Maternal Vitamin D Supplementation and Infantile Rickets: Secondary Analysis of a Randomized Trial.

BACKGROUND: The role of maternal vitamin D supplementation in the prevention of infantile rickets is unknown, particularly in low- and middle-income countries without routine infant vitamin D supplementation. Through secondary analysis of a randomized, placebo-controlled trial in Bangladesh, we examined the dose-ranging effects of maternal vitamin D supplementation on the risk of biochemical rickets at 6 to 12 months of age. METHODS: Pregnant women (n = 1300) were randomized into 5 groups: placebo, or vitamin D 4200 IU/week, 16 800 IU/week, or 28 000 IU/week from second trimester to delivery and placebo until 6 months postpartum; or 28 000 IU/week prenatally and until 6 months postpartum. Infants underwent biochemical rickets screening from 6 to 12 months of age (n = 790). Relative risks (RR) and 95% confidence intervals (95% CI) of biochemical rickets were estimated for each group versus placebo. RESULTS: Overall, 39/790 (4.9%) infants had biochemical rickets. Prevalence was highest in the placebo group (7.8%), and the risk was significantly lower among infants whose mothers received combined prenatal and postpartum vitamin D at 28 000 IU/week (1.3%; RR, 0.16; 95% CI, 0.03-0.72). Risks among infants whose mothers received only prenatal supplementation (4200 IU, 16 800 IU, 28 000 IU weekly) were not significantly different from placebo: 3.8% (RR, 0.48; 95% CI, 0.19-1.22), 5.8% (RR, 0.74; 95% CI, 0.33-1.69), and 5.7% (RR, 0.73; 95% CI, 0.32-1.65), respectively. CONCLUSIONS: Maternal vitamin D supplementation (28 000 IU/week) during the third trimester of pregnancy until 6 months postpartum reduced the risk of infantile biochemical rickets. Further research is needed to define optimal postpartum supplementation dosing during lactation.

Delayed Puberty Including Constitutional Delay: Differential and Outcome.

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in both male and female individuals. This article reviews the causes of delayed puberty focusing on CDGP, including new advances in the understanding of the genetics underpinning CDGP, a clinical approach to discriminating CDGP from other causes of delayed puberty, outcomes, as well as current and potential emerging management options.

Improved Glycemic Outcomes With Diabetes Technology Use Independent of Socioeconomic Status in Youth With Type 1 Diabetes.

OBJECTIVE: Technology use in type 1 diabetes (T1D) is impacted by socioeconomic status (SES). This analysis explored relationships between SES, glycemic outcomes, and technology use. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of HbA1c data from 2,822 Australian youth with T1D was undertaken. Residential postcodes were used to assign SES based on the Index of Relative Socio-Economic Disadvantage (IRSD). Linear regression models were used to evaluate associations among IRSD quintile, HbA1c, and management regimen. RESULTS: Insulin pump therapy, continuous glucose monitoring, and their concurrent use were associated with lower mean HbA1c across all IRSD quintiles (P < 0.001). There was no interaction between technology use and IRSD quintile on HbA1c (P = 0.624), reflecting a similar association of lower HbA1c with technology use across all IRSD quintiles. CONCLUSIONS: Technology use was associated with lower HbA1c across all socioeconomic backgrounds. Socioeconomic disadvantage does not preclude glycemic benefits of diabetes technologies, highlighting the need to remove barriers to technology access.

Radiation-induced angiosarcoma of the breast: retrospective analysis at a regional treatment centre.

BACKGROUND: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer. METHODS: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England. RESULTS: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41-78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4-16.0)-this interval has decreased over the last 24 years (r2 = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342-14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646-30.88]; P = 0.0086). CONCLUSION: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted.

Molecular epidemiology of Clostridioides difficile isolates in a non-outbreak setting at a comprehensive cancer center.

