Left vocal cord paralysis, lung function and exercise capacity in young adults born extremely preterm with a history of neonatal patent ductus arteriosus surgery—A national cohort study

Background: Left vocal cord paralysis (LVCP) is a known complication of patent ductus arteriosus (PDA) surgery in extremely preterm (EP) born neonates; however, consequences of LVCP beyond the first year of life are insufficiently described. Both voice problems and breathing difficulties during physical activity could be expected with an impaired laryngeal inlet. More knowledge may improve the follow-up of EP-born subjects who underwent PDA surgery and prevent confusion between LVCP and other diagnoses. Objectives: Examine the prevalence of LVCP in a nationwide cohort of adults born EP with a history of PDA surgery, and compare symptoms, lung function, and exercise capacity between groups with and without LVCP, and vs. controls born EP and at term. Methods: Adults born EP (<28 weeks' gestation or birth weight <1,000 g) in Norway during 1999–2000 who underwent neonatal PDA surgery and controls born EP and at term were invited to complete questionnaires mapping voice-and respiratory symptoms, and to perform spirometry and maximal treadmill exercise testing. In the PDA-surgery group, exercise tests were performed with a laryngoscope positioned to evaluate laryngeal function. Results: Thirty out of 48 (63%) eligible PDA-surgery subjects were examined at mean (standard deviation) age 19.4 (0.8) years, sixteen (53%) had LVCP. LVCP was associated with self-reported voice symptoms and laryngeal obstruction during exercise, not with lung function or peak oxygen consumption (VO2peak). In the PDA-surgery group, forced expiratory volume in 1 second z-score (z-FEV1) was reduced compared to EP-born controls (n = 30) and term-born controls (n = 36); mean (95% confidence interval) z-FEV1 was −1.8 (−2.3, −1.2), −0.7 (−1.1, −0.3) and −0.3 (−0.5, −0.0), respectively. For VO2peak, corresponding figures were 37.5 (34.9, 40.2), 38.1 (35.1, 41.1), and 43.6 (41.0, 46.5) ml/kg/min, respectively. Conclusions: LVCP was common in EP-born young adults who had undergone neonatal PDA surgery. Within the PDA-surgery group, LVCP was associated with self-reported voice symptoms and laryngeal obstruction during exercise, however we did not find an association with lung function or exercise capacity. Overall, the PDA-surgery group had reduced lung function compared to EP-born and term-born controls, whereas exercise capacity was similarly reduced for both the PDA-surgery and EP-born control groups when compared to term-born controls.publishedVersio

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.publishedVersio

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Source localization of pre-REM negativity

Raske øyebevegelser (REM) under søvn er en beskrivelse av REM-søvnstadiet, det er velkjent at REM-søvn spiller en viktig rolle i søvn. Derfor å finne nøyaktig hjerne aktivering før REM kan bidra til å belyse hjerneområdene som er involvert for å produsere denne viktige hendelsen. Denne studien tar sikte på å finne hjerne aktivering i før REM aktiviteten. For å gjøre det er det nødvendig å finne start tiden for øyebevegelsene. En algoritme for å oppdage øyets bevegelsesutbrudd ble først utviklet og evaluert i søvn- og våkne data, deretter ble hjerne aktivering av før REM aktiviteten funnet. Etterpå ble en T-test implementert for å finne betydelig aktivering under før REM aktiviteten. Datasettet som ble brukt i studien ble registrert av Human Sleep Lab fra International Institute of Integrative Sleep Medicine og ble analysert ved hjelp av MNE åpen kildekode-python-pakke. Algoritmen er en forbedret metode basert på en tidligere laget øyebevegelsesalgoritme av Takahashi i 1997. Resultatene viste at algoritmen hadde en tilbakekalling på 0,97, en presisjon på 0,69 og en F1-score på 0,80. I tillegg ble den nye algoritmen testet for å kategorisere REM-søvnstadiet, hvor denne tilnærmingen ble funnet å identifisere REM-søvn i hele nattesøvnen. For å lokalisere før REM aktiviteten ble to metoder for hjerne aktivering implementert, og områdene med betydelig aktivering i før REM aktiviteten ble identifisert. Resultatene antyder at før REM aktiviteten har den viktigste aktiviseringen i striatum og de orbitofrontale regionene. Disse resultatene viser at algoritmen kan finne øyebevegelser i REM søvn og finne REM søvn stadiet. Imidlertid er forbedring av algoritmen nødvendig før algoritmens resultat kan stole på uten visuell inspeksjon av resultatene. Hjerne aktivering i striatum og orbitofrontal regioner indikerer hjernens bruk av belønning eller straff, og en beslutningsprosess i hjernen er aktiv. For videre forskning anbefales det å se på algoritmekriteriene og øke algoritmens presisjon. Før REM aktiveringen i REM søvn bør også undersøkes nærmere for å finne flere forbindelser til hjernesykdommer

