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PurposeFew studies have assessed the presentation, management, and outcomes of sepsis in low-income countries (LICs). We sought to characterize these aspects of sepsis and to assess mortality predictors in sepsis in two referral hospitals in Rwanda.Materials and methodsThis was a retrospective cohort study in two public academic referral hospitals in Rwanda. Data was abstracted from paper medical records of adult patients who met our criteria for sepsis.ResultsOf the 181 subjects who met eligibility criteria, 111 (61.3%) met our criteria for sepsis without shock and 70 (38.7%) met our criteria for septic shock. Thirty-five subjects (19.3%) were known to be HIV positive. The vast majority of septic patients (92.7%) received intravenous fluid therapy (median = 1.0 L within 8 hours), and 94.0% received antimicrobials. Vasopressors were administered to 32.0% of the cohort and 46.4% received mechanical ventilation. In-hospital mortality for all patients with sepsis was 51.4%, and it was 82.9% for those with septic shock. Baseline characteristic mortality predictors were respiratory rate, Glasgow Coma Scale score, and known HIV seropositivity.ConclusionsSeptic patients in two public tertiary referral hospitals in Rwanda are young (median age = 40, IQR = 29, 59) and experience high rates of mortality. Predictors of mortality included baseline clinical characteristics and HIV seropositivity status. The majority of subjects were treated with intravenous fluids and antimicrobials. Further work is needed to understand clinical and management factors that may help improve mortality in septic patients in LICs.

Background: Little is known regarding the effectiveness of pain protocols and guideline use in Emergency Departments (ED) in Sub-Saharan Africa. Therefore, to shed light on this research gap, this study had the following objectives: 1) to evaluate if the implementation of the Essential Pain Management (EPM) course combined with mentorship to use the World Health Organization (WHO) pain ladder-based protocol improves the quality of pain management among trauma patients at the ED of two teaching hospitals in Rwanda; and 2) to determine barriers to implementing the WHO pain ladder-based protocol among trauma patients in the same settings. Methods: This was a pre- and post-intervention study. The intervention was 1-day essential pain management training for ED clinical staff followed by 1 week mentorship on the use of the WHO pain ladder-based protocol. Results: We enrolled 261 patients (47.5% pre versus 52.5% post intervention), most of them were aged between 21 and 40 (60% pre versus 33% post intervention), and male (76% pre versus 73% post intervention). The quality of pain management at the ED improved as shown by the decrease of the number of patients with undocumented pain scores from 58% to 24% after the intervention (p-value > 0.001) and the increase of the number of patients with mild pain from 37% to 62% (p-value > 0.001). In addition, patients who were satisfied with the quality of pain management increased significantly from 42% before the intervention to 80% (p-value > 0.001). Barriers to the implementation of the WHO pain ladder-based protocol were identified related to staff (i.e. inadequate experience), to the hospital (i.e. poor documentation), and to patients (i.e. reluctance to report pain). Conclusion: The implementation of the EPM course along with mentorship to use the WHO pain ladder-based protocol significantly improved the quality of pain management for trauma patients in EDs of both referral hospitals. Despite this, some barriers remain unfixed such as inadequate staff experience, poor documentation, and patient's reluctance to report pain. Appropriate interventions should be implemented to address the identified barriers and ensure adequate pain management for patients admitted at EDs in public hospitals in Rwanda.

Beginning in 2020, the COVID-19 pandemic limited onsite international activities and challenged us to plan and implement new ways of collaboration. We reviewed our online trials during a three-year period to better understand how to use digital technologies to continue knowledge and skills transfer. In this cross-national case study, we compare two illustrative cases: Japanese experts training Indonesian health professionals for participatory school health education, and Swiss experts training Malagasy health providers for respectful obstetric and newborn emergencies. We first describe our cases, referring to Vargo’s framework for summarizing reports on digital technology usage. Second, we draw commonalities between the two cases. Third, gleaned from these experiences during the pandemic, we offer a practical framework for efficient and effective international collaboration using new technologies. For both cases, basic digital technologies, such as online meetings and e-mailing, were used and training sessions were successfully conducted. Trusting relationships between the training and participant groups were in place before the pandemic. This led to enthusiasm for continuing learning even after the pandemic started. Our case comparison presents the usefulness of digital technologies for continuing international collaboration and highlights the importance of human factors, such as trusting relationships and enthusiasm to pursue a shared goal, as the basic condition for success.

