Impact of Renal Denervation on Urinary Peptide-Based Biomarkers in Hypertension.

BACKGROUND: Catheter-based renal denervation (RDN) reduces blood pressure in hypertension. Urinary peptides are associated with cardiovascular and renal disease and provide prognostic information. We aimed to investigate the effect of RDN on urinary peptide-based classifiers associated with chronic kidney and heart disease and to identify urinary peptides affected by RDN. METHODS: This single-arm, single-center study included patients undergoing catheter-based RDN. Urine samples were collected before and 24 months after RDN and were analyzed using capillary electrophoresis coupled with mass spectrometry. Predefined urinary peptide-based classifiers for chronic kidney disease (CKD273), coronary artery disease (CAD238), and heart failure (HF1) were applied. RESULTS: This study included 48 patients (33% female) with uncontrolled hypertension. At 24 months after RDN, systolic blood pressure (165±17 versus 148±20 mm Hg; P<0.0001), diastolic blood pressure (90±17 versus 81±13 mm Hg; P<0.0001), and mean arterial pressure (115±15 versus 103±13 mm Hg; P<0.0001) decreased significantly. A total of 103 urinary peptides from 37 different proteins, mostly collagens, altered following RDN. CAD238, a 238 coronary artery-specific polypeptide-based classifier, significantly improved following RDN (Cohen's d, -0.632; P=0.0001). The classification scores of HF1 (P=0.8295) and CKD273 (P=0.6293) did not change significantly. CONCLUSIONS: RDN beneficially affected urinary peptides associated with coronary artery disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01888315.

Ultra-long-term efficacy and safety of catheter-based renal denervation in resistant hypertension: 10-year follow-up outcomes.

BACKGROUND: Randomized sham-controlled trials have confirmed the efficacy and safety of catheter-based renal denervation in hypertension. Data on the very long-term effects of renal denervation are scarce. AIMS: This study evaluates the 10-year safety and efficacy of renal denervation in resistant hypertension. METHODS: This prospective single-center study included patients with resistant hypertension undergoing radio-frequency renal denervation between 2010 and 2012. Office blood pressure, 24-h ambulatory blood pressure, antihypertensive medication, color duplex sonography, and renal function were assessed after 1-, 2- and 10-years. RESULTS: Thirty-nine patients completed the 10-year follow-up (mean follow-up duration 9.4 ± 0.7 years). Baseline office and 24-h ambulatory systolic blood pressure were 164 ± 23 mmHg and 153 ± 16 mmHg, respectively. After 10 years, 24-h ambulatory and office systolic blood pressure were reduced by 16 ± 17 mmHg (P < 0.001) and 14 ± 23 mmHg (P = 0.001), respectively. The number of antihypertensive drugs remained unchanged from 4.9 ± 1.4 to 4.5 ± 1.2 drugs (P = 0.087). The estimated glomerular filtration rate declined within the expected range from 69 (95% CI 63 to 74) to 60 mL/min/1.73m2 (95% CI 53 to 68; P < 0.001) through 10-year follow-up. Three renal artery interventions were documented for progression of pre-existing renal artery stenosis in two patients and one patient with new-onset renal artery stenosis. No other adverse events were observed during the follow-up. CONCLUSION: Renal denervation was safe and sustainedly reduced ambulatory and office blood pressure out to 10 years in patients with resistant hypertension.

Comparison of three creatinine-based equations to predict adverse outcome in a cardiovascular high-risk cohort: an investigation using the SPRINT research materials.

