Maternal cardiovascular events in autoimmune rheumatic diseases and antiphospholipid syndrome pregnancies.

OBJECTIVE:: Antiphospholipid syndrome (APS) and autoimmune rheumatic diseases (ARDs) are known to increase the risk for cardiovascular events (CVEs) in the general population., However, research in pregnancy is limited. We compared the occurrence of acute CVEs in pregnant women with and without ARDs or primary APS using a Californian population-based cohort. STUDY DESIGN:: This was a retrospective cohort study of pregnant individuals who delivered singleton infants in California between 2005 and 2020. Birth certificates were linked by the Study of Outcomes of Mothers and Infants to maternal records. The study was approved by institutional review boards of the State of California and the University of California San Diego. Pregnancies with ARDs were identified by ≥1 International Classification of Diseases (ICD) code for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthritis, Sjogren’s syndrome, and other ARDs (systemic sclerosis, inflammatory myositis, and vasculitides) in maternal hospital discharge, emergency, or ambulatory surgery records. Lupus nephritis (LN) was defined as SLE plus glomerulonephritis, renal failure, nephritic or nephrotic syndrome, or proteinuria. Primary APS included women with APS without concurrent ARDs. Women without ARDs or APS comprised the reference group. Acute CVEs during pregnancy and up to 6 weeks postpartum were identified by ICD codes and compared between groups. CVEs were classified as myocardial infarction, cardiovascular accident, heart failure and peripartum cardiomyopathy, inflammatory heart diseases, cardiac dysrhythmias, and venous thromboembolism (VTE). Covariates identified and adjusted for include age, race and ethnicity, insurance, education, prepregnancy body mass index, preexisting hypertension, diabetes, hyperlipidemia, depression, and substance use disorders. A log linear regression with a Poisson distribution was used to estimate the adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for the associations of ARDs and APS with CVEs. Analyses were performed using Statistical Analysis Software (SAS), version 9.4 (SAS Institute, Cary, NC). Causal mediation analyses were performed for potential mediators, such as gestational diabetes, gestational hypertension, and preeclampsia. RESULTS:: Overall, 19,340 women had ARDs, 7758 had primary APS, and 7,004,334 had neither condition. The ARD and APS groups had more traditional cardiovascular risk factors. Acute CVEs were observed in 2.0% of ARD cases (388/19,340), 7.0% of primary APS cases (540/7,758), and 0.4% of reference group cases (24,402/7,004,334). The aRR for CVEs in the ARD and APS groups in comparison with the reference group was 4.1-fold (95% CI, 3.7–4.5) and 14.7-fold (95% CI, 13.5–16.0), respectively (Table). Of the 388 CVEs that occurred in women with ARDs, 164 (42%) were VTEs, 96 (25%) were heart failure or peripartum cardiomyopathy, and 92 (24%) were cardiac dysrhythmias. In primary APS cases, 453 of 540 (83%) CVEs were VTE. Acute CVEs occurred in 3.1% (159/8,422) of patients with overall SLE, in 10.7% (55/513) of patients with SLE with APS, and in 8.5% (77/903) of patients with SLE with LN (Table). The aRR for CVEs was 6-fold higher among those with SLE (95% CI, 5.3–6.8) and was notably increased with concurrent APS or LN, with aRRs of 18.1 (95% CI, 13.9–23.6) and 12.7 (95% CI, 10.1–15.9), respectively (Figure). The risks for both VTE and non-VTE CVEs was increased among pregnancies affected by ARD and APS (Figure). Five of 6 in-hospital deaths in ARD pregnancies (5/388 or 1.3%) occurred among women with acute CVEs (Table). The risks for CVEs were higher during all perinatal periods. In mediation analyses, 11.2% of the excess risk for CVE in ARD pregnancies was mediated by preeclampsia, whereas <0.5% was mediated by gestational diabetes or hypertension. CONCLUSION:: Pregnancies affected by ARDs and APS had both more traditional cardiovascular risk factors and about a 4-fold and 15-fold higher CVE risk, respectively, than the reference group. Pregnancies affected by SLE with APS (18.1-fold) and LN (12.7-fold) had substantial increased risks for CVEs. VTEs were the most frequently observed CVEs. The in-hospital mortality rate for any acute CVE in ARD pregnancies was 1.3% (Table)

Post-Pandemic Cities: An Urban Lexicon of Accelerations/Decelerations

COVID-19 has stimulated renewed societal and academic debate about the future of cities and urban life. Future visons have veered from the ‘death of the city’ to visual renderings and limited experiments with 15-minute neighbourhoods. Within this context, we as a diverse group of urban scholars sought to examine the emergent ‘post’-COVID city through the production of an urban lexicon that investigates its socio-material contours. The urban lexicon makes three contributions. First, to explore how the pandemic has accelerated certain processes and agendas while at the same time, other processes, priorities and sites have been decelerated and put on hold. Second, to utilise this framing to examine the impacts of the pandemic on how cities are governed, on how urban geographies are managed and lived, and with how care emerged as a vital urban resource. Third, to tease out what might be temporary intensifications and what may become configurational in a variety of urban domains, including governance, platforming, density, crowds, technosolutionism, dwelling, respatialisation, reconcentration, care, improvisation, and atmosphere. The urban lexicon proposes a vocabulary for delineating, describing, and understanding some of the key aspects of the emergent post-pandemic city

Equity, data and the surveillance gap in antimicrobial resistance: A call for inclusive action

Antimicrobial resistance (AMR) is a growing global health concern that spans human, animal, and environmental health, making it a quintessential One Health issue. Global AMR surveillance systems such as the World Health Organisation’s (WHO) Global Antimicrobial Resistance and Use Surveillance System (GLASS) have created important opportunities for countries to collect andreport AMR data systematically across sectors and settings. These systems also include the capacity to capture variables such as sex, age, and infection origin (community-acquired or healthcare-associated). This can facilitate the use of equity indicators and provide a foundation for more inclusive and responsive AMR analysis. This commentary highlights the value of building on these existing systems by expanding the routine collection and analysis of both basic and advanced equity-related variables and indicators using the human health sector as an entry point. Incorporating variables such as location of residence, education level, occupation, socio-economic status, disability, and ethnicity enables an intersectional analysis. This can enhance understanding of who is most affected by AMR and why, and inform effective responses. Recognising that AMR surveillance data often comes from health facilities, we also explore the benefits of complementing it with community-level and community-led approaches to better reflect diverse realities and patterns of AMR across populations and contexts. By integrating equity considerations into AMRdata systems, countries and global stakeholders can strengthen the design, implementation, and targeting of interventions. These steps support more responsive health systems and contribute to AMR solutions that are not only scientifically sound but also socially inclusive. Embedding equity in AMR surveillance is a vital step toward achieving the full promise of One Health – ensuring that responses are informed, effective, and reflective of the diverse communities they are meant to serve

Clinical Acceptability of Automatically Generated Lymph Node Levels and Structures of Deglutition and Mastication for Head and Neck Radiation Therapy

BACKGROUND AND PURPOSE: Auto-contouring of complex anatomy in computed tomography (CT) scans is a highly anticipated solution to many problems in radiotherapy. In this study, artificial intelligence (AI)-based auto-contouring models were clinically validated for lymph node levels and structures of swallowing and chewing in the head and neck. MATERIALS AND METHODS: CT scans of 145 head and neck radiotherapy patients were retrospectively curated. One cohort (n = 47) was used to analyze seven lymph node levels and the other (n = 98) used to analyze 17 swallowing and chewing structures. Separate nnUnet models were trained and validated using the separate cohorts. For the lymph node levels, preference and clinical acceptability of AI vs human contours were scored. For the swallowing and chewing structures, clinical acceptability was scored. Quantitative analyses of the test sets were performed for AI vs human contours for all structures using overlap and distance metrics. RESULTS: Median Dice Similarity Coefficient ranged from 0.77 to 0.89 for lymph node levels and 0.86 to 0.96 for chewing and swallowing structures. The AI contours were superior to or equally preferred to the manual contours at rates ranging from 75% to 91%; there was not a significant difference in clinical acceptability for nodal levels I-V for manual versus AI contours. Across all AI-generated lymph node level contours, 92% were rated as usable with stylistic to no edits. Of the 340 contours in the chewing and swallowing cohort, 4% required minor edits. CONCLUSIONS: An accurate approach was developed to auto-contour lymph node levels and chewing and swallowing structures on CT images for patients with intact nodal anatomy. Only a small portion of test set auto-contours required minor edits

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity

Acylcarnitine enrichment as a characteristic of rheumatoid arthritis fibroblast-like synoviocyte metabolic fingerprint

Objective: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) alter their metabolism to support their activation. We aimed to analyse the full spectrum of metabolic alterations associated with RA by performing untargeted metabolomics in RA FLS vs. non-inflamed (NI) FLS. Methods: Untargeted annotated metabolomics was performed using mass spectrometry on ten primary RA and seven NI FLS culture extracts and 220 serum samples from participants with early RA from the randomised controlled NORD-STAR trial. Carnitine-related proteins were measured with Western blot. FLS bioenergetic profile was assessed with a Seahorse flux analyser. Results: Metabolomics analysis based on 138 annotated metabolites revealed a distinct metabolic fingerprint between RA and NI FLS. Of the 12 metabolites enriched in RA FLS, 11 were acylcarnitines. Pro-inflammatory stimulation of NI FLS also led to acylcarnitine accumulation. RA FLS exhibited lower levels of CD36, a fatty acid transporter, but similar levels of L-carnitine transporter, and carnitine palmitoyltransferase 1 A and 2 compared to NI FLS. Seahorse analyses showed no difference in fatty acid oxidation between RA and NI FLS; however, RA FLS displayed mitochondrial dysfunction and energetic impairment. Serum acylcarnitine content decreased after 24 weeks of treatment with methotrexate combined with abatacept or tocilizumab in patients with early RA achieving remission. Conclusion: Acylcarnitine accumulation is a characteristic of RA FLS metabolic fingerprint and could be linked to mitochondrial dysfunction. In patients with early RA, acylcarnitine content in serum decreases after successful anti-rheumatic treatment. These results indicate a dysregulation in acylcarnitine metabolism in RA at the joint level and systemically.</p

Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

Constitutive NF-κB activation in IECs induces inflammatory cytokines and chemokines in the lamina propria, but does not result in overt tissue damage unless acute inflammatory insults are present, causing TNF-dependent destruction and barrier disruption