Abstract Background Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. Methods Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13–18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. Results The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. Conclusion Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Résumé : Cet article examine une spécificité de l’anthroponymie mbɔsí, notamment la diversité des types et des formes d’anthroponymes mbɔsí. Notre objectif est de faire l’inventaire des types et des formes d’anthroponymes mbɔsí, et de déterminer leur rendement dans la société mbɔsí. Ainsi, notre recherche signale les types d’anthroponymes suivants : Les anthroponymes individuels et les anthroponymes collectifs, sans oublier les anthroponymes gémellaires et ceux se référant aux sexes. Les formes d’anthroponymes mbɔsí sont les suivantes : Les formes simples, les formes dupliquées et surtout les formes complexes. Celles-ci renferment les syntagmes nominaux ou verbaux, les phrases entières et les proverbes. Le rendement de la diversité des types et des formes d’anthroponymes mbɔsí est évalué comme suit : Les divers types d’anthroponymes permettent de nommer les différentes entités de la société mbɔsí. Alors que les diverses formes d’anthroponymes permettent de véhiculer à travers les noms de personnes, non seulement les faits sociaux et environnementaux, mais aussi les confidences et les valeurs morales et culturelles du peuple mbɔsí. D’où, le glissement de l’anthroponymie mbɔsí vers une autre forme d’expression culturelle, la littérature. Mots clés : diversité, types, formes, anthroponymes, mbɔsí.

Purpose: Few studies have assessed the presentation, management, and outcomes of sepsis in low-income countries (LICs). We sought to characterize these aspects of sepsis and to assess mortality predictors in sepsis in two referral hospitals in Rwanda. Materials and methods: This was a retrospective cohort study in two public academic referral hospitals in Rwanda. Data was abstracted from paper medical records of adult patients who met our criteria for sepsis. Results: Of the 181 subjects who met eligibility criteria, 111 (61.3%) met our criteria for sepsis without shock and 70 (38.7%) met our criteria for septic shock. Thirty-five subjects (19.3%) were known to be HIV positive. The vast majority of septic patients (92.7%) received intravenous fluid therapy (median = 1.0 L within 8 hours), and 94.0% received antimicrobials. Vasopressors were administered to 32.0% of the cohort and 46.4% received mechanical ventilation. In-hospital mortality for all patients with sepsis was 51.4%, and it was 82.9% for those with septic shock. Baseline characteristic mortality predictors were respiratory rate, Glasgow Coma Scale score, and known HIV seropositivity. Conclusions: Septic patients in two public tertiary referral hospitals in Rwanda are young (median age = 40, IQR = 29, 59) and experience high rates of mortality. Predictors of mortality included baseline clinical characteristics and HIV seropositivity status. The majority of subjects were treated with intravenous fluids and antimicrobials. Further work is needed to understand clinical and management factors that may help improve mortality in septic patients in LICs. [ABSTRACT FROM AUTHOR]

Abstract Critical care is underprioritized. A global call to action is needed to increase equitable access to care and the quality of care provided to critically ill patients. Current challenges to effective critical care in resource-constrained settings are many. Estimates of the burden of critical illness are extrapolated from common etiologies, but the true burden remains ill-defined. Measuring the burden of critical illness is epidemiologically challenging but is thought to be increasing. Resources, infrastructure, and training are inadequate. Millions die unnecessarily due to critical illness. Solutions start with the implementation of first-step, patient care fundamentals known as Essential Emergency and Critical Care. Such essential care stands to decrease critical-illness mortality, augment pandemic preparedness, decrease postoperative mortality, and decrease the need for advanced level care. The entire healthcare workforce must be trained in these fundamentals. Additionally, physician and nurse specialists trained in critical care are needed and must be retained as leaders of critical care initiatives, researchers, and teachers. Context-specific research is mandatory to ensure care is appropriate for the patient populations served, not just duplicated from high-resourced settings. Governments must increase healthcare spending and invest in capacity to treat critically ill patients. Advocacy at all levels is needed to achieve universal health coverage for critically ill patients.

