Citations

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy defined by new-onset hypertension occurring after 20 weeks of pregnancy, with end organ damage. Pro-inflammatory changes are also observed in these patients. Although the clinical features of PE are resolved soon after delivery, affected patients face a higher risk and earlier onset of cardiovascular disease (CVD). It is unknown what leads to this persistent elevated risk, and long-term alterations of the maternal immune system could be involved. Study objective: Our goal was to address the immune alterations and functional changes in the first year postpartum in PE as compared to normotensive (NT) pregnancies. Hypothesis: We hypothesize that the maternal immune profile is altered in the postpartum period in PE vs NT patients, with a proinflammatory bias and altered function in PE patients. Brief Statement of Methods: We prospectively followed 31 women (PE=15, NT=16) and collected blood 24 hours, and 3, 6, and 12 months postpartum. Plasma and peripheral blood mononuclear cells (PBMC) were isolated and stored for analysis. Inflammatory mediators were quantified through multiplex assays, and PBMCs profile were defined through flow cytometry as well as following inflammatory stimuli to assess their functional changes through intracellular cytokine staining and expression of activation markers. Summary of Results: PE patients had elevated CD3+ T cell frequencies at 3 and 12 months postpartum compared to NT patients. Both groups showed reduced CD14+ monocytes across postpartum timepoints compared with 24 hours. PE was also associated with increased amounts of pro-inflammatory cytokines (such as IL1α, IL9, IFNγ), chemokines and growth factors at multiple timepoints throughout the first year postpartum; NT patients had decreased amounts of pro-inflammatory cytokines. Intracellular staining showed altered immune cell functions in PE, with decreased IL-6 production following polyI:C stimulation and decreased IL-10+ monocytes after LPS and polyI:C at 3 months postpartum. At 3 months, PE patients had increased markers of activation (i.e. CD69+) in both NK cells and T cells, the latter following PMA/Ionomycin stimulation. Statement of Conclusions: Pregnancy itself induces lasting immune changes persisting to 12 months postpartum, even in NT patients, whilst PE complicated pregnancies have sustained inflammation and altered immune function in the postpartum period. Overall, this work will provide essential insight into an understudied period that many women experience and help to identify long lasting immunological changes that could impact long term maternal health. Future work will explore the impact of this sustained inflammation on epigenetic modifications in immune cells. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Purpose: Supervised walking exercise is a critical component of rehabilitation for patients with peripheral artery disease (PAD); however, various barriers could limit participation in such programs, highlighting the need for accessible exercise strategies that may facilitate a gradual transition to more intensive physical activity while improving vascular function and walking performance in this population. We examined the hypothesis that static muscular stretching would improve microvascular function and walking ability in patients with PAD. Methods: Thirty-six PAD patients, classified as Fontaine Stage II or III, were randomized into stretching or non-stretching groups. The stretching group performed daily calf stretching using an ankle dorsiflexion splint for 30 minutes, 5 days a week, for 4 weeks. The six-minute walk test (6MWT) and a vascular occlusion test were used to assess changes in walking ability and calf microvascular function before and after the intervention. Results: Microvascular hyperemic reperfusion significantly increased in the treatment group (4958±1111 to 5749±1459 %*s, p=0.034), with no change observed in the control group (5502±1231 to 5022±1160 %*s, p=0.155). 6MWT total walking distance increased in all participants (260±88 to 285±85 m, p=0.004). A moderate but non-significant correlation was observed between the changes in 6MWT and total walking distance and reperfusion index in the treatment group (r=0.45, p=0.26). Conclusions: Static muscular stretching improves microvascular perfusion in the calf muscles, which may contribute to improvement in walking ability in patients with PAD. This low-cost and time-saving intervention may serve as a gradual transition to traditional supervised walking exercise rehabilitation, especially in patients with severely impaired walking ability.

Abstract Introduction Patients with Parkinson’s disease commonly underreport sleep symptoms, but the extent to which such mismatch may be present in people with isolated RBD (iRBD) is unknown. We evaluated how the patient–bedpartner (PT–BP) mismatch in night-time and daytime sleep complaints relates to cognition, apathy, dopaminergic degeneration, and cortical structure in iRBD. Methods We retrospectively analyzed 425 iRBD participants (2018–2025) from the North American Prodromal Synucleinopathy (NAPS) Consortium with clinicodemographic data, dopamine transporter (DAT) imaging, and magnetic resonance imaging. Using Scales for Outcomes in Parkinson’s Disease (SCOPA)-Sleep, PT–BP mismatch was classified into overestimator (PT>BP), concordant (PT=BP), and underestimator (PT< BP) groups, separately for complaints during night and day. Outcomes included cognition (CDR-Sum of Boxes [CDR-SB], CDR-global, and individual subdomain tests), pareidolia, apathy, subregional DAT uptake, and cortical thickness. Group differences were tested with analysis of covariance adjusting for age, sex, disease duration, education, clinician-rated OSA treatment inadequacy, and the corresponding patient-reported SCOPA-Sleep domain (night or day), and estimated total intracranial volume for cortical thickness; pairwise tests used Bonferroni correction. Results The PT–BP mismatch was common (night – overestimator 127/425, 29.9% and underestimator 116/425, 27.3%; day – overestimator 77/425, 18.1% and underestimator 134/425, 31.5%). For night-time mismatch, underestimators showed lower CDR-SB and lower CDR-global than overestimators. In addition, underestimators exhibited more illusory responses, fewer correct noise rejections, and fewer total correct responses than overestimator and concordant groups. For daytime mismatch, CDR-SB was lower in underestimators versus overestimators; CDR-global was lower in underestimators and concordant participants versus overestimators. No significant associations were found for apathy. Subregional DAT uptake did not differ by mismatch group. Cortical thickness analyses revealed thinner right transverse gyrus in underestimator and concordant groups compared to the overestimator group and thinner left superior temporal gyrus in underestimator group compared to overestimator group, for night-time mismatch only. Conclusion The PT–BP subjective sleep mismatch can be used as a clinical marker associated with overall cognitive decline and cortical thinning in auditory and language processing areas, which may underlie impairment in perceptual interpretation and hallucination proneness. Further research is warranted to seek longitudinal change and phenoconversion in mismatch groups. Support (if any) #U19-AG071754 (NAPS Consortium)

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.

Background: Given the faster onset and shorter duration of action of ultra-rapid insulin lispro-aabc (URLi, Lyumjev™ insulin), compared with insulin lispro (a rapid-acting insulin [RAI]), the present study investigated the safety and glycemic outcomes of MiniMed™ 780G advanced hybrid closed-loop (AHCL) use with URLi in youths and adults with T1D. Methods: This 19-site, single-arm, clinical trial enrolled children and adolescents (aged 7–17 years) and adults (aged 18–80 years) with T1D who underwent a run-in period (∼2 weeks) using open loop or automated basal only with an RAI (aspart or lispro), followed by a 3-month study period using URLi with AHCL (AHCL + URLi). End-of-study glycemic metrics and A1c were compared to predefined thresholds and to data from baseline/run-in. Use of recommended optimal settings (ROS, 100 mg/dL glucose target with an active insulin time [AIT] of 2 h) was also assessed. Results: In an intention-to-treat population ( N = 101 pediatric and N = 110 adult participants), percentage of time in range (%TIR) during the last ∼6 weeks of the study period was significantly greater than the predefined thresholds for both the pediatric and adult participants. A1c was unchanged in the pediatric cohort but significantly reduced in the adult cohort (from 7.4 ± 0.9% to 6.9 ± 0.6% [ P < 0.001]). Compared with run-in, study period %TIR and percentage of time in tight target range (%TITR) were significantly increased (pediatric mean %TIRΔ [17.4%] and %TITRΔ [16.0%], respectively, and adult mean %TIRΔ [10.6%] and %TITRΔ [11.6%], respectively; P < 0.001 for all). Additionally, % time above range for both groups was significantly reduced. Use of ROS allowed more participants to achieve recommended glycemic targets. There were no severe hypoglycemia or diabetic ketoacidosis events. Most caregivers agreed that mealtime versus premeal URLi delivery simplified pediatric meal management. Conclusions: Similar to previous studies investigating automated URLi delivery, URLi use in the MiniMed™ 780G system was safe, and glycemic outcomes were favorable for pediatric and adult participants.

Abstract We present chromosome-level, phased diploid genome assemblies of two widely used human fibroblast cell lines: BJ (46,XY) and IMR-90 (46,XX). Using Oxford Nanopore, PacBio HiFi, and Hi-C sequencing data, we generated assemblies spanning 5.9 and 6.0 Gbp with diploid quality values exceeding QV 60. To validate structural integrity, we developed KaryoScope, an alignment-free tool for generating computational karyograms from k-mer feature databases. We identify &gt;50 000 structural variants relative to T2T-CHM13v2.0, the majority of which are heterozygous and cell-line-specific. Combining reference-based and de novo gene annotation, we uncover a previously unreported 1 Mbp homozygous duplication at the 16p11.2 locus in BJ, demonstrating that even karyotypically normal cell lines can harbor clinically relevant submicroscopic rearrangements. We show that mapping publicly available short-read, RNA-seq, and ChIP-seq data to sample-matched diploid assemblies substantially improves read alignment and enables haplotype phasing of 23%–28% of short reads. The BJ and IMR-90 assemblies and associated variant calls are publicly available as a resource for the research community.

Abstract Background Presacral tumours are rare and heterogeneous lesions arising within a complex anatomical space, resulting in variability in diagnosis and management. Increasing incidental detection and evolving surgical and oncological strategies have highlighted the need for contemporary guidance. The aim of this study was to establish an international expert consensus on the optimal diagnosis and management of presacral tumours. Methods An international panel of colorectal surgeons from high-volume units was convened. Evidence- and practice-based statements were developed after domain-based literature reviews and refined through five online and two in-person meetings. Consensus was achieved using a modified Delphi process with anonymous voting. Results In total, 16 colorectal surgeons participated in the study. Ten domains were identified resulting in the development of 22 statements based on expert opinion and retrospective studies. After two rounds, unanimous (100%) agreement was achieved for all statements. High-resolution MRI with structured synoptic reporting is endorsed as central to risk stratification. Selective image-guided transperineal or parasacral biopsy is recommended for high-risk lesions where histology would alter management. Complete surgical resection is defined as the operative goal, with approach tailored to tumour biology and anatomy; minimally invasive surgery is considered appropriate in selected cases. Non-operative surveillance is supported for carefully selected asymptomatic, low-risk cystic lesions. Postoperative surveillance is recommended in a risk-adapted manner according to histopathology and margin status. Conclusion This international consensus provides a pragmatic, risk-stratified framework for the multidisciplinary diagnosis and management of presacral tumours. These recommendations aim to reduce practice variation, support decision-making in specialized centres, and inform future prospective collaborative research.

ABSTRACT Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC‐bearing mice, we observed reduced survival, accompanied by impaired CD4 + and CD8 + T cell responses and a marked expansion of FOXP3 + Tregs exhibiting elevated IL‐10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α‐ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate‐driven metabolic reprogramming as a central mechanism of age‐related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

Importance Young adults (YAs; ages 18-39 years) diagnosed with cancer face unique psychosocial challenges, including high distress and poor health-related quality of life (HRQOL). There are few efficacious interventions tailored to their needs. Objective To evaluate the efficacy of Bright IDEAS-YA, a problem-solving skills training intervention tailored for YAs, in reducing distress and improving HRQOL. Design, Setting, and Participants This randomized clinical trial was conducted at 3 academic medical centers and enrolled participants between February 2021 and March 2024. Eligible participants were aged 18 to 39 years, within 4 months of a first cancer diagnosis, and undergoing systemic therapy. Participants completed surveys at baseline and 3, 6, 12, and 24 months. Intervention Bright IDEAS-YA is a 6-session, one-on-one intervention that teaches a structured approach to problem-solving. Enhanced usual care (EUC) included standard psychosocial care plus a list of adolescent and YA resources. Main Outcomes and Measures Primary outcomes were depression and anxiety (Patient-Reported Outcomes Measurement Information System Short Forms) and HRQOL (Functional Assessment of Cancer Therapy-General) at 6 months. Problem-solving ability (Social Problem-Solving Inventory-Revised Short Form) was examined as a mediator. Analyses used linear mixed effects models and mediation analysis. Results Of the 1128 YAs screened, 344 YAs (median [IQR] age, 31.27 [25.78-36.38] years; 251 female [62.5%]) enrolled, with 171 allocated to intervention and 173 allocated to control. Overall, 296 YAs (86.0%) and 280 YAs (81.4%) completed 3- and 6-month surveys, respectively. At 6 months, the intervention group showed significantly greater improvements than EUC in depression (effect size estimate, −3.23 points; 95% CI, −4.93 to −1.53 points; P &amp;lt; .001), anxiety (effect size estimate,−2.43 points; 95% CI, −4.05 to −0.81 points; P = .003), and HRQOL (effect size estimate, 3.40 points; 95% CI, 0.34 to 6.45 points; P = .03). These changes were clinically meaningful. Mediation analyses showed that improvements in depression and anxiety were partially due to increased problem-solving ability, particularly reductions in negative problem orientation. Sex and education were moderators of treatment effect, with the treatment effect on anxiety being greater for males (effect size estimate, −5.29 points; 95% CI, −7.97 to −2.60 points) and the treatment effect on anxiety (effect size estimate, −6.94 points; 95% CI, −10.50 to −3.43 points) and depression (effect size estimate, −7.47 points; 95% CI, −11.20 to −3.74 points; P &amp;lt; .001) being greater for those with lower education. Conclusions and Relevance In this randomized clinical trial of Bright IDEAS-YA, intervention participants had significantly reduced distress and improved HRQOL relative to control. These findings suggest that Bright IDEAS-YA may be offered as supportive care for YAs with cancer to improve psychosocial outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT04585269