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Background: Accurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis., Methods: We conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated., Results: Preoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading., Conclusion: When planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered., (© 2024. The Author(s).)

Purpose: Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promising clinical results in the treatment of ovarian cancer. Analysis of biomarker subgroups consistently revealed higher benefits for patients with homologous recombination deficiency (HRD). The test that is most often used for the detection of HRD in clinical studies is the Myriad myChoice assay. However, other assays can also be used to assess biomarkers, which are indicative of HRD, genomic instability (GI), and BRCA1 / 2 mutation status. Many of these assays have high potential to be broadly applied in clinical routine diagnostics in a time-effective decentralized manner. Here, we compare the performance of a multitude of alternative assays in comparison with Myriad myChoice in high-grade serous ovarian cancer (HGSOC)., Methods: DNA from HGSOC samples was extracted from formalin-fixed paraffin-embedded tissue blocks of cases previously run with the Myriad myChoice assay, and GI was measured by multiple molecular assays (CytoSNP, AmoyDx, Illumina TSO500 HRD, OncoScan, NOGGO GISv1, QIAseq HRD Panel and whole genome sequencing), applying different bioinformatics algorithms., Results: Application of different assays to assess GI, including Myriad myChoice, revealed high concordance of the generated scores ranging from very substantial to nearly perfect fit, depending on the assay and bioinformatics pipelines applied. Interlaboratory comparison of assays also showed high concordance of GI scores., Conclusion: Assays for GI assessment not only show a high concordance with each other but also in correlation with Myriad myChoice. Thus, almost all of the assays included here can be used effectively to assess HRD-associated GI in the clinical setting. This is important as PARPi treatment on the basis of these tests is compliant with European Medicines Agency approvals, which are methodologically not test-bound.

The aim of this survey was to increase the knowledge on the characteristics and health concerns of long-term survivors (LTS; survival > 5 years) after ovarian cancer in order to tailor follow-up care. This international survey was initiated by the NOGGO and was made available to members of ENGOT and GCIG. The survey is anonymous and consists of 68 questions regarding sociodemographic, medical (cancer) history, health concerns including distress, long-term side effects, and lifestyle. For this analysis, 1044 LTS from 14 countries were recruited. In total, 58% were diagnosed with FIGO stage III/IV ovarian cancer and 43.4% developed recurrent disease, while 26.0% were receiving cancer treatment at the time of filling in the survey. LTS who survived 5-10 years self-estimated their health status as being significantly worse than LTS who survived more than 10 years ( p = 0.034), whereas distress also remained high 10 years after cancer diagnosis. Almost half of the cohort (46.1%) reported still having symptoms, which were mainly lymphedema (37.7%), fatigue (23.9%), pain (21.6%), polyneuropathy (16.9%), gastrointestinal problems (16.6%), and memory problems (15.5%). Almost all patients (94.2%) regularly received follow-up care. Specialized survivorship care with a focus on long-term side effects, lifestyle, and prevention should be offered beyond the typical five years of follow-up care.

Background: This study relates to emerging concepts of appropriate trial designs to evaluate effects of intervention on the accumulation of irreversible disability in multiple sclerosis (MS). Major starting points of our study are the known limitations of current definitions of disability progression by rater-based clinical assessment and the high relevance of gait and balance dysfunctions in MS. The study aims to explore a novel definition of disease progression using repeated instrumental assessment of relevant motor functions performed by patients in their home setting., Methods: The study is a prospective single-center observational cohort study with the primary outcome acquired by participants themselves, a home-based assessment of motor functions based on an RGB-Depth (RGB-D) camera, a camera that provides both depth (D) and color (RGB) data. Participants are instructed to perform and record a set of simple motor tasks twice a day over a one-week period every 6 months. Assessments are complemented by a set of questionnaires. Annual research grade assessments are acquired at dedicated study visits and include clinical ratings as well as structural imaging (MRI and optical coherence tomography). In addition, clinical data from routine visits is provided semiannually by treating neurologists. The observation period is 24 months for the primary endpoint with an additional clinical assessment at 27 month to confirm progression defined by the Expanded Disability Status Scale (EDSS). Secondary analyses aim to explore the time course of changes in motor parameters and performance of the novel definition against different alternative definitions of progression in MS. The study was registered at Deutsches Register für Klinische Studien (DRKS00027042)., Discussion: The study design presented here investigates disease progression defined by marker-less home-based assessment of motor functions against 3-month confirmed disease progression (3 m-CDP) defined by the EDSS. The technical approach was chosen due to previous experience in lab-based settings. The observation time per participant of 24, respectively, 27 months is commonly conceived as the lower limit needed to study disability progression. Defining a valid digital motor outcome for disease progression in MS may help to reduce observation times in clinical trials and add confidence to the detection of progression events in MS., Competing Interests: HR was a paid employee of Motognosis GmbH until March 2023. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dorsch, Röhling, Zocholl, Hafermann, Paul and Schmitz-Hübsch.)