Dans cet article, nous mettons en exergue la dimension poétique de l’anthroponymie mbɔsí. Il s’agit de prouver le fait que certains anthroponymes du peuple mbɔsí présentent fortement des aspects littéraires, outre leur mission primordiale de désignation des personnes. Notre recherche analyse spécifiquement les différents procédés stylistiques de création des anthroponymes mbɔsí. L’objectif est de déterminer non seulement ces procédés stylistiques, mais aussi l’influence considérable de ceux-ci exercent sur les anthroponymes mbɔsí. Ainsi, nous présentons tout d’abord les procédés rhétoriques et syntaxiques de création des anthroponymes mbɔsí, puis la diversité des propriétés littéraires que les procédés stylistiques transfèrent aux anthroponymes mbɔsí. Enfin, cette recherche mentionne le glissement de l’anthroponymie mbɔsí vers une autre forme d’expression culturelle, à savoir la littérature. En effet, l’anthroponymie mbɔsí fonctionne comme un genre littéraire, grâce à l’influence des procédés stylistiques

Abstract Background There are a number of factors that may contribute to high mortality and morbidity of women and newborns in low-income countries. These include a shortage of competent health care providers (HCP) and a lack of sufficient continuous professional development (CPD) opportunities. Strengthening the skills and building the capacity of HCP involved in the provision of maternal, newborn and child health (MNCH) is essential to ensure quality care for mothers, newborns and children. To address this challenge in Rwanda, mentorship of HCPs was identified as an approach that could help build capacity, improve the provision of care and accelerate the reduction in maternal and neonatal mortality and morbidity. In this paper, we describe the development and implementation of a novel mentorship model named Four plus One (4+ 1) for MNCH in Rwanda. Methods The mentorship model built on the basis of inter-professional collaboration (IPC) was developed in early 2017 through consultations with different key actors. The design phase included refresher courses in specific skills and training course on mentoring. Field visits were conducted in 10 hospitals from June 2017 to February 2020. Hospital management teams (MT) were involved in the development and implementation of this mentorship model to ensure ownership of the program. Results Upon completion of planned visits to each hospital, a total of 218 HCPs were involved in the process. Reports prepared by mentors upon each mentorship visit and compiled by Training Support and Access Model (TSAM) for MNCH’CPD team, highlighted the mothers and newborns who were saved by both mentors and mentees. Also, different logbooks of mentees showed how the capacity of staff was strengthened, thereby suggesting effectiveness of the model. Through different mentorship coordination meetings, the model was much appreciated by the MTs of hospitals, especially the IPC component of the model and confirmed the program ‘effectiveness. Conclusion The initiation of a mentorship model built on IPC together with the involvement of the leadership of the hospital may be the cause effect of reduction of specific mortality and improve MNCH in low resource settings even when there are a limited number of specialists in the health facilities.

Radio telescopes are used to accurately measure the time of arrival (ToA) of radio pulses in pulsar timing experiments that target mostly millisecond pulsars (MSPs) due to their high rotational stability. This allows for detailed study of MSPs and forms the basis of experiments to detect gravitational waves. Apart from intrinsic and propagation effects, such as pulse-topulse jitter and dispersion variations in the interstellar medium, timing precision is limited in part by the following: polarization purity of the telescope's orthogonally polarized receptors, the signal-to-noise ratio of the pulsar profile, and the polarization fidelity of the system. Using simulations, we present how fundamental limitations in recovering the true polarization reduce the precision of ToA measurements. Any real system will respond differently to each source observed depending on the unique pulsar polarization profile. Using the profiles of known MSPs, we quantify the limits of observing system specifications that yield satisfactory ToA measurements, and we place a practical design limit beyond which improvement of the system results in diminishing returns. Our aim is to justify limits for the front-end polarization characteristics of next-generation radio telescopes, leading to the Square Kilometre Array. [ABSTRACT FROM AUTHOR]

