Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide (SEM) and tirzepatide (TZP) were initially approved for type 2 diabetes management but are increasingly used for weight loss. Limited data exist on real-world use among patients with rheumatic and musculoskeletal diseases (RMDs). This study aimed to describe characteristics and trends in SEM and TZP initiation among individuals with RMDs and to identify factors associated with weight loss. We conducted a retrospective analysis using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry. Adults with RMD prescribed SEM or TZP between 2018 and 2024 were included. Patients with an evaluation and management visit before first GLP-1 RA prescription were classified as new users. The primary outcome was percent change in body weight from baseline to 12 months. Multivariable linear regression assessed factors associated with percent weight change, and logistic models identified predictors of ≥5%, ≥10%, and ≥15% weight loss. Among 60,198 patients with RMD treated with GLP-1 RAs (72% SEM), 80.5% were female, and 54.9% had diabetes; the mean age was 57.0 years, and body mass index was 36.4. GLP-1 RA use increased from 0.1% in 2018 to 6.8% in 2024. At 12 months, SEM and TZP users lost 5.8% and 8.2% of body weight, respectively. TZP users lost 2.2% (95% confidence interval [CI] 1.9-2.5) more weight than SEM users, and those without diabetes lost 1.8% (95% CI 1.5-2.1) more than those with diabetes. GLP-1 RA use is increasing among patients with RMD and is associated with clinically meaningful weight loss, particularly with TZP and in individuals without diabetes.
Systemic sclerosis is a rare autoimmune connective tissue disease characterized by progressive fibrosis of the skin and internal organs, vasculopathy, and the presence of specific autoantibodies. Despite its low prevalence, systemic sclerosis is associated with high morbidity. Early features often include Raynaud phenomenon, hand edema, and fatigue. Diagnosis requires a comprehensive approach, including clinical assessment, laboratory evaluation, imaging, and pulmonary function testing. The American College of Rheumatology and European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism) provide classification criteria and updated treatment recommendations. Management focuses on addressing eight disease domains: Raynaud phenomenon, digital ulcers, pulmonary artery hypertension, interstitial lung disease, renal crisis, gastrointestinal involvement, skin fibrosis, and musculoskeletal involvement. Vasodilator therapy is first-line treatment for Raynaud phenomenon, whereas phosphodiesterase-5 inhibitors and intravenous iloprost are used to treat digital ulcers. Combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists is first-line treatment for pulmonary artery hypertension. Mycophenolate mofetil is the preferred treatment for interstitial lung disease.
Lupus nephritis (LN) is a major driver of morbidity and kidney failure in systemic lupus erythematosus, and its management has grown substantially more complex with the emergence of targeted therapies. Between 2024 and 2025, the American College of Rheumatology, the European Alliance of Associations for Rheumatology, and Kidney Disease: Improving Global Outcomes each released updated recommendations grounded in a largely shared evidence base but differing in scope, clinical profiling, and operational emphasis. This review compares the three frameworks, highlighting key areas of convergence and divergence relevant to contemporary clinical practice. The main themes include the shift toward early combination regimens targeting complementary immune pathways, driven by the emergence of targeted therapies such as belimumab, voclosporin, and obinutuzumab; the incorporation of clinical profiling to guide therapy selection and monitoring; strategies aimed at rapid glucocorticoid minimization; and the growing recognition of renoprotective therapy as a central pillar of LN care within a chronic kidney disease management strategy.