Background: Novel creatinine-based equations have recently been proposed but their predictive performance for cardiovascular outcomes in participants at high cardiovascular risk in comparison to the established CKD-EPI 2009 equation is unknown. Method: In 9361 participants from the United States included in the randomized controlled SPRINT trial, we calculated baseline estimated glomerular filtration rate (eGFR) using the CKD-EPI 2009, CKD-EPI 2021, and EKFC equations and compared their predictive value of cardiovascular events. The statistical metric used is the net reclassification improvement (NRI) presented separately for those with and those without events. Results: During a mean follow-up of 3.1 ± 0.9 years, the primary endpoint occurred in 559 participants (6.0%). When using the CKD-EPI 2009, the CKD-EPI 2021, and the EKFC equations, the prevalence of CKD (eGFR <60 ml/min/1.73 m2 or >60 ml/min/1.73 m2 with an ACR ≥30 mg/g) was 37% vs. 35.3% (P = 0.02) vs. 46.4% (P < 0.001), respectively. The corresponding mean eGFR was 72.5 ± 20.1 ml/min/1.73 m2 vs. 73.2 ± 19.4 ml/min/1.73 m2 (P < 0.001) vs. 64.6 ± 17.4 ml/min/1.73 m2 (P < 0.001). Neither reclassification according to the CKD-EPI 2021 equation [CKD-EPI 2021 vs. CKD-EPI 2009: NRIevents: -9.5% (95% confidence interval (CI) -13.0% to -5.9%); NRInonevents: 4.8% (95% CI 3.9% to 5.7%)], nor reclassification according to the EKFC equation allowed better prediction of cardiovascular events compared to the CKD-EPI 2009 equation (EKFC vs. CKD-EPI 2009: NRIevents: 31.2% (95% CI 27.5% to 35.0%); NRInonevents: -31.1% (95% CI -32.1% to -30.1%)). Conclusion: Substituting the CKD-EPI 2009 with the CKD-EPI 2021 or the EKFC equation for calculation of eGFR in participants with high cardiovascular risk without diabetes changed the prevalence of CKD but was not associated with improved risk prediction of cardiovascular events for both those with and without the event.

Patient and dermatologists' perspectives on augmented intelligence for melanoma screening: A prospective study.

BACKGROUND: Artificial intelligence (AI) shows promising potential to enhance human decision-making as synergistic augmented intelligence (AuI), but requires critical evaluation for skin cancer screening in a real-world setting. OBJECTIVES: To investigate the perspectives of patients and dermatologists after skin cancer screening by human, artificial and augmented intelligence. METHODS: A prospective comparative cohort study conducted at the University Hospital Basel included 205 patients (at high-risk of developing melanoma, with resected or advanced disease) and 8 dermatologists. Patients underwent skin cancer screening by a dermatologist with subsequent 2D and 3D total-body photography (TBP). Any suspicious and all melanocytic skin lesions ≥3 mm were imaged with digital dermoscopes and classified by corresponding convolutional neural networks (CNNs). Excisions were performed based on dermatologist's melanoma suspicion, study-defined elevated CNN risk-scores and/or melanoma suspicion by AuI. Subsequently, all patients and dermatologists were surveyed about their experience using questionnaires, including quantification of patient's safety sense following different examinations (subjective safety score (SSS): 0-10). RESULTS: Most patients believed AI could improve diagnostic performance (95.5%, n = 192/201). In total, 83.4% preferred AuI-based skin cancer screening compared to examination by AI or dermatologist alone (3D-TBP: 61.3%; 2D-TBP: 22.1%, n = 199). Regarding SSS, AuI induced a significantly higher feeling of safety than AI (mean-SSS (mSSS): 9.5 vs. 7.7, p < 0.0001) or dermatologist screening alone (mSSS: 9.5 vs. 9.1, p = 0.001). Most dermatologists expressed high trust in AI examination results (3D-TBP: 90.2%; 2D-TBP: 96.1%, n = 205). In 68.3% of the examinations, dermatologists felt that diagnostic accuracy improved through additional AI-assessment (n = 140/205). Especially beginners (<2 years' dermoscopic experience; 61.8%, n = 94/152) felt AI facilitated their clinical work compared to experts (>5 years' dermoscopic experience; 20.9%, n = 9/43). Contrarily, in divergent risk assessments, only 1.5% of dermatologists trusted a benign CNN-classification more than personal malignancy suspicion (n = 3/205). CONCLUSIONS: While patients already prefer AuI with 3D-TBP for melanoma recognition, dermatologists continue to rely largely on their own decision-making despite high confidence in AI-results. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04605822).

Identifying predictors of translocation success in rare plant species.

