Citations

Abstract Context Preclinical studies demonstrate that treatment with calcitriol attenuates skeletal complications in mice with X-linked hypophosphatemia (XLH). Objective This work aimed to assess serum markers of mineral metabolism, nephrocalcinosis, skeletal microarchitecture, growth, and evidence of rickets following calcitriol monotherapy in children and adults with XLH. Methods A 1-year, prospective, single-arm, open-label study was conducted comparing baseline and 12-month outcomes. Participants were recruited from outpatient endocrinology clinics in the United States. Data were collected in a research unit. Eligible participants were aged 4 years or older, not pregnant, with baseline 25-hydroxyvitamin D of 20 ng/mL or greater and normal serum calcium. Participants were treated with calcitriol, with dose based on serum and urinary calcium concentrations, for 1 year. The primary end points were change in serum phosphate and nephrocalcinosis (all participants) and rickets severity score (children). Secondary end points included changes in additional markers of mineral metabolism, skeletal microarchitecture parameters via high-resolution peripheral quantitative computed tomography (all participants), and height z-scores (children). Results Serum phosphate did not change over 12 months of optimized calcitriol treatment. Rickets improved in 2 of 4 children with open epiphyses; height z-scores were unchanged. Nephrocalcinosis scores remained stable. Adults had increased cortical thickness at the radius diaphysis (P = .012). Serum alkaline phosphatase decreased in children (P = .021) and parathyroid hormone trended lower both in children (P = .065) and adults (P = .063). Four participants developed mild hypercalcemia and 2 developed hypercalciuria that resolved with calcitriol titration. Conclusion Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.

ABSTRACT Patient outcomes in advanced renal cell carcinoma (RCC) remain poor, with five‐year survival rates ranging from ~10% to 30%. Early projections of therapeutic outcomes could optimize precision medicine and accelerate drug development. While machine learning (ML) models integrating tumor growth inhibition (TGI) metrics have improved survival predictions over traditional models, their application in RCC remains unexplored. Herein, we used TGI metrics and baseline data to evaluate parametric (PM) and semi‐parametric (SPM) survival models alongside ML approaches for predicting progression‐free (PFS) and overall survival (OS) in 1839 RCC patients from four trials (evaluating sunitinib, axitinib, sorafenib, interferon‐alpha, and avelumab + axitinib). Data were split into training (70%) and testing (30%), and feature selection was used to determine parsimonious and robust models. Bootstrap resampling ( n = 100) was employed for models' validation, and performance was assessed using C‐index and Integrated Brier Score. In brief, training data results demonstrated that tree‐based ML models (random survival forest (RSF) and XGBoost) outperformed PM and SPM models in predicting PFS (C‐index: 0.783–0.785 vs. 0.725–0.738 for PM and SPM; p < 0.05) and OS (C‐index: 0.77–0.867 vs. 0.750–0.758 for PM and SPM; p < 0.05), with RSF achieving better prediction of PFS and OS using only 3–5 covariates, compared to 9–35 with other tested methods. Tree‐based methods were also superior in the testing data. SHapley Additive exPlanations revealed nonlinear relationships among top predictors, including TGI metrics, underscoring the ability of tree‐based methods to capture complex prognostic interactions. Further validation is required to confirm models' generalizability to additional therapies and patients with differing tumor severity.

Abstract The sections in this article are: Physiological Effects of Vitamin D and its Active Metabolites on Calcium and Phosphorus Homeostasis Sources of Vitamin D Transport of Vitamin D and its Metabolites in Plasma Metabolism of Vitamin D 3 to 25‐Hydroxyvitamin D 3 Metabolism of 25‐Hydroxyvitamin D 3 Regulation of the 25‐Hydroxyvitamin D 3 –1α‐Hydroxylase Enzyme Parathyroid Hormone Phosphorus Concentrations Calcium: Direct Effects 1,25‐Dihydroxyvitamin D 3 Calcitonin Hydrogen Ion Sex Steroids Glucocorticoids Pituitary Hormones Thyroid Hormone Pregnancy Catabolism of 1,25‐Dihydroxyvitamin D 3 Physiological Adaptations that Occur in Response to Changes in Serum Calcium and Phosphate Concentrations Hypocalcemia and Hypercalcemia Hypophosphatemia and Hyperphosphatemia Pathophysiology and Physiology of the 1,25‐Dihydroxyvitamin D 3 System Mechanisms of Action of 1,25‐Dihydroxyvitamin D 3 1,25‐Dihydroxyvitamin D 3 in the Intestine Processes in the Cell That Are Mediated by 1,25‐Dihydroxyvitamin D 3 Intestinal Brush Border Events Induced by 1,25‐Dihydroxyvitamin D 3 Events at the Contraluminal Border Effects of 1,25‐Dihydroxyvitamin D 3 on the Intestinal Cell 1,25‐Dihydroxyvitamin D 3 in the Kidney

Abstract The sections in this article are: Intrarenal Hemodynamic Control of Sodium Excretion Effects of Peritubular Starling Forces on Sodium Excretion Effects of Medullary Blood Flow on Sodium Excretion Effects of Renal Perfusion Pressure on Sodium Excretion Neural Control of Sodium Excretion Sodium Intake and Body Fluid Volumes Low‐Pressure Baroreceptors Renal Sympathetic Nerve Activity Hormonal Control of Sodium Excretion Renin–Angiotensin–Aldosterone System Renal Prostaglandin System Renal Kallikrein–Kinin System Natriuretic Hormone Atrial Natriuretic Peptide Summary

Background Valvular heart disease contributes to symptomatic heart failure, but its prevalence and prognostic significance in advanced heart failure is not well understood. Methods This retrospective population‐based cohort study included adult residents of Olmsted County, Minnesota, with advanced heart failure (2007–2018). Patients were classified by echocardiographic regurgitation and stenosis of aortic, mitral, tricuspid, and pulmonic valves at the time of advanced heart failure. We examined the associations of aortic stenosis, mitral regurgitation, and tricuspid regurgitation with risks of cardiovascular and all‐cause death through 2023 using Cox proportional hazards models. Results There were 936 patients with advanced heart failure (mean age, 76.9 years; 44.5% women, 43.4% with heart failure with preserved ejection fraction). Moderate or greater regurgitation was observed in 2.8% (n=26) of aortic, 26% (n=244) of mitral, 42% (n=389) of tricuspid, and 4.3% (n=40) of pulmonic valves, while moderate or greater stenosis was observed in 9.7% (n=91) of aortic and 1.8% (n=17) of mitral valves. No patients had clinically significant tricuspid or pulmonic stenosis. After adjustment for age, sex, left ventricular ejection fraction, right ventricular function, serum sodium, Charlson comorbidity index, body mass index, and systolic blood pressure, moderate and severe aortic stenosis were associated with increased cardiovascular death compared with patients without aortic stenosis (hazard ratio [HR], 1.42 [95% CI, 1.01–2.01]; and HR, 1.55 [95% CI, 1.02–2.36]), respectively. Conclusions Tricuspid regurgitation, mitral regurgitation, and aortic stenosis were the most observed valvular pathologies of moderate or greater severity in advanced heart failure. Only moderate or greater aortic stenosis was independently associated with cardiovascular death in advanced heart failure.