The aim of this study is to describe characteristics of children with the International League of Associations for Rheumatology (ILAR)-defined juvenile idiopathic arthritis (JPsA) and to assess whether more sensitive and specific criteria for defining JPsA can be identified. A retrospective observational multicentre study was conducted including patients with a diagnosis of JPsA according to ILAR criteria. In this population, we identified clusters using as variables the clinical criteria of JPsA according to ILAR and the CASPAR clinical criteria. In addition, we defined as undifferentiated arthritis patients that met the ERA criteria, as defined by ILAR, and presented psoriatic features such as psoriasis or a history of psoriasis or psoriatic arthritis in a first-degree relative. 73 patients were enrolled. Three clinical clusters were found using unsupervised principal component analysis for the patients. Cluster 1 differed significantly for older patients and psoriasis. In contrast, Cluster 2 was mainly characterised by dactylitis and Cluster 3 was defined by family history of psoriasis and a significant prevalence of dactylitis. We also showed a statistically significant presence of familiarity for psoriatic arthritis in Cluster 2. The significance for all parameters evaluated did not change even when we included the patients with undifferentiated arthritis, except for MTX treatment, which was significantly more common in Cluster 2 (p=0.02), and tenosynovitis, also in Cluster 2 (p=0.05). Moreover, we evaluated our cohort by the Vancouver criteria. Combining the ILAR, CASPAR, and Vancouver criteria only two patients remain undifferentiated. Our study showed three clinical clusters with diverse demographic and clinical characteristics, indicating JPsA heterogeneity. The findings highlight the need to look beyond ILAR criteria for clinical variables, including family history of psoriatic arthritis. The ILAR, CASPAR, and Vancouver criteria improve the diagnosis of paediatric psoriatic spectrum arthritis. This complex disease population needs larger cohorts and clinical data, especially on axial involvement, to better categorisation and treatment.
Synovial tissue (ST) biopsy has evolved from an experimental procedure into a clinically relevant tool that provides unparalleled access to the inflamed joint in rheumatoid arthritis (RA). Initially performed through blind needle and arthroscopic techniques, the adoption of minimally invasive ultrasound-guided biopsy has enabled safe, reproducible, and patient-acceptable tissue sampling across large and small joints. Histopathological evaluation, including the Krenn Synovitis Score and recognition of distinct pathotypes, has provided diagnostic and prognostic insights, while comparative analyses have highlighted shared inflammatory pathways with osteoarthritis and psoriatic arthritis. The integration of high-dimensional technologies such as bulk and single-cell transcriptomics, spatial profiling, and proteomics has uncovered novel stromal and immune cell subsets and linked tissue signatures to therapeutic outcomes. Landmark biopsy-driven trials (R4RA and STRAP) have demonstrated the feasibility of stratifying treatment on the basis of synovial biology, positioning synovial biopsy as a cornerstone in the long journey towards precision RA management.
The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
The study investigated the relationship among the human microbiota in the development and progression of inflammatory bowel diseases (IBD), specifically Crohn's Disease (CD) and Ulcerative Colitis (UC), as well as Spondyloarthritis (SpA), comparing paediatric and adult populations. The research elaborated the distinct characteristics and impacts of CD, UC, and SpA across age groups. It further explored the developmental stages of the paediatric microbiota, identifying factors like delivery method, feeding, and antibiotics as critical influencers. It examined specific dysbiosis patterns in paediatric IBD and SpA associated to disease activity. Subsequently, it addressed the adult microbiota's stability and variations due to diet, lifestyle, and medications, detailing microbial alterations in adult CD, UC, and SpA. A comparative analysis underscores age-related differences in microbiota composition, clinical manifestations, and treatment responses, indicating greater yet weaker microbial populations in adults. In paediatric patients, there was a marked decrease in Faecalibacterium prausnitzii and other bacteria responsible for producing short-chain fatty acids. In contrast, adults tended to show a more persistent form of dysbiosis and lower microbiome resilience. These disparities in microbial and metabolic phenotypes were strongly associated with the activity of the disease and the response to the treatment, which suggests the potential of microbiota-based biomarkers to create age-specific diagnostic and therapeutic approaches. This research found that microbiota play a great role in the inflammatory diseases and they can be of great use in the current treatments as well as serve as a biomarker. The new targeted therapies underscored the necessity of patient specific microbiome studies to enhance diagnostics and therapies of these disorders throughout the lifespan.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease manifested as persistent mucosal inflammation and immune dysregulation. As key regulators of intestinal immune homeostasis, macrophages are pivotal in the amplification of inflammation and tissue repair in UC. However, the molecular mechanisms associated with ferroptosis in macrophages remain unclear. We integrated single-cell and bulk colonic transcriptomes to map ferroptosis-associated programs in UC macrophages, prioritized candidate regulators using network/ML frameworks, and performed targeted experimental validation. We identified a ferroptosis-associated transcriptional program enriched in UC macrophages and derived a four-gene signature (HIF1A, S100A8, CYBB, GLS) linked to redox/iron stress. Among them, CYBB encodes NOX2 (the catalytic subunit of NADPH oxidase), and emerged as a key node associated with enhanced oxidative/iron stress and coordinated changes in ferroptosis-related markers in macrophages. This study systematically delineates the ferroptosis-associated transcriptional network in macrophages of UC, providing a systems-level framework linking macrophage redox/iron imbalance to ferroptosis vulnerability in UC and nominating CYBB-centered pathways for mechanistic interrogation and stratification-oriented biomarker development, thereby offering novel theoretical insights for immune metabolism mechanisms and targeted therapies in UC.