In oncology, phase II clinical trials are often planned as single-arm two-stage designs with a binary endpoint, for example, progression-free survival after 12 months, and the option to stop for futility after the first stage. Simon's two-stage design is a very popular approach but depending on the follow-up time required to measure the patients' outcomes the trial may have to be paused undesirably long. To shorten this forced interruption, it was proposed to use a short-term endpoint for the interim decision, such as progression-free survival after 3 months. We show that if the assumptions for the short-term endpoint are misspecified, the decision-making in the interim can be misleading, resulting in a great loss of statistical power. For the setting of a binary endpoint with nested measurements, such as progression-free survival, we propose two approaches that utilize all available short-term and long-term assessments of the endpoint to guide the interim decision. One approach is based on conditional power and the other is based on Bayesian posterior predictive probability of success. In extensive simulations, we show that both methods perform similarly, when appropriately calibrated, and can greatly improve power compared to the existing approach in settings with slow patient recruitment. Software code to implement the methods is made publicly available.

Multiple sclerosis (MS) is the most common chronic central nervous system inflammatory disease. Individual courses are highly variable, with complete remission in some patients and relentless progression in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared with progressive MS (PMS). We differentiated neurons and astrocytes that were then stressed with inflammatory cytokines typically associated with MS phenotypes. TNF-α/IL-17A treatment increased neurite damage in MS neurons from both clinical phenotypes. In contrast, TNF-α/IL-17A-reactive BMS astrocytes cultured with healthy control neurons exhibited less axonal damage compared with PMS astrocytes. Accordingly, single-cell transcriptomic BMS astrocyte analysis of cocultured neurons revealed upregulated neuronal resilience pathways; these astrocytes showed differential growth factor expression. Furthermore, supernatants from BMS astrocyte/neuronal cocultures rescued TNF-α/IL-17-induced neurite damage. This process was associated with a unique LIF and TGF-β1 growth factor expression, as induced by TNF-α/IL-17 and JAK-STAT activation. Our findings highlight a potential therapeutic role of modulation of astrocyte phenotypes, generating a neuroprotective milieu. Such effects could prevent permanent neuronal damage.

Background: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA., Methods: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca -/- ), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography., Results: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity., Conclusion: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ ΔKRKR ) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ ΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ ΔKRKR mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ ΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation., (© 2023. The Author(s).)

Objective: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease., Methods: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021., Results: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy., Conclusion: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cut-offs on self-report depression screening tools are designed to identify many more people than those who meet criteria for major depressive disorder. In a recent analysis of the European Health Interview Survey (EHIS), the percentage of participants with Patient Health Questionnaire-8 (PHQ-8) scores ≥10 was reported as major depression prevalence., Objective: We used a Bayesian framework to re-analyse EHIS PHQ-8 data, accounting for the imperfect diagnostic accuracy of the PHQ-8., Methods: The EHIS is a cross-sectional, population-based survey in 27 countries across Europe with 258 888 participants from the general population. We incorporated evidence from a comprehensive individual participant data meta-analysis on the accuracy of the PHQ-8 cut-off of ≥10. We evaluated the joint posterior distribution to estimate the major depression prevalence, prevalence differences between countries and compared with previous EHIS results., Findings: Overall, major depression prevalence was 2.1% (95% credible interval (CrI) 1.0% to 3.8%). Mean posterior prevalence estimates ranged from 0.6% (0.0% to 1.9%) in the Czech Republic to 4.2% (0.2% to 11.3%) in Iceland. Accounting for the imperfect diagnostic accuracy resulted in insufficient power to establish prevalence differences. 76.4% (38.0% to 96.0%) of observed positive tests were estimated to be false positives. Prevalence was lower than the 6.4% (95% CI 6.2% to 6.5%) estimated previously., Conclusions: Prevalence estimation needs to account for imperfect diagnostic accuracy., Clinical Implications: Major depression prevalence in European countries is likely lower than previously reported on the basis of the EHIS survey., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

