Background Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia ≥1.5 × 109 /L, absence of a secondary cause, and evidence of ...eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti–IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. Objective The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. Methods Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. Results Eighteen of 161 patients (11%) tested were Fip1-like 1–platelet-derived growth factor receptor α ( FIP1L1-PDGFRA ) mutation—positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-α (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). Conclusion This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.
Background Anti–IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized. Objective We sought to characterize the ...hematologic and immunologic effects of anti-IL-5 in human subjects. Methods The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G. Results Twenty-three patients responded to anti–IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3+ cells by 20- and 13-fold, respectively ( P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor α expression, and increased percentage of CD4+ and CD8+ cells producing intracellular IL-5 ( P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo. Conclusions Anti–IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3+ cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor α and lymphocyte IL-5 production after anti–IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide ...investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.
The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.
Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).
Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
To identify prognostic factors for survival in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization with doxorubicin-eluting beads (DEBs).
In a retrospective, ...single-center analysis, tumor- and patient-related factors were recorded for univariate and multivariate analyses via Kaplan-Meier and Cox regression. Infiltrative HCC phenotype and portal vein invasion (PVI) were correlated, and patients with either or both were classified as having radiographically advanced (RAdv) HCC. The primary endpoint was overall survival, which was calculated from the time of first DEB chemoembolization procedure.
A total of 168 patients underwent 248 procedures, of which 215 (86.7%) were outpatient procedures. Mean length of stay was 0.33 days, and 25 patients (10.1%) were readmitted within 30 days. A total of 33 patients underwent liver transplantation and were excluded from survival analyses. A total of 130 had cirrhosis; 62, 50, and 18 had Child class A, B, and C disease, respectively. Forty-one patients had infiltrative HCC phenotype, 28 of whom also had PVI. Multivariate analysis of survival in all patients showed α-fetoprotein (AFP), performance status (PS), RAdv HCC, Child classification, albumin level, and ascites to predict survival. In patients without RAdv HCC, AFP, PS, Child classification, albumin level, and International Normalized Ratio were independent predictors. Increased bilirubin level was not an independent risk factor for death.
Independent prognostic factors in patients with HCC undergoing DEB chemoembolization have been identified. Increased bilirubin level was not an independent risk factor. These data can be used in HCC patient selection and counseling for DEB chemoembolization.
Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used ...across cohorts may represent a limitation to pooling data in international consortia. Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality.
Key Points
Question: To inform future suicide research in multisite international consortia, it is important to examine how different suicide measures relate to each other and whether they can be used interchangeably. Findings: Findings suggest that detailed instruments (such as the Columbia Suicide Severity Rating Scale and Beck Scale for Suicidal Ideation) provide valuable information on suicidal thoughts and behavior and share a core factor with items on suicidal ideation from depression severity rating scale (such as the Hamilton Depression Rating Scale or the Beck Depression Inventory). Importance: Results from international collaborations can mitigate biases by harmonizing distinct suicide risk assessment instruments and items related to suicide. Next Steps: Pooling data within international suicide research consortia may reveal novel clinical, biological, and cognitive correlates of suicidal thoughts and/or behavior.
Background Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive–compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, ...structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. Methods We performed a mega-analysis pooling structural MRI scans from the Obsessive–compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Results Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. Limitations This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Conclusion Our results provide evidence for structural network–level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.
Background and aims
The World Health Organization's (WHO's) proposed International Classification of Diseases, 11th edition (ICD‐11) includes several major revisions to substance use disorder (SUD) ...diagnoses. It is essential to ensure the consistency of within‐subject diagnostic findings throughout countries, languages and cultures. To date, agreement analyses between different SUD diagnostic systems have largely been based in high‐income countries and clinical samples rather than general population samples. We aimed to evaluate the prevalence of, and concordance between diagnoses using the ICD‐11, The WHO's ICD 10th edition (ICD‐10) and the Diagnostic and Statistical Manual of Mental Disorders, 4th and 5th editions (DSM‐IV, DSM‐5); the prevalence of disaggregated ICD‐10 and ICD‐11 symptoms; and variation in clinical features across diagnostic groups.
Design
Cross‐sectional household surveys.
Setting
Representative surveys of the general population in 10 countries (Argentina, Australia, Brazil, Colombia, Iraq, Northern Ireland, Poland, Portugal, Romania and Spain) of the World Mental Health Survey Initiative.
Participants
Questions about SUDs were asked of 12 182 regular alcohol users and 1788 cannabis users.
Measurements
Each survey used the World Mental Health Survey Initiative version of the WHO Composite International Diagnostic Interview version 3.0 (WMH‐CIDI).
Findings
Among regular alcohol users, prevalence (95% confidence interval) of life‐time ICD‐11 alcohol harmful use and dependence were 21.6% (20.5–22.6%) and 7.0% (6.4–7.7%), respectively. Among cannabis users, 9.3% (7.4–11.1%) met criteria for ICD‐11 harmful use and 3.2% (2.3–4.0%) for dependence. For both substances, all comparisons of ICD‐11 with ICD‐10 and DSM‐IV showed excellent concordance (all κ ≥ 0.9). Concordance between ICD‐11 and DSM‐5 ranged from good (for SUD and comparisons of dependence and severe SUD) to poor (for comparisons of harmful use and mild SUD). Very low endorsement rates were observed for new ICD‐11 feature for harmful use (‘harm to others’). Minimal variation in clinical features was observed across diagnostic systems.
Conclusions
The World Health Organization's proposed International Classification of Diseases, 11th edition (ICD‐11) classifications for substance use disorder diagnoses are highly consistent with the ICD 10th edition and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV). Concordance between ICD‐11 and the DSM 5th edition (DSM‐5) varies, due largely to low levels of agreement for the ICD harmful use and DSM‐5 mild use disorder. Diagnostic validity of self‐reported ‘harm to others’ is questionable.
PDF