The cleavage of full-length transfer RNAs generates functional small RNAs called tRNA-derived small RNAs (tsRNAs or tDRs). This review synthesizes recent advances in our understanding of tDRs, summarizing the molecular mechanisms of their biogenesis and illuminating their function in modulating pathways important in the cellular stress response. Key structural motifs appear to be critical determinants of tDR function by modulating binding to partner proteins and RNAs. Finally, the role of tDRs in the pathogenesis of various diseases and the feasibility of targeting them with novel molecular tools are discussed. In summary, tDRs are an evolutionarily conserved class of small RNAs important for the cellular response to stress and are emerging as a promising target for human diseases.
Cyclophosphamide remains a cornerstone of remission induction therapy in granulomatosis with polyangiitis (GPA); however, the presence of resistant patients necessitating a switch to alternative agents, such as rituximab, remains a clinical challenge. Identifying predictors of cyclophosphamide resistance could improve patient stratification and optimise treatment strategies. This retrospective cohort study included 75 patients diagnosed with GPA and treated at Ankara Bilkent City Hospital between 2018 and 2023.Clinical and laboratory data were extracted from electronic medical records. Baseline characteristics, organ involvement, and serological profiles were compared between cyclophosphamide-responsive and cyclophosphamide-resistant patients. Logistic regression analysis was performed to identify independent predictors of treatment resistance. 75 patients with GPA analysed. The mean age was 46.1years (SD=14.0).56 patients received cyclophosphamide as first-line therapy, of whom 34 (60.7%) achieved remission, while 22 (39.3%) switched to rituximab. Of these, 17 patients (30.4%) were classified as cyclophosphamide-resistant, while 5 patients (8.9%) switched due to other reasons. Younger age was a significant predictor of cyclophosphamide resistance (OR=0.915, 95%CI:0.856-0.977, p=0.008). The presence of arthritis showed a trend toward association (OR=5.191, 95%CI:0.960-28.065, p=0.056) but did not reach statistical significance. No significant differences were observed in gender, ANCA subtypes, major organ involvement, or comorbidity burden between groups. Our findings suggest that younger age is associated with a higher likelihood of cyclophosphamide resistance in GPA, potentially indicating a more aggressive disease course. Although arthritis showed a potential association with resistance, further studies are needed to confirm its role.
Osteoarthritis (OA) is increasingly recognized as a metabolically influenced inflammatory disease, particularly in the context of obesity. Wnt1-inducible signaling pathway protein 1 (WISP1), a downstream mediator of Wnt/β-catenin signaling, has been implicated in adipose tissue inflammation and cartilage remodeling; however, clinical data regarding circulating serum WISP1 levels in obesity-associated OA remain limited. This study aimed to investigate the relationship between serum WISP1 concentrations and OA status in obese adults. This cross-sectional study included 180 participants classified into three groups: healthy non-obese controls (n = 60), obese individuals without OA (n = 60), and obese individuals with OA (n = 60). Clinical, anthropometric, metabolic, and inflammatory parameters were recorded. Serum WISP1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Group comparisons, correlation analyses, logistic regression models, and receiver operating characteristic (ROC) analyses were performed. Serum WISP1 concentrations differed significantly among groups, showing a stepwise increase from healthy controls to obese OA (-) and obese OA (+) participants (p < 0.001). WISP1 remained independently associated with osteoarthritis among obese individuals after adjustment for age, sex, body mass index, HOMA-IR, diuretic use and C-reactive protein (OR 1.003; 95% CI 1.001-1.005). Although obese participants demonstrated adverse metabolic and inflammatory profiles compared with controls, most metabolic parameters did not distinguish OA subgroups within obesity. ROC analysis demonstrated good discriminatory performance of WISP1 for distinguishing obese OA (+) from obese OA (-) groups (AUC 0.807, 95% CI 0.727-0.879, p < 0.001). Serum WISP1 concentrations are elevated in obese individuals with osteoarthritis and are independently associated with OA status beyond conventional measures of adiposity and systemic inflammation. These findings suggest that WISP1 may serve as a potential biomarker associated with metabolic-inflammatory processes. Given the cross-sectional nature of the study, the observed findings should be interpreted as associations, and causal relationships cannot be inferred. Further longitudinal and externally validated studies are needed to clarify its clinical utility and biological significance.
Pleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease (ILD) with defining histology of intra-alveolar fibrosis with septal elastosis (AFE), suggesting unique cellular disease processes. Here, we present a binational single-nucleus RNA sequencing atlas of PPFE, based on explanted lungs from 40 patients. Immunofluorescence microscopy, RNA in situ hybridization, micro-computed tomography (CT), and hierarchical phase-contrast (HiP) synchrotron CT provided spatial context. We identify PPFE-associated adventitial and elastofibrotic fibroblasts as key drivers of elastotic remodeling within an inflammatory microenvironment, maintained by immune cells forming tertiary lymphoid structures. Spatial mapping reveals an intriguing zonation of AFE, maintained by intercellular circuits between PPFE-associated cell types. Comparative analysis with idiopathic pulmonary fibrosis highlights CTHRC1+ fibrotic fibroblasts and aberrant basaloid cells as conserved profibrotic cellular machinery mediating collagen deposition across ILDs. This integrative atlas defines the cellular landscape of PPFE and dissects elastotic from fibrotic remodeling, providing a molecular rationale for niche-specific therapeutic strategies.
Lupus nephritis (LN) represents one of the most severe manifestations of childhood systemic lupus erythematosus (cSLE), often progressing rapidly and resulting in renal impairment or even end-stage renal disease. Early diagnosis and precise assessment of disease activity are essential for guiding therapy and improving clinical outcomes. However, conventional serological and urinary biomarkers exhibit limited sensitivity and specificity, while renal biopsy, although the diagnostic gold standard, is invasive and unsuitable for longitudinal monitoring. Surface-enhanced Raman spectroscopy (SERS), a noninvasive analytical approach, offers substantial potential for detecting the molecular characteristics of LNs. In this study, a high-throughput SERS microspot array plate platform was established to perform dual-modal serum and urine SERS metabolic fingerprint analyses in healthy controls (n = 40), systemic lupus erythematosus (n = 40), and LN patients (n = 60). The dual-modal fusion model demonstrated superior performance over single-modal models in both LN diagnosis and disease activity assessment, achieving notably enhanced sensitivity, specificity, and overall accuracy. Furthermore, dual-modal SERS profiling revealed key biomolecular alterations associated with immune activation, inflammatory responses, and renal injury in children, providing molecular-level insights into the pathophysiological mechanisms underlying cSLE and LN.
