Search Results (73)

Considering the high plasticity of FoxP3⁺ regulatory T (Treg) cells and Interleukin (IL)-17-producing Th17 cells, we hypothesized that a Th17 inflammatory milieu may impair the functional properties of Treg cells in chronic inflammatory arthritides. Therefore, a cross-sectional explorative analysis was set up in patients with psoriatic arthritis (PsoA), rheumatoid arthritis, or spondyloarthritis to investigate the features of Th17 and Treg cells. T cell subpopulation counts, FOXP3 mRNA expression, CpG methylation of the FOXP3 gene, and the suppressive capacity of isolated Treg cells were determined. Ex vivo analysis of PsoA-derived peripheral blood lymphocytes showed a Th17-mediated inflammation. It was accompanied by demethylation of the FOXP3 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated FOXP3 mRNA expression nor in increased suppressive Treg cell capacity. To clarify this conundrum, in vitro stimulation of isolated Treg cells with Th17-inducing cytokines (IL-1β, IL-6, IL-23, TGFβ), recombinant IL-17, or the anti-IL-17A antibody secukinumab was performed, demonstrating that cell culture conditions polarizing towards Th17, but not IL-17 itself, impair the suppressive function of Treg cells, accompanied by diminished FOXP3 mRNA expression due to hypermethylation of the FOXP3 promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies. Full article

Background: High rates of vitamin D deficiency have been reported in population-based studies, including those conducted in Germany. The goal of this study was to evaluate vitamin D levels and associated factors in a clinical cohort of German patients presenting to a rheumatology clinic. Methods: We conducted a retrospective observational study of electronic health record data from patients presenting to a rheumatology clinic in southern Germany. Data included demographic characteristics and vitamin D levels as measured by the Elecsys^® Vitamin D total III assay (Roche). Associations between vitamin D levels and patient characteristics were evaluated by Pearson correlation analyses, t-tests, and multiple regression analyses. We also explored seasonal changes. Results: A total of 4979 patients were included; 3230 (64.9%) were female and the mean (standard deviation [SD]) age was 53.6 (15.2) years. The mean (SD) vitamin D level was 27.4 (14.0) ng/mL (range, 3–240 ng/mL). Overall, 1540 (30.9%) had vitamin D levels in the deficient range (<20 ng/mL), 1774 (35.6%) had sufficient vitamin D (20 to 30 ng/mL), 1597 (32.1%) had optimal vitamin D levels (>30 to 70 ng/mL), and 68 (1.4%) had levels >70 ng/mL. Lower vitamin D levels were significantly associated with younger age, male sex, and higher body mass index. Mean levels were significantly lower during winter months and the percentages of patients with vitamin D deficiency were higher. Conclusions: Our data indicate that low levels of vitamin D are common in clinical cohorts, particularly in men, younger adults, overweight individuals, and during winter months. Patient education and/or supplementation may help to address this issue and potentially improve patient health. Full article

Background/Objectives: Obesity and depression, in conjunction with multimorbidity, are interconnected conditions increasingly managed in general practitioner (GP) settings, yet these associations remain insufficiently studied in older patients. This study investigates the prevalence of depression across different body mass index (BMI) classes and includes age and gender differences in multimorbid older patients, offering a novel perspective on subgroup-specific patterns. Further the agreement between GP depression diagnoses and the Geriatric Depression Scale (GDS) is studied and patient-specific factors that may affect the agreement are explored, aiming to improve future diagnostics for vulnerable subgroups. Methods: Data were provided by the baseline assessment of the MultiCare Study, a prospective multicenter observational cohort of multimorbid patients aged 65+ years recruited from 158 GP practices across eight study centers in Germany. Data from 2568 study participants were analyzed based on GP-coded International Classification of Diseases (ICD) diagnoses, structured GP questionnaires, and patient questionnaires. Assessments included data on the BMI and depression (15 item version of the GDS). Agreement between GP diagnoses of depression and GDS assessment was measured using Cohen’s kappa. Four logistic regression models were used to examine the effects of patient-specific factors on the agreement of depression diagnosis (match or mismatch). Results: GPs diagnosed depression in 17.3% of cases, compared to the detection of depressive symptoms in 12.4% of the patients by GDS (cut-off ≥ 6 points). The highest prevalence rates were observed in patients with obesity class III (25.0% by GP; 21.7% by GDS). Women were significantly more likely to receive a depression diagnosis by a GP across most BMI classes (except obesity classes II and III). The detection of depressive symptoms by GDS was significantly more prevalent in older multimorbid obese patients (≥75 years), except for patients with obesity class III. The overall agreement between GP diagnosis and GDS assessment was weak (κ = 0.156, p < 0.001). The highest agreement was found for people with obesity class III (κ = 0.256, p < 0.05). Factors associated with a True Positive depression diagnosis (match by both GDS and GP) were female gender (odds ratio (OR) = 1.83, p < 0.05), widowhood (OR = 2.43, p < 0.01), limited daily living skills (OR = 3.14, p < 0.001), and a higher level of education (OR = 2.48, p < 0.01). A significantly lower likelihood of a False Negative depression diagnosis was found for patients with obesity class III. Conclusions: This study highlights the significant prevalence of depression among multimorbid older adults across different BMI classes, particularly in those with obesity class III. The weak diagnostic agreement between GP diagnosis and GDS assessment suggests a need for improved diagnostic practices in primary care. Implementing standardized screening tools and fostering collaboration with mental health specialists could enhance the identification and management of depression in this vulnerable population. Full article

