Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity.

PURPOSE OF REVIEW: The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care. RECENT FINDINGS: Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% -new variants in known genes as well as identification of novel genes- causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity. While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.

Exploring Genetic Testing for Rare Disorders of Obesity: Experience and Perspectives of Pediatric Weight Management Providers.

Background: This study describes experiences and perspectives of pediatric weight management (PWM) providers on the implementation of genetic testing for rare causes of obesity. Methods: Purposive and snowball sampling recruited PWM providers via email to complete a 23-question survey with multiple choice and open-ended questions. Analyses include descriptive statistics, Fisher's exact test, one-way ANOVA with Tukey's post hoc test, and qualitative analysis. Results: Of the 55 respondents, 80% reported ordering genetic testing. Respondents were primarily physicians (82.8%) in practice for 11-20 years (42%), identified as female (80%), White (76.4%), and non-Hispanic (92.7%) and provided PWM care 1-4 half day sessions per week. Frequently reported patient characteristics that prompted testing did not vary by provider years of experience (YOE). These included obesity onset before age 6, hyperphagia, dysmorphic facies, and developmental delays. The number of patient characteristics that prompted testing varied by YOE (p = 0.03); respondents with 6-10 YOE indicated more patient characteristics than respondents with >20 YOE (mean 10.3 vs. mean 6.2). The reported primary benefit of testing was health information for patients/families; the primary drawback was the high number of indeterminate tests. Ethical concerns expressed were fear of increasing weight stigma, discrimination, and impact on insurance coverage. Respondents (42%) desired training and guidance on interpreting results and counseling patients and families. Conclusions: Most PWM providers reported genetic testing as an option for patient management. Provider training in genetics/genomics and research into provider and family attitudes on the genetics of obesity and the value of genetic testing are next steps to consider.

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fasting plasma samples from individuals undergoing bariatric surgery (n = 71 Roux-en-Y gastric bypass [RYGB], n = 22 gastric banding), lifestyle intervention (n = 66), or usual care (n = 14) were profiled for 139 metabolites before and 2 years after weight loss. Principal component analysis grouped correlated metabolites into factors. Association of preintervention metabolites was tested with preintervention clinical features and changes in T2D markers. Association between change in metabolites/metabolite factors and change in T2D remission markers, homeostasis model assessment of ß-cell function, homeostasis model assessment of insulin resistance, and glycated hemoglobin (HbA1c) was assessed. RESULTS: Branched-chain amino acids (BCAAs) were associated with preintervention adiposity. Changes in BCAAs (valine, leucine/isoleucine) and branched-chain ketoacids were positively associated with change in HbA1c (false discovery rate q value ≤ 0.001) that persisted after adjustment for percentage weight change and RYGB (p ≤ 0.02). In analyses stratified by RYGB or other weight loss method, some metabolites showed association with non-RYGB weight loss. CONCLUSIONS: This study confirmed known metabolite associations with obesity/T2D and showed an association of BCAAs with HbA1c change after weight loss, independent of the method or magnitude of weight loss.

Neonatal Hypoglycemia following Late Preterm Antenatal Corticosteroid Administration in Individuals with Diabetes in Pregnancy.

OBJECTIVE: Antenatal corticosteroid (ACS) administration is standard practice for pregnant individuals delivering in the late preterm period, though no guidelines are in place for those with diabetes. This study aims to characterize the prevalence of neonatal hypoglycemia after ACS administration in pregnant individuals with diabetes delivering in the late preterm period. STUDY DESIGN: This is a retrospective, single-center, case-control study of individuals with diabetes who delivered between 340/7 and 366/7 weeks' gestation at a large academic medical center from 2016 to 2021. A total of 169 individuals were included in the analysis; 87 received corticosteroids and 82 did not. The proportion of neonates with hypoglycemia, neonatal intensive care unit (NICU) admission, respiratory distress syndrome, and hyperbilirubinemia were compared between parents who received ACSs versus those who did not. RESULTS: The prevalence of neonatal hypoglycemia (40.2 vs. 23.2%, p = 0.027), requiring treatment (40.3 vs. 22.4%, p = 0.041), and hyperbilirubinemia (35.6 vs 18.5%, p = 0.018) was greater for neonates born to individuals with diabetes who received late preterm ACSs compared with those who did not. There was no difference in NICU admission and respiratory distress between the groups. These results remained unchanged after controlling for confounders including gestational age at delivery and birth weight. CONCLUSION: This study demonstrates that late preterm corticosteroid administration to pregnant individuals with diabetes increases the risk for neonatal hypoglycemia without changing the rates of respiratory morbidity. KEY POINTS: · Late preterm ACS in diabetic patients resulted in higher rates of neonatal hypoglycemia.. · There are no differences in rates of respiratory distress syndrome and transient tachypnea of the newborn between the ACS group and control group.. · There was no noted difference in rate of NICU admission and length of stay between the two groups..

