[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.

Mother of all bonds: Influences on spatial association across the lifespan in capuchins.

In humans, being more socially integrated is associated with better physical and mental health and/or with lower mortality. This link between sociality and health may have ancient roots: sociality also predicts survival or reproduction in other mammals, such as rats, dolphins, and non-human primates. A key question, therefore, is which factors influence the degree of sociality over the life course. Longitudinal data can provide valuable insight into how environmental variability drives individual differences in sociality and associated outcomes. The first year of life-when long-lived mammals are the most reliant on others for nourishment and protection-is likely to play an important role in how individuals learn to integrate into groups. Using behavioral, demographic, and pedigree information on 376 wild capuchin monkeys (Cebus imitator) across 20 years, we address how changes in group composition influence spatial association. We further try to determine the extent to which early maternal social environments have downstream effects on sociality across the juvenile and (sub)adult stages. We find a positive effect of early maternal spatial association, where female infants whose mothers spent more time around others also later spent more time around others as juveniles and subadults. Our results also highlight the importance of kin availability and other aspects of group composition (e.g., group size) in dynamically influencing spatial association across developmental stages. We bring attention to the importance of-and difficulty in-determining the social versus genetic influences that parents have on offspring phenotypes. RESEARCH HIGHLIGHTS: Having more maternal kin (mother and siblings) is associated with spending more time near others across developmental stages in both male and female capuchins. Having more offspring as a subadult or adult female is additionally associated with spending more time near others. A mother's average sociality (time near others) is predictive of how social her daughters (but not sons) become as juveniles and subadults (a between-mother effect). Additional variation within sibling sets in this same maternal phenotype is not predictive of how social they become later relative to each other (no within-mother effect).

Relevance of histopathological findings for predictive scoring of short-term treatment response to plasma exchange in severe ANCA-associated renal vasculitides.

Introduction: Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid loss of kidney function, affecting both renal and overall patient survival. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems including the kidney, and among most frequent causes of RPGN. We here aimed to validate a recently described scoring system for short-term treatment response to therapeutic plasma exchange (PLEX) in a well-characterized and independent cohort of severe renal AAV presenting with RPGN. Furthermore, we compared this scoring with established classification systems in renal AAV including histopathological findings. Methods: We here directly compare the scoring system with retrospective data about PLEX treatment in our own clinical practice and according to current recommendations in a cohort of 53 patients with severe AAV presenting with RPGN confirmed by kidney biopsy. Results: We here confirm that PLEX scoring is capable to identify patients at risk for short-term poor outcome in severe AAV presenting with RPGN (p<0.0001). Furthermore, multiple stepwise regression analysis revealed that the PLEX score with renal biopsy performed best to predict poor outcome in this patient population (p<0.0001). Conclusion: Our observations underscore the relevance of performing a kidney biopsy in this patient population that is often challenged in the setting of intensive care treatment, requirement of KRT with need for anticoagulation and bleeding risk. Therefore, validation of our observations and this recent scoring system for treatment response to PLEX in independent cohorts would be of great clinical relevance in the treatment of patients with severe AAV presenting with RPGN.

[Therapeutic Pathways in Sarcoidosis. A Position Paper of the German Society of Respiratory Medicine (DGP)]. / Therapie der Sarkoidose. Ein Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis.

Serum Uric Acid Associates with Systemic Complement C3 Activation in Severe ANCA-Associated Renal Vasculitides.

Involvement of the complement system is key to the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis, but immunometabolic implications, especially on serum uric acid (UA) levels, still need to be elucidated. A total of 34 patients with biopsy-proven ANCA-associated renal vasculitis between 2015 and 2020 were retrospectively enrolled. Serum UA levels were correlated with clinical and histopathological characteristics, separated for critically ill (CI, n = 19), myeloperoxidase (MPO)-ANCA (n = 21) and proteinase 3 (PR3)-ANCA (n = 13) subgroups. We here identified inverse correlations of serum UA levels and complement C3 levels in the total cohort (p = 0.005) and the CI subgroup (p < 0.001). Intrarenal complement C4d deposition in venules correlated with serum UA levels in the total cohort (p = 0.007) and in the CI subgroup (p = 0.016). Significant associations of serum UA levels and tubulitis in areas of scarred cortex (t-IFTA) were identified in the total cohort (p = 0.008), and both subgroups of CI (p = 0.034) and MPO-ANCA (p = 0.029). In PR3-ANCA, interstitial fibrosis (ci) was observed as the strongest association with serum UA levels (p = 0.022). Our observations broaden our current understanding of contributory metabolic factors that influence the initial disease course in ANCA-associated renal vasculitis.

