Abstract Cardiovascular–kidney–metabolic (CKM) syndrome represents a continuum of interrelated adiposity, insulin resistance, cardiovascular disease, kidney dysfunction, and metabolic disturbances that evolve across the lifespan. Emerging evidence demonstrates that both biological sex and sociocultural gender significantly shape CKM risk, progression, and clinical expression. CKM syndrome pathogenesis reflects complex multisystem interactions involving adipose tissue dysfunction, neurohormonal activation, inflammatory signaling, and vascular impairment, all of which exhibit important sex-specific patterns. This review examines CKM syndrome from a sex- and gender-informed perspective, highlighting how endogenous and exogenous sex hormones, reproductive transitions, pregnancy-related complications, and dietary exposures shape the long-term CKM syndrome risk. Particular attention is given to the roles of estrogen and testosterone in modulating adipose biology, vascular function, and metabolic regulation. Polycystic ovary syndrome is discussed as a model of androgen excess and multisystem metabolic vulnerability that accelerates CKM features. Finally, we address brain vulnerability within CKM syndrome, emphasizing shared inflammatory, vascular, and neuroendocrine mechanisms linking metabolic dysfunction to cognitive decline and neuropsychiatric disorders. Recognizing these interconnected and sex-specific influences is critical for advancing precision prevention and treatment strategies across the CKM syndrome spectrum. Graphical abstract
A workgroup assembled by the Alzheimer's Association recently described a conceptual framework for Alzheimer's disease biological staging based on amyloid and tau PET imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer's disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer's Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer's Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer's disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer's disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer's Disease Neuroimaging Initiative cohort. This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer's disease into four biological stages with distinct characteristics.
Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants and phenotypes. Here, we examine 2157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2157 proteins follow a bimodal distribution (median r = 0.30). We evaluate protein measure associations with genetic variants, and find approximately 25-30
Importance:The management of patent ductus arteriosus (PDA) in preterm infants is controversial. Objective:To determine whether expectant management compared with active treatment of a protocol-defined PDA in preterm infants decreases the incidence of death or bronchopulmonary dysplasia (BPD). Design, Setting, and Participants:A randomized clinical trial including infants born at 22 to 28 weeks' gestation and diagnosed with a protocol-defined PDA between the age of 48 hours and 21 days at screening. The trial was conducted from December 2018 to December 2024 at 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. The final date of follow-up was June 2025. Interventions:Infants with PDA were randomized to expectant management (n = 242) or active treatment (n = 240; acetaminophen, ibuprofen, or indomethacin) to close the PDA. Main Outcomes and Measures:The primary outcome was death or BPD at 36 weeks' postmenstrual age. The secondary outcomes included the components of the primary outcome and other morbidities of prematurity. Results:A total of 482 infants were randomized (median gestational age, 25 weeks [IQR, 24 to 27 weeks]; median birth weight, 760 g [IQR, 620 to 935 g]). The trial was stopped for futility and safety after the 50% interim analysis for the primary outcome due to higher survival in the expectant management group. The incidence of death or BPD was 80.9% (195/241) of infants in the expectant management group vs 79.6% (191/240) of infants in the active treatment group (adjusted risk difference, 1.2% [95% CI, -5.7% to 8.1%]; P = .73). The incidence of death before 36 weeks' postmenstrual age was 4.1% (10/241) of infants in the expectant management group vs 9.6% (23/240) of infants in the active treatment group (adjusted risk difference, -5.6% [95% CI, -10.1% to -1.2%]; P = .01). Infections resulting in death occurred in 0.8% (2/241) of infants in the expectant management group vs 3.8% (9/240) of infants in the active treatment group. Conclusions and Relevance:In extremely preterm infants with a protocol-defined PDA, death or BPD did not differ between the expectant management group and the active treatment group. Survival was substantially higher with expectant management. Trial Registration:ClinicalTrials.gov Identifier: NCT03456336.
Introduction Tumor necrosis factor alpha (TNF-α) is elevated 2-fold in women with preeclampsia. Preclinical investigation shows TNF-α blockade reduces maternal blood pressure in reduced uterine perfusion pressure (RUPP) rats and attenuates the reduction in fetal weight. However, the benefits versus harms of this therapy on fetal growth and underlying pathogenesis are unknown. Thus, this study tested the hypothesis that maternal treatment with the soluble TNF-α inhibitor Etanercept (Etan) during late gestation improves placental perfusion, nutrient transport, and morphology, thereby improving fetal growth in the RUPP model of preeclampsia compared with Sham controls. We further hypothesized that maternal Etan treatment is associated with improved blood pressure and inflammatory profiles in offspring. Methods Sham or RUPP surgery was performed at gestational day (GD) 14, with vehicle or Etan (0.4 mg/kg, s.c.) administered at GD18. Results Fetal weight (p = 0.0365) and survival (p = 0.0002) were reduced in RUPP (p = 0.0365) at GD20; only fetal weight was improved in Etan-RUPP (p = 0.0480). At GD20, uterine artery resistance index (UARI) was increased in RUPP (p = 0.0094), but attenuated in Etan-RUPP, indicating improved placental perfusion. Impaired placental transport and morphology were evident in RUPP, with no improvement in Etan-RUPP. Birthweight was improved in Etan-RUPP (p = 0.0312), although total NK cells (p = 0.0376) were increased in female Etan-RUPP offspring. Circulating AT1-AA activity was elevated in adult male and female RUPP offspring (p = 0.0013, p = 0.0006), but attenuated in female Etan-RUPP offspring. Discussion: These results suggest improved fetal growth in Etan-RUPP, independent of placental morphology or nutrient transporter expression, with sex-specific effects on inflammation in adult RUPP offspring.
