Clinical and histological comparison of IgA nephritis and renal IgA vasculitis.

BACKGROUND: IgA nephritis (IgAN) and renal IgA vasculitis (IgAV) show renal IgA deposits, but whether these two diseases are distinct entities or a spectrum of the same condition is under debate. In this study, we add perspective by contrasting the clinical course and histological presentation using the Oxford classification and the National Institutes of Health lupus nephritis activity index (LN-AI) and chronicity index (LN-CI) in IgAN and IgAV. METHODS: In this single-center, retrospective study, kidney biopsies of 163 adult patients with IgAN and 60 adult patients with IgAV were compared according to the Oxford MEST-C Score, LN-AI, and LN-CI. At the time of biopsy, clinical presentation was compared in terms of age, arterial hypertension, diabetes mellitus, extrarenal manifestations, as well as estimated glomerular filtration rate, proteinuria, and urine sediment. IgAV patients and all IgAN patients with crescents received immunosuppressive treatment. After biopsy, kidney function was followed until patients reached end-stage renal disease (ESRD) or they died. RESULTS: The clinical course and kidney histology differ in IgAN and IgAV. IgAV patients showed more microhematuria and nephritic sediment, while IgAN patients had a greater history of arterial hypertension, more proteinuria, and a higher risk for ESRD. These clinical differences were associated with histological differences, as kidney biopsies of IgAN patients were characterized by glomerulosclerosis and tubular atrophy, while kidney biopsies of IgAV patients were characterized by endocapillary hypercellularity and crescents. Overall, tubular atrophy and a LN-CI ≥ 4 were associated with a higher risk for ESRD in IgAN and IgAV. CONCLUSION: Our study supports the notion that IgAN and IgAV follow distinct courses, suggesting that they require different treatment strategies. Moreover, we make a point that the Oxford classification and LN-CI can be useful in categorizing and predicting long-term prognosis not only in IgAN, but also in IgAV.

Occupational Health Literacy Scale (OHLS): development and validation of a domain-specific measuring instrument.

Occupational health literacy (OHL) is a domain-specific approach that can empower people to make health-appropriate decisions in the work environment. OHL comprises the knowledge, skills and willingness of people to access and process health-related information and to apply it in work situations. The aim of this study was to evolve a conceptual model and validate a scale for OHL, that can be used in many sectors in the Western industrial countries, which does not yet exist. After piloting, item selection and alteration were carried out in a pretest with n = 163 working adults in diverse small- and medium-sized enterprises in Germany. The resulting OHL items were validated in a main survey with n = 828 participants working in small- and medium-sized enterprises and among them 47.5% people with migration background. The final 12-item questionnaire had good structural characteristics and is reliable and valid for measuring OHL. Using exploratory structural equation modeling, good fit indices (root mean square error of approximation = 0.063, comparative fit index = 0.940) confirmed a two-factor structure: (i) knowledge and skill-based processing of health information (internal consistency α = 0.88) and (ii) willingness and responsibility for occupational health (α = 0.74). The OHL scale fills the gap regarding domain-specific OHL questionnaires for working adults in diverse sectors in Western industrial countries. The Occupational Health Literacy Scale can be used to identify the needs of employees and companies and then to adapt and evaluate health promotion measures. Further research could include validation and use in other countries and large companies.

MicroRNA-374b induces endothelial-to-mesenchymal transition and early lesion formation through the inhibition of MAPK7 signaling.

Endothelial-mesenchymal transition occurs during intimal hyperplasia and neointima formation via mechanisms that are incompletely understood. Endothelial MAPK7 signaling is a key mechanosensitive factor that protects against endothelial-mesenchymal transition, but its signaling activity is lost in vessel areas that are undergoing pathological remodeling. At sites of vascular remodeling in mice and pigs, endothelial MAPK7 signaling was lost. The TGFß-induced microRNA-374b targets MAPK7 and its downstream effectors in endothelial cells, and its expression induces endothelial-mesenchymal transition. Gain-of-function experiments, where endothelial MAPK7 signaling was restored, precluded endothelial-mesenchymal transition. In human coronary artery disease, disease severity is associated with decreased MAPK7 expression levels and increased miR-374b expression levels. Endothelial-mesenchymal transition occurs in intimal hyperplasia and early lesion formation and is governed in part by microRNA-374b-induced silencing of MAPK7 signaling. Restoration of MAPK7 signaling abrogated these pathological effects in endothelial cells expressing miR-374b. Thus, our data suggest that the TGFß-miR-374b-MAPK7 axis plays a key role in the induction of endothelial-mesenchymal transition during intimal hyperplasia and early lesion formation and might pose an interesting target for antiatherosclerosis therapy. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Precision prevention in occupational health: a conceptual analysis and development of a unified understanding and an integrative framework.

Introduction: Precision prevention implements highly precise, tailored health interventions for individuals by directly addressing personal and environmental determinants of health. However, precision prevention does not yet appear to be fully established in occupational health. There are numerous understandings and conceptual approaches, but these have not yet been systematically presented or synthesized. Therefore, this conceptual analysis aims to propose a unified understanding and develop an integrative conceptual framework for precision prevention in occupational health. Methods: Firstly, to systematically present definitions and frameworks of precision prevention in occupational health, six international databases were searched for studies published between January 2010 and January 2024 that used the term precision prevention or its synonyms in the context of occupational health. Secondly, a qualitative content analysis was conducted to analyze the existing definitions and propose a unified understanding. Thirdly, based on the identified frameworks, a multi-stage exploratory development process was applied to develop and propose an integrative conceptual framework for precision prevention in occupational health. Results: After screening 3,681 articles, 154 publications were reviewed, wherein 29 definitions of precision prevention and 64 different frameworks were found, which can be summarized in eight higher-order categories. The qualitative content analysis revealed seven themes and illustrated many different wordings. The proposed unified understanding of precision prevention in occupational health takes up the identified themes. It includes, among other things, a contrast to a "one-size-fits-all approach" with a risk- and resource-oriented data collection and innovative data analytics with profiling to provide and improve tailored interventions. The developed and proposed integrative conceptual framework comprises three overarching stages: (1) data generation, (2) data management lifecycle and (3) interventions (development, implementation and adaptation). Discussion: Although there are already numerous studies on precision prevention in occupational health, this conceptual analysis offers, for the first time, a proposal for a unified understanding and an integrative conceptual framework. However, the proposed unified understanding and the developed integrative conceptual framework should only be seen as an initial proposal that should be critically discussed and further developed to expand and strengthen both research on precision prevention in occupational health and its practical application in the workplace.

Occupational health literacy and work ability: a moderation analysis including interpersonal and organizational factors in healthy organizations.

Introduction: Healthy organizations approach to occupational safety and health should holistically include individual, interpersonal, and organizational levels. There is an empirical research gap in considering different levels in organizations for health promotion in the context of maximizing work ability. This study aims to investigate the association of (1) occupational health literacy (on an individual level), (2) health-oriented leadership (interpersonal level), (3) participation possibilities in health, and (4) values of health in companies (both organizational levels) on work ability. Additionally, we examined the potentially moderating role of health-oriented leadership, participation possibilities in health, and values of health between occupational health literacy and work ability. Methods: Cross-sectional data were obtained from 828 employers and employees in small and medium-sized enterprises. Self-report measures included occupational health literacy, health-oriented leadership, work ability, participation possibilities in health at work, and values of health in the company. Occupational health literacy comprises two factors: a knowledge-/skill-based approach to occupational health and a willingness/responsibility for occupational health. Participation possibilities in health are measured regarding participatory opportunities and co-creation of health at work. Values of health in the company capture the importance of health in the workplace and the scope for improving employees' health. Data were analyzed using latent regression and latent moderation analyses controlling for age, gender, and educational level. Results: Occupational health literacy (knowledge-/skill-based), health-oriented leadership, participation possibilities in health, and values of health in companies showed positive associations with work ability. Health-oriented leadership on an interpersonal level was found to moderate the positive relationship between (knowledge-/skill-based) occupational health literacy and work ability. Participation possibilities in health on an organizational level acted as a moderator on the relationship between both occupational health literacy factors and work ability. Discussion: Individual, interpersonal, and organizational factors play important roles in maintaining work ability in healthy organizations. This study highlights the importance of promoting occupational health literacy among employees and leaders, creating a healthy workplace through health-oriented leadership, and providing participatory opportunities for co-creation in health promotion at work. Future research should further explore these factors' roles in different industries and contexts and how they may be addressed effectively in tailored workplace interventions.

Precision prevention in worksite health-A scoping review on research trends and gaps.

OBJECTIVES: To map the current state of precision prevention research in the workplace setting, specifically to study contexts and characteristics, and to analyze the precision prevention approach in the stages of risk assessment/data monitoring, data analytics, and the health promotion interventions implemented. METHODS: Six international databases were searched for studies published between January 2010 and May 2023, using the term "precision prevention" or its synonyms in the context of worksite health promotion. RESULTS: After screening 3,249 articles, 129 studies were reviewed. Around three-quarters of the studies addressed an intervention (95/129, 74%). Only 14% (18/129) of the articles primarily focused on risk assessment and data monitoring, and 12% of the articles (16/129) mainly included data analytics studies. Most of the studies focused on behavioral outcomes (61/160, 38%), followed by psychological (37/160, 23%) and physiological (31/160, 19%) outcomes of health (multiple answers were possible). In terms of study designs, randomized controlled trials were used in more than a third of all studies (39%), followed by cross-sectional studies (18%), while newer designs (e.g., just-in-time-adaptive-interventions) are currently rarely used. The main data analyses of all studies were regression analyses (44% with analyses of variance or linear mixed models), whereas machine learning methods (e.g., Algorithms, Markov Models) were conducted only in 8% of the articles. DISCUSSION: Although there is a growing number of precision prevention studies in the workplace, there are still research gaps in applying new data analysis methods (e.g., machine learning) and implementing innovative study designs. In the future, it is desirable to take a holistic approach to precision prevention in the workplace that encompasses all the stages of precision prevention (risk assessment/data monitoring, data analytics and interventions) and links them together as a cycle.

The Urine Light Chain/eGFR Quotient as a Tool to Rule out Cast Nephropathy in Myeloma-Associated Kidney Failure.

Kidney involvement with resulting kidney failure leads to increased mortality in patients with multiple myeloma (MM). Cast nephropathy (CN), in particular, if left untreated, quickly leads to kidney failure requiring dialysis and has a very poor prognosis for the affected patient. The gold standard for diagnosing kidney involvement is a kidney biopsy. However, due to bleeding risk, this cannot be done in every patient. We recently reported that a quotient of urine light chain (LCurine) to glomerular filtration rate (eGFR) is a non-invasive diagnostic tool for patients with kidney involvement in MM. But this quotient has not yet been tested in everyday clinical practice. In this study, our LCurine/eGFR ratio was tested on 67 patients in two centers. Enrollment took place between January 2019 and September 2023. A total of 18 of the 67 patients had CN. With the threshold defined in our initial paper, we were able to show a sensitivity of 100% with a specificity of 85.7% for CN in patients with MM. As a result, the LCurine/eGFR quotient recognizes 100% of all CN and can therefore detect this group, which has a very poor prognosis, without the need for a kidney biopsy.

Occupational resource profiles for an addressee orientation in occupational health management: a segmentation analysis.