Ribotyping was performed on Clostridioides difficile isolates from patients with malignancies. Thirty-one (27.9%) isolates from 111 episodes of colitis were recovered representing 14 ribotypes with 25 (80.6%) belonging to 6 ribotypes (014/020, 1/VPI/077/087, 05/015, 015/046, 05/053, 106/174). We identified three novel ribotypes with 1 carrying gene encoding for binary toxin.

Safety and Efficacy of the Sientra Silicone Gel Round and Shaped Breast Implants: 6-Year Results of the US Post-Approval Study.

BACKGROUND: After approval of Sientra silicone gel breast implants in March of 2012, the U.S. Food and Drug Administration required completion of a 10-year U.S. post-approval study. We present results from the first 6 years of this study. METHODS: An ongoing, open-label, prospective, multicenter study is being conducted to evaluate the long-term clinical performance of Sientra implants in patients receiving breast augmentation, reconstruction, and revision in the post-market environment. Enrollment of 5197 patients (10,327 implants) was completed on March 6, 2015, (4046 primary augmentation, 895 revision-augmentation, 149 primary reconstruction, and 107 revision-reconstruction). Analyses were conducted at year 6 (database lock: January 24, 2022). RESULTS: Across all cohorts who received an implant, the Kaplan-Meier risk of investigator-reported Baker grade III/IV capsular contracture was 4.1 percent (3.9 percent with submuscular placement and 6.7 percent with subglandular placement), the risk of reoperation was 11.6 percent, and the risk of implant removal was 7.8 percent (5.9 percent with implant replacement and 2.0 percent without replacement). The primary reason (over 50 percent) for reoperation was aesthetic (e.g., style/size change). The Kaplan-Meier risk of rupture, calculated for patients who underwent explantation or MRI for rupture evaluation, was 5.8 percent. Overall, 82.6 percent of patients were highly satisfied/happy with their implant. No cases of breast implant-associated anaplastic large cell lymphoma were reported. CONCLUSIONS: Six-year results of the post-approval study were consistent with the 10-year core study and provide additional evidence in a large dataset supporting the comprehensive safety and effectiveness profile of the Sientra implants.

Estimation of skeletal muscle mass in 4-year-old children using the D3-creatine dilution method.

BACKGROUND: Given limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh. METHODS: Following D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer. RESULTS: SMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91). CONCLUSIONS: The D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach. IMPACT: The D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

Multicenter Pivotal Study Demonstrates Safety and Efficacy of a New Cellulite Procedure: 3-Month Results.

BACKGROUND: Cellulite is an aesthetic condition affecting the appearance of skin in certain body regions and is associated with body dissatisfaction, psychosocial stress, and decreased quality of life. Previous studies established the safety and feasibility of a novel, minimally invasive device to identify and release septa responsible for cellulite depressions: targeted verifiable subcision (TVS). OBJECTIVES: The objective of this single-arm, open-label, multicenter study was to evaluate the safety and efficacy of TVS for reducing the appearance of moderate to severe cellulite in adult women. METHODS: Adult women aged 21 to 55 years and a BMI < 30 kg/m2 with moderate or severe cellulite on the buttocks and/or thighs were eligible to enroll at 9 sites. Endpoint data included results from 4 of the postprocedural follow-up visits at 24 hours, 7 days, 30 days, and 90 days. The primary endpoints were a mean ≥1 point reduction in the Cellulite Severity Scale at 90 days and no related serious adverse events at 30 days. RESULTS: Seventy-four female participants with a mean BMI of 24.8 ±â€…2.7 and age of 41.4 ±â€…7.4 years received this single procedure. The mean improvement in Cellulite Severity Scale (N = 68) was 1.5 ±â€…0.9 (P < 0.0001). There were no device-related serious adverse events at 30 days. CONCLUSIONS: TVS for selectively identifying and verifiably releasing septa responsible for cellulite depressions is an effective and safe means to improve the appearance of moderate to severe cellulite in adult women.

Multicenter Pivotal Study Demonstrates Safety and Efficacy of a New Cellulite Procedure: Final Results at 12 Months.