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The absolute and relative risk of venous thromboembolism (VTE) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely unexplored. We conducted a nationwide cohort study to explore this. This nationwide, population-based matched cohort study in Sweden included all individuals with biopsy-confirmed MASLD (1965-2017). MASLD was histologically classified into simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH), non-cirrhotic fibrosis, and cirrhosis. Each MASLD case was matched to up to five general population comparators. VTE events were identified using the Swedish National Patient Register up until 2021. We included 11,073 individuals with MASLD and 50,078 comparators. During a median follow-up of 18.6 years., incident VTE occurred in 1,291 patients with MASLD and 4,067 comparators. The incidence rate of VTE was higher in MASLD (7.6 vs. 3.4 per 1,000 person-years), yielding an adjusted hazard ratio (aHR) of 1.78 (95%CI: 1.65-1.91). The absolute risk difference was 3.9 per 1,000 person-years, equating to 1 extra VTE per 26 patients with MASLD over 10 years. MASLD was associated with a higher incidence of VTE triggered by cancer, hospitalization, and surgery. Higher aHRs were observed in women compared to men, and in patients with baseline cancer or metabolic disorders compared to those without. The risk of portal vein thrombosis (PVT) was markedly elevated (aHR=3.40; 95%CI: 2.93-3.95), increasing progressively with MASLD severity (P=0.003). Findings were similar when siblings were used as comparators to account for intrafamilial confounding. Biopsy-confirmed MASLD was associated with a higher incidence of VTE, particularly PVT.
This multicenter retrospective cohort compared romosozumab outcomes between oral glucocorticoid users and non-users. Bone turnover marker responses and lumbar spine bone mineral density gains were similar, whereas total hip bone mineral density gains were smaller among glucocorticoid users. To investigate the impact of oral glucocorticoids (GC) on the effectiveness of romosozumab by comparing outcomes between GC users and non-users after adjusting for patient background. This multicenter, retrospective cohort study analyzed patients who completed 12 months of therapy (n = 428). Inverse probability of treatment weighting was employed to construct a pseudo-population with balanced baseline characteristics, yielding 40 GC users and 39.8 non-users (95.3% female, mean age 76.6 years; mean lumbar spine T-score -2.7; mean GC dose 5.4 mg/day [prednisolone equivalent]). Percentage changes in bone turnover markers (BTMs) and bone mineral density (BMD) over 12 months were compared between groups. Factors affecting BMD changes were identified using multivariable analysis. GC use did not significantly affect the changes in PINP and TRACP-5b levels. The 12-month increase in lumbar spine BMD was comparable between groups (GC users 9.7% vs. non-users 10.7%; P = 0.55). In contrast, the increase in total hip BMD was significantly lower in GC users compared with non-users (2.8% vs. 5.6%; P = 0.003). Multivariable analysis revealed that baseline PINP was significantly associated with the BMD increase at the lumbar spine, whereas daily GC dose was a significant factor for the total hip. Oral GC use did not significantly affect changes in BTMs or BMD increases at the lumbar spine. Smaller gains in total hip BMD were observed in GC users, which may have reflected not only GC use but also underlying disease-related factors.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis occurring predominantly in patients with eosinophilic asthma. Glucocorticoids (GCs) are the cornerstone of treatment for EGPA to achieve disease remission, however, relapses despite GCs therapy are common. Mepolizumab (Nucala®) is a humanised monoclonal antibody that binds interleukin (IL)-5 and randomised controlled trials have shown that it effectively targets eosinophil-driven manifestations of EGPA. Since the vasculitic component of EGPA may not be solely driven by eosinophils, the aim of this retrospective observational study is to use real-world evidence to assess clinical outcomes following treatment with mepolizumab (Nucala®). A retrospective, observational, cohort study will be conducted in 10 hospital centres specialised in the treatment and monitoring of patients with EGPA in Greece. Data will be retrospectively collected and analysed from medical records of 70 patients with EGPA treated with mepolizumab (Nucala®) for ≥ 6 months, covering the period from September, 2021, to December, 2024.
Comment on "Methotrexate-Induced Accelerated Nodulosis: A Case Series" [Subramanian R et al, Mediterr J Rheumatol 2024;35(4):680-683].