Any experiment involving living organisms requires justification of the need and moral defensibleness of the study. Statistical planning, design, and sample size calculation of the experiment are no less important review criteria than general medical and ethical points to consider. Errors made in the statistical planning and data evaluation phase can have severe consequences on both results and conclusions. They might proliferate and thus impact future trials-an unintended outcome of fundamental research with profound ethical consequences. Unified statistical standards are currently missing for animal review boards in Germany. In order to accompany, we developed a biometric form to be filled and handed in with the proposal at the concerned local authority on animal welfare. It addresses relevant points to consider for biostatistical planning of animal experiments and can help both the applicants and the reviewers in overseeing the entire experiment(s) planned. Furthermore, the form might also aid in meeting the current standards set by the 3+3R's principle of animal experimentation: Replacement, Reduction, Refinement as well as Robustness, Registration, and Reporting. The form has already been in use by the concerned local authority of animal welfare in Berlin, Germany. In addition, we provide reference to our user guide giving more detailed explanation and examples for each section of the biometric form. Unifying the set of biostatistical aspects will help both the applicants and the reviewers to equal standards and increase quality of preclinical research projects, also for translational, multicenter, or international studies., (© 2022 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Background: Knife crime has increased considerably in recent years in Northern Europe. Affected patients often require immediate surgical care due to traumatic organ injury. Yet, little is known about clinically relevant routine laboratory parameters in stab injury patients and how these are associated with intensive care unit (ICU) admission, hospitalization and number of surgeries., Methods: We retrospectively analyzed 258 stab injury cases between July 2015 and December 2021 at an urban Level I Trauma Center. Annual and seasonal incidences, injury site, injury mechanism, Injury Severity Score (ISS), and surgical management were evaluated. First, correlations between routine laboratory parameters for hematology, coagulation, and serum biochemistry (peak, and Δ (change from admission to peak within 3 days following admission)) and length of hospital stay, ICU stay, and number of surgeries were assessed using Spearman's rank correlation coefficients. Second, multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify parameters predictive of clinical outcomes. Third, longitudinal developments of routine laboratory parameters were assessed during hospital admission., Results: In 2021, significantly more stab injuries were recorded compared with previous years and occurred less during winter compared with other seasons. Mean ISS was 8.3 ± 7.3, and ISS was positively correlated with length of hospital and ICU stay (r = 0.5-0.8, p < 0.001). Aspartate transaminase (AST) (Δ) (r = 0.690), peak C-reactive protein (CrP) (r = 0.573), and erythrocyte count (Δ) (r = 0.526) showed the strongest positive correlations for length of ICU stay for penetrating, thoracoabdominal, and organ injuries, respectively. No correlations were observed between routine laboratory parameters and number of surgeries. For patients with penetrating injuries, LASSO-selected predictors of ICU admission included ISS, pH and lactate at admission, and Δ values for activated partial thromboplastin time (aPTT), K + , and erythrocyte count. CrP levels on day 3 were significantly higher in patients with penetrating (p = 0.005), thoracoabdominal (p = 0.041), and organ injuries (p < 0.001) compared with those without., Conclusion: Our data demonstrate an increase in stab injury cases in 2021 and an important link between changes in routine laboratory parameters and ICU admission and hospitalization. Monitoring ISS and changes in AST, CrP, erythrocyte count, pH, lactate, aPTT, and K + may be useful to identify patients at risk and adjust surgical and ICU algorithms early on., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maleitzke, Zhou, Zocholl, Fleckenstein, Back, Plewe, Weber, Winkler, Stöckle, Tsitsilonis and Märdian.)