BACKGROUND: Safety and efficacy endpoints for the single-arm, multicenter, open-label pivotal study, CONtrolled Focal Fibrous Band Release Method (CONFFIRM) [NCT04743635] assessing targeted verifiable subcision (TVS) for the treatment of cellulite were met at 3 months postprocedure and have been published. Final, 12-month data describing durability of treatment effect and safety are presented here for the first time. OBJECTIVES: The authors sought to evaluate safety and efficacy out to 12 months of initial treatment for a single TVS procedure performed employing the Avéli device (Revelle Aesthetics, Inc.; Mountain View, CA) to treat cellulite on the buttock and thigh areas of adult females. METHODS: Effectiveness was determined by 3 independent physicians employing the Cellulite Severity Scale and Global Aesthetic Improvement Scale to assess improvement of baseline photographs when compared with 3-, 6- and 12-month posttreatment photographs. Blinded participant-reported outcomes and safety evaluations were also performed at all postprocedure time points. RESULTS: Clinically significant improvement in primary endpoint Cellulite Severity Scale scores were sustained out to 1 year, improving by 1.50 (P < .0001) at 3 months, 1.54 points at 6 months, and 1.48 points at 12 months. Adverse events were mild and mostly resolved by the 12-month visit. CONCLUSIONS: A single TVS treatment has durable efficacy and safety in reducing cellulite on the buttocks and thighs of women with moderate to severe cellulite out to 12 months posttreatment.

Hereditary Rickets: A Quick Guide for the Pediatrician.

With the increased discovery of genes implicated in vitamin D metabolism and the regulation of calcium and phosphate homeostasis, a growing number of genetic forms of rickets are now recognized. These are categorized into calciopenic and phosphopenic rickets. Calciopenic forms of hereditary rickets are caused by genetic mutations that alter the enzymatic activity in the vitamin D activation pathway or impair the vitamin D receptor action. Hereditary forms of phosphopenic rickets, on the other hand, are caused by genetic mutations that lead to increased expression of FGF23 hormone or that impair the absorptive capacity of phosphate at the proximal renal tubule. Due to the clinical overlap between acquired and genetic forms of rickets, identifying children with hereditary rickets can be challenging. A clear understanding of the molecular basis of hereditary forms of rickets and their associated biochemical patterns allow the health care provider to assign the correct diagnosis, avoid non-effective interventions and shorten the duration of the diagnostic journey in these children. In this mini-review, known forms of hereditary rickets listed on the Online Mendelian Inheritance in Man database are discussed. Further, a clinical approach to identify and diagnose children with hereditary forms of rickets is suggested.

Does the Skeletal Phenotype of Osteogenesis Imperfecta Differ for Patients With Non-COL1A1/2 Mutations? A Retrospective Study in 113 Patients.

BACKGROUND: Osteogenesis imperfecta (OI) is a heritable disease characterized by bone fragility and other extra skeletal manifestations. Most patients with OI have mutations in the COL1A1 or COL1A2 genes. However, a significant minority of patients with clinical OI have non-COL1A1/2 mutations, which have become easier to detect with the use of genetic panels. Traditional understanding of OI pathogenesis was expanded because of these new mutations, and their phenotypic-genotypic relationship is largely unknown. We hypothesized that patients with non-COL1A1/2 mutations have different skeletal clinical presentations from those with OI caused by COL1A1/2 mutations. METHODS: Patients were categorized into 4 groups according to our modified functional classification, namely, quantitative COL1A1/2 haploinsufficiency (group 1), qualitative COL1A1/2 dominant negative mutations (group 2), mutations indirectly affecting type I collagen synthesis, processing and posttranslational modification (group 3) and mutations altering osteoblast differentiation and function (group 4). Both group 3 and 4 were classified as non-COL1A1/2 mutation group. RESULTS: Of 113 OI patients included, 51 had COL1A1/2 quantitative haploinsufficiency mutations (group 1), 39 had COL1A1/2 qualitative dominant negative mutations (group 2), and 23 patients had OI caused by mutations in 1 of 9 other noncollagen genes (groups 3/4). Patients with non-COL1A1/2 mutations (groups 3 and 4) have severe skeletal presentations. Specifically, OI patients with non-COL1A1/2 mutations experienced more perinatal fractures, vertebral compression fractures and had more long bone deformities. Although the occurrence of scoliosis was similar, the cobb angle was larger in the non-COL1A1/2 mutation group. Radial head dislocations, ossification of interosseous membrane, extraskeletal ossification, cervical kyphosis, and champagne glass deformity of the pelvis were more frequent in this group. CONCLUSIONS: The clinical phenotype of OI in patients with non-COL1A1/2 is severe and has unique features. This information is useful for clinical diagnosis and prognosis. LEVEL OF EVIDENCE: Level III.