Amygdala AVPR1A mediates susceptibility to chronic social isolation in females.

Females are more sensitive to social exclusion, which could contribute to their heightened susceptibility to anxiety disorders. Chronic social isolation stress (CSIS) for at least 7 weeks after puberty induces anxiety-related behavioral adaptations in female mice. Here, we show that Arginine vasopressin receptor 1a ( Avpr1a )-expressing neurons in the central nucleus of the amygdala (CeA) mediate these sex-specific effects, in part, via projections to the caudate putamen. Loss of function studies demonstrate that AVPR1A signaling in the CeA is required for effects of CSIS on anxiety-related behaviors in females but has no effect in males or group housed females. This sex-specificity is mediated by AVP produced by a subpopulation of neurons in the posterodorsal medial nucleus of the amygdala that project to the CeA. Estrogen receptor alpha signaling in these neurons also contributes to preferential sensitivity of females to CSIS. These data support new therapeutic applications for AVPR1A antagonists in women.

Lack of Age-Appropriate Reference Intervals Causing Potentially Missed Alerts in Clinical Reports of Dyslipidemia.

This study shows that only 12.5% of laboratory reports (2/16) included age-appropriate pediatric reference ranges for all lipid and lipoproteins. The use of erroneous reference range(s) could lead to missed alerts of dyslipidemia in up to 97.3% (total cholesterol), 93.6% (high-density lipoprotein cholesterol), 94.8% (low-density lipoprotein cholesterol), and 87.8% (triglycerides) of youth in the population-based National Health and Nutrition Examination Survey cohort. These findings highlight the potential missed opportunities for reinforcing lifestyle counseling for dyslipidemia in addition to obesity in youth.

The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that "program" obesity from conception.

Understanding the developmental origins of health and disease is integral to overcome the global tide of obesity and its metabolic consequences, including atherosclerotic cardiovascular disease, type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. The rising prevalence of obesity has been attributed, in part, to environmental factors including the globalization of the western diet and unhealthy lifestyle choices. In this review we argue that how and when such exposures come into play from conception significantly impact overall risk of obesity and later health outcomes. While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically "program" obesity.

Efficient Cas9-based Genome Editing Using CRISPR Analysis Webtools in Severe Early-onset-obesity Patient-derived iPSCs.

The CRISPR system is an adaptive defense mechanism used by bacteria and archaea against viruses and plasmids. The discovery of the CRISPR-associated protein Cas9 and its RNA-guided cleavage mechanism marked the beginning of a new era in genomic engineering by enabling the editing of a target region in the genome. Gene-edited cells or mice can be used as models for understanding human diseases. Given its high impact in functional genomic experiments on different model systems, several CRISPR/Cas9 protocols have been generated in the past years. The technique uses a straightforward "cut and stitch" mechanism, but requires an accurate step-by-step design. One of the key points is the use of an efficient programmable guide RNA to increase the rate of success in obtaining gene-specific edited clones. Here, we describe an efficient editing protocol using a ribonucleotide protein (RNP) complex for homology-directed repair (HDR)-based correction of a point mutation in an induced pluripotent stem cell (iPSC) line generated from a 14-year-old patient with severe early-onset obesity carrying a de novo variant of ARNT2. The resulting isogenic iPSC line, named CUIMCi003-A-1, has a normal karyotype, expresses stemness markers, and can be differentiated into progenies from all three germ layers. We provide a detailed workflow for designing a single guide RNA and donor DNA, and for isolating clonal human iPSCs edited with the desired modification. This article also focuses on parameters to consider when selecting reagents for CRISPR/Cas9 gene editing after testing their efficiency with in silico tools. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Design of sgRNAs and PCR primers Basic Protocol 2: Testing the efficiency of sgRNAs Basic Protocol 3: Design of template or donor DNA Basic Protocol 4: Targeted gene editing Basic Protocol 5: Selection of positive clones Basic Protocol 6: Freezing, thawing, and expansion of cells Basic Protocol 7: Characterization of edited cell lines.

Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms.

BACKGROUND: Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the OCRL gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy. METHODS: This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of OCRL and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing. RESULTS: A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height <3rd percentile) was noted in 81% (n=111) individuals, and 15% (n=20) received growth hormone therapy. Undescended testis was reported in 47% (n=64), and median age of onset of puberty was 15 years. Additional features were dental problems (n=77, 56%), bone fractures (n=63, 46%), hypophosphataemia (n=60, 44%), developmental delay and behavioural issues. OCRL is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing Ghrh, Sst, Oxt, Pomc and pituitary cells expressing Gh and Prl. CONCLUSIONS: There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of OCRL in the hypothalamus and the pituitary.

Derivation and characterization of the induced pluripotent stem cell line CUIMCi004-A from a patient with a novel frameshift variant in exon 18a of OCRL.

OCRL encodes for an inositol polyphosphate 5-phosphatase, located in the trans-Golgi network, endosomes, endocytic clathrin-coated pits, primary cilia. Mutations in OCRL causes Lowe syndrome (LS), a rare and complex disorder characterized by congenital cataracts, renal tubular dysfunction, and mental retardation. Here we generated an induced pluripotent stem cell (iPSC) line from Peripheral Blood Mononuclear Cell (PBMCs) of a 5-year-old boy with severe obesity carrying a novel pathogenic variant in the brain-expressed isoform of OCRL. The Sendai virus approach was used for reprogramming. The iPSC line CUIMCi004-A may serve as a useful resource to further investigate the tissue-specific function of OCRL.

The Families Improving Health Together (FIT) Program: Initial evaluation of retention and research in a multispecialty clinic for children with obesity.

BACKGROUND: Obesity affects ∼17% of US children, with parallel increases in multiple comorbidities, especially among African-, Asian-, Hispanic-, and Native-Americans. Barriers to patient retention in pediatric obesity programs include lack of centralized care, and frequent subspecialty MD visits which conflict with patient school attendance and parental work attendance as well as with support service utilization. Lack of integration of multispecialty clinical care with interdisciplinary research is a major barrier to fuller exploration of the treatment, prevention, and understanding of obesity in childhood. OBJECTIVE: To test the hypothesis, a novel multispecialty/interdisciplinary clinical and research infrastructure with strong emphasis on a primary obesity care physician for children with early-onset (<9 years) obesity (Families Improving health Together [FIT]) could promote lower patient attrition (primary goal) and foster productive research in pediatric obesity (secondary goal). RESULTS: Data support the hypotheses. Over 15 months, FIT reported a >90% participant retention (p < 0.001 vs. expected rate based on other studies of similar programs). Though 90% of children had at least one adiposity-related comorbidity and 70% had at least two, there was no need for additional subspecialist visits with cardiologists, endocrinologists, gastroenterologists, or molecular geneticists. Three abstracts were presented at national meetings, and two manuscripts were published all with junior faculty as primary authors. CONCLUSION: This pilot study suggests that an integrated multispecialty/interdisciplinary approach to children with obesity improves patient retention and can be integrated successfully with research.

Recombinant growth hormone therapy for cystic fibrosis in children and young adults.

BACKGROUND: Cystic fibrosis (CF) is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with CF often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant human growth hormone (rhGH), has been proposed as a potential intervention. This is an update of a previously published review. OBJECTIVES: To evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life and clinical status of children and young adults with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 12 January 2021. We also searched ongoing trials registers: clinicaltrials.gov from the United States - date of latest search 19 Jun 2021; WHO International Clinical Trials Registry Platform (ICTRP) - date of latest search 05 March 2018 (not available in 2021).  We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Web of Science, Scopus and Proceedings First. Date of latest search: 21 Jun 2021.  SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of rhGH compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults (aged up to 25 years) diagnosed with CF (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. We assessed the quality of the evidence using the GRADE system. MAIN RESULTS: We included eight trials (291 participants, aged between five and 23 years) in the current version of the review. Seven trials compared standard-dose rhGH (approximately 0.3 mg/kg/week) to no treatment and one three-arm trial (63 participants) compared placebo, standard-dose rhGH (0.3 mg/kg/week) and high-dose rhGH (0.5 mg/kg/week). Six trials lasted for one year and two trials for six months. We found that rhGH treatment may improve some of the pulmonary function outcomes, but there was no difference between standard and high-dose levels (low-certainty evidence, limited by inconsistency across the trials, small number of participants and short duration of therapy). The trials show evidence of improvement in the anthropometric parameters (height, weight and lean body mass) with rhGH therapy, again no differences between dose levels. We found improvement in height for all comparisons (very low- to low-certainty evidence), but improvements in weight and lean body mass were only reported for standard-dose rhGH versus no treatment (very low-certainty evidence). There is some evidence indicating a change in the level of fasting blood glucose with rhGH therapy, however, it did not cross the clinical threshold for diagnosis of diabetes in the trials of short duration (low-certainty evidence). There is low- to very low-certainty evidence for improvement of pulmonary exacerbations with no further significant adverse effects, but this is limited by the short duration of trials and the small number of participants. One small trial provided inconsistent evidence on improvement in quality of life (very low-certainty evidence). There is limited evidence from three trials in improvements in exercise capacity (low-certainty evidence). None of the trials have systematically compared the expense of therapy on overall healthcare costs. AUTHORS' CONCLUSIONS: When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF-related diabetes. No significant changes in quality of life, clinical status or side-effects were observed in this review due to the small number of participants. Long-term, well-designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.