The fundamental goal of a rare plant translocation is to create self-sustaining populations with the evolutionary resilience to persist in the long term. Yet, most plant translocation syntheses focus on a few factors influencing short-term benchmarks of success (e.g., survival and reproduction). Short-term benchmarks can be misleading when trying to infer future growth and viability because the factors that promote establishment may differ from those required for long-term persistence. We assembled a large (n = 275) and broadly representative data set of well-documented and monitored (7.9 years on average) at-risk plant translocations to identify the most important site attributes, management techniques, and species' traits for six life-cycle benchmarks and population metrics of translocation success. We used the random forest algorithm to quantify the relative importance of 29 predictor variables for each metric of success. Drivers of translocation outcomes varied across time frames and success metrics. Management techniques had the greatest relative influence on the attainment of life-cycle benchmarks and short-term population trends, whereas site attributes and species' traits were more important for population persistence and long-term trends. Specifically, large founder sizes increased the potential for reproduction and recruitment into the next generation, whereas declining habitat quality and the outplanting of species with low seed production led to increased extinction risks and a reduction in potential reproductive output in the long-term, respectively. We also detected novel interactions between some of the most important drivers, such as an increased probability of next-generation recruitment in species with greater seed production rates, but only when coupled with large founder sizes. Because most significant barriers to plant translocation success can be overcome by improving techniques or resolving site-level issues through early intervention and management, we suggest that by combining long-term monitoring with adaptive management, translocation programs can enhance the prospects of achieving long-term success.

Identificación de pronosticadores del éxito de reubicación en especies raras de plantas Resumen El objetivo fundamental de la reubicación de plantas raras es la creación de poblaciones autosuficientes con resiliencia evolutiva que persistan a la larga. De todas maneras, la mayoría de las síntesis de estas reubicaciones se enfocan en unos cuantos factores que influyen sobre los parámetros a corto plazo del éxito (supervivencia y reproducción). Los parámetros a corto plazo pueden ser engañosos si se intenta inferir el crecimiento y la viabilidad en el futuro ya que los factores que promueven el establecimiento pueden diferir de aquellos requeridos para la persistencia a largo plazo. Ensamblamos un conjunto grande de datos representativos en general (n = 275) de las reubicaciones de plantas en riesgo bien documentadas y monitoreadas (7.9 años en promedio) para identificar los atributos de sitio más importantes, las técnicas de manejo y los rasgos de las especies para seis parámetros de ciclos de vida y medidas poblacionales del éxito de reubicación. Usamos el algoritmo de bosque aleatorio para cuantificar la importancia relativa de las 29 variables de pronosticadores para cada medida del éxito. Los factores en los resultados de las reubicaciones variaron con los marcos temporales y las medidas de éxito. Las técnicas de manejo tuvieron la mayor influencia relativa sobre la obtención de parámetros de ciclos de vida y tendencias poblacionales a corto plazo, mientras que los atributos de sitio y los rasgos de la especie fueron más importantes para la persistencia poblacional y las tendencias a largo plazo. En específico, las grandes cantidades de fundadores incrementaron el potencial de reproducción y reclutamiento de la siguiente generación, mientras que la declinación de la calidad del hábitat incrementó el riesgo de extinción y el trasplante de especies con baja producción de semillas redujo el rendimiento del potencial reproductivo a la larga. También detectamos interacciones novedosas entre algunos de los factores más importantes, como el aumento en la probabilidad del reclutamiento en la siguiente generación en especies con tasas mayores de producción de semillas, pero sólo cuando se emparejó con grandes cantidades de fundadores. Ya que las barreras más significativas para el éxito de la reubicación de plantas pueden superarse al mejorar las técnicas o resolver los temas a nivel de sitio por medio de un manejo y una intervención temprana, sugerimos que con la combinación del monitoreo a largo plazo con el manejo adaptativo los programas de reubicación pueden aumentar el prospecto de lograr el éxito a largo plazo.

Hidden sodium in effervescent-tablet dietary supplements and over-the-counter drugs: a comparative cross-sectional study.

OBJECTIVE: Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. DESIGN: Comparative cross-sectional study. SETTING AND METHODS: The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health's Dietary Supplement Label Database). RESULTS: The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9-417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3-474.0 mg). CONCLUSION: Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed.

Radio frequency-based renal denervation: a story of simplicity?

Radio frequency-based renal denervation is a safe and effective way of lowering blood pressure, a common condition associated with high cardiovascular risk. Several catheters have been developed to administer energy to the renal arteries and their side branches, thereby modulating sympathetic renal activity. The Symplicity Flex™ and Symplicity Spyral™ are first- and second-generation devices, respectively, for radio frequency-based renal denervation. There is a continuous need to further improve and adjust interventional antihypertensive therapies. Several randomized controlled trials have been conducted to investigate the safety and efficacy of these catheters and most were able to show radio frequency-based renal denervation to be feasible, safe and effective in lowering blood pressure in hypertensive patients with and without concomitant antihypertensive medication. Herein, the authors discuss the pathophysiologic concepts of renal denervation and its procedural approaches, report catheter designs, summarize clinical trials outcomes and, finally, discuss real-world evidence.

High blood pressure causes illness and death worldwide. Treatment of high blood pressure is usually based on lifestyle modification and blood pressure-lowering drugs. Renal denervation represents a minimally invasive approach to lower blood pressure by interrupting the nerves surrounding the renal arteries. These nerves are involved in the body's fight-or-flight and rest-and-digest systems, the so-called autonomous nervous system. The Spyral™ catheter system uses radio frequency energy to modulate renal nerve activity. Trials have consistently shown that renal denervation is safe. The first-generation catheter was a monoelectrode catheter called Symplicity Flex™ and several points in the renal artery had to be treated. The second-generation device called the Symplicity Spyral™ catheter, on the other hand, has a multielectrode design and consequently fewer ablation points are sufficient for complete denervation. Caused by the positive effects on blood pressure and the consistent safety reports, renal denervation is considered by current guidelines as an alternative and additive treatment approach in patients with high blood pressure.

A randomized, placebo-controlled, trial to assess the photosensitizing, phototoxic and carcinogenic potential of hydrochlorothiazide in healthy volunteers.

BACKGROUND AND AIMS: Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart failure. Whether HCT exhibits phototoxic properties thereby causing skin cancer remains unknown. This study aimed to examine the photosensitizing, phototoxic and carcinogenic potential of HCT in a randomized, placebo-controlled, double-blind trial in vivo and also in vitro . METHODS: The trial assigned 30 healthy, normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg/day or placebo for 15 days. Photosensitivity of the skin with and without the effect of HCT treatment were assessed. Following whole-body ultraviolet A (UVA) and B (UVB, 311 nm) irradiation, phototoxic and carcinogenic reactions by measuring urinary excretion of pyrimidine dimers were evaluated. For the in-vitro studies, human keratinocytes (HaCaT) were incubated with HCT, irradiated with UVB, and analysed for markers of inflammation, apoptosis and carcinogenesis. RESULTS: Skin photosensitivity following exposure to UVA and UVB remained unchanged from baseline to 15-day follow-up in both groups (UVA change HCT 0.0 J/cm 2 vs. placebo 0.0 J/cm 2 ; P  = 0.99; UVB change HCT 0.0 J/cm 2 vs. placebo -0.2 J/cm 2 ; P  = 0.06). Pyrimidine dimers were not detected in either group. In vitro , combination of HCT and UVB irradiation did not induce the expression of oxidative stress marker proteins, inflammatory proteins, apoptotic proteins or activation of oncoproteins. CONCLUSION: HCT did not increase photosensitivity for UVA or UVB in healthy volunteers compared with placebo, and was not associated with phototoxic or carcinogenic reactions. In vitro , HCT was also not associated with phototoxicity or carcinogenesis (NCT04654312).

Histological examination of renal nerve distribution, density, and function in humans.

BACKGROUND: Renal denervation is optimised when guided by knowledge of nerve distribution. AIMS: We aimed to assess sympathetic nerve distribution along the renal arteries, especially in post-bifurcation vessel segments. METHODS: Renal arteries and surrounding tissue from 10 body donors were collected and examined histologically. Immunohistochemical staining was used to analyse nerve distribution and to identify afferent and efferent sympathetic nerves. RESULTS: A total of 6,781 nerves surrounding 18 renal arteries were evaluated. The mean lumen-nerve distance of the left renal artery (2.32±1.95 mm) was slightly greater than the right (2.29±2.03 mm; p=0.161); this varied across the arteries' courses: 3.7±2.3 mm in proximal segments, 2.5±2.0 mm in middle segments, 1.9±1.6 mm in distal prebifurcation segments and 1.3±1.0 mm in post-bifurcation segments (p<0.001). The number of nerves per quadrant was highest in the proximal segments (13.7±18.6), followed by the middle (9.7±7.9), distal prebifurcation (8.0±7.6), and distal post-bifurcation (4.3±4.0) segments (p<0.001). Circumferentially, the number of nerves was highest in the superior (7.8±9.4) and the ventral (7.6±13.1) quadrants (p=0.638). The mean tyrosine hydroxylase (TH) to calcitonin gene-related peptide (CGRP) ratio increased from proximal (37.5±33.5) to distal (72.0±7.2 in the post-bifurcation segments; p<0.001). Thirty-eight neuroganglia were identified along 14 (78%) renal arteries. CONCLUSIONS: Nerves converge to the renal arteries' lumen in the distal segments and along branches, resulting in the lowest number of nerves per quadrant and the shortest lumen-nerve distance in the distal post-bifurcation segments. Efferent nerves occur predominantly, and the ratio of efferent to afferent nerves continues to increase in the vessels' course.

Arterial Hypertension-clinical trials update 2023.

Arterial hypertension is associated with increased morbidity and mortality and research in the field is highly dynamic. This summary reviews the most important clinical trials published in 2022 and early 2023. Findings on new pharmacological approaches to treat resistant hypertension are presented and new knowledge about the optimal timing of the antihypertensive medication intake is discussed. It is focused on optimal blood pressure treatment targets and the problem of treatment and guideline inertia is acknowledged. Information about pregnancy-related hypertension is presented and blood pressure control following percutaneous thrombectomy after ischemic stroke is discussed. Finally, novel clinical data on device-based approaches to treat hypertension are summarized. The hypertension trials update summarizes the most important clincal trials on hypertension research in 2022 and early 2023. CTD - chlorthalidone, CV - cardiovascular, HCT - hydrochlorothiazide, SBP - systolic blood pressure, RDN - renal denervation *depicts systolic blood pressure only.

Diagnostic performance of augmented intelligence with 2D and 3D total body photography and convolutional neural networks in a high-risk population for melanoma under real-world conditions: A new era of skin cancer screening?

BACKGROUND: Convolutional neural networks (CNNs) have outperformed dermatologists in classifying pigmented skin lesions under artificial conditions. We investigated, for the first time, the performance of three-dimensional (3D) and two-dimensional (2D) CNNs and dermatologists in the early detection of melanoma in a real-world setting. METHODS: In this prospective study, 1690 melanocytic lesions in 143 patients with high-risk criteria for melanoma were evaluated by dermatologists, 2D-FotoFinder-ATBM and 3D-Vectra WB360 total body photography (TBP). Excision was based on the dermatologists' dichotomous decision, an elevated CNN risk score (study-specific malignancy cut-off: FotoFinder >0.5, Vectra >5.0) and/or the second dermatologist's assessment with CNN support. The diagnostic accuracy of the 2D and 3D CNN classification was compared with that of the dermatologists and the augmented intelligence based on histopathology and dermatologists' assessment. Secondary end-points included reproducibility of risk scores and naevus counts per patient by medical staff (gold standard) compared to automated 3D and 2D TBP CNN counts. RESULTS: The sensitivity, specificity, and receiver operating characteristics area under the curve (ROC-AUC) for risk-score-assessments compared to histopathology of 3D-CNN with 95% confidence intervals (CI) were 90.0%, 64.6% and 0.92 (CI 0.85-1.00), respectively. While dermatologists and augmented intelligence achieved the same sensitivity (90%) and comparable classification ROC-AUC (0.91 [CI 0.80-1.00], 0.88 [CI 0.77-1.00]) with 3D-CNN, their specificity was superior (92.3% and 86.2%, respectively). The 2D-CNN (sensitivity: 70%, specificity: 40%, ROC-AUC: 0.68 [CI 0.46-0.90]) was outperformed by 3D CNN and dermatologists. The 3D-CNN showed a higher correlation coefficient for repeated measurements of 246 lesions (R = 0.89) than the 2D-CNN (R = 0.79). The mean naevus count per patient varied significantly (gold standard: 210 lesions; 3D-CNN: 469; 2D-CNN: 1324; p < 0.0001). CONCLUSIONS: Our study emphasises the importance of validating the classification of CNNs in real life. The novel 3D-CNN device outperformed the 2D-CNN and achieved comparable sensitivity with dermatologists. The low specificity of CNNs and the lack of automated counting of TBP nevi currently limit the use of augmented intelligence in clinical practice.

Educational level-dependent melanoma awareness in a high-risk population in Switzerland.

Introduction: The worldwide incidence of melanoma has been increasing rapidly in recent decades with Switzerland having one of the highest rates in Europe. Ultraviolet (UV) radiation is one of the main risk factors for skin cancer. Our objective was to investigate UV protective behavior and melanoma awareness in a high-risk cohort for melanoma. Methods: In this prospective monocentric study, we assessed general melanoma awareness and UV protection habits in at-risk patients (≥100 nevi, ≥5 dysplastic nevi, known CDKN2A mutation, and/or positive family history) and melanoma patients using questionnaires. Results: Between 01/2021 and 03/ 2022, a total of 269 patients (53.5% at-risk patients, 46.5% melanoma patients) were included. We observed a significant trend toward using a higher sun protection factor (SPF) in melanoma patients compared with at-risk patients (SPF 50+: 48% [n=60] vs. 26% [n=37]; p=0.0016). Those with a college or university degree used a high SPF significantly more often than patients with lower education levels (p=0.0007). However, higher educational levels correlated with increased annual sun exposure (p=0.041). Neither a positive family history for melanoma, nor gender or Fitzpatrick skin type influenced sun protection behavior. An age of ≥ 50 years presented as a significant risk factor for melanoma development with an odd's ratio of 2.32. Study participation resulted in improved sun protection behavior with 51% reporting more frequent sunscreen use after study inclusion. Discussion: UV protection remains a critical factor in melanoma prevention. We suggest that melanoma awareness should continue to be raised through public skin cancer prevention campaigns with a particular focus on individuals with low levels of education.

Human epidermis organotypic cultures, a reproducible system recapitulating the epidermis in vitro.

The translatability of research is highly dependent on models that recapitulate human tissues and organs. Here, we describe a procedure for the generation of human epidermis organotypic cultures (HEOCs) from primary keratinocytes isolated from foreskin and adult skin as well as from an immortalized keratinocyte cell line (KerTr). We tested several media conditions to develop a defined HEOC growing and expansion media. We characterized the HEOCs and show that in optimal culture conditions they express the proliferation marker Ki67, the basement membrane protein collagen 17 (col17) and the epidermal differentiation markers keratin 15 (K15), keratin 14 (K14), keratin 5 (K5), keratin 10 (K10), keratin 1 (K1), transglutaminase 1 (TGM1), transglutaminase 3 (TGM3) and filaggrin (FLG). Thus, they recapitulate the human epidermis and are stratified from the basal layer to the stratum corneum. These HEOC can be generated reproducibly on a large scale, making it an invaluable model for screening therapeutic compounds and also for the study of pathologies affecting the epidermis.

Association of hydrochlorothiazide treatment compared with alternative diuretics with overall and skin cancer risk: a propensity-matched cohort study.

