Search

Background: Language barriers in healthcare can lead to misdiagnosis, inappropriate treatment, and increased medical errors. Efforts to mitigate these include using interpreters and translation tools, but these measures often fall short, particularly when cultural nuances are overlooked. Consequently, medical professionals may have to rely on their staff or patients' relatives for interpretation, compromising the quality of care., Objective: This formative pilot study aims to assess the feasibility of Translatly, a digital translation platform, in clinical practice. Specifically, the study focuses on evaluating: 1. how healthcare professionals overcome language barriers and their acceptance of an on-demand video telephony platform, 2. the feasibility of the platform during medical consultations, and 3. identifying potential challenges for future development., Methods: The study included ethnographic interviews with healthcare professionals and an observational pilot to assess the use of the Tranlatly platform in clinical practice. Translatly was developed to make real-time translation easy and accessible on both Android and iOS devices. The system's backend architecture uses Java-based services hosted on DigitalOcean. The app securely exchanges data between mobile devices and servers, with user information and call records stored in a MySQL database. An admin panel helps manage the system, and Firebase integration enables fast push notifications to ensure that healthcare professionals can connect with translators whenever they need to. The platform was piloted in a German university hospital with 170 volunteer non-professional translators, mainly medical students, supporting translation in over 20 languages, including Farsi, Dari and Arabic., Results: Ethnographic research conducted by interviewing healthcare professionals in Frankfurt am Main and other German cities revealed that current practices for overcoming language barriers often rely on family members or digital tools like Google Translate, raising concerns about accuracy and emotional distress. Respondents preferred an on-demand translation service staffed by medically experienced translators, such as medical students, who understand medical terminology and can empathize with patients. The observational pilot study recorded 39 requests for translation services, 16 (41%) of which were successfully completed. The translations covered 6 different languages and were carried out by a team of 10 translators. Most requests came from departments such as infectious diseases (5, 31.25%) and emergency (4, 25%). Challenges were identified around translator availability, with 23 (59%) of requests going unanswered, which was further evidenced by user feedback., Conclusions: The pilot study demonstrates the feasibility of the Translatly platform in real-world healthcare settings. It shows potential to improve communication and patient outcomes by addressing language barriers. Despite its potential, challenges such as translator availability highlight the need for further development.

Background: Tajikistan has embarked on health reforms to orient the health system towards primary health care (PHC). The health labour market analysis (HLMA) was initiated by the Ministry of Health with the World Health Organization (WHO) on policy questions related to the PHC workforce team. This article presents the results with focus on family doctors as a critical part of the PHC team, providing lessons for strengthening family medicine and PHC in the European Region and central Asia., Methods: The HLMA framework was used to guide the analysis. The data for analysis were provided by the Ministry of Health and Social Protection of the Population of the Republic of Tajikistan. Descriptive means were used to analyse the data. A Technical Working Group guided the process., Results: There has been an increase in the number of health workers in the country over the last 7 years. However, there is a huge shortage of family doctors when compared with norms, with decreasing family doctor densities over the last 7 years. Family doctors have the highest vacancy rates among specialists and also constitute the highest proportion of specialists who migrate. There is inequitable distribution of doctors across the regions. Overall number of enrolments and graduates in family medicine are declining. Although salaries in PHC are higher than in hospitals, the overall health workforce salaries are lower than the national average. While there have been efforts to retain and attract doctors to PHC in rural and remote regions, challenges exist. The attraction of doctors to narrow specialties may be leading to undermining PHC and family medicine. While the optimal skill-mix and availability of nurses provide an opportunity to strengthen multi-disciplinary teams at the PHC level, shortages and unequal distribution of doctors are affecting health services coverage and health indicators., Conclusions: Application of the HLMA framework has helped identify the bottlenecks in the health labour market flows and the possible explanations for them. The policy considerations emerging out of the HLMA have contributed to improving evidence-based planning for retention and recruitment of the PHC workforce, improvements in medical and nursing education, and higher investments in the PHC workforce and particularly in family doctors. Implementation of the Action Plan will require political commitment, financial resources, strong inter-sectoral collaboration, stakeholder management, and cross-country learning of best practices. Through this process, Tajikistan has shown the way forward in implementing the Central Roadmap for health and well-being in Central Asia and the Framework for Action on the Health and Care Workforce in the WHO European Region., (© 2024. The Author(s).)

Approximately 2% of the German population suffer from psoriasis. HybridVITA has developed a mobile application (app) that enables psoriasis patients to independently document the progression of the disease and the current psychological stress at home. The HybridVITA app was created in close collaboration with user groups to ensure optimal adaptation to their needs. Two interactive workshops were held with the user groups and the technical developers of the app as a core element of the developmental process. The workshops identified the needs and suggestions for improvement of the various user groups and formulated user stories for the further development of the app using the Scrum method. The participatory approach of the workshop enabled the project team to gather valuable practical knowledge at an early stage of development. The team's awareness of potential obstacles during the early stages of the project enabled them to proactively identify and address these issues prior to implementing the app in dermatological care. We are confident that a patient-centered and participatory approach to health app development can provide valuable insights for developers., (© 2024. The Author(s).)

Background: Psoriasis vulgaris (PsV) and psoriatic arthritis (PsA) are complex, multifactorial diseases significantly impacting health and quality of life. Predicting treatment response and disease progression is crucial for optimizing therapeutic interventions, yet challenging. Automated machine learning (AutoML) technology shows promise for rapidly creating accurate predictive models based on patient features and treatment data., Objective: This study aims to develop highly accurate machine learning (ML) models using AutoML to address key clinical questions for PsV and PsA patients, including predicting therapy changes, identifying reasons for therapy changes, and factors influencing skin lesion progression or an abnormal Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score., Methods: Clinical study data from 309 PsV and PsA patients were extensively prepared and analyzed using AutoML to build and select the most accurate predictive models for each variable of interest., Results: Therapy change at 24 weeks follow-up was modeled using the extreme gradient boosted trees classifier with early stopping (area under the receiver operating characteristic curve [AUC] of 0.9078 and logarithmic loss [LogLoss] of 0.3955 for the holdout partition). Key influencing factors included the initial systemic therapeutic agent, the Classification Criteria for Psoriatic Arthritis score at baseline, and changes in quality of life. An average blender incorporating three models (gradient boosted trees classifier, ExtraTrees classifier, and Eureqa generalized additive model classifier) with an AUC of 0.8750 and LogLoss of 0.4603 was used to predict therapy changes for 2 hypothetical patients, highlighting the significance of these factors. Treatments such as methotrexate or specific biologicals showed a lower propensity for change. An average blender of a random forest classifier, an extreme gradient boosted trees classifier, and a Eureqa classifier (AUC of 0.9241 and LogLoss of 0.4498) was used to estimate PASI (Psoriasis Area and Severity Index) change after 24 weeks. Primary predictors included the initial PASI score, change in pruritus levels, and change in therapy. A lower initial PASI score and consistently low pruritus were associated with better outcomes. BASDAI classification at onset was analyzed using an average blender of a Eureqa generalized additive model classifier, an extreme gradient boosted trees classifier with early stopping, and a dropout additive regression trees classifier with an AUC of 0.8274 and LogLoss of 0.5037. Influential factors included initial pain, disease activity, and Hospital Anxiety and Depression Scale scores for depression and anxiety. Increased pain, disease activity, and psychological distress generally led to higher BASDAI scores., Conclusions: The practical implications of these models for clinical decision-making in PsV and PsA can guide early investigation and treatment, contributing to improved patient outcomes., (©Daniel Schaffert, Igor Bibi, Mara Blauth, Christian Lull, Jan Alwin von Ahnen, Georg Gross, Theresa Schulze-Hagen, Johannes Knitza, Sebastian Kuhn, Johannes Benecke, Astrid Schmieder, Jan Leipe, Victor Olsavszky. Originally published in JMIR Formative Research (https://formative.jmir.org), 27.06.2024.)

Introduction: Psoriatic arthritis (PsA), a disease with complex inflammatory musculoskeletal manifestations, complicates psoriasis in up to 30% of patients. In this study, we aimed to determine the effect of an interdisciplinary dermatological-rheumatological consultation (IDRC) for patients with psoriasis with musculoskeletal symptoms., Methods: This prospective study enrolled 202 patients with psoriasis. Patients with musculoskeletal pain (MSP) (n = 115) participated in an IDRC 12 weeks after enrollment. The outcome was evaluated after 24 weeks., Results: In 12/79 (15.2%) patients seen in the IDRC, the prior diagnosis was changed: eight with a first diagnosis of PsA, four with a diagnosis of PsA rescinded. Treatment was modified in 28% of patients. Significant improvements in Psoriasis Area and Severity Index (PASI) (from 5.3 to 2.0; p < 0.001) and Dermatology Life Quality Index (DLQI) (from 6.7 to 4.5; p = 0.009) were observed. By comparing changes in PASI and DLQI over the study period, an improvement in PASI of 0.7 ± 1.4 points (p = 0.64) and in DLQI of 2.9 ± 1.5 points (p = 0.051) could be attributed to participation in the IDRC., Conclusion: An IDRC of patients with psoriasis with MSP leads to a valid diagnosis of PsA and improvement in quality of life. Based on these results, an IDRC is a valuable and time efficient way for psoriasis patient with MSP to receive optimal care., (© 2023. The Author(s).)

Background: Rapid digitalization in health care has led to the adoption of digital technologies; however, limited trust in internet-based health decisions and the need for technical personnel hinder the use of smartphones and machine learning applications. To address this, automated machine learning (AutoML) is a promising tool that can empower health care professionals to enhance the effectiveness of mobile health apps., Objective: We used AutoML to analyze data from clinical studies involving patients with chronic hand and/or foot eczema or psoriasis vulgaris who used a smartphone monitoring app. The analysis focused on itching, pain, Dermatology Life Quality Index (DLQI) development, and app use., Methods: After extensive data set preparation, which consisted of combining 3 primary data sets by extracting common features and by computing new features, a new pseudonymized secondary data set with a total of 368 patients was created. Next, multiple machine learning classification models were built during AutoML processing, with the most accurate models ultimately selected for further data set analysis., Results: Itching development for 6 months was accurately modeled using the light gradient boosted trees classifier model (log loss: 0.9302 for validation, 1.0193 for cross-validation, and 0.9167 for holdout). Pain development for 6 months was assessed using the random forest classifier model (log loss: 1.1799 for validation, 1.1561 for cross-validation, and 1.0976 for holdout). Then, the random forest classifier model (log loss: 1.3670 for validation, 1.4354 for cross-validation, and 1.3974 for holdout) was used again to estimate the DLQI development for 6 months. Finally, app use was analyzed using an elastic net blender model (area under the curve: 0.6567 for validation, 0.6207 for cross-validation, and 0.7232 for holdout). Influential feature correlations were identified, including BMI, age, disease activity, DLQI, and Hospital Anxiety and Depression Scale-Anxiety scores at follow-up. App use increased with BMI >35, was less common in patients aged >47 years and those aged 23 to 31 years, and was more common in those with higher disease activity. A Hospital Anxiety and Depression Scale-Anxiety score >8 had a slightly positive effect on app use., Conclusions: This study provides valuable insights into the relationship between data characteristics and targeted outcomes in patients with chronic eczema or psoriasis, highlighting the potential of smartphone and AutoML techniques in improving chronic disease management and patient care., (©Igor Bibi, Daniel Schaffert, Mara Blauth, Christian Lull, Jan Alwin von Ahnen, Georg Gross, Wanja Alexander Weigandt, Johannes Knitza, Sebastian Kuhn, Johannes Benecke, Jan Leipe, Astrid Schmieder, Victor Olsavszky. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.11.2023.)

