An Untargeted Metabolomics Analysis of Antipsychotic Use in Bipolar Disorder

BackgroundSecond generation antipsychotic (SGA) use in bipolar disorder is common and has proven effective in short‐term trials. There continues to be a lack of understanding of the mechanisms underlying many of their positive and negative effects in bipolar disorder. This study aimed to describe the metabolite profiles of bipolar subjects treated with SGAs by comparing to metabolite profiles of bipolar subjects treated with lithium, and schizophrenia subjects treated with SGAs.MethodsCross‐sectional, fasting untargeted serum metabolomic profiling was conducted in 82 subjects diagnosed with bipolar I disorder (n = 30 on SGAs and n = 32 on lithium) or schizophrenia (n = 20). Metabolomic profiles of bipolar subjects treated with SGAs were compared to bipolar subjects treated with lithium and schizophrenia subjects treated with SGAs using multivariate methods.ResultsPartial lease square discriminant analysis (PLS‐DA) plots showed separation between bipolar subjects treated with SGAs, bipolar subjects treated with lithium, or schizophrenia subjects treated with SGAs. Top influential metabolite features were associated with several pathways including that of polyunsaturated fatty acids, pyruvate, glucose, and branched chain amino acids.ConclusionsThe findings from this study require further validation in pre‐ and posttreated bipolar and schizophrenia subjects, but suggest that the pharmacometabolome may be diagnosis specific.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115928/1/cts12324.pd

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

Proceedings from the Ice Hockey Summit III: Action on Concussion

Objectives The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these five objectives: (1) describe sport related concussion (SRC) epidemiology, (2) classify prevention strategies, (3) define objective, diagnostic tests, (4) identify treatment and (5) integrate science and clinical care into prioritized action plans and policy. Methods Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches and officials) voted to prioritize these action items in the final Summit session. Results (1) establish a national and international hockey data base for SRCs at all levels; (2) eliminate body checking in Bantam youth hockey games; (3) expand a behavior modification program (Fair Play) to all youth hockey levels; (4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues; (5) establish objective tests to diagnose concussion at point of care (POC); and (6) mandate baseline testing to improve concussion diagnosis for all age groups. Conclusions Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity and consequences of concussion in the sport of ice hockey

Liver Cancer Incidence and Area-Level Geographic Disparities in Pennsylvania—A Geo-Additive Approach

Many neighborhood socioeconomic index measures (nSES) that capture neighborhood deprivation exist but the impact of measure selection on liver cancer (LC) geographic disparities remains unclear. We introduce a Bayesian geoadditive modeling approach to identify clusters in Pennsylvania (PA) with higher than expected LC incidence rates, adjusted for individual-level factors (age, sex, race, diagnosis year) and compared them to models with 7 different nSES index measures to elucidate the impact of nSES and measure selection on LC geospatial variation. LC cases diagnosed from 2007–2014 were obtained from the PA Cancer Registry and linked to nSES measures from U.S. census at the Census Tract (CT) level. Relative Risks (RR) were estimated for each CT, adjusted for individual-level factors (baseline model). Each nSES measure was added to the baseline model and changes in model fit, geographic disparity and state-wide RR ranges were compared. All 7 nSES measures were strongly associated with high risk clusters. Tract-level RR ranges and geographic disparity from the baseline model were attenuated after adjustment for nSES measures. Depending on the nSES measure selected, up to 60% of the LC burden could be explained, suggesting methodologic evaluations of multiple nSES measures may be warranted in future studies to inform LC prevention efforts

Defining aggressive prostate cancer: a geospatial perspective

Abstract Background Spatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets. Methods Using the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign “aggressive” status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression). Results The number of “aggressive” PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging. Conclusions Using D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies

Evaluation of ES-derived neural progenitors as a potential source for cell replacement therapy in the gut

