Valve-sparing root replacement after the Ross procedure.

OBJECTIVES: The Ross procedure is a preferred treatment for infants and children with aortic valve disease. Progressive neoaortic root dilation and neoaortic insufficiency can occur after the Ross procedure, and because of the young age of these patients, valve-sparing aortic root replacement procedures have advantages compared with the Bentall procedure. The aim of this study is to describe our experience with different techniques of aortic valve-sparing root replacement in this unique cohort of patients. METHODS: Patients undergoing valve-sparing aortic root replacement with a history of the Ross procedure between January 2001 and March 2021 were identified. A retrospective chart review was performed, and clinical characteristics of these patients were analyzed. The results of different types of valve-sparing aortic root replacement were also compared. RESULTS: Forty-two patients who had previously undergone a Ross procedure in childhood presented for reintervention for neoaortic root or valve pathology. Seventeen of these patients were considered for valve-sparing aortic root replacement but underwent bioprosthetic or mechanical valve replacement, and 25 patients underwent successful valve-sparing aortic root replacement. Patients who underwent valve-sparing aortic root replacement received a traditional aortic root remodeling procedure with or without suture annuloplasty (Yacoub technique, group 1, n = 7), an aortic root reimplantation procedure (David technique, group 2, n = 11), or a modified root remodeling procedure that also used a geometric annuloplasty ring (group 3, n = 7). Patient demographics and comorbidities were similar between groups. Mean follow-up for these 3 cohorts was 14 years, 4 years, and 1 year, respectively. Overall survival was good, with 1 early death due to hemorrhage in group 2 and 1 death due to malignancy in group 1. Eight patients (7 in group 1; 1 in group 2) required subsequent aortic valve replacements due to neoaortic insufficiency, whereas none in group 3 have required any reintervention. Overall, patients requiring valve replacement after valve-sparing aortic root replacement had lower grades of preoperative neoaortic insufficiency and higher grades of postoperative neoaortic insufficiency. Greater than mild postoperative neoaortic insufficiency was associated with the need for subsequent neoaortic valve replacement. CONCLUSIONS: Valve-sparing aortic root replacement is safe in patients with a prior Ross procedure. Reimplantation offers superior durability compared with the traditional remodeling procedure. Greater than mild neoaortic insufficiency on postoperative echocardiogram should prompt additional attempts at valve repair. A modified remodeling procedure with geometric ring annuloplasty that is personalized to the patient's individual anatomy is safe with good short-term results, but longer follow-up is needed.

Comparison of dietary and physical activity behaviors in women with and without polycystic ovary syndrome: a systematic review and meta-analysis of 39 471 women.

BACKGROUND: Lifestyle (dietary and/or physical activity [PA]) modification is recommended as first-line therapy to manage polycystic ovary syndrome (PCOS). Current recommendations are based on healthy lifestyle practices for the general public since evidence for unique lifestyle approaches in PCOS is limited and low quality. OBJECTIVE AND RATIONALE: We aimed to synthesize evidence on dietary and PA behaviors between women with PCOS and those without PCOS. Primary outcomes were overall diet quality, total energy intake and total PA, and secondary outcomes included macronutrients, micronutrients, food groups, foods, glycemic indices, sedentary time and sitting levels. We conducted this work to identify any unique lifestyle behaviors in women with PCOS that could underlie the propensity of weight gain and obesity in PCOS and be targeted for precision nutrition and PA interventions. These findings could be used to inform future practice recommendations and research that more effectively address complications (weight gain, obesity, diabetes, infertility, cardiovascular disease and mental health) in this high-risk population. SEARCH METHODS: Databases of MEDLINE, Web of Science, Scopus and CINAHL were searched until 15 February 2022 to identify observational studies documenting dietary and PA behaviors between women with PCOS and without PCOS (Controls). Studies on children, adolescents (<18 years), pregnant or menopausal-aged women (>50 years) were excluded. Data were pooled by random-effects models and expressed as (standardized) mean differences (MD) and 95% CIs. The risk of bias was assessed by the Newcastle-Ottawa scale (NOS). OUTCOMES: Fifty-four studies (N = 39 471 participants; [n = 8736 PCOS; 30 735 Controls]) were eligible (96%; [52/54] NOS scores ≥ 7). Women with PCOS had higher cholesterol (MD: 12.78, 95% CI: 1.48 to 24.08 mg/day; P = 0.03; I2 = 19%), lower magnesium (MD: -21.46, 95% CI: -41.03 to -1.91 mg/day; P = 0.03; I2 = 76%), and a tendency for lower zinc (MD: -1.08, 95% CI: -2.19 to -0.03 mg/day; P = 0.05; I2 = 96%) intake, despite lower alcohol consumption (MD: -0.95, 95% CI: -1.67 to 0.22 g/day; P = 0.02; I2 = 0%) versus Controls. Also, women with PCOS had lower total PA (standardized mean difference: -0.38, 95% CI: -0.72 to 0.03; P = 0.03; I2 = 98%). Conversely, energy, macronutrients (carbohydrate, fat, protein, fiber), micronutrients (folic acid, iron, calcium, sodium), glycemic index and glycemic load were similar (all: P ≥ 0.06). Most eligible studies reported lower total adherence to healthy eating patterns or poorer consumption of major food groups (grains, fruits, vegetables, proteins, seeds, nuts, dairy) in women with PCOS, as described narratively since variable study methodology did not permit meta-analyses. WIDER IMPLICATIONS: Collective evidence supports that women with PCOS have a lower overall diet quality, poorer dietary intakes (higher cholesterol, lower magnesium and zinc) and lower total PA, despite lower alcohol consumption versus those without PCOS. Considerable heterogeneity among studies reinforces the need for research to address any relative contributions of other factors (e.g. genetic, metabolic or sociodemographic) to the observed differences. These clarifications may contribute to future evidence-based guideline recommendations on monitoring and managing PCOS in the era of precision lifestyle medicine.