Background: Rheumatic immune-related adverse events (R-irAEs) occur in 5-15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer and R-irAEs outcomes with particular focus on adverse effects of anti-inflammatory treatment., Methods: In this prospective, multicenter, long-term, observational study, R-irAEs were comprehensively analyzed in patients with malignant melanoma (MM, n=50) and non-small cell lung cancer (NSCLC, n=41) receiving ICI therapy who were enrolled in the study between August 1, 2018, and December 11, 2022., Results: After a median follow-up of 33 months, progressive disease or death occurred in 66.0% and 30.0% of MM and 63.4% and 39.0% of patients with NSCLC. Male sex (progression-free survival (PFS): p=0.013, and overall survival (OS): p=0.009), flare of a pre-existing condition (vs de novo R-irAE, PFS: p=0.010) and in trend maximum glucocorticoid (GC) doses >10 mg and particularly ≥1 mg/kg prednisolone equivalent (sex-adjusted PFS: p=0.056, OS: p=0.051) were associated with worse cancer outcomes. Patients receiving disease-modifying antirheumatic drugs (DMARDs) showed significantly longer PFS (n=14, p=0.011) and OS (n=20, p=0.018). Effects of these variables on PFS and/or OS persisted in adjusted Cox regression models. Additionally, GC treatment negatively correlated with the time from diagnosis of malignancy and the latency from ICI start until R-irAE onset (all p<0.05). R-irAE features and outcomes were independent of other baseline patient characteristics in both studied cancer entities., Conclusion: Male sex, flare of pre-existing rheumatologic conditions and extensive GC treatment appeared to be linked with unfavorable cancer outcomes, while DMARD use had a favorable impact. These findings challenge the current dogma of restrictive DMARD use for R-irAE and thus may pave the way to better strategies and randomized controlled trials for the growing number of patients with R-irAE., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Noncommunicable diseases (NCDs) and maternal newborn and child health (MNCH) are two deeply intertwined health areas that have been artificially separated by global health policies, resource allocations and programming. Optimal MNCH care can provide a unique opportunity to screen for, prevent and manage early signs of NCDs developing in both the woman and the neonate. This paper considers how NCDs, NCD modifiable risk factors, and NCD metabolic risk factors impact MNCH. We argue that integrated management is essential, but this faces challenges that manifest across all levels of domestic health systems. Progress toward Sustainable Development targets requires joined-up action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akselrod, Banerjee, Collins, Acharya, Artykova, Askew, Berdzuli, Diorditsa, Eggers, Farrington, Jakab, Ferreira-Borges, Mikkelsen, Azzopardi-Muscat, Olsavszky, Park, Sobel, Tran, Vujnovic, Weber, Were, Yaqub, Berlina, Dunlop and Allen.)

Background and Aims: In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor-Like Type 1 ( ACVRL1 ) gene encoding ALK1, the receptor for bone morphogenetic protein (BMP) 9/BMP10, which regulates blood vessel development. Here, we established an HHT mouse model with exclusive liver involvement and adequate life expectancy to investigate ALK1 signaling in liver vessel formation and metabolic function., Approach and Results: Liver sinusoidal endothelial cell (LSEC)-selective Cre deleter line, Stab2-iCreF3 , was crossed with Acvrl1 -floxed mice to generate LSEC-specific Acvrl1 -deficient mice ( Alk1HEC-KO ). Alk1HEC-KO mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines Wnt2 , Wnt9b , and R-spondin-3 ( Rspo3 ) led to disruption of metabolic liver zonation in Alk1HEC-KO mice and in liver specimens of patients with HHT. Furthermore, prion-like protein doppel ( Prnd ) and placental growth factor ( Pgf ) were upregulated in Alk1HEC-KO hepatic endothelial cells, representing candidates driving the organ-specific pathogenesis of HHT. In LSEC in vitro , stimulation or inhibition of ALK1 signaling counter-regulated Inhibitors of DNA binding (ID)1-3, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1-3 function confirmed regulation of Wnt2 and Rspo3 by the BMP9/ALK1/ID axis., Conclusions: Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ-specific endothelial differentiation and angiocrine signaling. The long-term surviving Alk1HEC-KO HHT model offers opportunities to develop targeted therapies for this severe disease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Numerous cutaneous reactions following COVID-19 vaccination have already been described. Vasculitis, however, is a rare adverse event, occurring mainly after the first COVID-19 vaccination. Herein, we report a patient with IgA-positive cutaneous leukocytoclastic vasculitis, unresponsive to a moderate dose of systemic corticosteroid that erupted after the second dose of the Pfizer/BioNTech vaccine. Since booster vaccinations are being administered, we intend to raise awareness among clinicians and to highlight this potential reaction and its therapeutic approach.