Generation of the iPSC line CUIMCi003-A derived from a patient with severe early onset obesity.

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH/PAS) transcription factor involved in the development of paraventricular nucleus of the hypothalamus (PVH) through the heterodimerization with Single-minded 1 (SIM1) (Michaud et al., 2000). Using a Sendai virus-based approach, the four reprogramming factors OCT3/4, SOX2, KLF4 and C-MYC were delivered into Peripheral Blood Mononuclear Cell (PBMCs) from a 14-year-old girl with early onset obesity carrying a de novo variant (p.P130A) in ARNT2. The resulting iPSC line CUIMCi003-A had a normal karyotype, showed pluripotency and three germ layer differentiation capacity in vitro and was heterozygous for the de novo ARNT2 variant.

Relationship of TSH Levels with Cardiometabolic Risk Factors in US Youth and Reference Percentiles for Thyroid Function.

CONTEXT: Thyroid hormones play an important role in metabolic homeostasis, and higher levels have been associated with cardiometabolic risk. OBJECTIVE: To examine the association of cardiometabolic risk factors with TSH levels in US youth. METHODS: Cross-sectional study of youth aged 12 to 18 years without known thyroid abnormalities from 5 National Health and Nutrition Examination Survey cycles (n = 2818) representing 15.4 million US children. Subclinical hypothyroidism (SH) was defined as thyrotropin (TSH) levels of 4.5 to 10 mIU/L. Assessed cardiometabolic risk factors include abdominal obesity (waist circumference >90th percentile), hypertriglyceridemia (triglyceride ≥130 mg/dL), low high-density lipoprotein cholesterol (<40 mg/dL), elevated blood pressure (systolic and diastolic blood pressure ≥90th percentile), hyperglycemia (fasting blood glucose ≥100 mg/dL, or known diabetes), insulin resistance (homeostatic model for insulin resistance > 3.16), and elevated alanine transferase (≥ 50 for boys and ≥44 U/L for girls). Age and sex- specific percentiles for thyroid parameters were calculated. RESULTS: In this cohort of youth (51.3% male), 31.2% had overweight/obesity. The prevalence of SH was 2.0% (95% CI 1.2-3.1). The median TSH levels were higher in youth with overweight/obesity (P < 0.001). Adjusting for age, sex, race/ethnicity, and obesity, youth with TSH in the fourth quantile had higher odds of abdominal obesity (OR 2.53 [1.43-4.46], P = .002), insulin resistance (OR 2.82 [1.42-5.57], P = .003), and ≥2 cardiometabolic risk factors (CMRF) (OR 2.20 [1.23-3.95], P = .009). CONCLUSION: The prevalence of SH is low in US youth. The higher odds of insulin resistance and cardiometabolic risk factors in youth with TSH levels >75th percentile requires further study.

Effect of TSH on Non-Alcoholic Fatty Liver Disease (NAFLD) independent of obesity in children of predominantly Hispanic/Latino ancestry by causal mediation analysis.

BACKGROUND: Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD. OBJECTIVE: To assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls. DESIGN AND METHODS: In this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed. RESULTS: Sixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children's Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4th quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001). CONCLUSIONS: The association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.

Vitamin K supplementation for cystic fibrosis.

