Garovic, Vesna D.

Abstract Models that estimate the probability of an adverse clinical outcome require an operational cutoff to translate continuous estimated probabilities into discrete labels that can trigger clinical action. Although statistical methods identify ‘optimal’ cut-offs, threshold selection ultimately reflects value judgments regarding harm tolerance, resource allocation, and workflow feasibility. We describe a governance-informed approach to selecting a deployment threshold for an asthma exacerbation (AE) prediction model integrated into clinical workflows. Using prevalence-adjusted performance metrics and real-world provider capacity modeling, we evaluated multiple candidate thresholds and quantified downstream workload and missed-event trade-offs. We demonstrate that statistically optimal thresholds may produce operationally infeasible alert volumes or unacceptable miss rates. We propose a structured threshold governance framework integrating statistical performance, clinical utility, stakeholder input, and human oversight safeguards. This case illustrates how threshold decisions should be treated as organizational governance processes rather than purely technical optimizations.

Abstract Introduction: Contrast-induced acute kidney injury, also referred to as contrast-induced nephropathy (CIN), is a potentially serious renal complication asso ciated with the use of iodinated contrast media (CM) in patients at risk. With the dramatic growth in contrast enhanced imaging services worldwide, including pro cedures involving exposure to iodinated CM, efforts to reduce the occurrence of CIN have received consider able attention in recent years. To date, these efforts have met with little success since the 12% prevalence of CIN today remains unchanged from 2 decades ago. Methods:We conducted a systematic literature review of the most recent evidence available from published reports of contemporary (2000-2008) prospective, randomized, controlled trials that have investigated CIN either by comparing CM or by comparing pre ventive strategies. The objective was to critically re view the findings in light of several aspects of study design and then to establish a set of parameters for consideration in the planning of future CIN trials so as to optimize the strength of evidence obtained. Results:Whether future CIN trials are investigat ing comparative CM nephrotoxicity or dealing with prophylactic strategies for risk reduction, the com plexities that must be addressed include a stan dardized definition of CIN, appropriate timing of SCr measurements with timing standardized for all subjects in a given study population, awareness of study population risk profile, hydration proto cols, and pharmacological prophylactic strategies. Conclusions: Large, well-designed trials (ideally with hard clinical outcome measures) that consider all the complexities involved in CIN and its preven tion are needed before the clinical community has the evidence-based direction required for optimized patient care.

Abstract Background Women with advanced chronic kidney disease (CKD) encounter reproductive health challenges, including reduced fertility, menstrual irregularity, and sexual dysfunction. This study examined changes in sex hormones in patients with CKD, their correlation with sexual function, and changes after transplant. Methods This study recruited women aged 18–51 years with CKD stages 3b-5 from outpatient clinics and dialysis units. Exclusion criteria included active pregnancy, menopause, prior hysterectomy/bilateral oophorectomy, or use of hormonal contraceptives/therapy. Data were collected at enrollment and at 6 months post-transplant. Results Thirty-eight subjects met eligibility criteria and enrolled in the trial (8 in CKD stage 3b, 10 in CKD stage 4, and 20 in CKD stage 5/5D). Sexual dysfunction (25/38, 65.8%), defined as total female sexual function index score < 26.55, and menstrual irregularities (17/38, 44.7%) were common, with abnormal elevation of luteinizing hormone present in the follicular phase in the majority of patients. There was a significant negative association between total female sexual function index score and prolactin (β = -0.26, P = 0.03) and dehydroepiandrosterone sulfate (β = -0.07, P = 0.01) after adjusting for age. After transplant, there was also a significant improvement in both prolactin and dehydroepiandrosterone sulfate levels, although sexual dysfunction persisted. Conclusions This study highlights the complex interplay between advanced CKD, reproductive endocrinology, and sexual health. Significant hormonal dysregulation and associated reproductive challenges were observed. The prominent role of dehydroepiandrosterone sulfate in sexual dysfunction among women with CKD requires further study.

BACKGROUND: Hypertension, the leading cause of cardiovascular mortality, remains suboptimally controlled. Large language models (LLMs) could improve hypertension control by augmenting clinical decision-making, but their reliability for guideline-driven tasks is unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by 3 LLMs. METHODS: Fifty-one vignettes were constructed and submitted to the LLMs (GPT-4, Gemini, Medical Large Language Model [by Google; MedLM]) and a hypertension expert to generate the responses. Three blinded reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM versus expert) providing the response. RESULTS: GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the 3 LLMs (Gemini 35%, MedLM 14%) but was lower than expert responses (68%). Interrater reliability for accuracy ratings was higher for LLM-generated responses (GPT-4 [intraclass correlation coefficient, 0.30], Gemini [intraclass correlation coefficient, 0.61], and MedLM [intraclass correlation coefficient, 0.58]), with lower agreement for expert responses (intraclass correlation coefficient, 0.23). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. CONCLUSIONS: Among the 3 tested LLMs, GPT-4 demonstrated closer agreement to expert decisions, thereby showing greater potential for supporting hypertension management. Despite their potential, current LLM versions are inferior to expert recommendations. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

Background We aimed to assess the longitudinal changes of glycocalyx, a proteoglycan/glycoprotein layer that lines and protects endothelial cells in normotensive pregnancies (NPs); to correlate glycocalyx parameters with kidney injury markers (podocin‐positive to nephrin‐positive [P/N] ratio); and to explore changes in P/N ratio in preeclampsia. Methods Plasma and urine samples and glycocalyx measurements using side‐stream darkfield imaging were collected at each trimester from pregnant women (n=31). Plasma glycocalyx components were measured by ELISA, and urinary P/N‐positive extracellular vesicles by flow cytometry. Results In NPs (n=26), glycocalyx degradation increased from the first to the second trimester ( P =0.008) and returned to first‐trimester values in the third trimester ( P =0.008). Microvascular perfusion decreased from the first to the second trimester ( P =0.006) and increased back to first‐trimester values by the third trimester ( P =0.039). Plasma syndecan 1 level showed a steady increase from the first to the second trimester ( P <0.001) and further in the third trimester ( P <0.001); hyaluronic acid increased from the first to the second trimester ( P =0.016) without further changes. Glycocalyx degradation was associated with an increase in P/N ratio from the first to the second trimester of NPs and remained stable through the third trimester. P/N ratio strongly correlated with elevated syndecan 1 and hyaluronic acid levels in the third trimester. Comparison of P/N ratios between NP and preeclampsia (n=5) showed higher values in preeclampsia across all trimesters ( P =0.028). Conclusions Glycocalyx changes during NPs are associated with elevated urinary podocyte markers. Increase in P/N ratio across NPs, and further in preeclampsia, suggests that podocyte injury in preeclampsia is extension of physiological changes in pregnancy, which may predate its clinical presentation.

ABSTRACT Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic β-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role β-cell senescence in diabetes progression. In contrast, β-cell senescence also promotes immune surveillance, promoting β-cell survival and function. Thus, a better understanding of senescent cells’ phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent β-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21 Cip1 ) and Cdkn2a (encoding p16 Ink4a ) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a -expressing β-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a + cells was sufficient to induce secondary senescence and β-cell dysfunction in vitro . JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored β-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT

Abstract The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077‐5114, 2023.

Abstract Preeclampsia and other hypertensive disorders of pregnancy are major contributors to maternal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and eclampsia. The body undergoes important physiological changes during pregnancy to allow for normal placental and fetal development. Several mechanisms have been proposed that may lead to preeclampsia, including abnormal placentation and placental hypoxia, impaired angiogenesis, excessive pro‐inflammatory response, immune system imbalance, abnormalities of cellular senescence, alterations in regulation and activity of angiotensin II, and oxidative stress, ultimately resulting in upregulation of multiple mediators of endothelial cell dysfunction leading to maternal disease. The clinical implications of preeclampsia are significant as there are important short‐term and long‐term health consequences for those affected. Preeclampsia leads to increased risk of preterm delivery and increased morbidity and mortality of both the developing fetus and mother. Preeclampsia also commonly leads to acute kidney injury, and women who experience preeclampsia or another hypertensive disorder of pregnancy are at increased lifetime risk of chronic kidney disease and cardiovascular disease. An understanding of normal pregnancy physiology and the pathophysiology of preeclampsia is essential to develop novel treatment approaches and manage patients with preeclampsia and hypertensive disorders of pregnancy. © 2023 American Physiological Society. Compr Physiol 13:4231‐4267, 2023.