Purpose: To compare different assessment methods for peri-implant inflammation to evaluate potential risk factors and to generate a comprehensive algorithm for clinical staging, treatment, and evaluation of success in periorbital implants. Materials and Methods: In this hospital-based cross-sectional study, 111 periorbital implants in 40 patients with orbital defects after exenteration were clinically analyzed. Skin reaction according to Holgers (SRH), probing depth (PD) , and sulcus fluid flow rate (SFFR), as well as patient-specific data, such as age, sex, smoking and irradiation status, cleaning agent and frequency, defect etiology, implant system, implant location, time span since implantation, and type of retention, were assessed and statistically analyzed via mixed-model calculations. Success was defined as the absence of necessary invasive or antibiotic treatment. Results: A total of 62 implants (55.9%) had been placed in male patients and 49 implants (44.1%) in female patients. There were 18 patients (52 implants, 46.8%) who had received radiotherapy. Mean inflammation levels were low. PD and SFFR were highly correlated, whereby PD increased significantly with time after implantation. SRH ≥ 2 was correlated significantly with higher PD and SFFR values. While 80% of the implants did not require invasive or antibiotic treatment, 45% of the patients presented at least one affected implant. The data gathered allowed for the definition of a staging and treatment algorithm for peri-implantitis in periorbital implants. No patient-specific factors showed a significant impact on peri-implant inflammation. Conclusion: Periorbital implant restorations with magnetic abutments are a safe treatment option for orbital defects. PD and SRH were proven to be valuable quick assessment tools and should be complemented by SFFR, if inconclusive. The established parameters for the staging of peri-implant tissue health and clinical success can serve as a viable tool for reliable and comparable assessment in clinical and scientific settings. Further studies are necessary to assess the suggested treatment algorithm.

We consider the case of pediatric dose-finding trials with extremely limited sample size. The operating characteristics of the standard design, the Continual Reassessment Method (CRM), are only well described for sample sizes of about 20 patients or more. In this simulation study, we assume the situation of a pediatric trial with only 10 patients and a preceding dose-finding trial in adults. Based on the adult data, we reduce the set of pediatric doses and formulate (partially) informative prior distributions for the pediatric trial. Our simulations show that such small pediatric dose-finding trials with robustified priors may provide sufficient operating characteristics.

Background: While repeated shutdown and lockdown measures helped contain the spread of SARS-CoV-2 during the COVID-19 pandemic, social distancing and self-isolation negatively impacted global mental health in 2020 and 2021. Although suicide rates did reportedly not increase during the first months of the pandemic, long-term data, and data on the quality of serious violent suicide attempts (SVSAs) are not available to date., Materials and Methods: Orthopaedic trauma patient visits to the emergency department (ED), ED trauma team activations, and SVSAs were retrospectively evaluated from January 2019 until May 2021 in four Level-I Trauma Centers in Berlin, Germany. SVSAs were assessed for suicide method, injury pattern and severity, type of treatment, and length of hospital stay., Results: Significantly fewer orthopaedic trauma patients presented to EDs during the pandemic ( n = 70,271) compared to the control ( n = 84,864) period ( p = 0.0017). ED trauma team activation numbers remained unchanged. SVSAs (corrected for seasonality) also remained unchanged during control ( n = 138) and pandemic ( n = 129) periods, and no differences were observed for suicide methods, injury patterns, or length of hospital stay., Conclusion: Our data emphasize that a previously reported rise in psychological stress during the COVID-19 pandemic does not coincide with increased SVSA rates or changes in quality of SVSAs., (Copyright © 2022 Maleitzke, Zocholl, Topp, Dimitrov-Discher, Daus, Reaux, Zocholl, Conze, Kolster, Weber, Fleckenstein, Scheutz Henriksen, Stöckle, Fuchs, Gümbel, Spranger, Ringk and Märdian.)

(1) Background: A complete tumor resection during primary cytoreductive surgery has been reported to be the most important and perhaps the only independent prognostic factor in advanced ovarian cancers. The goal of complete cytoreduction needs to be weighed against the potential morbidities and long-term survival outcomes. (2) Methods: in this retrospective analysis of a prospectively obtained database, 208 consecutive patients with advanced ovarian cancer who underwent a conventional primary cytoreductive surgery (150 patients) or TROMP technique (58 patients) were included. Progression-free and overall survival rates were calculated using Kaplan-Meier analysis as well as the 95% confidence interval of the hazard ratio between treatment groups. (3) Results: After a median follow-up phase of more than 3 years (range 1-72 months), there are no statistically significant differences between both groups in progression-free and overall survival rates. Albeit, the TROMP group included statistically significant more advanced-stage cases compared to the conventional surgery group. (4) Conclusions: the TROMP technique is a promising tool for successful primary cytoreductive surgery in a selected group of patients with high tumor burdens in order to achieve optimal surgical results and survival outcomes without introducing any additional risks or complications.

(1) Background: Perineural invasion (PNI) is a common characteristic of pancreatic ductal adenocarcinoma (PDAC) and is present in most resection margins. We hypothesized that curative pancreatic tumor resection with long-term survival could only be achieved in PNI-negative patients. (2) Material and Methods: A retrospective investigation of PDAC patients who underwent curative-intended surgery during the period 2008 to 2019 was performed at our institution. (3) Results: We identified 571 of 660 (86.5%) resected patients with well-annotated reports and complete datasets. Of those, 531 patients (93%) exhibited tumors with perineural invasion (Pn1), while 40 (7%) were negative for PNI (Pn0). The majority of patients in the Pn1 group presented advanced tumor stage and positive lymph node infiltration. Patients in the Pn0 group showed an improved disease-free and long-term survival compared to the Pn1 group (p < 0.001). Subgroup analysis of all R0-resected patients indicated improved long-term survival and disease-free survival of R0 Pn0 patients when compared to R0 Pn1 patients (p < 0.001). (4) Conclusion: Our study confirmed that Pn0 improves the long-term survival of PDAC-resected cancer patients. Furthermore, PNI significantly challenges the long-term survival of formally curative (R0) resected patients. We provide new insights into the dynamics of PNI in pancreatic cancer patients which are needed to define subgroups of patients for risk stratification and multimodal treatment strategies.

Pharmacological application of teleost calcitonin (CT) has been shown to exert chondroprotective and anti-resorptive effects in patients with rheumatoid arthritis (RA). However, the role of endogenous CT that signals through the calcitonin receptor (CTR) remains elusive. Collagen II antibody-induced arthritis (CAIA) was stimulated in wild type (WT) and CTR-deficient (Calcr -/- ) mice. Animals were monitored over 10 or 48 days. Joint inflammation, cartilage degradation, and bone erosions were assessed by clinical arthritis score, histology, histomorphometry, gene expression analysis, and μ-computed tomography. CAIA was accompanied by elevated systemic CT levels and CTR expression in the articular cartilage. Inflammation, cartilage degradation, and systemic bone loss were more pronounced in Calcr -/- CAIA mice. Expression of various pro-inflammatory, bone resorption, and catabolic cartilage markers were exclusively increased in Calcr -/- CAIA mice. Endogenous CT signaling through the mammalian CTR has the potential to protect against joint inflammation, cartilage degradation, and excessive bone remodeling in experimental RA., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Objectives: Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling., Methods: Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT., Results: CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1β, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time., Conclusion: This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It is controversially discussed whether immune-deficient mice experience severity in the absence of infection. Because a comprehensive analysis of the well-being of immune-deficient mice under specific pathogen free conditions is missing, we used a multi-parametric test analyzing, corticosterone, weight, nest building and facial expression over a period of 9 month to determine the well-being of two immune-deficient mouse lines (recombination activating gene 2- and interferon gamma receptor-deficient mice). We do not find evidence for severity when comparing immune-deficient mice to their heterozygous immune-competent littermates. Our data challenge the assumption that immune-deficiency per se regardless of housing conditions causes severity. Based on our study we propose to use objective non-invasive parameters determined by laboratory animal science for decisions concerning severity of immune-deficient mice., Competing Interests: The authors declare that they do not have any competing interests.