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial.

BACKGROUND: We report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours. METHODS: In phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3-6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs). RESULTS: At data cut-off (27 July 2021), 21 patients aged 3-17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months). CONCLUSION: In paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.

Comprehensive evaluation of disparities in cardiometabolic and reproductive risk between Hispanic and White women with polycystic ovary syndrome in the United States: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis to comprehensively compare cardiometabolic and reproductive health risk between Hispanic and White women with polycystic ovary syndrome in the United States in response to the call by the international guideline for polycystic ovary syndrome to delineate health disparities. DATA SOURCES: Databases of MEDLINE, Web of Science, and Scopus were initially searched through October 25, 2020, and confirmed on February 1, 2021. STUDY ELIGIBILITY CRITERIA: Observational studies comparing glucoregulatory, lipid profile, anthropometric, blood pressure, androgen, ovarian morphology, oligoanovulation, and infertility status between Hispanic and White women with polycystic ovary syndrome were included. The primary outcome was metabolic syndrome risk. Furthermore, major cardiovascular events (stroke, coronary heart disease, and heart failure) and mortality rate (cardiovascular death and total mortality) data were evaluated. Studies on adolescents (<2 years after menarche), pregnant, or menopausal-aged women (>50 years) were excluded. METHODS: Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Risk of bias was assessed by the Newcastle-Ottawa Scale. RESULTS: A total of 11 studies (n=2267; 589 Hispanic and 1678 White women) were eligible. All studies, including both White and Hispanic women, had high-quality assessment (Newcastle-Ottawa Scale score of ≥8). Hispanic women exhibited comparable metabolic syndrome prevalence (7% [95% confidence interval, -1 to 14]; P=.06; I2=0%); however, Hispanic women exhibited higher modified Ferriman-Gallwey score (0.60 [95% confidence interval, -0.01 to 1.21]; P=.05; I2=0%), fasting insulin (5.48 µIU/mL [95% confidence interval, 3.11-7.85]; P≤.01; I2=40.0%), and homeostatic model assessment of insulin resistance (1.20 [95% confidence interval, 0.50-1.89]; P≤.01; I2=43.0%) than White women. The 2 groups had comparable glucose, lipid profile, waist circumference, blood pressure, and androgen status (all P≥.08). Findings about group differences in certain reproductive outcomes (ie, ovarian dysmorphology and infertility) were contradictory and described only narratively as inclusion in the meta-analyses was not possible. No study reported on cardiovascular events or mortality. CONCLUSION: Hispanic women with polycystic ovary syndrome exhibited greater impairments in glucoregulatory status than White women. Disparities in reproductive risks could not be concluded. The degree to which glucoregulatory aberrations translate into patient-pressing diseases (diabetes mellitus and infertility) remains a major roadblock given the paucity of available evidence. Our observations have supported the consideration of these disparities in the diagnostic, monitoring, and management practices for polycystic ovary syndrome and reinforced the need to elucidate mechanisms that account for the observed disparities to foster equity in polycystic ovary syndrome care.

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.

OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. METHODS: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. RESULTS: UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). CONCLUSION: These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.