Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases.

Denosumab has been used successfully to treat disease-associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3-year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12-year-old with recurrent ABC of the pelvis, a 14-year-old with CGCG of the mandible, and a 12-year-old with cherubism. All were started on a 1-year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1-month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40BACKGROUND: Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology. METHODS: We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology. RESULTS: We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (rg = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways. CONCLUSIONS: LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders

Two Small Planets Transiting HD 3167

We report the discovery of two super-Earth-sized planets transiting the bright (V = 8.94, K = 7.07) nearby late G-dwarf HD 3167, using data collected by the K2 mission. The inner planet, HD 3167 b, has a radius of 1.6 R_e and an ultra-short orbital period of only 0.96 days. The outer planet, HD 3167 c, has a radius of 2.9 R_e and orbits its host star every 29.85 days. At a distance of just 45.8 +/- 2.2 pc, HD 3167 is one of the closest and brightest stars hosting multiple transiting planets, making HD 3167 b and c well suited for follow-up observations. The star is chromospherically inactive with low rotational line-broadening, ideal for radial velocity observations to measure the planets' masses. The outer planet is large enough that it likely has a thick gaseous envelope which could be studied via transmission spectroscopy. Planets transiting bright, nearby stars like HD 3167 are valuable objects to study leading up to the launch of the James Webb Space Telescope.Comment: Accepted by ApJL. 6 pages, 1 figure, 2 table

Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling.

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism

Relationships Effecting College Students’ Perception of Family Influence Impacting their Health and Lifestyle

The purpose of this cross-sectional, nonexperimental descriptive design study was to determine college students’ perception of family influence impacting their health and lifestyle. The sample included 120 college students in a faithbased institution and each student completed a Likert-type survey (4-point agreement scale) that investigated their perception of health, and the degree of influence peers and family had on their health. This second data analysis reports correlations between variables and group differences related to health perceptions and behaviours. The strongest correlation is between ‘family demonstration of positive health habits’ and ‘personal health practices being like my families’ (r = 0.671, p \u3c 0.01), a moderate relationship supported by other weaker positive correlations to specific health outcomes. Negative correlations between ‘my friends display more positive health habits than family’ and both ‘family has influenced my idea of health’ and ‘my health practices are similar to my family’ indicate the potential for other contextual factors to effect family impact. While differences relating to health influence and outcomes between groups formed by age, gender, ethnicity, family structure and religion were found, the variable related to most healthy lifestyle transmission elements was ‘My family demonstrates positive health habits’. Recommendations supporting improved societal health are offered, together with suggestions for further research. Group classifications that are fixed but might inform interactions with elements of cohorts are identified, together with group memberships which might be changed to enhance health options. Caution in the generalisation of these findings is advised due to the explained limitations of this study

OP21 Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: The prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service

Background Anti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of a drug. We sought to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in a sample of healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab. Methods Serum was obtained from a random sample of 498 anti-TNF-naïve healthy adults recruited to the Exeter Ten Thousand study and tested for total anti-drug antibodies to infliximab and adalimumab. Using recommendations for confirmatory anti-drug antibody validation, we used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile to define assay thresholds. We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs. non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests). Results The 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/ml and 5.9 AU/ml, respectively. Using the manufacturer’s recommended threshold of 10 AU/ml for both total anti-TNF antibody assays, in healthy individuals, the prevalence of positive antibodies to infliximab and adalimumab was 1% (5/498) and 0.2% (1/498), respectively. Using the manufacturer’s threshold, at the time of last testing, of 7447 and 4054 patients treated with infliximab and adalimumab; 20.9% (n = 1,554) and 8.0% (n = 326) had clearing antibodies and 26.5% (n = 1973) and 12.1% (n = 490) had non-clearing antibodies, respectively (Figure 1). Using our newly defined threshold in the same cohorts; 21.1% (n = 1573) and 8.4% (n = 339) had clearing antibodies and 28.0% (n = 2083) and 20.0% (n = 812) had non-clearing antibodies, to infliximab and adalimumab, respectively. Amongst patients with at least two tests, most developed persistent antibodies (Figure 2). Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies. graphic graphic Conclusion We report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