An Approach to the Patient With Delayed Puberty.

Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population.

Effect of maternal prenatal and postpartum vitamin D supplementation on offspring bone mass and muscle strength in early childhood: follow-up of a randomized controlled trial.

BACKGROUND: Maternal vitamin D status during pregnancy and lactation is a modifiable factor that may influence offspring musculoskeletal outcomes. However, few randomized trials have tested the effects of prenatal or postpartum vitamin D supplementation on offspring bone and muscle development. OBJECTIVES: The aim was to examine hypothesized effects of improvements in early-life vitamin D status on childhood musculoskeletal health in Dhaka, Bangladesh. METHODS: In a previously completed, double-blind, dose-ranging trial, healthy pregnant women (n = 1300) were recruited at 17-24 weeks' gestation and randomly assigned to a prenatal/postpartum regimen of 0/0, 4200/0, 16,800/0, 28,000/0, or 28,000/28,000 IU cholecalciferol (vitamin D3)/wk until 26 wk postpartum. In this new report, we describe additional follow-up at 4 y of age (n = 642) for longer-term outcomes. Bone mineral content (BMC) and areal bone mineral density (aBMD) were measured by DXA. Grip strength was tested using a hand-held dynamometer. The primary comparison was children of women assigned to 28,000 IU/wk prenatally compared with placebo. Differences are expressed as means and 95% CIs. RESULTS: Total-body-less-head (TBLH) BMC, TBLH aBMD, and grip strength were similar in the combined high-dose prenatal (28,000/0 and 28,000/28,000 IU/wk) compared with placebo groups (mean difference [95% CI] = 0.61 g [-10.90, 12.13], 0.0004 g/cm2 [-0.0089, 0.0097], and 0.02 kg [-0.26, 0.31], respectively). In dose-ranging analyses, TBLH BMC and aBMD, whole-body BMC and aBMD, and grip strength in each of the prenatal vitamin D groups were not significantly different from placebo (P > 0.05 for all comparisons). Only head aBMD was greater in children of women assigned to the 28,000/28,000-IU regimen compared with placebo (mean difference [95% CI] = 0.024 g/cm2 [0.0009, 0.047], P = 0.042); the effect was attenuated upon adjustment for child height, weight, and sex (P = 0.11). CONCLUSIONS: Maternal prenatal, with or without postpartum, vitamin D supplementation does not improve child BMC, aBMD, or grip strength at 4 y of age. The MDIG trial and present follow-up study were registered prospectively at www.clinicaltrials.gov as NCT01924013 and NCT03537443, respectively.

Vascular Function and Distribution of Adiponectin Isomers during Puberty in Children and Adolescents with Obesity.

INTRODUCTION: Youth with obesity have abnormal vascular function that relates to the anti-atherogenic adipose-derived hormone, adiponectin. The distribution of adiponectin isomers changes during normal puberty, but there are no data in relation to vascular function. We aimed to evaluate vascular function, adiponectin, and its isomers longitudinally in peri-pubertal youth with obesity and controls. METHODS: The study is a cohort longitudinal study involving 30 children and adolescents with obesity (body mass index [BMI] z-score 2.31 ± 0.24; age 12.8 ± 3 years, 17 male participants) and 28 age-/sex-matched healthy controls (12.8 ± 3 years, 14 male participants). Vascular function (flow-mediated dilatation [FMD], glyceryl trinitrate-mediated dilatation [GTN]), total adiponectin and isomers, and laboratory and clinical variables were assessed at 0, 18, and 36 months. RESULTS: FMD and GTN were stable during puberty in both groups, remaining consistently lower in obese children (p = 0.02, p < 0.001). The change in total (p = 0.02) and high-molecular weight (HMW) (p = 0.02) adiponectin differed between the groups: falling in controls by the end of puberty but not falling further during puberty in obesity. In obesity, impaired GTN was associated longitudinally with lower total (B = 7.85, p = 0.006) and HMW (B = 3.72, p = 0.03) adiponectin. In controls, more favourable GTN was longitudinally associated with a lower BMI z-score (B = -3.04, p = 0.027) and lower waist circumference (B = -0.35, p = 0.009). CONCLUSIONS: Vascular dysfunction and lower levels of adiponectin are associated in children and adolescents with obesity during puberty and do not deteriorate further. Healthy children's better vascular function, within the normal range, is associated with a lower BMI z-score and waist circumference.

Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history.

We assessed the diagnostic utility of genetic panel testing to detect pathogenic variants associated with osteogenesis imperfecta in children presenting with multiple fractures. Thirty-five percent of children had a pathogenic variant. A history of a femur fracture or a first fracture occurring under 2 years of age were significant clinical predictors. PURPOSE: The use of next-generation sequencing (NGS) genetic panels offers a comprehensive rapid diagnostic test to evaluate for pathogenic variants in the expanding list of genes associated with osteogenesis imperfecta (OI). We aimed to assess the diagnostic utility of this method in children with a clinically significant fracture history. METHODS: NGS panel testing was performed in 87 children presenting with multiple long bone or vertebral fractures. Subjects with a known family history of OI were excluded. Associations between genetic findings and clinical characteristics were analyzed in a retrospective observational study. RESULTS: Thirty-five percent of patients were found to have a disease-causing variant, with a higher detection rate in those patients with extra-skeletal features of OI (94 vs. 20%, p < 0.001). In subjects with extra-skeletal clinical OI features, 69% were found to have pathogenic variants in COL1A1 or COL1A2. In children without extra-skeletal features, 14 of 70 (20%) had pathogenic variants, of which 7 were variants in type 1 collagen, and the remaining 7 variants were associated with osteoblast function or signaling (PLS3, SP7, LRP5). Clinical predictors for detecting a disease-causing variant included a history of having a first fracture that occurred under 2 years of age (Odds ratio 5.5, 95%CI 1.8, 16.9) and a history of a femur fracture (Odds ratio 3.3, 95%CI 1.0, 11.1). CONCLUSION: NGS panel testing will detect causative pathogenic variants in up to a third of children with a clinically significant fracture history, particularly where there is a history of early femur fracture.

Transient neonatal hyperinsulinism: early predictors of duration.

OBJECTIVES: Hyperinsulinism is the most common cause of recurrent hypoglycemia in infants, with transient and permanent forms. Currently, there are no effective tools to predict severity and time to resolution in infants with transient hyperinsulinism (tHI). Therefore, our objective was to assess whether early glucose trends predict disease duration in tHI. METHODS: A retrospective, pilot cohort of infants admitted with tHI was phenotyped for clinical and laboratory parameters. Blood glucose (BG) values were collected from the first documented hypoglycemia for 120 h (five days). RESULTS: In 27 neonates with tHI, the presence of fetal distress (p=0.001) and higher mean daily BG (p=0.035) were associated with shorter time to resolution of hypoglycemia. In a further sensitivity analysis that grouped the cohort by the presence or absence of fetal distress, we found that in neonates without fetal distress, lower mean daily glucose was associated with longer disease duration (R2=0.53, p=0.01). CONCLUSIONS: Our pilot data suggests that predictors for disease duration of tHI may be elicited in the first week of life, and that tHI associated with fetal distress may represent a distinct clinical entity with a shorter time course.