Background: Psoriasis is a chronic inflammatory skin disease. The visibility of erythematous plaques on the skin as well as the pain and itchiness caused by the skin lesions frequently leads to psychological distress in patients. Smartphone apps are widespread and easily accessible. Earlier studies have shown that apps can effectively complement current management strategies for patients with psoriasis. However, no analysis of such apps has been published to date., Objective: The aim of this study is to systematically identify and objectively assess the quality of current publicly available German apps for patients with psoriasis using the Mobile Application Rating Scale (MARS) and compile brief ready-to-use app descriptions., Methods: We conducted a systematic search and assessment of German apps for patients with psoriasis available in the Google Play Store and Apple App Store. The identified apps were randomly assigned to 1 of 3 reviewers, who independently rated them using the German MARS (MARS-G). The MARS-G includes 15 items from 4 different sections (engagement, functionality, aesthetics, and information) to create an overall mean score for every app. Scores can range from 1 for the lowest-quality apps to 5 for the highest-quality apps. Apps were ranked according to their mean MARS-G rating, and the highest-ranked app was evaluated independently by 2 patients with psoriasis using the user version of the MARS-G (uMARS-G). Furthermore, app information, including origin, main function, and technical aspects, was compiled into a brief overview., Results: In total, we were able to identify 95 unique apps for psoriasis, of which 15 were available in both app stores. Of these apps, 5 were not specifically intended for patients with psoriasis, 1 was designed for clinical trials only, and 1 was no longer available at the time the evaluation process began. Consequently, the remaining 8 apps were included in the final evaluation. The mean MARS-G scores ranged from 3.51 to 4.18. The app with the highest mean MARS-G score was Psoriasis Helferin (4.18/5.00). When rated by patients, however, the app was rated lower in all subcategories, resulting in a mean uMARS-G score of 3.48. Most apps had a commercial background and a focus on symptom tracking. However, only a fraction of the apps assessed used validated instruments to measure the user's disease activity., Conclusions: App quality was heterogeneous, and only a minority of the identified apps were available in both app stores. When evaluated by patients, app ratings were lower than when evaluated by health care professionals. This discrepancy highlights the importance of involving patients when developing and evaluating health-related apps as the factors that make an app appealing to users may differ between these 2 groups., Trial Registration: Deutsches Register Klinischer Studien DRKS00020963; https://tinyurl.com/ye98an5b., (©Christian Lull, Jan Alwin von Ahnen, Georg Gross, Victor Olsavszky, Johannes Knitza, Jan Leipe, Astrid Schmieder. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 26.05.2022.)

Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC (Ctnnb1 OE-SEC ) generated by using a BM-SEC-restricted Cre mouse line (Stab2-iCreF3) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII-PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1 OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1 OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease., (© 2021. The Author(s).)

The epidemiology of neglected tropical diseases (NTD) is persistently underprioritized, despite NTD being widespread among the poorest populations and in the least developed countries on earth. This situation necessitates thorough and efficient public health intervention. Romania is at the brink of becoming a developed country. However, this South-Eastern European country appears to be a region that is susceptible to an underestimated burden of parasitic diseases despite recent public health reforms. Moreover, there is an evident lack of new epidemiologic data on NTD after Romania's accession to the European Union (EU) in 2007. Using the national ICD-10 dataset for hospitalized patients in Romania, we generated time series datasets for 2008-2018. The objective was to gain deep understanding of the epidemiological distribution of three selected and highly endemic parasitic diseases, namely, ascariasis, enterobiasis and cystic echinococcosis (CE), during this period and forecast their courses for the ensuing two years. Through descriptive and inferential analysis, we observed a decline in case numbers for all three NTD. Several distributional particularities at regional level emerged. Furthermore, we performed predictions using a novel automated time series (AutoTS) machine learning tool and could interestingly show a stable course for these parasitic NTD. Such predictions can help public health officials and medical organizations to implement targeted disease prevention and control. To our knowledge, this is the first study involving a retrospective analysis of ascariasis, enterobiasis and CE on a nationwide scale in Romania. It is also the first to use AutoTS technology for parasitic NTD., Competing Interests: The authors have declared that no competing interests exist.

Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood-brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCre tg / wt ;Ctnnb1(Ex3) fl / wt ( Ctnnb1 OE - EC ) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln . Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1 OE - EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1 OE - EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Koch, Sandorski, Heil, Schmid, Kürschner, Hoffmann, Winkler, Staniczek, de la Torre, Sticht, Schledzewski, Taketo, Trogisch, Heineke, Géraud, Goerdt and Olsavszky.)

The Class H scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are two of the most highly expressed genes in liver sinusoidal endothelial cells (LSECs). While Stab1-deficient (Stab1KO) and Stab2-deficient (Stab2KO) mice are phenotypically unremarkable, Stab1/2-double-deficient (StabDKO) mice exhibit perisinusoidal liver fibrosis, glomerulofibrotic nephropathy and a reduced life expectancy. These conditions are caused by insufficiently scavenged circulating noxious blood factors. The effects of either Stab-single- or double-deficiency on LSEC differentiation and function, however, have not yet been thoroughly investigated. Therefore, we performed comprehensive transcriptomic analyses of primary LSECs from Stab1KO, Stab2KO and StabDKO mice. Microarray analysis revealed dysregulation of pathways and genes involved in established LSEC functions while sinusoidal endothelial marker gene expression was grossly unchanged. 82 genes were significantly altered in Stab1KO, 96 genes in Stab2KO and 238 genes in StabDKO compared with controls; 42 genes were found to be commonly dysregulated in all three groups and all of these genes were downregulated. These commonly downregulated genes (CDGs) were categorized as "potential scavengers," "cell adhesion molecules," "TGF-β/BMP-signaling" or "collagen and extracellular matrix (ECM) components". Among CDGs, Colec10, Lumican and Decorin, were the most strongly down-regulated genes and the corresponding proteins impact on the interaction of LSECs with chemokines, ECM components and carbohydrate structures. Similarly, "chemokine signaling," "cytokine-cytokine receptor interaction" and "ECM-receptor interaction," were the GSEA categories which represented most of the downregulated genes in Stab1KO and Stab2KO LSECs. In summary, our data show that loss of a single Stabilin scavenger receptor - and to a greater extent of both receptors - profoundly alters the transcriptomic repertoire of LSECs. These alterations may affect LSEC-specific functions, especially interactions of LSECs with the ECM and during inflammation as well as clearance of the peripheral blood., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The application of machine learning (ML) for use in generating insights and making predictions on new records continues to expand within the medical community. Despite this progress to date, the application of time series analysis has remained underexplored due to complexity of the underlying techniques. In this study, we have deployed a novel ML, called automated time series (AutoTS) machine learning, to automate data processing and the application of a multitude of models to assess which best forecasts future values. This rapid experimentation allows for and enables the selection of the most accurate model in order to perform time series predictions. By using the nation-wide ICD-10 (International Classification of Diseases, Tenth Revision) dataset of hospitalized patients of Romania, we have generated time series datasets over the period of 2008-2018 and performed highly accurate AutoTS predictions for the ten deadliest diseases. Forecast results for the years 2019 and 2020 were generated on a NUTS 2 (Nomenclature of Territorial Units for Statistics) regional level. This is the first study to our knowledge to perform time series forecasting of multiple diseases at a regional level using automated time series machine learning on a national ICD-10 dataset. The deployment of AutoTS technology can help decision makers in implementing targeted national health policies more efficiently.

Liver sinusoidal endothelial cells (LSECs) control organ functions, metabolism, and development through the secretion of angiokines. LSECs express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiological homeostasis and liver regeneration. Stab2-iCre tg/wt ;Hgf fl/fl (Hgf ΔLSEC ) mice were generated to abrogate Hgf expression selectively in LSECs from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver/body weight ratios were not altered, total body weight and total liver weight were reduced in Hgf ΔLSEC . Necrotic organ damage was more marked in Hgf ΔLSEC mice, and regeneration was delayed 72 hours after PH. This was associated with decreased hepatocyte proliferation at 48 hours after PH. Molecularly, Hgf ΔLSEC mice showed down-regulation of Hgf/c-Met signaling and decreased expression of Deptor in hepatocytes. In vitro knockdown of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis after partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Brahma-related gene 1 (Brg1), a catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, is known to be involved in proliferative cell processes. Liver regeneration is initiated spontaneously after injury and leads to a strong proliferative response. In this study, a hepatocyte-specific Brg1 gene knockout mouse model was used to analyse the role of Brg1 in liver regeneration by performing a 70% partial hepatectomy (PH). After PH, Brg1 was significantly upregulated in wildtype mice. Mice with hepatocyte-specific Brg1 gene knockout showed a significantly lower liver to body weight ratio 48 h post-PH concomitant with a lower hepatocellular proliferation rate compared to wildtype mice. RNA sequencing demonstrated that Brg1 controlled hepatocyte proliferation through the regulation of the p53 pathway and several cell cycle genes. The data of this study reveal a crucial role of Brg1 for liver regeneration by promoting hepatocellular proliferation through modulation of cell cycle genes and, thus, identify Brg1 as potential target for therapeutic approaches.

The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cre tg/wt mice were crossed to Rosa26 N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICD OE-HEC ). In NICD OE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of Wls HEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICD OE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo . Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner. SIGNIFICANCE: Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell- and context-specific fashion., (©2018 American Association for Cancer Research.)

Postnatal liver development is characterized by hepatocyte growth, proliferation, and functional maturation. Notably, canonical Wnt signaling in hepatocytes has been identified as an important regulator of final adult liver size and metabolic liver zonation. The cellular origin of Wnt ligands responsible for homeostatic liver/body weight ratio (LW/BW) remained unclear, which was also attributable to a lack of suitable endothelial Cre driver mice. To comprehensively analyze the effects of hepatic angiocrine Wnt signaling on liver development and metabolic functions, we used endothelial subtype-specific Stab2-Cre driver mice to delete Wls from hepatic endothelial cells (HECs). The resultant Stab2-Cre tg/wt ;Wls fl/fl (Wls-HECKO) mice were viable, but showed a significantly reduced LW/BW. Specifically, ablation of angiocrine Wnt signaling impaired metabolic zonation in the liver, as shown by loss of pericentral, β-catenin-dependent target genes such as glutamine synthase (Glul), RhBg, Axin2, and cytochrome P450 2E1, as well as by extended expression of periportal genes such as arginase 1. Furthermore, endothelial subtype-specific expression of a c-terminally YFP-tagged Wls fusion protein in Wls-HECKO mice (Stab2-Cre tg/wt ;Wls fl/fl ;Rosa26:Wls-YFP fl/wt [Wls-rescue]) restored metabolic liver zonation. Interestingly, lipid metabolism was altered in Wls-HECKO mice exhibiting significantly reduced plasma cholesterol levels, while maintaining normal plasma triglyceride and blood glucose concentrations. On the contrary, zonal expression of Endomucin, LYVE1, and other markers of HEC heterogeneity were not altered in Wls-HECKO livers., Conclusion: Angiocrine Wnt signaling controls liver growth as well as development of metabolic liver zonation in mice, whereas intrahepatic HEC zonation is not affected. (Hepatology 2017)., (© 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Liver sinusoidal endothelial cells (LSEC) represent a unique, organ-specific type of discontinuous endothelial cells. LSEC instruct the hepatic vascular niche by paracrine-acting angiocrine factors. Recently, we have shown that LSEC-specific transcriptional regulator GATA4 induces expression of BMP2 in cultured endothelial cells (EC) in vitro. Furthermore, angiocrine Bmp2 signaling in the liver in vivo was demonstrated to control iron homeostasis. Here, we investigated GATA4-dependent autocrine BMP2 signaling in endothelial cells by gene expression profiling. GATA4 induced a large cluster of inflammatory endothelial response genes in cultured EC, which is similar to previously identified virus-induced and interferon-associated responses. Treating the cells with the BMP2 inhibitor Noggin counter-regulated the GATA4-dependent inflammatory phenotype of EC, indicating that BMP2 is indeed the major driver. In contrast to continuous EC, LSEC were less prone to activation by BMP2. Notably, GATA4-dependent induction of the inflammatory EC response gene cluster was attenuated by over-expression of the LSEC-specific transcriptional modifier LMO3 while hepatocyte activation was fully preserved, indicating conserved BMP2 synthesis. In summary, our data suggest that transcriptional counter-regulation by GATA4 and LMO3 in LSEC prevents autocrine induction of an inflammatory phenotype, while maintaining angiocrine BMP2-mediated cell-cell communication in the liver vascular niche., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.

Microvascular endothelial cells (ECs) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific ECs control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal endothelial cells (LSECs) are uniquely differentiated to fulfill important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSECs. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSECs using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2 fl/fl (Bmp2 LSECKO ) mice caused massive iron overload in the liver and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is nonredundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ but also for the homeostasis of the whole organism., (© 2017 by The American Society of Hematology.)

This analysis of the Romanian health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The Romanian health care system is a social health insurance system that has remained highly centralized despite recent efforts to decentralize some regulatory functions. It provides a comprehensive benefits package to the 85% of the population that is covered, with the remaining population having access to a minimum package of benefits. While every insured person has access to the same health care benefits regardless of their socioeconomic situation, there are inequities in access to health care across many dimensions, such as rural versus urban, and health outcomes also differ across these dimensions. The Romanian population has seen increasing life expectancy and declining mortality rates but both remain among the worst in the European Union. Some unfavourable trends have been observed, including increasing numbers of new HIV/AIDS diagnoses and falling immunization rates. Public sources account for over 80% of total health financing. However, that leaves considerable out-of-pocket payments covering almost a fifth of total expenditure. The share of informal payments also seems to be substantial, but precise figures are unknown. In 2014, Romania had the lowest health expenditure as a share of gross domestic product (GDP) among the EU Member States. In line with the government's objective of strengthening the role of primary care, the total number of hospital beds has been decreasing. However, health care provision remains characterized by underprovision of primary and community care and inappropriate use of inpatient and specialized outpatient care, including care in hospital emergency departments. The numbers of physicians and nurses are relatively low in Romania compared to EU averages. This has mainly been attributed to the high rates of workers emigrating abroad over the past decade, exacerbated by Romania's EU accession and the reduction of public sector salaries due to the economic crisis. Reform in the Romanian health system has been both constant and yet frequently ineffective, due in part to the high degree of political instability. Recent reforms have focused mainly on introducing cost-saving measures, for example, by attempting to shift some of the health care costs to drug manufacturers by claw-back and to the population through co-payments, and on improving the monitoring of health care expenditure., (World Health Organization 2016 (acting as the host organization for, and secretariat of, the European Observatory on Health Systems and Policies).)

Background: The Romanian health system is struggling to retain its health workers, who are currently facing strong incentives for migration to Western European health systems. Retention issues, coupled with high levels of migration, complicate Romania's efforts in providing basic health services for rural, underserved, and marginalized populations, as well as in achieving equitable health access for all. The WHO Global Code of Practice on International Recruitment of Health Personnel (the Code) aims to promote ethical international recruitment and health systems strengthening. We explore Romania's implementation of the Code's principles and recommendations., Methods: We analysed peer-reviewed and grey literature, in English and Romanian, and sought secondary data from the websites of Romania's largest medical universities. The analysis was guided by the following themes and recommendations in the Code: health personnel development and health systems sustainability, international cooperation, data gathering, information exchange, and implementation and monitoring of the Code., Results: Romania's implementation of the Code was observed to be limited. Gaps were identified with regards to several aspects of the Romanian health system, including the lack of support to health personnel training, recruitment, and retention in order to increase the appeal for health providers to practice in Romania and in underserved areas. In terms of international cooperation, the Code recommends various policy instruments to guide recruitment, including bilateral agreements. However, we could not determine which of these instruments were used as a result of the Code and whether or not they were effective. We identified little evidence of initiatives for health workers' professional and personal support. Insufficient data and few information exchange platforms exist on health workforce issues, hindering active sharing of data on migration with European Union and WHO audiences. We could not identify any evidence of monitoring of the Code's implementation to date., Conclusions: In the absence of major system reforms, health workers will continue to migrate to urban areas and abroad. Romanian policymakers should address more of the Code's recommendations by developing a national policy for human resources for health, a central database to aid health workforce planning and management, stronger platforms for information exchange and civil society engagement, and updated and transparent bilateral agreements.