INTRODUCTION: Hydrochlorothiazide (HCT) has been suggested to induce photosensitivity, thereby increasing the incidence of skin cancers. After a pharmacovigilance alert, HCT was frequently withdrawn or substituted by other diuretics. The aim of this study was to compare the association of exposure to HCT with cancer risk versus alternative diuretics. METHODS: A retrospective cohort study was conducted based on data from the AOK PLUS, a large German statutory health insurance fund. Patients with HCT treatment were propensity score matching to patients using non-HCT diuretics. Incidence of cancer of any kind and, specifically, skin cancer was assessed in both groups. Time-to-incident cancer diagnosis was evaluated and compared between the groups. RESULTS: A total of 199 708 patients were included in the final analysis ( n  = 76 855 in the HCT group; n  = 122 853 in the non-HCT-diuretics group). After propensity score matching, 122 554 patients remained in the sample ( n  = 61 277 for both groups, of which >96% had hypertension, mean age 73 years, 61% female). HCT treatment was associated with a lower incidence of cancer of any kind compared with non-HCT diuretics (incidence rate ratio per 100 patient years 0.84 95% confidence interval: 0.82-0.87). HCT treatment was associated with a small albeit significantly higher incidence rate ratio of skin cancer (1.15 95% confidence interval: 1.06-1.24) with significant variances over time. Although numerically higher, the difference accounts to only 0.05 more skin cancer diagnoses in 100 patient-years. CONCLUSION: HCT treatment compared with alternative diuretics was associated with a lower all-cancer risk and a numerically small increased skin cancer risk in a large German population. Risk-benefit evaluation should be executed in patients with increased skin cancer risk and treatment with HCT. Furthermore, advice for skin protection is warranted in all patients taking thiazide or thiazide-like diuretics.

Objective hand eczema severity assessment with automated lesion anatomical stratification.

Hand eczema (HE) is one of the most frequent dermatoses, known to be both relapsing and remitting. Regular and precise evaluation of the disease severity is key for treatment management. Current scoring systems such as the hand eczema severity index (HECSI) suffer from intra- and inter-observer variance. We propose an automated system based on deep learning models (DLM) to quantify HE lesions' surface and determine their anatomical stratification. In this retrospective study, a team of 11 experienced dermatologists annotated eczema lesions in 312 HE pictures, and a medical student created anatomical maps of 215 hands pictures based on 37 anatomical subregions. Each data set was split into training and test pictures and used to train and evaluate two DLMs, one for anatomical mapping, the other for HE lesions segmentation. On the respective test sets, the anatomy DLM achieved average precision and sensitivity of 83% (95% confidence interval [CI] 80-85) and 85% (CI 82-88), while the HE DLM achieved precision and sensitivity of 75% (CI 64-82) and 69% (CI 55-81). The intraclass correlation of the predicted HE surface with dermatologists' estimated surface was 0.94 (CI 0.90-0.96). The proposed method automatically predicts the anatomical stratification of HE lesions' surface and can serve as support to evaluate hand eczema severity, improving reliability, precision and efficiency over manual assessment. Furthermore, the anatomical DLM is not limited to HE and can be applied to any other skin disease occurring on the hands such as lentigo or psoriasis.

Closing the gap - development of an analytical methodology using volumetric absorptive microsampling of finger prick blood followed by LC-HRMS/MS for adherence monitoring of antihypertensive drugs.

Volumetric absorptive microsampling (VAMS), an emerging microsampling technique, is a promising tool for adherence monitoring. This study focused on development of an analytical methodology to improve VAMS-based strategies for adherence assessment by analyzing angiotensin-converting-enzyme (ACE) inhibitors, loop diuretics, a potassium-sparing diuretic, and a thiazide diuretic. Development included sample preparation, chromatographic conditions, mass spectrometry settings, validation, and demonstrating proof of concept. Quantification of analytes, by name furosemide, hydrochlorothiazide, lisinopril, torasemide, and the active metabolites, canrenone, enalaprilat, and ramiprilat in finger prick blood (FPB), was validated based on international guidelines. Selectivity, carryover, and within/between-run accuracy and precision were in accordance with the recommendations. The matrix effect was evaluated at three different hematocrit levels (HT: 20%, 40%, 60%) and the coefficients of variation did not exceed 15%. Dilution integrity (1:10 and 1:20) was given for all analytes except lisinopril, yet for lisinopril, the therapeutic range was already covered by the calibration range. Long-term stability in VAMS tips was tested for 2 weeks at 24 °C in the dark and revealed no degradation of analytes. The proof of concept was performed by analyzing 35 intakes of ACE-inhibitors and diuretics in 18 VAMS and matched plasma samples. Hereby, determined concentration in FPB and plasma cannot be used interchangeably, and thus specific reference ranges for whole blood must be established. Nevertheless, the VAMS-based strategy was shown to be suitable for assessing adherence of all classes of antihypertensive drugs used in the guidelines to manage hypertension.