Impact of Systemic Sclerosis-Associated Interstitial Lung Disease With and Without Pulmonary Hypertension on Survival: A Large Cohort Study of the German Network for Systemic Sclerosis.

BACKGROUND: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis. RESEARCH QUESTION: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact? STUDY DESIGN AND METHODS: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival. RESULTS: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk. INTERPRETATION: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival.

A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy.

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log2SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for "metabolism" and "biological oxidations". These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.

Corrigendum: Reproducibility and rigor in rheumatology research.

[This corrects the article DOI: 10.3389/fmed.2022.1073551.].

A Transcriptome Array-Based Approach Links Proteinuria and Distinct Molecular Signatures to Intrarenal Expression of Type I Interferon IFNA5 in Lupus Nephritis.

In systemic lupus erythematosus (SLE), the relevance of non-hematopoietic sources of type I interferon in human autoimmunity has recently been recognized. Particularly, type I interferon production precedes autoimmunity in early skin lesions related to SLE. However, the relevance of intrarenal type I interferon expression has not been shown in lupus nephritis. From transcriptome array datasets, median-centered log2 mRNA expression levels of IFNα (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, and IFNA21), IFNω (IFNW1), and IFNß (IFNB1) in lupus nephritis were extracted specifically from microdissected tubulointerstitial (n = 32) and glomerular compartments (n = 32). We found an association between proteinuria and tubulointerstitial expression of type I interferon IFNA5 (p = 0.0142), while all others were not significantly associated. By contrast, no such correlation was observed between proteinuria and any type I interferon expression in the glomerular compartment in lupus nephritis. Interestingly, there was no difference between female and male patients (p = 0.8237) and no association between type I interferon IFNA5 expression and kidney function or lupus nephritis progression. Finally, we identified distinct molecular signatures involved in transcriptional regulation (GLI protein-regulated transcription, IRF7 activation, and HSF1-dependent transactivation) and receptor signaling (BMP signaling and GPCR ligand binding) in association with tubulointerstitial expression of type I interferon IFNA5 in the kidney. In summary, this transcriptome array-based approach links proteinuria to the tubulointerstitial expression of type I interferon IFNA5 in lupus nephritis. Because type I interferon receptor subunit I antagonism has recently been investigated in active SLE, the current study further emphasizes the role of type I interferons in lupus nephritis and might also be of relevance for mechanistic studies.

Case Report: High-dose immunoglobulins prior to plasma exchange in severe pulmonary renal syndrome.

Plasma exchange rapidly depletes pathogenic anti-neutrophil cytoplasmic autoantibodies (ANCAs) and is considered for induction therapy in severe ANCA-associated vasculitis. The aim of plasma exchange is to remove putative disease mediators from the circulation, such as toxic macromolecules and pathogenic ANCAs. To our knowledge, we here provide the first report of applying high-dose IVIGs prior to plasma exchange and assessment of ANCA autoantibody elimination in a patient with severe pulmonary renal syndrome due to ANCA-associated vasculitis. After high-dose application of intravenous immunoglobulins (IVIGs) prior to plasma exchange treatment, efficacy of myeloperoxidase (MPO)-ANCA autoantibody elimination was substantially increased, associated with rapid clearance of MPO-ANCA autoantibodies. High-dose IVIGs resulted in marked reduction of MPO-ANCA autoantibody levels and did not directly affect autoantibody clearance by plasma exchange itself, as also confirmed by comparable MPO-ANCAs in the exchange fluid relative to serum levels. Moreover, measurements of serum creatinine and albuminuria confirmed that high-dose IVIGs were well tolerated and did not exacerbate kidney injury.

Study protocol: a prospective single-center study for non-invasive biomonitoring of renal complications in cancer patients treated with immune checkpoint inhibitors.

Background: The advent of immune checkpoint inhibitors (ICIs) has powerfully broadened the scope of treatment options for malignancies with an ongoing increase of indications, but immune-related adverse events (irAEs) represent a serious threat to treatment success. Agents directed against programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) are known to cause renal complications with an incidence of 3%. In contrast, subclinical renal involvement is estimated to be much higher, up to 29%. We recently reported about urinary flow cytometry-based detection of urinary PD-L1-positive (PD-L1+) kidney cells correlating with tubular PD-L1-positivity that reflected susceptibility to develop ICI-related nephrotoxicity as an irAE attending ICI treatment. Therefore, we designed a study protocol to evaluate urinary detection of PD-L1+ kidney cells as a tool for non-invasive biomonitoring of renal complications in cancer patients treated with ICIs. Methods: A prospective, controlled, non-interventional, longitudinal, single-center observational study will be conducted at the Department of Nephrology and Rheumatology of the University Medical Center Göttingen, Germany. We intend to enroll approximately 200 patients treated with immunotherapy from the Departments of Urology, Dermatology, and Hematology and Medical Oncology of the University Medical Center Göttingen, Germany. First, we will assess clinical, laboratory, histopathological, and urinary parameters in addition to urinary cell collection. Then, we will perform a correlative analysis between urinary flow cytometry of different PD-L1+ cell of renal origin with the onset of ICI-related nephrotoxicity. Discussion: Because of growing ICI-treatment applicability with an expectable incidence of renal complications, providing cost-efficient and easily performable diagnostic tools for treatment-attendant and non-invasive biomonitoring becomes vital to improve both renal and overall survival rates in cancer patients receiving immunotherapy. Trial registration: https://www.drks.de, DRKS-ID DRKS00030999.

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.

Renal disease in sarcoidosis patients in a German multicentric retrospective cohort study.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease potentially affecting every organ system. Renal involvement is reportedly rare, and the evidence consists of case reports and cohort studies. Systematic investigations are scarce and show a varying prevalence ranging from <1% to 30-50%. METHODS: We retrospectively analyzed data from patients with a recent diagnosis of sarcoidosis from five tertiary care centers focusing on renal sarcoidosis. RESULTS: We analyzed data from 327 patients with sarcoidosis between 2001 and 2021. Of 327 patients, 109 (33.3%) had probable or definite renal sarcoidosis. 90 (27.5%) had histopathologic confirmation. 57 (64%) had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The most prominent associated finding was an elevated soluble interleukin-2 receptor. Patients with renal sarcoidosis more frequently received glucocorticoids than other non-renal sarcoidosis patients (92% vs. 78%, p < 0.01). Also, azathioprine (38% vs. 16%, p < 0.001) and mycophenolate mofetil (5% vs. 1%, p < 0.05) were more frequently used in renal sarcoidosis compared to non-renal sarcoidosis, whereas methotrexate was used less frequently (7% vs. 17%, p < 0.05). CONCLUSIONS: Our data of the largest cohort with biopsy-confirmed renal sarcoidosis demonstrate a higher prevalence (27.5% of all patients) than previously published with a relevant disease burden. The urinary findings in most cases were only mildly abnormal, and some patients did not have renal biopsy despite abnormal urinary results. A renal workup should be performed in all patients with a new diagnosis of sarcoidosis.

Anti-acid therapy in SSc-associated interstitial lung disease: long-term outcomes from the German Network for Systemic Sclerosis.

OBJECTIVES: Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). METHODS: We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan-Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. RESULTS: It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9-93.8); n = 290] and after 5 years [91.4% (89.2-93.8); n = 357 vs 70.9% (65.2-77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6-97.3); n = 745 vs 86.4% (82.9-90.1); n = 278] and after 5 years [66.8% (63.0-70.8); n = 286 vs 45.9% (39.6-53.2); n = 69; P < 0.0001]. CONCLUSION: GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.