports grants or contracts from Bayer AG; consulting fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; and payment or honoraria from Bayer AG, INARI Medical, MSD, Pfizer, and Bristol-Myers Squibb. S.R. reports grants or contracts from Actelion, AstraZeneca, Bayer, Janssen, and Novartis; consulting fees from Abbott, Acceleron, Actelion, Bayer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; payment or honoraria from Actelion, Bayer, BMS, Ferrer, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor. The remaining authors (A.C.M., C.A., D.B., L.B., D.F., N.M., F.J.M., C.N., C.O., and K.-H.S.) declare no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated., Methods: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses., Results: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools., Conclusion: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Left-to-right (L-R) shunts are characterized by a pathological connection between high- and low-pressure systems, leading to a mixing of oxygen-rich blood with low oxygenated blood. They are typically diagnosed by phase-contrast cardiac magnetic resonance imaging (MRI) which requires extensive planning. T2 is sensitive to blood oxygenation and may be able to detect oxygenation differences between the left (LV) and right ventricles (RV) caused by L-R shunts., Purpose: To test the feasibility of routine T2 mapping to detect L-R shunts., Study Type: Retrospective., Population: Patients with known L-R shunts (N = 27), patients with RV disease without L-R shunts (N = 21), and healthy volunteers (HV; N = 52)., Field Strength/sequence: 1.5 and 3 T/balanced steady-state free-precession (bSSFP) sequence (cine imaging), T2-prepared bSSFP sequence (T2 mapping), and velocity sensitized gradient echo sequence (phase-contrast MRI)., Assessment: Aortic (Qs) and pulmonary (Qp) flow was measured by phase-contrast imaging, and the Qp/Qs ratio was calculated as a measure of shunt severity. T2 maps were used to measure T2 in the RV and LV and the RV/LV T2 ratio was calculated. Cine imaging was used to calculate RV end-diastolic volume index (RV-EDVi)., Statistical Tests: Wilcoxon test, paired t-tests, Spearmen correlation coefficient, receiver operating curve (ROC) analysis. Significance level P < 0.05., Results: The Qp/Qs and T2 ratios in L-R shunt patients (1.84 ± 0.84 and 0.89 ± 0.07) were significantly higher compared to those in patients with RV disease (1.01 ± 0.03 and 0.72 ± 0.10) and in HV (1.04 ± 0.04 and 0.71 ± 0.09). A T2 ratio of >0.78 showed a sensitivity, specificity, and negative predictive value of 100%, 73.9%, and 100%, respectively, for the detection of L-R shunts. The T2 ratio was strongly correlated with the severity of the shunt (r = 0.83)., Data Conclusion: RV/LV T2 ratio is an imaging biomarker that may be able to detect or rule-out L-R shunts. Such a diagnostic tool may prevent unnecessary phase-contrast acquisitions in cases with RV dilatation of unknown etiology., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The Bloom syndrome DNA helicase BLM contributes to chromosome stability through its roles in double-strand break repair by homologous recombination and DNA replication fork restart during the replication stress response. Loss of BLM activity leads to Bloom syndrome, which is characterized by extraordinary cancer risk and small stature. Here, we have analyzed the composition of the BLM complex during unperturbed S-phase and identified a direct physical interaction with the Mcm6 subunit of the minichromosome maintenance (MCM) complex. Using distinct binding sites, BLM interacts with the N-terminal domain of Mcm6 in G1 phase and switches to the C-terminal Cdt1-binding domain of Mcm6 in S-phase, with a third site playing a role for Mcm6 binding after DNA damage. Disruption of Mcm6-binding to BLM in S-phase leads to supra-normal DNA replication speed in unperturbed cells, and the helicase activity of BLM is required for this increased replication speed. Upon disruption of BLM/Mcm6 interaction, repair of replication-dependent DNA double-strand breaks is delayed and cells become hypersensitive to DNA damage and replication stress. Our findings reveal that BLM not only plays a role in the response to DNA damage and replication stress, but that its physical interaction with Mcm6 is required in unperturbed cells, most notably in S-phase as a negative regulator of replication speed., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe., Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555)., Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran., Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation., Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim., Competing Interests: Declaration of interests FAK reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharpe & Dohme, the Netherlands Organisation for Health Research and Development, Actelion, the Dutch Heart foundation, and the Dutch Thrombosis Association, all outside the submitted work. SB reports congress and travel payments from Daiichi Sankyo and Bayer; honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and LeoPharma; and institutional grants from Sanofi, all outside the submitted work. WA reports research support from Bayer, and participating in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi all outside the submitted work. MB reports consulting and speaker fees from Bayer Healthcare, Daiichi Sankyo, and Sanofi Aventis outside the submitted work. FC reports research grant support from Bristol-Myers Squibb-Pfizer Alliance; fees for board memberships or symposia from Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Astra Zeneca; and travel support from Bayer, Bristol-Myers Squibb-Pfizer Alliance, Leo Pharma, and Actelion all outside the submitted work. KD reports unrestricted research support and speaker or consultant fees from Janssen outside the submitted work. DD reports speaker's honoraria from Bayer Vital, Daiichi Sankyo, and Bristol-Myers Squibb-Pfizer Alliance; and consulting fees from Bayer Vital and Daiichi Sankyo all outside the submitted work. KE reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis; and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk all outside the submitted work. GG reports personal fees or research grants, or both, from Bayer, Boehringer Ingelheim, Leo, Merck Sharpe & Dohme, and Pfizer outside the submitted work. MVH reports grants from the ZonMW Dutch Healthcare Fund; and grants and personal fees to the Leiden University Medical Center from Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, Bayer Health Care, Aspen, and Daiichi Sankyo, all outside the submitted work. DJ reports serving as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; serving as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI, and Sanofi; and receiving grants for clinical research from Daiichi Sankyo, Sanofi, and ROVI all outside the submitted work. MK reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer outside the submitted work. IML reports receiving consulting fees and research grants from, and being a member of scientific advisory boards for AOPOrphan Pharmaceuticals, Actelion-Janssen, Merck Sharpe & Dohme, United Therapeutics, Medtronic, Neutrolis, and Ferrer, in addition to being an investigator in trials involving these companies. ML reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi Sankyo, Merck Sharpe & Dohme, and Bristol-Myers Squibb-Pfizer Alliance; and project funding from Thermo Fisher Scientific all outside the submitted work. NM reports consulting fees, speaker fees, and project funding from Bayer and Bristol-Myers Squibb-Pfizer Alliance; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo all outside the submitted work. AOP reports speaker fees from SC Pfizer Romania, Servier Pharma, Novartis Pharma Services Romania, Bayer, and SC Sanience outside the submitted work. AS reports consulting fees from Pfizer outside the submitted work. SS reports consulting fees and speaker fees from Aspen and Boehringer Ingelheim; speaker fees from Bayer and Daiichi Sankyo; and project funding and speaker fees from Bristol-Myers Squibb-Pfizer Alliance all outside the submitted work. K-HS reports speaker and consulting fees from Merck Sharpe & Dohme, Janssen-Cilag, and Abbott outside the submitted work. FV reports research grants from Daiichi Sanyo, Boehringer-Ingelheim, Radiometer, and Biomerieux, outside the submitted work. SVK reports institutional research grants and personal consultancy or speaker fees from Actelion/Janssen, Bayer, Daiichi Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy or speaker fees from Bristol-Myers Squibb-Pfizer Alliance and Novartis all outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE)., Research Question: What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE?, Study Design and Methods: The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale., Results: In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1., Interpretation: In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management., Clinical Trial Registration: German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Acari represent the most diverse group within the arachnids with some 60,000 described species. It is generally believed that most species of mites are waiting to be discovered and described. Zootaxa was the most important journal for mite taxonomy during the last twenty years (2001 to 2020). It published 1305 papers by 1057 authors during these two decades, with descriptions of 3271 new taxa/names, which account for 24.4% of the total indexed in Zoological Record. The numbers of new synonyms of Acari in Zootaxa (334) also accounted for nearly a quarter (24.9%) of the total published during this period. These data indicate that Zootaxa has been an important and leading journal for acarologists to document the diversity of mites and ticks in the world.

Isotopic distributions of fragments from fission of the neutron-deficient ^{178}Hg nuclide are reported. This experimental observable is obtained for the first time in the region around lead using an innovative approach based on inverse kinematics and the coincidence between the large acceptance magnetic spectrometer VAMOS++ and a new detection arm close to the target. The average fragment N/Z ratio and prompt neutron M&#95;{n} multiplicity are derived and compared with current knowledge from actinide fission. A striking consistency emerges, revealing the unexpected dominant role of the proton subsystem with atomic number between the Z=28 and 50 magic numbers. The origin of nuclear charge polarization in fission and fragment deformation at scission are discussed.

Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.

The diagnostic strategy for chronic thromboembolic pulmonary hypertension (CTEPH) is composed of two components required for a diagnosis of CTEPH: the presence of chronic pulmonary embolism and an elevated pulmonary artery pressure. The current guidelines require that ventilation-perfusion single-photon emission computed tomography (VQ-SPECT) is used for the first step diagnosis of chronic pulmonary embolism. However, VQ-SPECT exposes patients to ionizing radiation in a radiation sensitive population. The prospective, multicenter, comparative phase III diagnostic trial C TEP H di agn osis E urope - MRI (CHANGE-MRI, ClinicalTrials.gov identifier NCT02791282 ) aims to demonstrate whether functional lung MRI can serve as an equal rights alternative to VQ-SPECT in a diagnostic strategy for patients with suspected CTEPH. Positive findings are verified with catheter pulmonary angiography or computed tomography pulmonary angiography (gold standard). For comparing the imaging methods, a co-primary endpoint is used. (i) the proportion of patients with positive MRI in the group of patients who have a positive SPECT and gold standard diagnosis for chronic pulmonary embolism and (ii) the proportion of patients with positive MRI in the group of patients with negative SPECT and gold standard. The CHANGE-MRI trial will also investigate the performance of functional lung MRI without i.v. contrast agent as an index test and identify cardiac, hemodynamic, and pulmonary MRI-derived parameters to estimate pulmonary artery pressures and predict 6-12 month survival. Ultimately, this study will provide the necessary evidence for the discussion about changes in the recommendations on the diagnostic approach to CTEPH., (Copyright © 2020 Lasch, Karch, Koch, Derlin, Voskrebenzev, Alsady, Hoeper, Gall, Roller, Harth, Steiner, Krombach, Ghofrani, Rengier, Heußel, Grünig, Beitzke, Hacker, Lang, Behr, Bartenstein, Dinkel, Schmidt, Kreitner, Frauenfelder, Ulrich, Hamer, Pfeifer, Johns, Kiely, Swift, Wild and Vogel-Claussen.)

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field.

To retrieve and assess the available data in the literature about the safety and efficacy of baroreflex activation therapy (BAT) in heart failure with reduced ejection fraction (HFrEF) patients, through a rapid systematic review of clinical studies. Rapid systematic review of literature. Searched electronic databases included PubMed, EMBASE, CENTRAL, Scopus, and Web of Science using Mesh and free terms for heart failure and BAT. No language restriction was used for the searches. We included full peer reviewed publications of clinical studies (randomized or not), including patients with HFrEF undergoing BAT, with or without control group, assessing safety and efficacy outcomes. One reviewer conducted the analysis of the selected abstracts and the full-text articles, performed data extraction, and evaluated the methodological quality of the selected articles. The methodological quality was assessed according to the Cochrane Collaboration instruments. A descriptive summary of the results is provided. Of the 441 citations screened, 10 publications were included (three were only conference abstracts), reporting data from three studies. Only one study was a randomized clinical trial. Two studies reported a 6 month following, and the other study analysed outcomes up to 41 months. The procedure seems to be safe when performed by a well-trained multi-professional team. An 86% rate of system and procedure-related complication-free was reported, with no cranial nerve injuries. Improvements in New York Heart Association class of heart failure, quality of life, 6 min walk test, and hospitalization rates, as well as in muscle sympathetic nerve activity. No meta-analysis was conducted because of the lack of homogeneity across studies; the results from each study are reported individually. BAT procedure seems to be safe if appropriate training is provided. Improvements in clinical outcomes were described in all included studies. However, several limitations do not allow us to make conclusive statements on the efficacy of BAT for HFrEF. New well-designed trials are still needed., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

