Infant BMI or Weight-for-Length and Obesity Risk in Early Childhood

Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity

Diabetes in childhood cancer survivors: emerging concepts in pathophysiology and future directions

With advancements in cancer treatment and supportive care, there is a growing population of childhood cancer survivors who experience a substantial burden of comorbidities related to having received cancer treatment at a young age. Despite an overall reduction in the incidence of most chronic health conditions in childhood cancer survivors over the past several decades, the cumulative incidence of certain late effects, in particular diabetes mellitus (DM), has increased. The implications are significant, because DM is a key risk factor for cardiovascular disease, a leading cause of premature death in childhood cancer survivors. The underlying pathophysiology of DM in cancer survivors is multifactorial. DM develops at younger ages in survivors compared to controls, which may reflect an “accelerated aging” phenotype in these individuals. The treatment-related exposures (i.e., chemotherapy, radiation) that increase risk for DM in childhood cancer survivors may be more than additive with established DM risk factors (e.g., older age, obesity, race, and ethnicity). Emerging research also points to parallels in cellular processes implicated in aging- and cancer treatment-related DM. Still, there remains marked inter-individual variability regarding risk of DM that is not explained by demographic and therapeutic risk factors alone. Recent studies have highlighted the role of germline genetic risk factors and epigenetic modifications that are associated with risk of DM in both the general and oncology populations. This review summarizes our current understanding of recognized risk factors for DM in childhood cancer survivors to help inform targeted approaches for disease screening, prevention, and treatment. Furthermore, it highlights the existing scientific gaps in understanding the relative contributions of individual therapeutic exposures and the mechanisms by which they exert their effects that uniquely predispose this population to DM following cancer treatment

Retrospective Dataset and Survey Analyses Identify Gaps in Data Collection for Craniopharyngioma and Priorities of Patients and Families Affected by the Disease

Introduction: Craniopharyngioma is a rare, low-grade tumor located in the suprasellar region of the brain, near critical structures like the pituitary gland. Here, we concurrently investigate the status of clinical and genomic data in a retrospective craniopharyngioma cohort and survey-based data to better understand patient-relevant outcomes associated with existing therapies and provide a foundation to inform new treatment strategies. Methods: Clinical, genomic, and outcome data for a retrospective cohort of patients with craniopharyngioma were collected and reviewed through the Children\u27s Brain Tumor Network (CBTN) database. An anonymous survey was distributed to patients and families with a diagnosis of craniopharyngioma to understand their experiences throughout diagnosis and treatment. Results: The CBTN repository revealed a large proportion of patients (40 - 70%) with specimens that are available for sequencing but lacked relevant quality of life (QoL) and functional outcomes. Frequencies of reported patient comorbidities ranged from 20 to 25%, which is significantly lower than historically reported. Survey results from 159 patients/families identified differences in treatment considerations at time of diagnosis versus time of recurrence. In retrospective review, patients and families identified preference for therapy that would improve QoL, rather than decrease risk of recurrence (mean 3.9 vs. 4.4 of 5) and identified endocrine issues as having the greatest impact on patients\u27 lives. Conclusions: This work highlights the importance of prospective collection of QoL and functional metrics alongside robust clinical and molecular correlates in individuals with craniopharyngioma. Such comprehensive measures will facilitate biologically relevant therapeutic strategies that also prioritize patient needs

Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome

Context: Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland characterized by the triad of a very thin/interrupted pituitary stalk, an ectopic (or absent) posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. Complex genetic patterns of inheritance of this disorder are increasingly recognized. Objective: The objective of this study was to identify a genetic cause of PSIS in an affected child. Methods: Whole exome sequencing (WES) was performed by using standard techniques, with prioritized genetic variants confirmed via Sanger sequencing. To investigate the effects of one candidate variant on mutant WDR11 function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C.T;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A.G;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Objectives The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. Methods Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use

The gut of the finch: uniqueness of the gut microbiome of the Galápagos vampire finch