Chronic recurrent multifocal osteomyelitis is a rare autoinflammatory bone disorder in children. Vitamin D regulates immune and inflammatory pathways, but its impact on chronic recurrent multifocal osteomyelitis remains unclear. This study investigated the relationship between serum 25-hydroxyvitamin D levels and clinical, laboratory, and radiological characteristics of pediatric chronic recurrent multifocal osteomyelitis. Pediatric chronic recurrent multifocal osteomyelitis patients and age- and sex-matched healthy controls were retrospectively evaluated. Serum 25-hydroxyvitamin D, inflammatory markers, clinical disease activity score, and whole-body magnetic resonance imaging findings were analyzed. Thirty-one chronic recurrent multifocal osteomyelitis patients and 31 controls were included. Chronic recurrent multifocal osteomyelitis patients had significantly lower 25-hydroxyvitamin D levels and a higher frequency of vitamin D deficiency (p<0.001). Serum 25-hydroxyvitamin D levels showed no correlation with C-reactive protein, erythrocyte sedimentation rate, or the neutrophil-to-lymphocyte ratio, but were inversely correlated with the clinical disease activity score (r=- 0.429 and p=0.020) and the number of magnetic resonance imaging-detected skeletal lesions (r=- 0.376 and p=0.044). Logistic regression confirmed vitamin D deficiency as independently associated with chronic recurrent multifocal osteomyelitis (odds ratio=0.59, 95% confidence interva: 0.41-0.88, and p=0.007). Vitamin D deficiency is highly prevalent in pediatric chronic recurrent multifocal osteomyelitis and correlates with disease severity, reflected by clinical activity and lesion burden, independent of systemic inflammation. These findings suggest vitamin D as a potential biomarker in chronic recurrent multifocal osteomyelitis and highlight the need for prospective studies assessing its therapeutic role. Die chronisch-rezidivierende multifokale Osteomyelitis (CRMO) ist eine seltene autoinflammatorische Knochenerkrankung im Kindesalter. Vitamin D reguliert immunologische und entzündliche Signalwege, jedoch ist sein Einfluss auf die CRMO bislang unklar. Diese Studie untersuchte den Zusammenhang zwischen den Serumspiegeln von 25-Hydroxyvitamin D [25(OH)D] und den klinischen, laborchemischen und radiologischen Merkmalen der pädiatrischen CRMO.Pädiatrische CRMO-Patienten sowie alters- und geschlechtsgematchte gesunde Kontrollen wurden retrospektiv bewertet. Analysiert wurden Serum-25(OH)D, Entzündungsmarker, der Clinical Disease Activity Score (CDAS) sowie Ganzkörper-MRT-Befunde.Insgesamt wurden 31 CRMO-Patienten und 31 Kontrollpersonen eingeschlossen. CRMO-Patienten wiesen signifikant niedrigere 25(OH)D-Spiegel und eine höhere Häufigkeit von Vitamin-D-Mangel auf (p<0,001). Die Serum-25(OH)D-Spiegel korrelierten nicht mit CRP, ESR oder NLR, zeigten jedoch eine inverse Korrelation mit dem CDAS (r=–0,429; p = 0.020) und der Anzahl der im MRT nachgewiesenen ossären Läsionen (r=–0,376; p=0,044). Die logistische Regression bestätigte Vitamin-D-Mangel als unabhängig mit CRMO assoziiert (OR=0.59, 95% CI 0.41–0.88, p=0.007).Vitamin-D-Mangel ist bei pädiatrischer CRMO sehr häufig und korreliert mit der Krankheitschwere, die sich in klinischer Aktivität und Läsionslast widerspiegelt – unabhängig von systemischen Entzündungsmarkern. Diese Ergebnisse deuten darauf hin, dass Vitamin D ein potenzieller Biomarker für die CRMO sein könnte, und unterstreichen den Bedarf an prospektiven Studien zur Bewertung seiner therapeutischen Bedeutung.