Karolina Kublickiene

Background: Maternal outcomes remain inequitable worldwide. Severe morbidity persists, and current risk assessment tools are largely arbitrary, focusing on biomedical factors while overlooking social determinants of health. There is a need for data-driven AI models to improve early pregnancy risk identification and management. Objective: The study aimed to develop and internally validate first-trimester AI-based antenatal risk assessment models across three geographically and socioethnically diverse populations (Sweden, Chile, and Singapore) and to compare their performance with existing clinical risk assessment strategies. Methods: We conducted a retrospective population-based study using routinely collected first-trimester data from over 700,000 pregnancies from Sweden, Chile, and Singapore. Separate machine learning models predicting a composite of adverse maternal and neonatal outcomes were trained and internally validated for each population. Input variables were limited to information available at or before 14 weeks’ gestation. Model discrimination, measured by the area under the receiver operating characteristic (AUROC) curve, was compared with corresponding proxies for real-world first-trimester risk assessment approaches in each setting. Model interpretability was assessed using Shapley additive explanations. Results: The prevalence of the composite adverse outcome was 10.40% (75,647/727,354) in Sweden, 21.94% (1302/5934) in Chile, and 16.25% (6145/37,813) in Singapore. In Sweden, the guideline-based risk assessment achieved an AUROC of 0.53, compared with 0.65 for the LightGBM (light gradient boosting machine) model ( P <.001). In Chile, the midwifery-led risk assessment achieved an AUROC of 0.52, versus 0.65 from the traditional machine learning LightGBM model ( P <.001). In Singapore, the health care professional–based risk assessment reached an AUROC of 0.56, compared with 0.60 for the LightGBM model ( P <.05). In the Swedish and Singapore cohorts, sociodemographic variables were among the most influential predictive features. At a false-positive rate of 50.0%, the sensitivities for predicting the primary composite adverse outcome were 69.17%, 69.62%, and 64.93% for the Sweden, Chile, and Singapore models, respectively. At a 30.0% false-positive rate operating point, the sensitivities were lower, at 50.38%, 55.38%, and 44.75%, respectively, but with higher positive predictive values of 16.31%, 34.53%, and 22.32%, respectively. The model calibration plots showed reasonable agreement in Sweden and Singapore, whereas the Chile model showed poorer calibration, with a calibration slope of approximately 1.45, indicating underconfidence. Conclusions: AI-based models developed using first-trimester data generally demonstrated improved performance compared with existing first-trimester clinical risk stratification strategies across three distinct populations. These findings suggest the potential feasibility of population-specific, AI-enabled risk stratification as a clinical decision support tool and highlight the potential value of integrating social, demographic, and behavioral determinants into antenatal risk assessment frameworks to support more equitable and personalized antenatal care.

Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood–brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to IS 200 and 900 μM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-β-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-β-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 µM and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 µM, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies.

Background. Chronic kidney disease [CKD] is characterized by increased glycoxidative stress, inflammation, and mitochondrial dysfunction. Advanced glycation end-products [AGEs] and their receptor [RAGE] mediate glycoxidative stress, whereas mitochondrial-derived peptides [MDPs], including humanin [HN], MOTS-c, and humanin-like 1 [HN-L1], regulate mitochondrial stress responses. We investigated links between AGE–RAGE activation and mitochondrial signaling in CKD. Methods. Serum AGEs, soluble RAGE isoforms, and MDPs were measured by ELISA in 160 adults with kidney failure undergoing living-donor kidney transplantation and in 80 controls, Results. CKD patients showed higher AGEs and esRAGE, lower AGEs/sRAGE ratios, and reduced MDPs. AGEs correlated positively with sRAGE, cRAGE, and HN, while MOTS-c was inversely associated with AGEs and the AGEs/sRAGE ratio. In multivariable analyses, HN remained independently associated with AGEs, sRAGE, and the AGEs/sRAGE ratio, whereas MOTS-c showed an inverse association with the AGEs/sRAGE ratio. CRP was associated with the AGEs/sRAGE ratio while PEW showed no associations with AGEs–RAGE components or MDP. Conclusions. CKD is characterized by increased glycoxidative stress and reduced MDPs, reflecting altered mitochondrial stress signaling. AGEs–RAGE and MDPs are biologically linked, suggesting partially overlapping but distinct pathophysiological pathways.

BACKGROUND: Adverse pregnancy outcomes are linked to increased risk of maternal cardiovascular disease. However, the association between preterm delivery (PTD) and long-term risk of stroke in the mother remains uncertain, particularly in the case of spontaneous PTD. METHODS: A systematic review and meta-analysis were performed to provide an up-to-date synthesis of the evidence on the association between PTD and long-term maternal stroke. PubMed, CINAHL, and Web of Science were searched for relevant articles published between January 1, 2000, and May 6, 2025. Eligible studies included cohort and case-control studies examining populations of parous women. Primary exposure was defined as any PTD; secondary exposures were spontaneous PTD and medically indicated PTD. The primary outcome was defined as any stroke; secondary outcomes were ischemic and hemorrhagic stroke. Two reviewers screened studies, extracted data, and performed quality assessments. Pooled unadjusted and adjusted effect estimates (as defined by the original study) were calculated separately using random effects inverse variance models. RESULTS: Eleven thousand twenty-five studies were screened for eligibility. Across 21 studies including a total of 8.7 million participants, PTD was consistently associated with increased stroke risk. The follow-up period ranged from 8 to 57 years. The primary meta-analysis demonstrated a positive association between any PTD and any stroke (adjusted risk ratio [aRR], 1.66 [95% CI, 1.34–2.05]). A high level of heterogeneity was observed ( I ² =97%, τ ² =0.15), possibly due to variations in exposure definition, outcome ascertainment, and follow-up durations. Spontaneous PTD (aRR, 1.37 [95% CI, 1.15–1.64]) and medically indicated PTD (aRR, 2.08 [95% CI, 1.70–2.54]) were associated with any stroke. PTD was positively associated with ischemic (aRR, 1.59 [95% CI, 1.45–1.75]) and hemorrhagic stroke (aRR, 1.44 [95% CI, 1.06–1.94]). CONCLUSIONS: Women who have experienced a PTD, including spontaneous PTD, may be at increased risk of stroke in later life. These women may benefit from targeted cardio-metabolic preventive interventions postpartum to reduce their risk.

Background: Ischemia/reperfusion injury (IRI) is considered one of the major risk factors involved in the development of delayed graft function that significantly impacts both the early and long-term function of allografts due to its harmful effects on cells. Purpose: This narrative review aims to explore the emerging aspects of IRI in organ transplantation, focusing on the still unclear relationships between IRI and the development of both T-cell-mediated and/or antibody-mediated rejections. Key findings: Recently, efforts aimed at increasing the knowledge of the mechanisms involved have revealed that IRI is connected to rejection processes through a complex of interconnected pathways. These pathways affect both the viability and the metabolism of immune cells, ultimately influencing graft outcomes. Therefore, these pathways demonstrate the complexity of immune responses after transplantation and play a role in both acute and chronic rejection processes. Conclusions: Improving graft outcomes requires an understanding of the multifaceted relationship between IRI and immune-mediated rejection, which is critical to improve graft outcomes. Further research is needed to clarify these mechanisms and develop targeted strategies to mitigate IRI and its impact on transplant rejection.

Background/Importance Balancing work and family life is a particular challenge for physicians, yet finding a good balance is crucial given that childcare responsibilities and institutional support strongly influence career trajectories. This study examined female fertility and gender differences in family founding, working hours and childcare responsibilities among physicians in Switzerland. Objective Characterize fertility and family-founding among women physicians, compare women’s and men’s family-founding attitudes, and examine how work patterns, caregiving responsibilities and perceived institutional support relate to reproductive outcomes. Design, Setting, and Participants Secondary analysis of an existing, anonymous, cross-sectional, web-based survey of the Swiss internal medicine workforce (fielded from December 2021 to April 2022). Main Outcomes and Measures Desire to have children, past or current intent to delay childbearing, self-reported female infertility, number of children, maternal age at first birth, perceived adequacy of external childcare, and employer respect of pregnancy-related working-hour limits. Group comparisons used Welch’s t-tests and chi-square tests, and associations with workload used linear regression models. Results This analysis included 682 physicians, 278 (41%) men and 404 (59%) women. Men’s age was 39±12 years (mean ± standard deviation [SD]), and women’s age was 36±10 years. The prevalence of self-reported infertility among female physicians was 27.7%, which exceeds Swiss general population estimates of 10-15% (pConclusions and Relevance In this national physician sample, women reported having fewer children and more frequently postponing having children than men, and experienced a higher prevalence of self-reported infertility than the Swiss population. Perceived childcare adequacy was suboptimal for both genders, and many reported insufficient adherences to pregnancy-related working-hour protections. Improving scheduling, enforcing maternity protections, increasing access to reliable childcare, and promoting equitable caregiving norms could enhance reproductive and professional outcomes for women in medicine in Switzerland.

Patients with chronic kidney disease (CKD) face an increased risk of early vascular aging, progressive vascular calcification, and premature death. With increasing age, mitochondrial function and mitochondrial DNA copy number (mtDNA-cn) decline. This has been identified as an independent predictor of frailty and mortality in cardiovascular diseases (CVDs) and cancer. However, the relationship between mtDNA-cn and vascular calcification in the context of a uremic milieu remains ambiguous. We hypothesize that a lower mtDNA-cn is associated with medial calcification, as both are linked to impaired vascular health and accelerated aging. mtDNA-cn was analyzed in 211 CKD5 patients undergoing renal transplantation (RTx) and 196 healthy controls using quantitative PCR (qPCR) for three mtDNA genes (mtND1, mtND4, and mtCOX1) and single-locus nuclear gene hemoglobin beta (HbB). In 32 patients, mtDNA-cn was also quantified one year after RTx. The association between mtDNA-cn and vascular calcification scores, circulatory cell-free (ccf) mtDNA in plasma, and the surrogate marker of biological aging (skin autofluorescence) and CVD risk was assessed. mtDNA-cn was significantly lower in CKD5 patients than in controls and correlated with biological age, vascular calcification, and CVD risk. One year after RTx there was a significant recovery of mtDNA-cn in male patients compared to baseline levels. mtDNA-cn and ccf-mtDNA were inversely correlated. This prospective study provides novel insights into the link between low mtDNA-cn and vascular aging. It demonstrates that RTx restores mtDNA levels and may improve oxidative phosphorylation capacity in CKD. Further investigation is warranted to evaluate mtDNA as a biologically relevant biomarker and a potential therapeutic target for early vascular aging in the uremic environment.

Background The existence of a “leaky pipeline” in leadership for medicine in Switzerland is apparent: 60% of residents and 51% of attending physicians are women; yet women make up only 32% of senior physicians and 16% of chief physicians. Here, we examined sex-specific and gender-sensitive factors affecting career ambitions for physicians in General Internal Medicine (GIM). Methods Using a cross-sectional survey among GIM physicians in Switzerland, we assessed women’s and men’s career ambitions; workplace-related factors including professional network, perceived supervisor’s support, workplace inclusiveness, and gender-related discrimination; personal factors such as Physician Well-being index and family situation; and demographics. The outcome was the probability of aspiring to a senior position (i.e., senior or chief physician) at a hospital. Chi-squared tests and multiple logistic regression identified the factors associated with this career aspiration and sex-disaggregated analysis tested for sex differences. Results The sample included 624 physicians, of which 40% were men (mean age = 37 years, standard deviation [SD] = 11 years), and 60% women (mean age = 35 years, SD = 10 years). Their workplace was mostly in hospitals (76%) or in private practice (21%). During medical school, the career aspiration of men and women did not differ (men vs. women: 14% vs. 12%, p=0.62). Yet, in their current aspiration towards leadership, men more frequently reported high aspirations than women (17% vs. 11%) in univariable analysis (p=0.03) and odds ratio [OR]: 1.74, 95% confidence interval [CI]; 1.06-2.85, after multivariable adjustment. Higher career aspiration was present among those who were more satisfied with their work (OR: 3.26, 95% CI: 1.56-7.73). In sex-stratified analyses, men with career aspiration were less likely to have a pathological Physician Well-being index than men without this aspiration (OR: 0.12, 95% CI: 0.02-0.50). Women with career aspiration were more likely to report gender discrimination, or to face a negative view on parenthood by their supervisors, compared to women without career aspiration (OR: 7.48, 95% CI: 1.71-39.0). However, having children or having adequate childcare were not associated with career aspiration among respondents of any sex. Conclusion Both female and male physicians had similar career aspirations at the beginning of their career during medical school, while the sex difference emerged as their careers progressed and different challenges emerged. Sex-specific associations among the women, with supervisors’ unfavorable views on parenthood and gender discrimination relating to leadership aspirations, provide evidence-based knowledge for workplace-tailored strategies to close the leak in the pipeline towards leadership positions in medicine.

While gendered psycho-socio-cultural factors are recognized as major determinants of cardiovascular health, their contribution to our understanding of their effect on hypertension (HTN) in each country is poorly understood. Therefore, we investigated the role of these factors in HTN prevalence, focusing on sex- and gender-specific differences across countries. Data from the Canadian Community Health Survey (2015–2016, N = 109,659, women: 56.6%) and the European Health Interview Survey (2013–2015, N = 316,333, women: 51.3%) were analyzed. Primary endpoint was defined as HTN prevalence within 1-year. Relationship and interaction between sex, gender, and country with HTN prevalence were assessed using multivariate models. Federated analysis was conducted using DataShield. Prevalence of HTN was higher in Canada compared to Europe (30.1% vs 22.4%, P < .001). Amongst European countries, living in the Central-East region was associated with a greater risk of developing HTN. Women in the southern and central-east regions had higher prevalence of HTN. There was a significant interaction between socioeconomic status and sex in country-stratified analysis. This was more evident in central-east and southern countries compared to northern, western nations and Canada, where women with lower socioeconomic status, income, and education had a greater risk of developing HTN. Similar trends were observed regardless of country in women who were divorced or widowed. While immigrants were at higher risk of HTN, those in northern and southern Europe were at lower risk compared to central-east region. Sex- and gender-related factors and country should be considered in the prevention and control of HTN.