Capital Region of Denmark

This paper concerns the spatial and intensity transformations that are required to adjust for the confounding effects of subject movement during functional MRI (fMRI) activation studies. An approach is presented that models, and removes, movement-related artifacts from fMRI time-series. This approach is predicated on the observation that movement-related effects are extant even after perfect realignment. Movement-related effects can be divided into those that are a function of position of the object in the frame of reference of the scanner and those that are due to movement in previous scans. This second component depends on the history of excitation experienced by spins in a small volume and consequent differences in local saturation. The spin excitation history thus will itself be a function of previous positions, suggesting an autoregression-moving average model for the effects of previous displacements on the current signal. A model is described as well as the adjustments for movement-related components that ensue. The empirical analyses suggest that (in extreme situations) over 90% of fMRI signal can be attributed to movement, and that this artifactual component can be successfully removed.

OBJECTIVE--To investigate whether semen quality has changed during the past 50 years. DESIGN--Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991). SUBJECTS--14,947 men included in a total of 61 papers published between 1938 and 1991. MAIN OUTCOME MEASURES--Mean sperm density and mean seminal volume. RESULTS--Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density. CONCLUSIONS--There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function.

, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population. A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. Clinical practice guidelines are defined as “systematically developed statements to assist practitioner and patient decisions about appropriate heath care for specific clinical circumstances.”1 (All references are available in the Supporting Information.) These guidelines on autoimmune hepatitis provide a data-supported approach to the diagnosis and management of this disease. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines;2 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines;3 and (4) the experience of the authors in the specified topic. These recommendations, intended for use by physicians, suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting the recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation.4 The grading system applied to the recommendations has been adapted from the American College of Cardiology and the American Heart Association Practice Guidelines, and it is given below (Table 1). AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CYP1A2, cytochrome P450 1A2; HCV, hepatitis C virus; IBD, inflammatory bowel disease; IgG, immunoglobulin G; LKM-1, liver/kidney microsome type 1; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibodies. Autoimmune hepatitis (AIH) is a generally unresolving inflammation of the liver of unknown cause. A working model for its pathogenesis postulates that environmental triggers, a failure of immune tolerance mechanisms, and a genetic predisposition collaborate to induce a T cell–mediated immune attack upon liver antigens, leading to a progressive necroinflammatory and fibrotic process in the liver.5,6 Onset is frequently insidious with nonspecific symptoms such as fatigue, jaundice, nausea, abdominal pain, and arthralgias at presentation,7 but the clinical spectrum is wide, ranging from an asymptomatic presentation8,9 to an acute severe disease.10,11 The diagnosis is based on histologic abnormalities, characteristic clinical and laboratory findings, abnormal levels of serum globulins, and the presence of one or more characteristic autoantibodies.12-16 Women are affected more frequently than men (sex ratio, 3.6:1).17-19 and the disease is seen in all ethnic groups20-34 and at all ages.21,35-44 There are no robust epidemiological data on AIH in the United States. In Norway and Sweden, the mean incidence is 1 to 2 per 100,000 persons per year, and its point prevalence is 11 to 17 per 100,000 persons per year.45,46 A similar incidence and prevalence can be assumed for the Caucasian population of North America. Data on the natural progression of untreated disease are derived principally from experiences published prior to the widespread use of immunosuppressive agents for AIH and before the detection of the hepatitis C virus (HCV).47-54 These studies showed that as many as 40% of patients with untreated severe disease died within 6 months of diagnosis,47,49 and that survivors frequently developed cirrhosis, esophageal varices and subsequent hemorrhage.47,49,50,55 An acute onset of illness is common (∼40%),56-63 and an acute severe presentation, characterized by within of clinical is that or in with laboratory findings, and These studies to the of immunosuppressive as the in and an autoimmune pathogenesis of the disease. studies before the of be in studies and one can that of patients with Liver has as an for the and the patient and The for AIH and a system by an in and in (Table The clinical for the diagnosis are to or or AIH in the of The system developed as a by which to the of in clinical (Table and can be applied in by the The is in the and a can be before and (Table A of or or a of or AIH at A of has a of a of and of A of of has a of a of and a of A the of the system in with A system has been to clinical and is based on the presence and level of by serum immunoglobulin or and the of (Table In the system with and in the diagnosis of AIH, but it has to be in The diagnosis of AIH requires the presence of characteristic clinical and laboratory and the of that hepatitis and (Table The clinical an of and the use of to be The laboratory of the levels of serum alanine or aspartate or IgG, and and AIH can be asymptomatic in of patients are men and serum levels at than findings, including the of cirrhosis, are similar asymptomatic patients and as many as of asymptomatic patients the of asymptomatic patients be followed by an to for in disease In the level be a of biliary primary sclerosing than the which can be to in the the the presence or of in with The of AIH be including antinuclear smooth muscle to liver/kidney microsome type 1 and type 1 (Table be to disease and 1 and autoimmune liver that AIH primary biliary and Liver at is to the diagnosis and to the In acute of liver from of hepatitis is the and is is specific for AIH, and the of in the the and be The generally the In all but the is with or is and liver of this to hepatitis in The on the of the disease. to patients with an insidious patients with acute severe failure more and and but and The of the is by a and characterized by about the the and with a inflammatory and patients of AIH and such as PSC, PBC, or autoimmune a histologic such as or the presence of one of In the system can be to assist in diagnosis (Table The of or suggest or such as liver hepatitis or a and diagnosis of AIH by the system to the of serum of and of to or that liver There is no to and and histologic generally the the are a diagnosis can be by the presence of such as or liver ANA, SMA, and the for the diagnosis of AIH (Table In North American of patients with AIH ANA, SMA, or and are more in AIH patients and are by or They are in the United are by but be with this can be by to cytochrome the of are specific to and can the of the the diagnosis of AIH, the of the in the or in with disease clinical and In are of disease and can be to on an of is in in of for and SMA, and for are is in in the diagnosis of AIH, liver is by clinical The for is on of and This the detection of ANA, SMA, and but the presence of of an clinical such as to liver type 1 and to liver microsome type of the presence of the is with to and 1 (Table that be in patients the are and specific for and inflammatory bowel disease are frequently in patients with and can be the (Table with evidence that the of is within the this a more be (Table and as in AIH, to the and to a These are to as or is a (Table has been are in patients with AIH are for ANA, SMA, and but are more in with the are are specific for the diagnosis of autoimmune liver and detection patients with more severe disease and are available for The and in AIH are in an for the use of in the diagnosis of The use of in the diagnosis of in the of acute or hepatitis of cause. The for antinuclear smooth muscle to liver/kidney microsome type 1 and The of the one or more are the diagnosis of autoimmune hepatitis (AIH) or primary biliary be are are including for to liver liver type 1 the of the The of suggest including primary sclerosing or genetic with AIH been in ethnic The primary genetic is with the and of with disease clinical to and been AIH is a to be to subsequent of patients or for genetic is AIH be in patients with and patients the genetic autoimmune by a on that the of the autoimmune is a in and within the that of T has an of and and The liver with are cytochrome P450 in to to cytochrome P450 liver (Table This is the AIH that a of and genetic for the patient and are The diagnosis of AIH be clinical and laboratory or ALT, and serum or SMA, or and are and that can including and been (Table that or or be by the (Table In patients for in AIH is including at and be (Table In patients with AIH and the be by for the in the of AIH 1 and type been based on but been as clinical or A type has been as its is in type 1 AIH and in type 2 1 AIH is characterized by the presence of ANA, or and of AIH of patients are with a incidence and of patients are than and are at with autoimmune are common autoimmune and the of is in of to as that patients with severe AIH are to 2 AIH is characterized by the presence of patients with type 2 AIH are and serum immunoglobulin levels are for the of which be immune are progression to and an acute severe is of autoimmune hepatitis based on the presence of and 1 or and 2 can be to characterize the clinical or to in clinical be to type 2 and can and genetic that of and AIH can that each of These nonspecific can the The prevalence of AIH patients with to be the but this prevalence to in the system of the system in a review of patients with showed that and as and AIH, Clinical is to the of the disease and to the process AIH patients that suggest in about of AIH patients in the of biliary and presence the clinical or as as an The system can a diagnosis of in of AIH are acute and liver of that can of AIH and liver and and such as and can a that AIH with that generally of the an clinical has been with and with of AIH ethnic patients a of at than a of acute disease than patients patients with American patients are with severe liver North a of and disease at and patients are frequently men with progressive and quality of care are that be disease within AIH can an acute severe that can be for a or autoimmune hepatitis as acute liver can be in the inflammatory in of in can a on In disease can a and autoimmune are in with severe acute the be immune the liver Autoimmune and are the common with AIH in North American type and autoimmune are the common in AIH In with AIH, autoimmune sclerosing can be with or In with AIH and IBD, contrast biliary of are in of In with AIH but IBD, biliary are in of are immune the of studies be in patients with AIH and IBD, as as in and to months of In a of patients with and of AIH type 1 with sclerosing on The diagnosis of AIH be in all patients with acute or hepatitis of including patients with acute severe studies be to in has been no to with AIH and all with AIH and studies to that patients with serum levels of at the of the or more than in with a serum level more than a at 6 of or at to in of untreated patients and are with a of These laboratory and of disease at are for and symptoms with such as and are for of of disease (Table The natural of autoimmune hepatitis is in patients no or symptoms and in laboratory and been in and for and (Table with an asymptomatic patients and natural There are no guidelines that this population no is in asymptomatic patients with but patients versus and more than untreated asymptomatic patients with disease a than versus The of be the of the versus the autoimmune hepatitis can and a and to a point can be is in asymptomatic in are to the to a are at for and with cirrhosis, or or and (Table is in patients laboratory or of liver with or benefit from and an of and can and of with or severe be for a benefit before and be in patients with severe below or below or of (Table The for in are similar to in (Table The disease process in to be more severe at than seen in of in diagnosis or immune such as autoimmune sclerosing than of at and the of the disease in are seen in The in and that in diagnosis and the at the of with evidence of inflammatory are to all in which the diagnosis of AIH has been be the diagnosis of autoimmune hepatitis or the for the are in in or the patient be to a before be in patients with serum or levels than at in with a serum level at of or (Table be in patients symptoms and laboratory and but the be and the of to a prior to (Table be in patients with or no disease or cirrhosis, but patients to be followed months (Table be in patients with or to the disease is severe and progressive and for the can be (Table be in patients with a severe below or below or of (Table be in at the of diagnosis of are in severe AIH (Table or a of in with is in the United or which is in (Table be to an level to a from be by every are and by been to The is of the or The of and is with a of than the versus and it is the preferred can the of to but this is to or the of In is preferred is appropriate as the in with severe a of are or patients with and with (Table The is appropriate in patients be for at 6 months or are at for including and with or (Table for and and in be at 6 for and be based on an of of the and be as appropriate to the a and The of agents such as be appropriate for on be for disease by and of the and patients from liver disease patients with AIH be hepatitis virus and hepatitis A virus be as as before is of been in than in and to the of There been no in with autoimmune but of 17 or more the of similar to in (Table the severe disease at presentation, the to with with or is generally in of liver is months of in is the in all reported for and it is in a of to (Table In a to has been in of a is of the of or on and use of or for all is with as has been in but the to for of A as for with autoimmune hepatitis to a more and be evidence of to or in be with with and to within in with or as in or a of with and to within in with The is and in can be of (Table be with in in with or (Table on be for disease at and for disease a and appropriate agents such as and be has been no or to has been The and of the with each be to the patient prior to the of (Table including and in of patients 2 of of the (Table with and are but it is than with are the common for in autoimmune is in of patients of and of or with and of in autoimmune hepatitis and (Table of patients with or which its The of in patients with autoimmune hepatitis is and the the of is or the is An but of is a with and that The has been reported in autoimmune has the in patients with inflammatory bowel The of is and the is failure (Table The of in patients with autoimmune hepatitis is and the of severe is These are by or for and the common of in patients is with and at immune in autoimmune hepatitis has been with an of (Table The incidence of in autoimmune hepatitis is 1 per and the of is a and are to or of The but of with than be the of the as a with at a of than versus They a of that tolerance for with be and with be for prior to the of experiences that and the are by the and the The is and to the of is than in but no than in with has been reported as as with before the is is the of is and the of an of type is in autoimmune hepatitis are similar to in the population the of and are and with autoimmune hepatitis than with in the of from is and of immunosuppressive be has a by the has been with in and levels of the are in the of for disease (Table with is a but been reported in this been of by experiences been and has been a the of in These findings, Autoimmune hepatitis can and this in immunosuppressive or no is a for the and of disease as levels The of has been reported be and be 2 before and the be in with liver disease and of are at for with of are at for of the population has a severe and all patients with a of this experience with but in at the of and the level of with of the The of severe the of in and the to by and for in or the of than of of The of with be with the patient prior to (Table be the of in and be in patients has a by the and it be in patients of AIH be by 2 prior to and by serum or levels at for at months be in patients with before or in is or (Table There is no or of The of can be based on a that is with a or on a that is to the and patients be given the to a that is of (Table of in the serum AST, and levels within 2 of laboratory and liver in than and the of 2 clinical and laboratory by of the laboratory serum or ALT, and and of liver inflammation liver is the and the of (Table The of is laboratory before of the of by to to patients and of patients laboratory prior to the of the in studies of the of be in studies as or of of in patients is the of and and of patients of inflammatory The that can of the laboratory and liver is and of an is it be by the that all patients can this or the of in the of is in are with or and it can the of of can induce and laboratory but Liver prior to of is the by which to of the disease and an of hepatitis is in of patients with serum and levels and of by liver prior to can an of a liver is before of immunosuppressive in of be at liver and immunoglobulin levels been of of requires a a of (Table are on a of to be for The of the disease and is by the of symptoms and and the of the laboratory of liver inflammation and are at and for months of are at months and every 6 months for 1 and failure and with it in at of patients and be within (Table of liver failure or liver can be by the model of liver disease of are to by including liver failure the of and of with or in with (Table at this level are for at 1 the of and are each in the serum level of are of patients clinical and laboratory within 2 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BACKGROUND: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

The concept of insight into psychosis has received scant attention in the psychiatric literature. Drawing on sources such as phenomenology, clinical research and experimental psychology, it is proposed that insight is not an 'all-or-none' phenomenon but is composed of three distinct, overlapping dimensions, namely, the recognition that one has a mental illness, compliance with treatment, and the ability to relabel unusual mental events (delusions and hallucinations) as pathological. A scheme is proposed to standardise the assessment of insights to assist further research.

In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi-squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P &amp;lt; 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

CONTEXT: Increasing prevalence of overweight in the population is a major concern globally; and in the United States, nearly one third of adults were classified as obese at the end of the 20th century. Few data have been presented regarding an association between variations in thyroid function seen in the general population and body weight. OBJECTIVE: The aim of this study was to investigate the association between thyroid function and body mass index (BMI) or obesity in a normal population. DESIGN: A cross-sectional population study (The DanThyr Study) was conducted. PARTICIPANTS: In all, 4649 participants were investigated, and 4082 were eligible for these analyses after exclusion of subjects with previous or present overt thyroid dysfunction. MAIN OUTCOME MEASURES: The study examined the association between category of serum TSH or serum thyroid hormones and BMI or obesity in multivariate models, adjusting for possible confounding. RESULTS: We found a positive association between BMI and category of serum TSH (P < 0.001) and a negative association between BMI and category of serum free T(4) (P < 0.001). No association was found between BMI and serum free T(3) levels. The difference in BMI between the groups with the highest and lowest serum TSH levels was 1.9 kg/m(2), corresponding to a difference in body weight of 5.5 kg among women. Similarly, the category of serum TSH correlated positively with weight gain during 5 yr (P = 0.04), but no statistically significant association was found with weight gain during 6 months (P = 0.17). There was an association between obesity (BMI > 30 kg/m(2)) and serum TSH levels (P = 0.001). CONCLUSIONS: Our results suggest that thyroid function (also within the normal range) could be one of several factors acting in concert to determine body weight in a population. Even slightly elevated serum TSH levels are associated with an increase in the occurrence of obesity.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

The ATLS Subcommittee, American College of Surgeons’ Committee on Trauma, and the International ATLS working group Author Information

CONTEXT: Estimates of lifetime risk of suicide in mental disorders were based on selected samples with incomplete follow-up. OBJECTIVE: To estimate, in a national cohort, the absolute risk of suicide within 36 years after the first psychiatric contact. DESIGN: Prospective study of incident cases followed up for as long as 36 years. Median follow-up was 18 years. SETTING: Individual data drawn from Danish longitudinal registers. PARTICIPANTS: A total of 176,347 persons born from January 1, 1955, through December 31, 1991, were followed up from their first contact with secondary mental health services after 15 years of age until death, emigration, disappearance, or the end of 2006. For each participant, 5 matched control individuals were included. MAIN OUTCOME MEASURES: Absolute risk of suicide in percentage of individuals up to 36 years after the first contact. RESULTS: Among men, the absolute risk of suicide (95% confidence interval [CI]) was highest for bipolar disorder, (7.77%; 6.01%-10.05%), followed by unipolar affective disorder (6.67%; 5.72%-7.78%) and schizophrenia (6.55%; 5.85%-7.34%). Among women, the highest risk was found among women with schizophrenia (4.91%; 95% CI, 4.03%-5.98%), followed by bipolar disorder (4.78%; 3.48%-6.56%). In the nonpsychiatric population, the risk was 0.72% (95% CI, 0.61%-0.86%) for men and 0.26% (0.20%-0.35%) for women. Comorbid substance abuse and comorbid unipolar affective disorder significantly increased the risk. The co-occurrence of deliberate self-harm increased the risk approximately 2-fold. Men with bipolar disorder and deliberate self-harm had the highest risk (17.08%; 95% CI, 11.19%-26.07%). CONCLUSIONS: This is the first analysis of the absolute risk of suicide in a total national cohort of individuals followed up from the first psychiatric contact, and it represents, to our knowledge, the hitherto largest sample with the longest and most complete follow-up. Our estimates are lower than those most often cited, but they are still substantial and indicate the continuous need for prevention of suicide among people with mental disorders.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Udgivelsesdato: September 2006

Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.