Evaluation of 4 Outcomes Measures in Microtia Treatment: Exposures, Infections, Aesthetics, and Psychosocial Ramifications.

BackgroundIn craniofacial microsomia, microtia and canal atresia pose formidable reconstructive challenges. We review our institutional experience in treating microtia and atresia to identify variables associated with 4 outcomes measures: complications, surgical revisions, aesthetic outcomes, and psychosocial function.MethodsCraniofacial microsomia patients treated at the University of California Los Angeles Craniofacial Clinic between 2008 and 2014 greater than 13 years of age (n = 68) were reviewed for microtia and atresia treatment and outcomes.ResultsIn total, 91.2% of patients diagnosed with craniofacial microsomia presented with microtia, affecting 75 ears. Both a male and right-sided predominance were observed. Fifty-six patients (90.3%) underwent autologous external ear reconstruction at an average age of 8.5 years. Age, type of incision, and size of cartilage framework did not predict total number of surgeries or complications. Severity of ear anomalies correlated with increased number of surgeries (P < 0.001) and decreased aesthetic outcomes (P < 0.001) but not complications. In total, 87.1% of patients with microtia had documented hearing loss, of which the majority were conductive and 18.5% were mixed sensorineural and conductive. Hearing deficits were addressed in 70.4% of patients with external hearing aids, bone anchored hearing aids, or canaloplasty. Of all variables, improvement of psychosocial function was correlated only to hearing loss treatment of any type (P = 0.01).ConclusionsOn evaluation of surgical and patient characteristics, severity of microtia predicted the total number of surgical revisions performed and aesthetic ratings. In addition, we found that the only factor that correlated with improved patient and parent-reported psychosocial outcomes was treatment of hearing loss

Nonalcoholic fatty liver disease and risk of incident young-onset hypertension:effect modification by sex

Background and aims: although nonalcoholic fatty liver disease (NAFLD) and hypertension are increasingly common among young adults, it is uncertain if NAFLD affects incidence of young-onset hypertension, and if the association is modified by sex. We investigated potential effect modification by sex on the association between NAFLD and incident hypertension in young adults (<40 years).Method and results: this cohort study comprised 85,789 women and 67,553 men aged <40 years without hypertension at baseline. Hepatic steatosis was assessed by liver ultrasound and classified as mild or moderate/severe. Hypertension was defined as blood pressure (BP) ≥130/80 mmHg; self-reported history of physician-diagnosed hypertension; or current use of BP-lowering medications. Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident hypertension by NAFLD status (median follow-up 4.5 years). A total of 25,891 participants developed incident hypertension (incidence rates per 103 person-years: 15.6 for women and 63.5 for men). Multivariable-adjusted HRs (95% CIs) for incident hypertension comparing no NAFLD (reference) with mild or moderate/severe NAFLD were 1.68 (1.56–1.80) and 1.83 (1.60–2.09) for women and 1.21 (1.17–1.25) and 1.23 (1.17–1.30) for men, respectively. Stronger associations were consistently observed between NAFLD and incident hypertension in women, regardless of obesity/central obesity (all p-values for interaction by sex <0.001).Conclusions: NAFLD is a potential risk factor for young-onset hypertension with a relatively greater impact in women and in those with more severe hepatic steatosis

Glycemic status, insulin resistance, and mortality from lung cancer among individuals with and without diabetes