Transcranial Focused Ultrasound Stimulation (tFUS) is a new, rapidly growing field related to the study and treatment of brain circuits. Establishing safety cutoffs for focused ultrasound is crucial for non-ablative neurological ultrasound experiments. In addition to potential focal heating, there is concern about temperature elevation at the skin surface. Much work has been performed at or near the FDA guideline of I_SPTA.3 = 720 mW/cm², which technically only applies to diagnostic, not therapeutic, ultrasound. Furthermore, evidence of brain tissue damage on histology in the focal region has been shown not to occur until I_SPTA.3 > 14 W/cm². Therefore, this study was conducted across a range of intensities between these two values, evaluating both subjective and objective side effects. Subjective side effects encompassed any discomfort experienced during and after focused ultrasound stimulation, while objective side effects included clinical findings of skin irritation, such as erythema, edema, or burns. This study also examined how the skin temperature at the skin–transducer interface would change in order to assess whether there would be significant heating. The subjects did not experience any unpleasant sensation at the point of stimulation, including heat or pain, and no objective findings of skin irritation were observed following stimulation and the removal of the transducer. In addition, there was no intensity-dependent effect on temperature, and the maximal rise in temperature was 1.45 °C, suggesting that these parameters do not result in the heating of the skin at the interface in such a way that poses a risk to subjects when operating at or below the intensities tested in this experiment. Full article

Background/Objectives: This retrospective observational study aimed to investigate the perioperative outcome in Malignant Peripheral Nerve Sheath Tumors (MPNSTs) with and without relation to Neurofibromatosis Type 1 (NF1) and to detect possible influencing factors. Methods: Clinical reports, histopathological evaluations, imaging, and treatment characteristics were reviewed in 35 operated MPNSTs in 33 patients. Possible predictive valuables included disease type, preoperative tumor volume, SUV and MIB-1 proliferation index, resection margins, the presence of metastasis, and whether radio-/chemotherapy was received. Results: Patients with NF1 were younger (mean age: 29 ± 13, 8–54 years) than sporadic cases (mean age: 45 ± 13, 24–67 years) and exhibited significantly larger preoperative tumor volumes (mean 299 vs. 18 cm³, p = 0.048). Most tumors were located in the facial/cervical/neck area (34%, n = 12), followed by the trunk (31%, n = 11), lower extremity (17%, n = 6), upper extremity (14%, n = 5), and intraspinal area (3%, n = 1). NF1-associated MPNSTs appeared predominantly on the trunk (39%) and sporadically in the facial/cervical/neck area (50%). Complete resection was possible in 66% and an improvement in or stability of function was achieved in most cases (motor 69%, sensory 74%), as well as a decrease in pain intensity (63%). NF1-associated MPNSTs exhibited more severe pain scores (median VRS scale 2, p = 0.002) compared to sporadic tumors (median VRS scale 0.5). Sporadic MPNSTs located at the head/facial/brachial plexus and upper extremities exhibited better preoperative functions compared to those on the lower extremities. In 12 cases with available [¹⁸F]FDG PET, the mean preoperative SUV (9.8 ± 7.2) positively correlated with the mean maximum MIB-1 index (34 ± 26%, p = 0.005) and the mean preoperative tumor volume (474.7 ± 68.6 cm³, p = 0.047). The overall survival (OS) was significantly longer in tumors with higher resection extents (R0, p = 0.01) and without accompanying metastasis (p = 0.046), and tended to be longer, but not significantly so, in sporadic MPNSTs. In six and seven tumors, with R1/R2 resection margins and present metastasis, respectively, solid or combined neo-/adjuvant radio-/chemotherapy led to a significantly shorter OS (p = 0.014). Conclusions: NF1-associated MPNSTs have larger tumor volumes, higher SUVs and MIB-1 proliferation indices, and a shorter overall survival period. Nevertheless, surgery can improve symptoms, particularly medication-resistant pain, and should also be considered in advanced disease for symptom control/improvement. Full article

This investigation pioneers an examination of the scarcely explored terrain of social diversity in medical education, assessing the complex impacts of socioeconomic status (SES), prior working experiences, and completed apprenticeships on a spectrum of psychological and academic facets among first-year medical students (n = 336) in an urban university setting. By utilizing a systematic and detailed approach, the study illuminates prior anatomical knowledge and various psychological constructs, marking a significant stride into a domain where knowledge remains profoundly limited. Analyses indicated that SES significantly affects financial anxiety (F(4, 331) = 17.391, p < 0.001) and academic behavioral confidence (F(4, 331) = 4.323, p = 0.002). Students with prior working experience reported higher self-perceived clinical experience but lower A-level grades (t(279.459) = −6.690, p < 0.001), competence in natural sciences (t(321.045) = −3.178, p = 0.002), and online competence (t(319.429) = −2.026, p = 0.044). Those who completed an apprenticeship showed higher resilience, academic confidence, self-efficacy, and greater concerns about balancing studies and work (t values ranging from 2.020 to 3.158, p < 0.05). Correlation analysis revealed a positive relationship between resilience (RQS) and coping with academic stress (CAS) (r = 0.632, p < 0.001), as well as between resilience and academic behavioral confidence (ABC) (r = 0.608, p < 0.001). Negative correlations were observed between resilience, coping with academic stress, academic confidence, and cognitive test anxiety (CTA) (r values from −0.235 to −0.404, p < 0.001). The findings emphasize the need for tailored support for students from diverse SES backgrounds and with varying experiences. The study highlights the value of a comprehensive approach in medical education, considering the diverse backgrounds and experiences of students. Future research should explore the long-term impact of these factors on professional competencies and patient care, leveraging the diversity of the student body for a holistic educational experience. Full article

Objective: The objective of this study was to assess the potential value of patient-reported outcomes (PROs) of depression, fibromyalgia symptoms, and pain in predicting non-inflammatory vs. inflammatory diagnoses in rheumatology patients. Methods: This retrospective, single-center study evaluated electronic health record (EHR) data from adults who were seen for their first rheumatology consultation and subsequently received a diagnosis of an inflammatory (e.g., rheumatoid arthritis or spondyloarthritis) or non-inflammatory (e.g., osteoarthritis or fibromyalgia) condition. The PROs evaluated included depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]), fibromyalgia symptom severity (FM SS), and pain. Results: A total of 3669 patients were evaluated, including patients with (n = 984; 26.82%) and without (n = 2685; 73.18%) inflammatory rheumatologic disease, of whom 141 (3.8%) had fibromyalgia. The non-inflammatory subgroup reported higher FM SS scores, and the inflammatory subgroup had higher pain and inflammatory markers. Bivariate models based on PHQ-2 and FM SS had a very low specificity (0.3%) for predicting non-inflammatory conditions, resulting in the misclassification of >99% of inflammatory cases. Adding pain, inflammatory markers, and other relevant EHR variables increased specificity but still resulted in a high level of misclassification. Conclusions: The PROs evaluated in this study are not suitable for predicting non-inflammatory vs. inflammatory rheumatologic disease, even when combined with other EHR variables. Full article

Background: This study aims to determine the rate of inflammatory rheumatic diseases (IRDs) in a cohort of initial referrals and the efficacy of prioritising appointments to the early arthritis clinic (EAC) based on symptom duration. Methods: In the present study, we used algorithm-based telephone triage to assign routine care appointments according to the time between symptom onset and request for an appointment (cut-off criterion: 6 months). This retrospective, monocentric analysis evaluated the effectiveness of our triage in identifying patients with IRDs as a function of the assigned appointment category (elective, EAC, or emergency appointment). Results: A total of 1407 patients were included in the study (34.7% male; 65.3% female). Of the 1407 patients evaluated, 361 (25.7%) presented with IRD. There were significant differences in the frequency of inflammatory diagnoses between appointment categories (p < 0.001): elective 13.8%, EAC 32.9%, and emergency 45.9%. The sample without the emergency category included a total of 1222 patients. The classification into “inflammatory” or “non-inflammatory” in this subsample was as follows: Sensitivity was 37.7%, and specificity was 92.6%. The positive predictive value (PPV) was 59.8%, and the negative predictive value (NPV) was 83.6%. Overall, 80.2% of patients were correctly assigned using the appointment category and C-reactive protein (CRP). Conclusions: The algorithm-based triage system presented here, which focuses on the time between symptom onset and request for an appointment, allows for the prioritisation of appointments in favour of patients with IRDs and thus earlier initiation of therapy. Full article

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case–control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = −2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2–13.5) g/dL versus 12.5 (12.2–13.4) g/dL in the control group; t (54) = −0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations. Full article

Implementation of marker-assisted selection (MAS) in modern beekeeping would improve sustainability, especially in breeding programs aiming for resilience against the parasitic mite Varroa destructor. Selecting honey bee colonies for natural resistance traits, such as brood-intrinsic suppression of varroa mite reproduction, reduces the use of chemical acaricides while respecting local adaptation. In 2019, eight genomic variants associated with varroa non-reproduction in drone brood were discovered in a single colony from the Amsterdam Water Dune population in the Netherlands. Recently, a new study tested the applicability of these eight genetic variants for the same phenotype on a population-wide scale in Flanders, Belgium. As the properties of some variants varied between the two studies, one hypothesized that the difference in genetic ancestry of the sampled colonies may underly these contribution shifts. In order to frame this, we determined the allele frequencies of the eight genetic variants in more than 360 Apis mellifera colonies across the European continent and found that variant type allele frequencies of these variants are primarily related to the A. mellifera subspecies or phylogenetic honey bee lineage. Our results confirm that population-specific genetic markers should always be evaluated in a new population prior to using them in MAS programs. Full article

[¹⁷⁷Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto^®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-³H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities. Full article

Understanding non-target-site resistance (NTSR) to herbicides represents a pressing challenge as NTSR is widespread in many weeds. Using giant duckweed (Spirodela polyrhiza) as a model, we systematically investigated genetic and molecular mechanisms of diquat resistance, which can only be achieved via NTSR. Quantifying the diquat resistance of 138 genotypes, we revealed an 8.5-fold difference in resistance levels between the most resistant and most susceptible genotypes. Further experiments suggested that diquat uptake and antioxidant-related processes jointly contributed to diquat resistance in S. polyrhiza. Using a genome-wide association approach, we identified several candidate genes, including a homolog of dienelactone hydrolase, that are associated with diquat resistance in S. polyrhiza. Together, these results provide new insights into the mechanisms and evolution of NTSR in plants. Full article

Honey bee colonies have great societal and economic importance. The main challenge that beekeepers face is keeping bee colonies healthy under ever-changing environmental conditions. In the past two decades, beekeepers that manage colonies of Western honey bees (Apis mellifera) have become increasingly concerned by the presence of parasites and pathogens affecting the bees, the reduction in pollen and nectar availability, and the colonies’ exposure to pesticides, among others. Hence, beekeepers need to know the health condition of their colonies and how to keep them alive and thriving, which creates a need for a new holistic data collection method to harmonize the flow of information from various sources that can be linked at the colony level for different health determinants, such as bee colony, environmental, socioeconomic, and genetic statuses. For this purpose, we have developed and implemented the B-GOOD (Giving Beekeeping Guidance by computational-assisted Decision Making) project as a case study to categorize the colony’s health condition and find a Health Status Index (HSI). Using a 3-tier setup guided by work plans and standardized protocols, we have collected data from inside the colonies (amount of brood, disease load, honey harvest, etc.) and from their environment (floral resource availability). Most of the project’s data was automatically collected by the BEEP Base Sensor System. This continuous stream of data served as the basis to determine and validate an algorithm to calculate the HSI using machine learning. In this article, we share our insights on this holistic methodology and also highlight the importance of using a standardized data language to increase the compatibility between different current and future studies. We argue that the combined management of big data will be an essential building block in the development of targeted guidance for beekeepers and for the future of sustainable beekeeping. Full article

Solid tumors of the cervicothoracic junction, the posterior mediastinum, or bilateral dorsal thoracic tumors represent a challenge in pediatric surgical oncology. The aim of this study was to evaluate trap-door thoracotomy and clamshell thoracotomy as surgical approaches. A single-center retrospective study of children with solid tumors in these specific localizations was performed. From 2015 to 2023, 26 children (17 girls; 9 boys) were treated at a median age of 54 months (range 8–229). Tumor resection was performed for neuroblastoma (n = 11); metastatic disease (n = 7); malignant rhabdoid tumor (n = 4); Ewing sarcoma (n = 1); inflammatory myofibroblastic tumor (n = 1); rhabdomyosarcoma (n = 1); and neurofibroma (n = 1). The surgical goal of macroscopic complete excision was achieved in all of the 14 children who underwent trap-door thoracotomy and in 11 of the 12 children who underwent clamshell thoracotomy. There were no major complications. At a median follow-up of 8 months (range 0–60), the disease was under local control or in complete remission in 66.7% of the children. In conclusion, surgical resection of solid tumors of the cervicothoracic junction in children can be performed safely and successfully with trap-door thoracotomy and with clamshell thoracotomy for posterior mediastinal or bilateral dorsal thoracic tumors. Full article

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients. Full article