BACKGROUND: Malabsorption and deficiency of fat-soluble vitamins K may occur in cystic fibrosis, a genetic disorder affecting multiple organs. Vitamin K is known to play an important role in both blood coagulation and bone formation, hence the role of supplementation of vitamin K in this category needs to be reviewed. This is an updated version of the review. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to investigate the hypotheses that vitamin K will decrease deficiency-related coagulopathy, increase bone mineral density, decrease risk of fractures and improve quality of life in people with CF. Also to determine the optimal dose and route of administration of vitamin K for people with CF (for both routine and therapeutic use). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 12 August 2019. SELECTION CRITERIA: Randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Three trials (total 70 participants, aged 8 to 46 years) assessed as having a moderate risk of bias were included. One trial compared vitamin K to placebo, a second to no supplementation and the third compared two doses of vitamin K. No trial in either comparison reported our primary outcomes of coagulation and quality of life or the secondary outcomes of nutritional parameters and adverse events. Vitamin K versus control Two trials compared vitamin K to control, but data were not available for analysis. One 12-month trial (n = 38) compared 10 mg vitamin K daily or placebo in a parallel design and one trial (n = 18) was of cross-over design with no washout period and compared 5 mg vitamin K/week for four-weeks to no supplementation for four-weeks. Only the 12-month trial reported on the primary outcome of bone formation; we are very uncertain whether vitamin K supplementation has any effect on bone mineral density at the femoral hip or lumbar spine (very low-quality evidence). Both trials reported an increase in serum vitamin K levels and a decrease in undercarboxylated osteocalcin levels. The cross-over trial also reported that levels of proteins induced by vitamin K absence (PIVKA) showed a decrease and a return to normal following supplementation, but due to the very low-quality evidence we are not certain that this is due to the intervention. High-dose versus low-dose vitamin K One parallel trial (n = 14) compared 1 mg vitamin K/day to 5 mg vitamin K/day for four weeks. The trial did report that there did not appear to be any difference in serum undercarboxylated osteocalcin or vitamin K levels (very low-quality evidence). While the trial reported that serum vitamin K levels improved with supplementation, there was no difference between the high-dose and low-dose groups. AUTHORS' CONCLUSIONS: There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed.

Psychosocial, behavioral and clinical correlates of children with overweight and obesity.

BACKGROUND: Psychological and behavioral correlates are considered important in the development and persistence of obesity in both adults and youth. This study aimed to identify such features in youth with severe obesity (BMI ≥ 120% of 95thpercentile of sex-specific BMI-for-age) compared to those with overweight or non-severe obesity. METHODS: Youth with BMI ≥ 85th percentile were invited to participate in a prospective research registry where data was collected on attributes such as family characteristics, eating behaviors, dietary intake, physical activity, perception of health and mental well-being, and cardiometabolic parameters. RESULTS: In a racially/ethnically diverse cohort of 105 youth (65% female, median age 16.1 years, range 4.62-25.5), 51% had severe obesity. The body fat percent increased with the higher levels of obesity. There were no differences in the self-reported frequency of intake of sugar sweetened beverages or fresh produce across the weight categories. However, the participants with severe obesity reported higher levels of emotional eating and eating when bored (p = 0.022), levels of stress (p = 0.013), engaged in fewer sports or organized activities (p = 0.044), and had suboptimal perception of health (p = 0.053). Asthma, depression and obstructive sleep apnea were more frequently reported in youth with severe obesity. The presence of abnormal HDL-C, HOMA-IR, hs-CRP and multiple cardiometabolic risk factors were more common among youth with severe obesity. CONCLUSIONS: Youth with severe obesity have identifiable differences in psychosocial and behavioral attributes that can be used to develop targeted intervention strategies to improve their health.

Clinical Course of Nonfunctional Pituitary Microadenoma in Children: A Single-Center Experience.

CONTEXT: Pituitary lesions consistent with microadenomas are increasingly discovered by MRI. Sparse data are available on the long-term clinical and imaging course of such lesions in children. OBJECTIVE: The aim of this study was to define the clinical and imaging course of pituitary lesions representing or possibly representing nonfunctioning microadenomas in children to guide clinical management. DESIGN: Retrospective observational study. METHODS: The clinical data warehouse at a tertiary care academic children's hospital was queried with the terms "pituitary" AND "microadenoma" and "pituitary" AND "incidentaloma." The electronic health records of the identified subjects were reviewed to extract data on the clinical and imaging course. RESULTS: A total of 78 children had nonfunctioning pituitary lesions incidentally discovered during clinical care, of which 44 (56%) were reported as presumed or possible microadenomas. In the children with microadenoma (median age 15 years, interquartile range 2), a majority (70%) underwent imaging for nonendocrine symptoms, the most common being headache (n = 16, 36%). No significant increase in the size of the microadenoma or cysts or worsening of pituitary function was seen over the average clinical follow-up of 4.5 ± 2.6 years. Four cases of drug-induced hyperprolactinemia resolved with discontinuation of the offending medication. CONCLUSIONS: Asymptomatic pituitary lesions representing cysts, microadenomas, or possible microadenomas follow a benign course in children. In the absence of new endocrine or visual symptoms, repeat MRI may not be needed, and if performed, should be done in no less than a year. When possible, it is prudent to discontinue hyperprolactinemia-inducing medications before imaging.