Introduction: In order to make sustainable decisions in precision prevention and health promotion, it is important to adequately assess people's demands and resources at work. To reach them in an addressee-oriented way, a segmentation of employers and employees based on occupational resources is a promising option. We identified profiles based on personal and perceived organizational resources. Furthermore, we used job demands for profile descriptions to obtain a deeper understanding of the profiles, characterizing people with similar occupational resources. Methods: Personal occupational resources (occupational health literacy and self-efficacy) and perceived organizational resources (job decision latitude and participation in health at work) were assessed among employers and employees (n = 828) in small- and medium-sized enterprises in Germany. Job demands, socioeconomic status, and hierarchy levels in the company were used for further profile descriptions. Results: A six-profile solution fitted best to the data based on cluster and profile analyses. One profile was characterized by above-average occupational resources, and another profile was characterized by below-average resources. The other four profiles showed that the individual and perceived organizational resources contrasted. Either organizational resources such as job decision latitude existed and personal resources were not highly developed or people had high individual motivation but few possibilities to participate in health at work. People with medium or high job demands as well as people with low socioeconomic status were most frequently in below-average resource profiles. Employers with high hierarchy levels were overrepresented in the above-average profiles with high organizational resources. Discussion: Following the segmentation of the addressees, organizations might be supported in identifying needs and areas for prevention and health promotion. Interventions can be optimally developed, tailored, and coordinated through a deeper understanding of job demands and resources. Especially employees with low socioeconomic status and high job demands might profit from an addressee-orientated approach based on resource profiles. For example, employees obtain an overview of their occupational resource profile to recognize the development potential for safe and healthy behavior at work. Follow-up research should be used to examine how this feedback to employers and employees is implemented and how it affects the sustainability of tailored interventions.

"How is your thesis going?"-Ph.D. students' perspectives on mental health and stress in academia.

Mental health issues among Ph.D. students are prevalent and on the rise, with multiple studies showing that Ph.D. students are more likely to experience symptoms of mental health-related issues than the general population. However, the data is still sparse. This study aims to investigate the mental health of 589 Ph.D. students at a public university in Germany using a mixed quantitative and qualitative approach. We administered a web-based self-report questionnaire to gather data on the mental health status, investigated mental illnesses such as depression and anxiety, and potential areas for improvement of the mental health and well-being of Ph.D. students. Our results revealed that one-third of the participants were above the cut-off for depression and that factors such as perceived stress and self-doubt were prominent predictors of the mental health status of Ph.D. students. Additionally, we found job insecurity and low job satisfaction to be predictors of stress and anxiety. Many participants in our study reported working more than full-time while being employed part-time. Importantly, deficient supervision was found to have a negative effect on Ph.D. students' mental health. The study's results are in line with those of earlier investigations of mental health in academia, which likewise reveal significant levels of depression and anxiety among Ph.D. students. Overall, the findings provide a greater knowledge of the underlying reasons and potential interventions required for advancing the mental health problems experienced by Ph.D. students. The results of this research can guide the development of effective strategies to support the mental health of Ph.D. students.

miRetrieve-an R package and web application for miRNA text mining.

microRNAs (miRNAs) regulate gene expression and thereby influence biological processes in health and disease. As a consequence, miRNAs are intensely studied and literature on miRNAs has been constantly growing. While this growing body of literature reflects the interest in miRNAs, it generates a challenge to maintain an overview, and the comparison of miRNAs that may function across diverse disease fields is complex due to this large number of relevant publications. To address these challenges, we designed miRetrieve, an R package and web application that provides an overview on miRNAs. By text mining, miRetrieve can characterize and compare miRNAs within specific disease fields and across disease areas. This overview provides focus and facilitates the generation of new hypotheses. Here, we explain how miRetrieve works and how it is used. Furthermore, we demonstrate its applicability in an exemplary case study and discuss its advantages and disadvantages.

microRNA Expression Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients and Differences from Patients Treated with Anti-VEGF Therapy.

Purpose: microRNAs (miRNAs) mediate the pathological mechanisms of diabetic retinopathy. In this study, we compared miRNA expression profiles in the vitreous between patients with proliferative diabetic retinopathy (PDR) and patients with a macular hole as non-diabetic controls, and between PDR patients treated with anti-vascular endothelial growth factor (VEGF) therapy and untreated PDR patients. Methods: Vitreous samples of non-diabetic and PDR patients were screened for miRNAs with quantitative polymerase chain reaction (qPCR) panels. miRNA candidates were validated in vitreous samples of a second, independent cohort. In addition, the effect of anti-VEGF therapy was investigated in the vitreous of a third study population consisting of PDR patients who had not received anti-VEGF therapy and PDR patients who had received preoperative anti-VEGF therapy. Results: During screening, seven miRNAs were found to be significantly higher in the vitreous of PDR patients, whereas two miRNAs were found to be significantly lower compared with non-diabetic controls. Validating the expression of these miRNAs in a second cohort resulted in the identification of six miRNAs that were expressed at significantly higher rates in the vitreous of PDR patients: hsa-miR-20a-5p, hsa-miR-23b-3p, hsa-miR-142-3p, hsa-miR-185-5p, hsa-miR-326, and hsa-miR-362-5p. Among these six miRNAs, hsa-miR-23b-3p levels were lower in the anti-VEGF-treated group of PDR patients compared with untreated PDR patients. Conclusions: In this study, we identified six miRNAs that are expressed more highly in PDR patients and one miRNA that is expressed at a lower levels in anti-VEGF-treated PDR patients. Translational Relevance: miRNAs identified in the vitreous of PDR patients may improve our understanding of the mechanisms leading to PDR.

The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy.

AIMS: To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. METHODS: Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed. In the Ins2Akita mouse model, levels of EPAC-1 expression as well as microRNA-7-5p were assessed by qPCR. Endothelial nitric oxide synthase was assessed by immunoblotting in the Ins2Akita model. RESULTS: Hypoxia induces the expression of microRNA-7-5p that translationally inhibits the expression of EPAC-1 in endothelial cells, resulting in hyperpermeability and the loss of eNOS activity. Activation of EPAC-1 by the cAMP analogue 8-pCPT-2'-O-Me-cAMP reduced the sensitivity of EPAC-1 to oxidative stress and restored the endothelial permeability to baseline levels. Additionally, 8-pCPT-2'-O-Me-cAMP rescued eNOS activity and NO production. In mouse models of retinopathy, i.e., oxygen-induced retinopathy and the spontaneous diabetic heterozygous Ins2Akita mice, EPAC-1 levels are decreased which is associated with an increase in microRNA-7-5p expression and reduced eNOS activity. CONCLUSION/INTERPRETATION: In retinopathy, EPAC-1 expression is decreased in a microRNA-7-mediated manner, contributing to endothelial dysfunction. Pharmacological activation of remnant EPAC-1 rescues endothelial function. Collectively, these data indicate that EPAC-1 resembles an efficacious and druggable target molecule for the amelioration of (diabetic) retinopathy.

Catecholamines facilitate VEGF-dependent angiogenesis via ß2-adrenoceptor-induced Epac1 and PKA activation.

Chronic stress has been associated with the progression of cancer and antagonists for ß-adrenoceptors (ßAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial ß2AR in angiogenesis can be envisioned. We therefore investigated the role of ß2AR-induced cAMP formation by analyzing the role of the cAMP effector molecules exchange factor directly activated by cAMP 1 (Epac1) and protein kinase A (PKA) in endothelial cells (EC). Epac1-deficient mice showed a reduced amount of pre-retinal neovascularizations in the model of oxygen-induced retinopathy, which is predominantly driven by vascular endothelial growth factor (VEGF). siRNA-mediated knockdown of Epac1 in human umbilical vein EC (HUVEC) decreased angiogenic sprouting by lowering the expression of the endothelial VEGF-receptor-2 (VEGFR-2). Conversely, Epac1 activation by ß2AR stimulation or the Epac-selective activator cAMP analog 8-p-CPT-2'-O-Me-cAMP (8-pCPT) increased VEGFR-2 levels and VEGF-dependent sprouting. Similar to Epac1 knockdown, depletion of the monomeric GTPase Rac1 decreased VEGFR-2 expression. As Epac1 stimulation induces Rac1 activation, Epac1 might regulate VEGFR-2 expression through Rac1. In addition, we found that PKA was also involved in the regulation of angiogenesis in EC since the adenylyl cyclase (AC) activator forskolin (Fsk), but not 8-pCPT, increased sprouting in Epac1-depleted HUVEC and this increase was sensitive to a selective synthetic peptide PKA inhibitor. In accordance, ß2AR- and AC-activation, but not Epac1 stimulation increased VEGF secretion in HUVEC.Our data indicate that high levels of catecholamines, which occur during chronic stress, prime the endothelium for angiogenesis through a ß2AR-mediated increase in endothelial VEGFR-2 expression and VEGF secretion.

Angiopoietin-1 is regulated by miR-204 and contributes to corneal neovascularization in KLEIP-deficient mice.

PURPOSE: Corneal neovascularization can cause loss of vision. The introduction of anti-VEGF therapy has been a major improvement in therapeutic options. Recently, we established Kelch-like Ect2-interacting protein (KLEIP/KLHL20) knockout mice as a model of spontaneous corneal neovascular dystrophy. The aim of the present study was to characterize corneal neovascularization in progressive corneal dystrophy in KLEIP(-/-) mice, to evaluate the efficacy of anti-VEGF therapy, and to identify novel molecular regulators in this experimental model. METHODS: Corneal neovascularization was assessed by immunohistochemistry. Vascular endothelial growth factor signaling was inhibited by injection of a blocking antibody. Microarrays were used to measure expression of mRNA and microRNA (miRNA) in dystrophic corneae. Results were validated by immunohistochemistry and Western blotting. RESULTS: Blood vessels and lymphatics grew from the limbus toward the dystrophic epithelium in corneae of KLEIP(-/-) mice. Blocking VEGF signaling did not reduce phenotype progression. Correspondingly, microarray analysis revealed no upregulation of canonical vascular growth factors in late dystrophy. During phenotype progression, angiopoietin-1 expression increased while miR-204 expression decreased. Bioinformatic analysis identified a binding site for miR-204 in the angiopoietin-1 gene. Validation by in vitro experiments confirmed regulation of angiopoietin-1 by miR-204. CONCLUSIONS: Vascular endothelial growth factor does not act as a major player in corneal neovascularization in KLEIP(-/-) mice. However, the proangiogenic factor angiopoietin-1 was strongly upregulated in late-stage phenotype, correlating with loss of miR-204 expression. Correspondingly, we identified miR-204 as a novel regulator of angiopoietin-1 in vitro. These findings may explain the incomplete efficacy of anti-VEGF therapy in the clinic and may provide new candidates for pharmaceutical intervention.

Breathing manoeuvre-dependent changes in myocardial oxygenation in healthy humans.

AIMS: CO2 is an intrinsic vasodilator for cerebral and myocardial blood vessels. Myocardial vasodilation without a parallel increase of the oxygen demand leads to changes in myocardial oxygenation. Because apnoea and hyperventilation modify blood CO2, we hypothesized that voluntary breathing manoeuvres induce changes in myocardial oxygenation that can be measured by oxygenation-sensitive cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: Fourteen healthy volunteers were studied. Eight performed free long breath-hold as well as a 1- and 2-min hyperventilation, whereas six aquatic athletes were studied during a 60-s breath-hold and a free long breath-hold. Signal intensity (SI) changes in T2*-weighted, steady-state free precession, gradient echo images at 1.5 T were monitored during breathing manoeuvres and compared with changes in capillary blood gases. Breath-holds lasted for 35, 58 and 117 s, and hyperventilation for 60 and 120 s. As expected, capillary pCO2 decreased significantly during hyperventilation. Capillary pO2 decreased significantly during the 117-s breath-hold. The breath-holds led to a SI decrease (deoxygenation) in the left ventricular blood pool, while the SI of the myocardium increased by 8.2% (P = 0.04), consistent with an increase in myocardial oxygenation. In contrast, hyperventilation for 120 s, however, resulted in a significant 7.5% decrease in myocardial SI/oxygenation (P = 0.02). Change in capillary pCO2 was the only independently correlated variable predicting myocardial oxygenation changes during breathing manoeuvres (r = 0.58, P < 0.01). CONCLUSION: In healthy individuals, breathing manoeuvres lead to changes in myocardial oxygenation, which appear to be mediated by CO2. These changes can be monitored in vivo by oxygenation-sensitive CMR and thus, may have value as a diagnostic tool.