Background Postoperative pain management (POPM) appeared to be weak in Rwanda. Aims The aim of this study was to compare POPM measures in a teaching hospital between 2013 and 2017. Methods A two-phase observational study in 2013 and 2017. was conducted. Participants were recruited prior to major surgery and followed for two postoperative days. A numerical rating scale (0–10) was administered to all participants in both years, and the International Pain Outcomes questionnaire was administered in 2017. Recruitment, consent, and data collection were performed in participants’ preferred language. Results One hundred adult participants undergoing major general, gynecologic, orthopedic, or urologic surgery were recruited in 2013 and 83 were recruited in 2017. Fourteen percent of participants in 2013 and 46% in 2017 scored their worst pain as severe (>6; P

Abstract Background Worldwide maternal mortality remains high, with approximately 830 maternal deaths occurring each day. About 90% of these deaths occur in low-income countries. Evidenced-based essential birth practices administered during routine obstetrical care and childbirth are key to reducing maternal and neonatal deaths. The WHO Safe Childbirth Checklist (SCC) is a low-cost tool designed to ensure birth attendants perform 29 essential birth practices (EBP) at four critical periods in the birth continuum. This study aimed to evaluate compliance with EBP in Masaka District Hospital both before and after the implementation of the WHO-SCC. Methods This quality improvement project took place in the Masaka District Hospital in Rwanda. Observations of the 29 EBPs were done before and after WHO SCC implementation. The implementation process consisted of providing training in the use of the checklist to all clinical staff and posting SCC posters at different locations in the maternity unit. Results A total 391 birth events were observed pre-intervention and 389 post-intervention. The overall EBP compliance rate increased from 46% pre-intervention to 56% post-intervention (P = 0.005). Significant improvements were seen in 11 out of 29 EBPs. Conclusion The implementation of the WHO SCC improved the overall EBP compliance rate in Masaka District Hospital. Determining the root cause of low compliance rate of some EBP may allow for more successful implementation of EBP interventions in the future. After further study, the SCC should be considered for scale up.

Background Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis. Methods and results We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis. Conclusion We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.

The authors show that increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) and pyruvate kinase muscle isozyme 2 (PKM2) expression is a common feature of a decompensated right ventricle in patients with pulmonary arterial hypertension and animal models. The authors find in vitro that overactivated PARP1 promotes cardiomyocyte dysfunction by favoring PKM2 expression and nuclear function, glycolytic gene expression, activation of nuclear factor κB-dependent proinflammatory factors. Pharmacologic and genetic inhibition of PARP1 or enforced tetramerization of PKM2 attenuates maladaptive remodeling improving right ventricular (RV) function in multiple rodent models. Taken together, these data implicate the PARP1/PKM2 axis as a critical driver of maladaptive RV remodeling and a new promising target to directly sustain RV function in patients with pulmonary arterial hypertension., Competing Interests: This research was supported by a grant from the Cardiovascular Medical Research and Education Fund to Drs Boucherat and Provencher. Dr Boucherat has been funded by the Canadian Institute of Health Research (IC121617). Dr Boucherat holds a junior scholar award from Fonds de Recherche du Québec: Santé. Dr Bonnet holds a distinguished research scholar from Fonds de Recherche du Québec: Santé. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH., Methods and Results: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH., Conclusion: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in some cardiovascular and lung diseases. Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with increased inflammation. Although PAH exhibits a higher prevalence among women, men have a poorer prognosis. We investigated the NLR as an independent predictor of transplant-free survival in PAH., Methods: We performed a retrospective analysis of 78 PAH patients from the Quebec PAHBiobank (71% female). We used univariate and multivariate (adjusted for age, sex, renal function, and disease severity) Cox regression analyses to assess the relationship between the NLR and transplant-free survival, in the whole sample, and according to sex. The NLR was categorized as high (≥ 4.8) or low (< 4.8) using receiver operating characteristic analysis. Unadjusted Kaplan-Meier analysis estimated survival per NLR category., Results: The NLR was higher in patients who died, compared to that in patients who had transplant-free survival ( P < 0.05). The NLR was an independent predictor of event-free survival in PAH (unadjusted hazard ratio: 1.11, 95% confidence interval: 1.04-1.18, which remained significant after adjustment for covariates). The high-NLR group had lower 1-, 3-, and 5-year survival compared to those with a low NLR ( P < 0.001). The NLR remains a predictor of survival in women., Conclusions: The NLR is an independent predictor of transplant-free survival in PAH. We report a potential sexual dimorphism in the ability of the NLR to predict mortality in PAH, emphasizing the importance of considering sex-related differences in the development of biomarkers in PAH., (© 2021 The Authors.)

Exercise intolerance is a cardinal symptom of pulmonary arterial hypertension (PAH) and strongly impacts patients' quality of life (QoL). Although central cardiopulmonary impairments limit peak oxygen consumption ( V' O 2peak ) in patients with PAH, several peripheral abnormalities have been described over the recent decade as key determinants in exercise intolerance, including impaired skeletal muscle (SKM) morphology, convective O 2 transport, capillarity and metabolism indicating that peripheral abnormalities play a greater role in limiting exercise capacity than previously thought. More recently, cerebrovascular alterations potentially contributing to exercise intolerance in patients with PAH were also documented. Currently, only cardiopulmonary rehabilitation has been shown to efficiently improve the peripheral components of exercise intolerance in patients with PAH. However, more extensive studies are needed to identify targeted interventions that would ultimately improve patients' exercise tolerance and QoL. The present review offers a broad and comprehensive analysis of the present literature about the complex mechanisms and their interactions limiting exercise in patients and suggests several gaps in knowledge that need to be addressed in the future for a better understanding of exercise intolerance in patients with PAH., Competing Interests: Conflict of interest: S. Malenfant has nothing to disclose. Conflict of interest: M. Lebret has nothing to disclose. Conflict of interest: É. Breton-Gagnon has nothing to disclose. Conflict of interest: F. Potus has nothing to disclose. Conflict of interest: R. Paulin has nothing to disclose. Conflict of interest: S. Bonnet has nothing to disclose. Conflict of interest: S. Provencher has nothing to disclose., (Copyright ©ERS 2021.)

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

Rationale: Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by abnormally elevated pulmonary pressures and right ventricular failure. Excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is one of the most important drivers of vascular remodeling in PAH, for which available treatments have limited effectiveness. Objectives: To gain insights into the mechanisms leading to the development of the disease and identify new actionable targets. Methods: Protein expression profiling was conducted by two-dimensional liquid chromatography coupled to tandem mass spectrometry in isolated PASMCs from controls and patients with PAH. Multiple molecular, biochemical, and pharmacologic approaches were used to decipher the role of NUDT1 (nudrix hyrolase 1) in PAH. Measurements and Main Results: Increased expression of the detoxifying DNA enzyme NUDT1 was detected in cells and tissues from patients with PAH and animal models. In vitro , molecular or pharmacological inhibition of NUDT1 in PAH-PASMCs induced accumulation of oxidized nucleotides in the DNA, irresolvable DNA damage (comet assay), disruption of cellular bioenergetics (Seahorse), and cell death (terminal deoxynucleotidyl transferase dUTP nick end labeling assay). In two animal models with established PAH (i.e., monocrotaline and Sugen/hypoxia-treated rats), pharmacological inhibition of NUDT1 using (S)-Crizotinib significantly decreased pulmonary vascular remodeling and improved hemodynamics and cardiac function. Conclusions: Our results indicate that, by overexpressing NUDT1, PAH-PASMCs hijack persistent oxidative stress in preventing incorporation of oxidized nucleotides into DNA, thus allowing the cell to escape apoptosis and proliferate. Given that NUDT1 inhibitors are under clinical investigation for cancer, they may represent a new therapeutic option for PAH.

Background: Proper hand hygiene (HH) practices have been shown to reduce healthcare-acquired infections. Several potential challenges in low-income countries might limit the feasibility of effective HH, including preexisting knowledge gaps and staffing., Aim: We sought to evaluate the feasibility of the implementation of effective HH practice at a teaching hospital in Rwanda., Methods: We conducted a prospective quality improvement project in the intensive care unit (ICU) at the Kigali University Teaching Hospital. We collected data before and after an intervention focused on HH adherence as defined by the World Health Organization '5 Moments for Hand Hygiene' and assuring availability of HH supplies. Pre-intervention data were collected throughout July 2019, and HH measures were implemented in August 2019. Post-implementation data were collected following a 3-month wash-in., Results: In total, 902 HH observations were performed to assess pre-intervention adherence and 903 observations post-intervention adherence. Overall, HH adherence increased from 25% (222 of 902 moments) before intervention to 75% (677 of 903 moments) after intervention ( P < 0.001). Improvement was seen among all health professionals (nurses: 19-74%, residents: 23-74%, consultants: 29-76%)., Conclusions: Effective HH measures are feasible in an ICU in a low-income country. Ensuring availability of supplies and training appears key to effective HH practices., Competing Interests: The authors report no conflicts of interest. This work was supported by the UVA Global Infectious Diseases Institute, National Institutes of Health Center for Advancing Translational Science (UL1TR003015/KL2TR003016), and National Institute Of Allergy And Infectious Diseases (K23AI163368).

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown., Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes., Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines., Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

Objective: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by the narrowing of pulmonary arteries (PAs). It is now established that this phenotype is associated with enhanced PA smooth muscle cells (PASMCs) proliferation and suppressed apoptosis. This phenotype is sustained in part by the activation of several DNA repair pathways allowing PASMCs to survive despite the unfavorable environmental conditions. PIM1 (Moloney murine leukemia provirus integration site) is an oncoprotein upregulated in PAH and involved in many prosurvival pathways, including DNA repair. The objective of this study was to demonstrate the implication of PIM1 in the DNA damage response and the beneficial effect of its inhibition by pharmacological inhibitors in human PAH-PASMCs and in rat PAH models. Approach and Results: We found in vitro that PIM1 inhibition by either SGI-1776, TP-3654, siRNA (silencer RNA) decreased the phosphorylation of its newly identified direct target KU70 (lupus Ku autoantigen protein p70) resulting in the inhibition of double-strand break repair (Comet Assay) by the nonhomologous end-joining as well as reduction of PAH-PASMCs proliferation (Ki67-positive cells) and resistance to apoptosis (Annexin V positive cells) of PAH-PASMCs. In vivo, SGI-1776 and TP-3654 given 3× a week, improved significantly pulmonary hemodynamics (right heart catheterization) and vascular remodeling (Elastica van Gieson) in monocrotaline and Fawn-Hooded rat models of PAH., Conclusions: We demonstrated that PIM1 phosphorylates KU70 and initiates DNA repair signaling in PAH-PASMCs and that PIM1 inhibitors represent a therapeutic option for patients with PAH.

Although a majority of the mammalian genome is transcribed to RNA, mounting evidence indicates that only a minor proportion of these transcriptional products are actually translated into proteins. Since the discovery of the first non-coding RNA (ncRNA) in the 1980s, the field has gone on to recognize ncRNAs as important molecular regulators of RNA activity and protein function, knowledge of which has stimulated the expansion of a scientific field that quests to understand the role of ncRNAs in cellular physiology, tissue homeostasis, and human disease. Although our knowledge of these molecules has significantly improved over the years, we have limited understanding of their precise functions, protein interacting partners, and tissue-specific activities. Adding to this complexity, it remains unknown exactly how many ncRNAs there are in existence. The increased use of high-throughput transcriptomics techniques has rapidly expanded the list of ncRNAs, which now includes classical ncRNAs (e.g., ribosomal RNAs and transfer RNAs), microRNAs, and long ncRNAs. In addition, splicing by-products of protein-coding genes and ncRNAs, so-called circular RNAs, are now being investigated. Because there is substantial heterogeneity in the functions of ncRNAs, we have summarized the present state of knowledge regarding the functions of ncRNAs in heart, lungs, and skeletal muscle. This review highlights the pathophysiologic relevance of these ncRNAs in the context of human cardiovascular, pulmonary, and muscle diseases.