<p>Abstract</p> <p>Background</p> <p>Stem cell-based therapy has recently been explored for the treatment of disorders of the enteric nervous system (ENS). Pluripotent embryonic stem (ES) cells represent an attractive cell source; however, little or no information is currently available on how ES cells will respond to the gut environment. In this study, we investigated the ability of ES cells to respond to environmental cues derived from the ENS and related tissues, both <it>in vitro</it> and <it>in vivo</it>.</p> <p>Methods</p> <p>Neurospheres were generated from mouse ES cells (ES-NS) and co-cultured with organotypic preparations of gut tissue consisting of the longitudinal muscle layers with the adherent myenteric plexus (LM-MP).</p> <p>Results</p> <p>LM-MP co-culture led to a significant increase in the expression of pan-neuronal markers (βIII-tubulin, PGP 9.5) as well as more specialized markers (peripherin, nNOS) in ES-NS, both at the transcriptional and protein level. The increased expression was not associated with increased proliferation, thus confirming a true neurogenic effect. LM-MP preparations exerted also a myogenic effect on ES-NS, although to a lesser extent. After transplantation <it>in vivo</it> into the mouse pylorus, grafted ES-NS failed to acquire a distinct phenotype al least 1 week following transplantation.</p> <p>Conclusions</p> <p>This is the first study reporting that the gut explants can induce neuronal differentiation of ES cells <it>in vitro</it> and induce the expression of nNOS, a key molecule in gastrointestinal motility regulation. The inability of ES-NS to adopt a neuronal phenotype after transplantation in the gastrointestinal tract is suggestive of the presence of local inhibitory influences that prevent ES-NS differentiation <it>in vivo</it>.</p

Hauptschule, Realschule oder Gymnasium? Ethnische Unterschiede am ersten Bildungsübergang

Im vorliegenden Beitrag werden ethnische Unterschiede in der schulischen Plazierung von Migrantenkindern und deutschen Schülerinnen und Schülern am Übergang von der Grundschule in die Sekundarstufe I untersucht. Hierzu werden Daten herangezogen, die an sechs Grundschulen in Baden-Württemberg erhoben wurden. Um einen Eindruck vom Ausmaß ethnischer Bildungsunterschiede zu gewinnen, wird zunächst gefragt, ob die festgestellten Muster in den Übergangsraten verschiedener Migrantengruppen auf Unterschiede in den Schulleistungen zurückgeführt werden können. Es zeigt sich, daß Schulnoten die zentralen Determinanten des Bildungsübergangs sind. Allerdings bleiben ethnische Unterschiede auch nach Kontrolle der Schulleistungen bestehen. Dies betrifft in erster Linie türkische und italienische Kinder mit Blick auf die Entscheidung für oder gegen den Hauptschulbesuch. Weiterhin wird untersucht, ob das durchschnittliche Leistungsniveau und der Migrantenanteil in der Schulklasse einen Einfluß auf den Bildungsübergang haben. Für das durchschnittliche Leistungsniveau in der Schulklasse ergeben sich in den Analysen keine bedeutsamen Effekte. Dagegen zeigt sich, daß mit steigenden Migrantenanteilen in der Schulklasse die Chancen auf den Besuch von Realschule und Gymnasium sinken. Nach Kontrolle der Migrantenkonzentration sind für keine ethnische Gruppe mehr signifikante Herkunftseffekte festzustellen

The effects of face expertise training on the behavioral performance and brain activity of adults with high functioning Autism Spectrum Disorders

The effect of expertise training with faces was studied in adults with ASD who showed initial impairment in face recognition. Participants were randomly assigned to a computerized training program involving either faces or houses. Pre- and post-testing included standardized and experimental measures of behavior and event-related brain potentials (ERPs), as well as interviews after training. After training, all participants met behavioral criteria for expertise with the specific stimuli on which they received training. Scores on standardized measures improved after training for both groups, but only the face training group showed an increased face inversion effect behaviorally and electrophysiological changes to faces in the P100 component. These findings suggest that individuals with ASD can gain expertise in face processing through training