Background: Darwin’s finches are a clade of 19 species of passerine birds native to the Galápagos Islands, whose biogeography, specialized beak morphologies, and dietary choices—ranging from seeds to blood—make them a classic example of adaptive radiation. While these iconic birds have been intensely studied, the composition of their gut microbiome and the factors influencing it, including host species, diet, and biogeography, has not yet been explored. Results: We characterized the microbial community associated with 12 species of Darwin’s finches using high-throughput 16S rRNA sequencing of fecal samples from 114 individuals across nine islands, including the unusual blood-feeding vampire finch (Geospiza septentrionalis) from Darwin and Wolf Islands. The phylum-level core gut microbiome for Darwin’s finches included the Firmicutes, Gammaproteobacteria, and Actinobacteria, with members of the Bacteroidetes at conspicuously low abundance. The gut microbiome was surprisingly well conserved across the diversity of finch species, with one exception—the vampire finch—which harbored bacteria that were either absent or extremely rare in other finches, including Fusobacterium, Cetobacterium, Ureaplasma, Mucispirillum, Campylobacter, and various members of the Clostridia—bacteria known from the guts of carnivorous birds and reptiles. Complementary stable isotope analysis of feathers revealed exceptionally high δ15N isotope values in the vampire finch, resembling top marine predators. The Galápagos archipelago is also known for extreme wet and dry seasons, and we observed a significant seasonal shift in the gut microbial community of five additional finch species sampled during both seasons. Conclusions: This study demonstrates the overall conservatism of the finch gut microbiome over short (< 1 Ma) divergence timescales, except in the most extreme case of dietary specialization, and elevates the evolutionary importance of seasonal shifts in driving not only species adaptation, but also gut microbiome composition

The gut of the finch: uniqueness of the gut microbiome of the Galápagos vampire finch.

BACKGROUND: Darwin's finches are a clade of 19 species of passerine birds native to the Galápagos Islands, whose biogeography, specialized beak morphologies, and dietary choices-ranging from seeds to blood-make them a classic example of adaptive radiation. While these iconic birds have been intensely studied, the composition of their gut microbiome and the factors influencing it, including host species, diet, and biogeography, has not yet been explored. RESULTS: We characterized the microbial community associated with 12 species of Darwin's finches using high-throughput 16S rRNA sequencing of fecal samples from 114 individuals across nine islands, including the unusual blood-feeding vampire finch (Geospiza septentrionalis) from Darwin and Wolf Islands. The phylum-level core gut microbiome for Darwin's finches included the Firmicutes, Gammaproteobacteria, and Actinobacteria, with members of the Bacteroidetes at conspicuously low abundance. The gut microbiome was surprisingly well conserved across the diversity of finch species, with one exception-the vampire finch-which harbored bacteria that were either absent or extremely rare in other finches, including Fusobacterium, Cetobacterium, Ureaplasma, Mucispirillum, Campylobacter, and various members of the Clostridia-bacteria known from the guts of carnivorous birds and reptiles. Complementary stable isotope analysis of feathers revealed exceptionally high δ15N isotope values in the vampire finch, resembling top marine predators. The Galápagos archipelago is also known for extreme wet and dry seasons, and we observed a significant seasonal shift in the gut microbial community of five additional finch species sampled during both seasons. CONCLUSIONS: This study demonstrates the overall conservatism of the finch gut microbiome over short (< 1 Ma) divergence timescales, except in the most extreme case of dietary specialization, and elevates the evolutionary importance of seasonal shifts in driving not only species adaptation, but also gut microbiome composition

Positive association between mammographic breast density and bone mineral density in the Postmenopausal Estrogen/Progestin Interventions Study

INTRODUCTION: Mammographic breast density is a strong independent risk factor for breast cancer. We hypothesized that demonstration of an association between mammographic breast density and bone mineral density (BMD) would suggest a unifying underlying mechanism influencing both breast density and BMD. METHODS: In a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions Study (PEPI), participants were aged 45 to 64 years and were at least 1 year postmenopausal. Mammographic breast density (percentage of the breast composed of dense tissue), the outcome, was assessed with a computer-assisted percentage-density method. BMD, the primary predictor, was measured with dual-energy X-ray absorptiometry. Women quitting menopausal hormone therapy to join PEPI were designated recent hormone users. RESULTS: The mean age of the 594 women was 56 years. The average time since menopause was 5.6 years. After adjustment for age, body mass index, and cigarette smoking, in women who were not recent hormone users before trial enrollment (n = 415), mammographic density was positively associated with total hip (P = 0.04) and lumbar (P = 0.08) BMD. Mammographic density of recent hormone users (n = 171) was not significantly related to either total hip (P = 0.51) or lumbar (P = 0.44) BMD. In participants who were not recent hormone users, mammographic density was 4% greater in the highest quartile of total hip BMD than in the lowest. In participants who were not recent hormone users, mammographic density was 5% greater in the highest quartile of lumbar spine BMD than in the lowest. CONCLUSION: Mammographic density and BMD are positively associated in women who have not recently used postmenopausal hormones. A unifying biological mechanism may link mammographic density and BMD. Recent exogenous postmenopausal hormone use may obscure the association between mammographic density and BMD by having a persistent effect on breast tissue