[Benefits of participatory involvement of patients in the development of a dermatological treatment app-A report from the practice]. / Nutzen der partizipatorischen Mitwirkung von PatientInnen an der Entwicklung einer dermatologischen Therapie-App ­ ein Bericht aus der Praxis.

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.

Automated Machine Learning Analysis of Patients With Chronic Skin Disease Using a Medical Smartphone App: Retrospective Study.

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.

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events.

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.

The Effect of an Interdisciplinary Dermatological-Rheumatological Consultation on the Outcome of Patients with Psoriasis with Musculoskeletal Pain: A Prospective, Single-Center Cohort Study.

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.

Integrating maternal, newborn, child health and non-communicable disease care in the sustainable development goal era.

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.

ALK1 controls hepatic vessel formation, angiodiversity, and angiocrine functions in hereditary hemorrhagic telangiectasia of the liver.

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.

Assessment of serological responses following vaccination campaigns with type 2 novel oral polio vaccine: a population-based study in Tajikistan in 2021.

BACKGROUND: Novel oral poliovirus vaccine type 2 (nOPV2) was used to control an outbreak of type 2 circulating vaccine derived poliovirus (cVDPV2) in Tajikistan, in 2021. We measured seroconversion and seroprevalence of type 2 polio antibodies in children who were reported to have received two doses of nOPV2 in outbreak response campaigns. METHODS: In this community serosurvey, children born after Jan 1, 2016 were enrolled from seven districts in Tajikistan. Dried blood spot cards were collected before nOPV2 campaigns and after the first and second rounds of the campaigns and were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) for microneutralisation assay to determine presence of polio antibodies. The primary endpoint was to assess change in seroprevalence and seroconversion against poliovirus serotype 2 after one and two doses of nOPV2. FINDINGS: 228 (97%) of 236 enrolled children were included in the analysis. The type 2 antibody seroprevalence was 26% (53/204; 95% CI 20 to 33) before nOPV2, 77% (161/210; 70 to 82) after one dose of nOPV2, and 83% (174/209; 77 to 88) after two doses of nOPV2. The increase in seroprevalence was statistically significant between baseline and after one nOPV2 dose (51 percentage points [42 to 59], p<0·0001), but not between the first and second doses (6 percentage points [-2 to 15], p=0·12). Seroconversion from the first nOPV2 dose, 67% (89/132; 59 to 75), was significantly greater than that from the second nOPV2 dose, 44% (20/45; 30 to 60; χ2 p=0·010). Total seroconversion after two nOPV2 doses was 77% (101/132; 68 to 83). INTERPRETATION: Our study demonstrated strong immune responses following nOPV2 outbreak response campaigns in Tajikistan. Our results support previous clinical trial data on the generation of poliovirus type 2 immunity by nOPV2 and provide evidence that nOPV2 can be appropriate for the cVDPV2 outbreak response. The licensure and WHO prequalification of nOPV2 should be accelerated to facilitate wider use of the vaccine. FUNDING: World Health Organization, Centers for Disease Control and Prevention, and Rotary International.

German Mobile Apps for Patients With Psoriasis: Systematic Search and Evaluation.

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.

Cutaneous leukocytoclastic vasculitis after second dose of mRNA COVID-19 vaccine.

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.

Retrospective analysis and time series forecasting with automated machine learning of ascariasis, enterobiasis and cystic echinococcosis in Romania.

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.

Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation.

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 ß-catenin in BM-SEC (Ctnnb1OE-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 Ctnnb1OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1OE-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.

Imbalanced Activation of Wnt-/ß-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation.

Endothelial wingless-related integration site (Wnt)-/ß-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-/ß-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-/ß-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-/ß-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-/ß-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

Exploring the transcriptomic network of multi-ligand scavenger receptor Stabilin-1- and Stabilin-2-deficient liver sinusoidal endothelial cells.

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-ß/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.

Time Series Analysis and Forecasting with Automated Machine Learning on a National ICD-10 Database.

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.

Angiocrine Hepatocyte Growth Factor Signaling Controls Physiological Organ and Body Size and Dynamic Hepatocyte Proliferation to Prevent Liver Damage during Regeneration.

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-iCretg/wt;Hgffl/fl (HgfΔLSEC) 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 HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice, and regeneration was delayed 72 hours after PH. This was associated with decreased hepatocyte proliferation at 48 hours after PH. Molecularly, HgfΔLSEC 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.