An overview is given on some of the main advances in the experimental methods, experimental results, theoretical models and ideas of the last few years in the field of nuclear fission. New approaches have considerably extended the availability of fissioning systems for the experimental study of nuclear fission, and have provided a full identification of all fission products in A and Z for the first time. In particular, the transition from symmetric to asymmetric fission around 226 Th, some unexpected structures in the mass distributions in the fission of systems around Z  =  80-84, and an extended systematics of the odd-even effect in the fission fragment Z distributions have all been measured (Andreyev et al 2018 Rep. Prog. Phys. 81 016301). Three classes of model descriptions of fission presently appear to be the most promising or the most successful. Self-consistent quantum-mechanical models fully consider the quantum-mechanical features of the fission process. Intense efforts are presently being made to develop suitable theoretical tools (Schunck and Robledo 2016 Rep. Prog. Phys. 79 116301) for modeling the non-equilibrium, large-amplitude collective motion leading to fission. Stochastic models provide a fully developed technical framework. The main features of the fission-fragment mass distribution have been well reproduced from mercury to fermium and beyond (Möller and Randrup 2015 Phys. Rev. C 91 044316). However, limited computer resources still impose restrictions, for example, on the number of collective coordinates and on an elaborate description of the fission dynamics. In an alternative semi-empirical approach (Schmidt et al 2016 Nucl. Data Sheets 131 107), considerable progress in describing the fission observables has been achieved by combining several theoretical ideas, which are essentially well known. This approach exploits (i) the topological properties of a continuous function in multidimensional space, (ii) the separability of the influence of fragment shells and the macroscopic properties of the compound nucleus, (iii) the properties of a quantum oscillator coupled to a heat bath of other nuclear degrees of freedom, (iv) an early freeze-out of collective motion, and (v) the application of statistical mechanics for describing the thermalization of intrinsic excitations in the nascent fragments. This new approach reveals a high degree of regularity and allows the calculation of high-quality data that is relevant to nuclear technology without specifically adjusting the empirical data of individual systems.

In view of the rapid development of information and communication technologies, the present study sheds light on how work-related smartphone use during non-work time affects employees' subsequent working day. Specifically, we examine work-related smartphone use and sleep quality as moderators of next-day self-control processes at work. Theorizing that work-related smartphone use and self-control demands deplete a common limited regulatory resource, we suggest a strengthening two-way interaction between work-related smartphone use during non-work time and next-day self-control demands at work in predicting employees' ego depletion at work. Moreover, in a three-way interaction, we analyze whether this interaction depends on employees' sleep quality, assuming that when intensive work-related smartphone use is followed by high-quality sleep, the taxed regulatory resource can replenish overnight. Results from our diary study covering 10 working days ( n = 63) indicate that after evenings with high work-related smartphone use, employees experience disproportionate levels of ego depletion when dealing with self-control demands at work. Sleep quality, however, attenuates this interaction. In cases of high sleep quality, next-day self-control processes at work are no longer affected by work-related smartphone use. Based on these findings, we discuss implications for employees and employers regarding work-related smartphone use and the relevance of sleep in replenishing drained resources.

