Targeting CD13/Aminopeptidase N as a Novel Therapeutic Approach for Scleroderma Fibrosis

Objective Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by the cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro‐inflammatory, pro‐arthritic, and pro‐angiogenic responses. In this study, we explored the antifibrotic potential of targeting the sCD13‐B1R axis in SSc. Methods The expression of CD13, B1R, and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo. Results Expression of the genes for CD13, B1R, and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc) SSc. Notably, single‐cell analysis of SSc skin biopsies revealed the highest BDKRB1 expression in COL8A1 ‐positive myofibroblasts, a population exclusively seen in SSc. Transforming growth factor beta (TGFβ) induced the expression of BDKRB1 and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The pro‐fibrotic responses of sCD13 or TGFβ were prevented by a B1R antagonist. Mice lacking Cd13 or Bdkrb1 were resistant to bleomycin‐induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect. Conclusion These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis and suggest that targeting the sCD13‐B1R signaling axis is a promising novel therapeutic approach for SSc.

Recommendations for Aligned Nomenclature of Peripheral Nervous System Disorders Across Rheumatology and Neurology

Association of Synovial Innate Immune Exhaustion With Worse Pain in Knee Osteoarthritis

Objective Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune‐regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA. Methods Synovial tissue biopsies from 122 patients with mild‐to‐severe knee OA pain (Knee Injury and OA Outcome Score [KOOS]) were analyzed to identify associations between synovial histopathology and worse pain. We then used spatial transcriptomics and proteomics of synovial tissue microenvironments (n = 32), followed by single‐cell RNA sequencing (n = 8), to identify synovial cell composition and cell‐cell communication networks in patients with more severe OA pain. Results Histopathological signs of synovial microvascular dysfunction and perivascular edema were associated with worse KOOS pain (−10.76; 95% confidence interval [CI] −18.90 to −2.61). Patients with worse pain had fewer immune‐regulatory macrophages, expanded fibroblast subsets, and enrichment in neurovascular remodeling pathways. Synovial macrophages from patients with worse pain expressed markers of immune exhaustion and decreased phagocytic function (−19.42%; 95% CI −35.96 to −2.89) and their conditioned media increased neuronal cell stress in dorsal root ganglia. Conclusion Although synovitis increases during OA, our findings suggest that exhaustion, dysfunction, and loss of immune‐regulatory macrophages is associated with worse pain and may be an important therapeutic target.

Efficacy and Safety of Zimlovisertib, Ritlecitinib, and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Objective We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin‐1 receptor–associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone. Methods This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C‐reactive protein (DAS28‐CRP) at week 12. Treatment‐emergent adverse events (TEAEs) were monitored. Results Overall, 460 patients were randomized. At week 12, zimlovisertib + tofacitinib demonstrated a greater magnitude of mean CFB in DAS28‐CRP (−2.65; 90% confidence interval [CI], −2.84 to −2.46) versus tofacitinib (−2.30; 90% CI, −2.49 to −2.11; P = 0.032); mean CFB with zimlovisertib + ritlecitinib (−2.35; 90% CI, −2.54 to −2.15) was similar to tofacitinib. TEAEs were reported in 246 patients (53.5%), with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by 9 patients (2.0%) and 10 patients reported serious AEs. One patient receiving tofacitinib died because of severe COVID‐19 infection. Safety profiles were similar across all treatment groups, with no evidence of additive/synergistic issues. Conclusion Zimlovisertib + tofacitinib was more effective than tofacitinib for the primary endpoint, whereas the efficacy of zimlovisertib + ritlecitinib did not achieve statistical significance versus tofacitinib. All treatments were well tolerated.

Autism Digital Phenotyping in Preschool‐ and School‐Age Children

ABSTRACT There is a critical need for scalable and objective tools for autism screening and outcome monitoring, which can be used alongside traditional caregiver and clinical measures. To address this need, we developed SenseToKnow, a tablet‐ or smartphone‐based digital phenotyping application (app), which uses computer vision and touch data to measure several autism‐related behavioral features, such as social attention, facial and head movements, and visual‐motor skills. Our previous work demonstrated that the SenseToKnow app can accurately detect and quantify behavioral signs of autism in 18–40‐month‐old toddlers. In the present study, we administered the SenseToKnow app on an iPad to 149 preschool‐ and school‐age children (45 neurotypical and 104 autistic) between 3 and 8 years of age. Results revealed significant group differences between autistic and neurotypical children in terms of several behavioral features, which remained after controlling for sex and age. Repeat administration with a subgroup demonstrated stability in the individual digital phenotypes. Examining correlations between the Vineland Adaptive Behavior Scales and individual digital phenotypes, we found that autistic children with higher levels of communication, daily living, socialization, motor, and adaptive skills exhibited higher levels of social attention and coordinated gaze with speech, less frequent head movements, higher complexity of facial movements, higher overall attention, lower blink rates, and higher visual motor skills, demonstrating convergent validity between app features and clinical measures. App features were also significantly correlated with ratings on the Social Responsiveness Scale. These results suggest that the SenseToKnow app can be used as an accessible, scalable, and objective digital tool to measure autism‐related behaviors in preschool‐ and school‐age children.

Lower Cortical Activation and Altered Functional Connectivity Characterize Passive Auditory Spatial Attention in ASD

ABSTRACT Autism Spectrum Disorder (ASD) is a developmental condition characterized by difficulties in social interaction, communication, and sensory processing. The ability to orient towards sounds is a key component of social interactions, yet auditory spatial attention remains relatively understudied in ASD, despite prior research indicating differences in this domain. Here, we investigate the neural signatures associated with passive auditory spatial attention in children with ASD ( n  = 21, ages 6–17) relative to age‐ and IQ‐matched Typically Developing (TD) children ( n  = 31), using source‐localized magnetoencephalography (MEG). Participants listened passively, while watching a silenced movie, to non‐social auditory stimuli designed to either remain lateralized to one hemifield ( stay trials) or to change in location from one side to the contralateral hemifield ( jump trials). Linear mixed effects modeling showed lower cortical activation in the auditory cortex in the ASD group in response to jump trials, relative to the TD group. Additionally, functional connectivity analyses showed higher alpha‐band functional connectivity in the ASD group between left auditory cortex seeds and right prefrontal and left parietal regions known to be recruited during auditory spatial attention. Right prefrontal alpha‐band connectivity estimates were associated with behaviorally assessed auditory processing scores, whereas left parietal connectivity estimates were associated with ASD symptomatology. Our results align with the hypothesis that auditory spatial attention generally, and specifically orientation to sounds even when experienced passively, differs in ASD versus TD children.

Water Main Break Rates in the United States and Canada

Key Takeaways A 2023 report on US and Canada water main breaks is one of the most thorough and statistically important ever undertaken and compares trends from previous studies in 2012 and 2018. Nearly 20%, or 452,000 miles, of water pipe are past their useful lives and need to be replaced, but they have not been because of a $452 billion shortfall in funding. Of a total inventory of 2.3 million miles of pipe, 33% of all water mains are more than 50 years old, representing 770,000 miles at risk. The United States and Canada experience 260,000 water main breaks annually with $2.6 billion in annual repair costs.

Titelbild: Bautechnik 11/2025

Abstract Zum Titelbild : Im Rahmen der Bundesgartenschau 2021 wurde mit dem Bastionskronenpfad eine neue Fußgängerbrücke für die Stadt Erfurt geschaffen. 1925 wurden auf der Zitadelle Peterberg durch den Bau der Lauentor‐Straße die Bastion Martin von der Bastion Gabriel getrennt. An dieser Stelle verbindet jetzt der Bastionskronenpfad die seitdem getrennten Bastionen durch eine neue Brückenkonstruktion, die mit einer zeitgemäßen und behutsamen Gestaltung in den historischen Bestand integriert wurde. Weitere Informationen im Beitrag von Hoffmann‐Berling et al. (Quelle: Steven Neukirch)

Post‐operative incidence of lymphedema after RARP with or without extended pelvic lymph node dissection in a cohort study

Abstract Objectives Lymphedema of the lower limbs and pubic area is a potential complication following extended pelvic lymph node dissection (ePLND) during robot‐assisted radical prostatectomy (RARP). The incidence of lymphedema after ePLND has not been systematically reported in the literature. This study aimed to determine the incidence of lymphedema, describe its clinical characteristics and identify specific risk factors in patients undergoing RARP with or without ePLND. Methods A retrospective cohort study was conducted at a tertiary referral centre between April 2016 and July 2020. Structured electronic case report forms (eCRFs) integrated into the electronic health record system were used to document intraoperative, perioperative and postoperative data. The primary endpoint was the incidence of lymphedema. Secondary endpoints included risk factors for and localization of the postoperative lymphedema. Results A total of 500 patients who underwent RARP were included, with 301 patients undergoing ePLND and 199 patients without any form of PLND. Median follow‐up period was 18 (range 3–49) months. Seventy‐eight out of 301 (26%) of patients who underwent ePLND developed lymphedema, compared to only 2 out of 199 (1%) patients without ePLND. In most patients (49/301, 16%), lymphedema was mild (grade 1), whereas 29 patients (10%) developed grade 2 lymphedema. Twenty‐six patients (9%) received decongestive lymphatic therapy. The most frequent site of lymphedema occurrence were the lower (54%) and the upper legs (40%). The number of nodes removed during RARP was identified as a risk factor for post‐operative lymphedema (OR 1.04; p  < 0.05). Conclusions In this cohort study, approximately one in four patients undergoing RARP with ePLND developed lower limb and/or midline oedema, whereas one in ten patients started decongestive lymphatic therapy for symptomatic lymphedema. These findings provide valuable information for patient counselling about the potential benefits and risks of ePLND.

Renal parenchymal volume analysis: Clinical and research applications