Five Planets Transiting a Ninth Magnitude Star

The Kepler mission has revealed a great diversity of planetary systems and architectures, but most of the planets discovered by Kepler orbit faint stars. Using new data from the K2 mission, we present the discovery of a five planet system transiting a bright (V = 8.9, K = 7.7) star called HIP 41378. HIP 41378 is a slightly metal-poor late F-type star with moderate rotation (v sin(i) = 7 km/s) and lies at a distance of 116 +/- 18 from Earth. We find that HIP 41378 hosts two sub-Neptune sized planets orbiting 3.5% outside a 2:1 period commensurability in 15.6 and 31.7 day orbits. In addition, we detect three planets which each transit once during the 75 days spanned by K2 observations. One planet is Neptune sized in a likely ~160 day orbit, one is sub-Saturn sized likely in a ~130 day orbit, and one is a Jupiter sized planet in a likely ~1 year orbit. We show that these estimates for the orbital periods can be made more precise by taking into account dynamical stability considerations. We also calculate the distribution of stellar reflex velocities expected for this system, and show that it provides a good target for future radial velocity observations. If a precise orbital period can be determined for the outer Jovian planet through future observations, it will be an excellent candidate for follow-up transit observations to study its atmosphere and measure its oblateness.Comment: Accepted by ApJL. 12 pages, 6 figures, 2 table

A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure

The ratio of the lengths of an individual's second to fourth digit (2D:4D) is commonly used as a noninvasive retrospective biomarker for prenatal androgen exposure. In order to identify the genetic determinants of 2D:4D, we applied a genome-wide association approach to 1507 11-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in whom 2D:4D ratio had been measured, as well as a sample of 1382 12- to 16-year-olds from the Brisbane Adolescent Twin Study. A meta-analysis of the two scans identified a single variant in the LIN28B gene that was strongly associated with 2D:4D (rs314277: p = 4.1 108) and was subsequently independently replicated in an additional 3659 children from the ALSPAC cohort (p = 1.53 106). The minor allele of the rs314277 variant has previously been linked to increased height and delayed age at menarche, but in our study it was associated with increased 2D:4D in the direction opposite to that of previous reports on the correlation between 2D:4D and age at menarche. Our findings call into question the validity of 2D:4D as a simplistic retrospective biomarker for prenatal testosterone exposure

The pain course: A randomised controlled trial examining an internet-delivered pain management program when provided with different levels of clinician support

© 2015 International Association for the Study of Pain. The present study evaluated an internet-delivered pain management program, the Pain Course, when provided with different levels of clinician support. Participants (n5490) were randomised to 1 of 4 groups: (1) Regular Contact (n5143), (2) Optional Contact (n5 141), (3) No Contact (n 5 131), and (4) a treatment-As-usual Waitlist Control Group (n 5 75). The treatment program was based on the principles of cognitive behaviour therapy and comprised 5 internet-delivered lessons provided over 8 weeks. The 3 Treatment Groups reported significant improvements (between-group Cohen's d; avg. reduction) in disability (ds ≤ 0.50; avg. reduction ≤ 18%), anxiety (ds≤0.44; avg. reduction≤32%), depression (ds≤0.73; avg. reduction≤36%), and average pain (ds≤0.30; avg. reduction ≤ 12%) immediately posttreatment, which were sustained at or further improved to 3-month follow-up. High treatment completion rates and levels of satisfaction were reported, and no marked or consistent differences were observed between the Treatment Groups. The mean clinician time per participant was 67.69 minutes (SD533.50), 12.85 minutes (SD524.61), and 5.44 minutes (SD 5 12.38) for those receiving regular contact, the option of contact, and no clinical contact, respectively. These results highlight the very significant public health potential of carefully designed and administered internet-delivered pain management programs and indicate that these programs can be successfully administered with several levels of clinical support

The potential shared role of inflammation in insulin resistance and schizophrenia:a bidirectional two-sample mendelian randomization study

BACKGROUND: Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. METHODS AND FINDINGS: We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. CONCLUSIONS: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance