Sophie Brunner-Ziegler

Background: Nutritional deficiencies are associated with poor prognosis in a wide range of illnesses. However, the prognostic impact of poor nutritional status with respect to long-term all-cause mortality in the general non-diseased population is not well described. Objectives: This study sought to report the prevalence, clinical associations, and prognostic consequences of poor nutritional status in a contemporary urban population in Germany. Methods: A cohort of 8398 participants from the LIFE-Adult Study was enrolled. Four objective nutritional scores, the Prognostic Nutritional Index (PNI), the Controlling Nutritional Status Score (CONUT), the Nutritional Risk Index (NRI), and the Triglyceride Cholesterol Body Weight Index (TCBI), were calculated at baseline, and participants’ nutritional status was classified according to score tertiles. The relationship between nutritional status and common risk factors as well as major diseases was assessed. In addition, the association between poor nutritional status at baseline and the risk of all-cause mortality during a seven-year follow-up period was examined. Results: According to the WHO definition of obesity, the LIFE-Adult Study cohort was, on average, overweight, with almost two-thirds of participants (67%) having a BMI ≥ 25 and only 1% being underweight. However, poor nutritional status was not associated with a specific BMI category. Higher age, female sex, cancer, and chronic kidney disease were more common, whereas active smoking and hypercholesterolemia were less prevalent among participants in the lowest PNI tertile (p < 0.01). In the overall population, the cumulative incidence of all-cause mortality was significantly higher among participants in the lowest PNI, NRI, and TCBI tertiles and the highest CONUT category (log-rank test, p < 0.01 for PNI, CONUT, and NRI, and p < 0.04 for TCBI, respectively). After adjustment for confounding factors, the lowest PNI and NRI tertiles and the highest and medium CONUT categories remained independently and significantly associated with an increased risk of all-cause mortality (all p < 0.01) in multivariable Cox regression analyses. TCBI was not associated with all-cause mortality in any regression model. Conclusions: Poor nutritional status is associated with increased mortality in the general population. Clinical trials are needed to prospectively evaluate the efficacy of nutritional interventions on health outcomes.

The presence of abnormal nailfold capillaries and antinuclear antibodies (ANA) is associated with increased all-cause mortality in patients presenting with incipient Raynaud’s phenomenon (RP). We conducted a retrospective analysis aiming to assess the association between abnormal nailfold capillaries, ANA, and mortality over a 20-year follow-up period. In 2958 patients with incipient RP without previously known connective tissue disease, nailfold capillaroscopies and laboratory tests for ANA and ANA-subsets were obtained. Of these, long-term follow-up data were available for 2922 patients. Over a median follow-up period of 23 (IQR 20.2–25.2) years, 832 patients died, of which 562 were women (25% of female patients) and 270 were men (41% of male patients). Compared to a demographically matched reference population, mortality was increased in female and male patients with RP (log-rank test < 0.001). In female patients with RP, the presence of ANA, anti-Scl-70 antibodies, and a grouping variable consisting of giant capillaries, reduced capillary density, and avascular fields was associated with an increase in all-cause mortality. The highest mortality was observed in patients presenting both abnormal nailfold capillaries and ANA. In the long-term, an excess mortality persists in patients with RP. Our study demonstrates prognostic associations between abnormal nailfold capillaries as well as ANA and mortality.

The Clinical Trials Information System (CTIS) enables a central joint registration of clinical trials in the EU and provides public access to key trial documents including informed consent documents. The increasing complexity and length of subject information sheets and informed consent forms (SIS/ICFs) can impact participant comprehension and willingness to enroll in a trial. This pilot study aimed to analyze the characteristics of actual SIS/ICFs from a sample of approved CTIS submissions, with a focus on Phase III trials. We consulted the CTIS public database to retrieve authorized Phase III trials. The final dataset comprised 67 drug trials submitted between January 1, 2023, and November 16, 2023. SIS/ICF page and word count, and readability scores were compared across countries, sponsorship, and other trial‐related characteristics. Exploratory analyses assessed document structure and page space utilization. The median SIS/ICF length was 16 pages (IQR 11–23) and 5746 words (IQR 3508–8626), with substantial variability. Industry‐sponsored trials had significantly longer SIS/ICFs than academic trials (mean difference + 8.1 pages, p < 0.01). German SIS/ICFs were on average 4.4 pages longer than Austrian SIS/ICFs ( p = 0.018). Exploratory analyses suggested that formatting choices, repetition, and expanded data protection sections contributed more to length differences than content allocation or readability, thus indicating that the main drivers of SIS/ICF length are modifiable in nature. These findings underscore the need for further research into the factors influencing document length, their implications for trial participants and how a further harmonization throughout the EU can be achieved for country‐specific documents.

The development of nitric oxide-donating antiphlogistics is intended to improve the tolerability of the parent compounds. The aim of the present study was to explore the potency and tolerability of nitric oxide-donating acetaminophen (NCX 701) in healthy volunteers and to test the hypothesis that NCX 701 could have additional anti-inflammatory efficacy in an experimental model of low-grade human endotoxemia. In this prospective, double-blind, placebo-controlled trial with parallel group design 40 healthy male volunteers were randomized to single oral treatment with NCX 701 (1–2 g), acetaminophen (1 g paracetamol) or placebo before lipopolysaccharide (2ng/kg) infusion. NCX 701 dose-dependently increased plasma and urine nitric oxide concentrations. Pooled analysis of both NCX 701 doses showed a significant, but obviously clinically irrelevant lowering effect on systolic and diastolic blood pressure during the first 5 h. Overall, peak levels of tumor necrosis factor-alpha correlated well with interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and von Willebrand Factor release across all cohorts. There was no major difference between NCX 701 and acetaminophen with respect to their effect on the lipopolysaccharide-induced secretion of inflammation and endothelium activation markers. Overall, a total of 61 adverse events were reported in all treatment arms, mainly related to lipopolysaccharide. Both acetaminophen and NCX 701 effectively reduced the proportion of subjects experiencing headache. Despite substantial nitric oxide release by NCX 701, which reduced arterial blood pressure, nitric oxide did not result in relevant inhibition of lipopolysaccharide-induced inflammation. ISRCTN registry number: ISTCTN-13,358,268.

Background: For primary Raynaud phenomenon (PRP), an otherwise unexplained vasospastic disposition is assumed. To test the hypothesis of an additional involvement of distinct ultrastructural microvascular alterations, we compared the nailfold capillary pattern of patients with PRP and healthy controls. Methods: A total of 120 patients with PRP (with a median duration of vasospastic symptoms of 60 [IQR: 3–120] months) were compared against 125 controls. In both groups, nailfold capillaroscopy was performed to record the presence of dilatations, capillary edema, tortuous capillaries, ramifications, hemorrhages, and reduced capillary density and to determine a semiquantitative rating score. Further, the capacity of finger skin rewarming was investigated by performing infrared thermography in combination with cold provocation. Results: Unspecific morphologic alterations were found in both, PRP, such as controls, whereby the risk for PRP was four times as high in the presence of capillary dilations (CI: 2.3–7.6) and five times as high if capillary density was reduced (CI: 1.9–13.5). Capillary density correlated with thermoregulatory capacity in both hands in the PRP group, but not in controls. In addition, a negative correlation between the microangiopathy score and the percentage degree of rewarming in both hands was found for patients with PRP only. Conclusion: We found specific differences within the microvascular architecture between patients with PRP and controls. As a conclusion, PRP may not be an entirely benign vasospastic phenomenon, but might be associated with subtle microcirculatory vasculopathy. In addition, we suggest that the implementation of a scoring system might serve as guidance in the diagnostic process at least of patients with long-standing PRP.