Objective: Conditional cash transfer programs are popular internationally and represent a large investment in child health. Evidence of their impact on child nutrition status remains weak and inconsistent, particularly for Bolsa Família, the Brazilian conditional cash transfer program and one of the world's largest. Our objective was to estimate the effect of the Brazilian conditional cash transfer program, Bolsa Família (BF), on child nutritional status as measured by length-for-age z-score (LAZ) and weight-for-age z-score (WAZ) at 24 months., Methods: We analyzed the 1703 children eligible for BF from the 2004 Pelotas Birth Cohort. Children were divided into three exposure groups by total amount of money their household received from BF in 24 months: no BF, low BF (≤R$1000) and high BF (>R$1000). Using a doubly robust semiparametric estimation method we estimated the effect of receiving low and high levels of BF on LAZ and WAZ at 24 months., Results: After adjustment for measured confounders, the expected difference in LAZ between children that received low or high levels of BF compared to no BF was -0.14 [95% confidence interval (CI): -0.27, -0.02] and -0.20 (95% CI: -0.33, -0.08) respectively. For WAZ the estimated differences were -0.04 (95% CI: -0.17, 0.08) for low levels versus no BF and -0.18 (95% CI: -0.30, -0.05) for high levels versus no BF. The expected difference in population LAZ had all eligible households received it and population LAZ under no BF was -0.15 (95% CI: -0.26, -0.04). Sensitivity analyses suggested only a strong confounder could explain away these results., Conclusions: Among participants of the 2004 Pelotas Birth Cohort, BF was associated with a reduction in LAZ and WAZ in 24 month old children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Aetiology of heart failure (HF) often remains obscure. We therefore evaluated the usefulness of a combined diagnostic approach including cardiac magnetic resonance imaging (CMRI) and endomyocardial biopsy (EMB) to assess the cause of unexplained cardiomyopathy underlying HF., Methods and Results: We retrospectively investigated 100 consecutive patients (36% women, mean age 53.6 ± 18.8 years) presenting with unexplained cardiomyopathy (HF with reduced ejection fraction or left ventricular hypertrophy; excluding ischaemic and valvular heart disease; left ventricular ejection fraction 31.6 ± 13.9%, Left ventricular end-diastolic pressure 18.2 ± 9.3 mmHg, heart rate 89 ± 26.6 b.p.m.; mean ± SEM) at the University Medical Center Mainz. We performed electrocardiography, echocardiography, CMRI, and cardiac catheterization with EMB analysed at a Food and Drug Administration-approved reference centre in 100%, 94%, 69%, and 100% of patients, respectively. On the basis of CMRI findings, electrocardiography, echocardiography, and medical history, the exact cause of cardiomyopathy remained uncertain in 37 of 69 cases (53.6%). In EMB, 25% of patients had viral replication, 23% had inflammation defined as lymphocytic infiltrations without active virus replication, 1% had giant cell myocarditis, and 1% had eosinophilic myocarditis. After diagnostic workup including EMB findings, the cause of cardiomyopathy remained unidentified in 14% of the cases, classified as idiopathic dilated cardiomyopathy or hypertrophic cardiomyopathy in 10% or 4%, respectively. EMB helped to discuss a causal treatment strategy of HF involving immunosuppression or antiviral treatment in 53% of patients, which was opted for in 12% of the patients., Conclusions: A comprehensive workup including imaging and EMB in an all-comer population of patients with HF may help physicians to improve diagnostics of unexplained cardiomyopathy in the majority of cases., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Nasal mites of the subfamily Speleognathinae associated with birds in the Afrotropical region are reviewed. The total of 37 species belonging to15 genera has been recorded so far in this region. All recorded species and genera are provided with improved diagnoses, data on their host associations and distribution are summarized, and a key to all species is constructed.

Previous research has provided strong evidence for affective commitment as a direct predictor of employees' psychological well-being and as a resource that buffers the adverse effects of self-control demands as a stressor. However, the mechanisms that underlie the beneficial effects of affective commitment have not been examined yet. Drawing on the self-determination theory, we propose day-specific flow experiences as the mechanism that underlies the beneficial effects of affective commitment, because flow experiences as peaks of intrinsic motivation constitute manifestations of autonomous regulation. In a diary study covering 10 working days with N = 90 employees, we examine day-specific flow experiences as a mediator of the beneficial effects of interindividual affective commitment and a buffering moderator of the adverse day-specific effects of self-control demands on indicators of well-being (ego depletion, need for recovery, work engagement, and subjective vitality). Our results provide strong support for our predictions that day-specific flow experiences a) mediate the beneficial effects of affective commitment on employees' day-specific well-being and b) moderate (buffer) the adverse day-specific effects of self-control demands on well-being. That is, on days with high levels of flow experiences, employees were better able to cope with self-control demands whereas self-control demands translated into impaired well-being when employees experienced lower levels of day-specific flow experiences. We then discuss our findings and suggest practical implications. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)