Fylkesvise forskjeller i forskrivning av klozapin

BAKGRUNN Nasjonale retningslinjer anbefaler å tilby klozapin til pasienter med schizofreni etter to mislykkede forsøk med andre antipsykotiske legemidler. En av hovedmålsettingene med innføringen av pakkeforløp i psykisk helsevern er å gi et likeverdig tilbud til pasienter uavhengig av hvor i landet de bor. Vi ønsket å undersøke forskrivningen av klozapin i ulike fylker i Norge. MATERIALE OG METODE Vi hentet aggregerte data fra Reseptregisteret, Norsk pasientregister og Statistisk sentralbyrå på forskrivning av klozapin, antall pasienter i kontakt med spesialisthelsetjenesten under diagnosen schizofreni og befolkningstall for året 2016. RESULTATER I 2016 var det på landsbasis 50 (95 % KI 48–52) brukere av klozapin per 100 000 innbyggere. Antallet var høyest i Troms (76 (95 % KI 63–89) per 100 000 innbyggere) og lavest i Akershus (38 (95 % KI 33–43) per 100 000 innbyggere). Vi fant ingen signifikant korrelasjon mellom forskrivningsraten av klozapin og andelen av befolkningen i fylket under behandling for schizofreni i spesialisthelsetjenesten. FORTOLKNING Forskrivningen av klozapin varierer mellom norske fylker og er ikke korrelert med andelen av befolkningen under behandling for schizofreni i spesialisthelsetjenesten. En mulig forklaring på de geografiske forskjellene er ulik grad av implementering av nasjonale retningslinjer

Clinical characteristics of patients with bipolar disorder and premorbid traumatic brain injury: a cross-sectional study

Background About one in ten diagnosed with bipolar disorder (BD) has experienced a premorbid traumatic brain injury (TBI), while not fulfilling the criteria of bipolar and related disorder due to another medical condition (BD due to TBI). We investigated whether these patients have similar clinical characteristics as previously described in BD due to TBI (i.e. more aggression and irritability and an increased hypomania/mania:depression ratio) and other distinct clinical characteristics. Methods Five hundred five patients diagnosed with BD type I, type II, or not otherwise specified, or cyclothymia were interviewed about family, medical, and psychiatric history, and assessed with the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms Clinician Rated 30 (IDS-C30). Principal component analyses of YMRS and IDS-C30 were conducted. Bivariate analyses and logistic regression analyses were used to compare clinical characteristics between patients with (n = 37) and without (n = 468) premorbid TBI. Results Premorbid TBI was associated with a higher YMRS disruptive component score (OR 1.7, 95% CI 1.1–2.4, p = 0.0077) and more comorbid migraine (OR 4.6, 95% CI 1.9–11, p = 0.00090) independently of several possible confounders. Items on disruptive/aggressive behaviour and irritability had the highest loadings on the YMRS disruptive component. Premorbid TBI was not associated with an increased hypomania/mania:depression ratio. Conclusions Disruptive symptoms and comorbid migraine characterize BD with premorbid TBI. Further studies should examine whether the partial phenomenological overlap with BD due to TBI could be explained by a continuum of pathophysiological effects of TBI across the diagnostic dichotomy