Background: The effects of glycemic status and insulin resistance on lung cancer remain unclear. We investigated the associations between both glycemic status and insulin resistance, and lung cancer mortality, in a young and middle-aged population with and without diabetes. Methods: This cohort study involved individuals who participated in routine health examinations. Lung cancer mortality was identified using national death records. Cox-proportional hazards models were used to calculate hazard ratios (HRs) with 95% CIs for lung cancer mortality risk. Results: Among 666,888 individuals (mean age 39.9±10.9 years) followed for 8.3 years (interquartile range, 4.6–12.7), 602 lung cancer deaths occurred. Among individuals without diabetes, the multivariable-adjusted HRs (95% CI) for lung cancer mortality comparing hemoglobin A1c categories (5.7–5.9, 6.0–6.4, and ≥ 6.5% or 36–38, 39–46, and ≥ 48 mmol/mol, respectively) with the reference (&lt; 5.7% or &lt; 36 mmol/mol) were 1.39 (1.13–1.71), 1.72 (1.33–2.20), and 2.22 (1.56–3.17), respectively. Lung cancer mortality was associated with fasting blood glucose categories in a dose-response manner (P for trend = 0.001) and with previously diagnosed diabetes. Insulin resistance (HOMA-IR ≥ 2.5) in individuals without diabetes was also associated with lung cancer mortality (multivariable-adjusted HR, 1.41; 95% CI, 1.13–1.75). These associations remained after adjusting for changing status in glucose, hemoglobin A1c, insulin resistance, smoking status, and other confounders during follow-up as time-varying covariates. Conclusions: Glycemic status within both diabetes and prediabetes ranges and insulin resistance were independently associated with an increased risk of lung cancer mortality. Keywords Diabetes mellitus, Glycated hemoglobin A1c, Hyperglycemia, Insulin resistance, Lung cancer<br/

Polymorphisms in HSD17B1: Early Onset and Increased Risk of Alzheimer's Disease in Women with Down Syndrome

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD. HSD17B1 encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol. Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31–78 years of age, were followed at 14–18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in the HSD17B1 gene region, and their association with incident AD was examined. Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 in COASY (rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1–3.1). Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen

Serum 25-hydroxyvitamin D levels and risk of colorectal cancer:an age-stratified analysis

Background and aims: the role of circulating 25-hydroxyvitamin D (25(OH)D) in prevention of early-onset colorectal cancer (CRC) in young adults under 50 years is uncertain. We evaluated the age-stratified associations (&lt;50 vs. ≥50 years) :circulating 25(OH)D levels and the risk of CRC in a large sample of Korean adults.Methods: our cohort study included 236,382 participants (mean [standard deviation] age, 38.0 [9.0] years) who underwent a comprehensive health examination, including measurement of serum 25(OH)D levels. Serum 25(OH)D levels were categorized as follows: &lt;10, 10–20, and ≥20 ng/mL. CRC, along with the histologic subtype, site, and invasiveness was ascertained through linkage with the national cancer registry. Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident CRC according to the serum 25(OH)D status, with adjustment for potential confounders.Results: during the 1,393,741 person-years of follow-up (median, 6.5 years; interquartile range, 4.5–7.5 years), 341 participants developed CRC (incidence rate, 19.2 per 105 person-years). Among young individuals aged &lt;50 years, serum 25(OH)D levels were inversely associated with the risk of incident CRC with HRs (95% CIs) of 0.61 (0.43–0.86) and 0.41 (0.27–0.63) for 25(OH)D 10-19 and ≥20 ng/mL, respectively, with respect to the reference (&lt;10 ng/mL) (p for trend &lt;0.001, time-dependent model). Significant associations were evident for adenocarcinoma, colon cancer, and invasive cancers. For those aged ≥50 years, associations were similar, although slightly attenuated compared to younger individuals. Conclusions: serum 25(OH)D levels may have beneficial associations with the risk of developing CRC for both early-onset and late-onset disease. <br/

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development

Modular metabolite assembly in C. elegans lysosome-related organelles

Signaling molecules derived from attachment of diverse primary metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that lysosome-related organelles (LROs) are required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Both modular glucosides and ascarosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism. We further show that cholinesterase (cest) homologs that localize to the LROs are required for assembly of both modular ascarosides and glucosides, mediating formation of ester and amide linkages between subsets of building blocks. Their specific biosynthesis suggests that modular glucosides, like ascarosides, serve dedicated signaling functions. Further exploration of LRO function and cest homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms

Modular metabolite assembly in C. elegans lysosome-related organelles

Signaling molecules derived from attachment of diverse primary metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that lysosome-related organelles (LROs) are required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Both modular glucosides and ascarosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism. We further show that cholinesterase (cest) homologs that localize to the LROs are required for assembly of both modular ascarosides and glucosides, mediating formation of ester and amide linkages between subsets of building blocks. Their specific biosynthesis suggests that modular glucosides, like ascarosides, serve dedicated signaling functions. Further exploration of LRO function and cest homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms