One-year outcome and adherence to pharmacological guidelines in first-episode schizophrenia: Results from a consecutive cohort study

Background Remission in schizophrenia is difficult to achieve. Antipsychotic drugs are critical in the treatment of schizophrenia. International guidelines for the pharmacological treatment of schizophrenia recommend a 3-step algorithm with clozapine being the third-line antipsychotic agent. This study investigated the 1-year outcome and the application of the guidelines for the pharmacological treatment of nonremitted first-episode schizophrenia (FES) patients during the first year of follow-up. Methods A sample of 78 FES patients from the Norwegian TIPS (Early Treatment and Intervention in Psychosis) 2 study was assessed at the end of the first year of follow-up. The symptom remission criteria were those defined by the Remission in Schizophrenia Working Group. The adherence to the pharmacological guidelines was assessed by reading the medical files and by a digital search of the words “clozapine,” “klozapin,” and “Leponex” in the hospital electronic data system. Results The majority (n = 53, 67.9%) of the patients included were nonremitted at the 1-year follow-up. The majority of the nonremitted patients received either none (7.5%), one (56.6%), or 2 types (15.1%) of antipsychotic drugs during the first year of follow-up. Only 2 (3.8%) received treatment with clozapine, and 3 (5.7%) in total were offered it. Conclusions For our FES sample, there was a low 1-year remission rate and a poor adherence to the pharmacological guidelines. Higher adherence to treatment guidelines with a more intensified antipsychotic treatment, which in some cases will include clozapine, will enhance the quality of treatment and may enhance the rates of remission for schizophrenia.publishedVersio

Cardiovascular risk assessment in patients with antiphospholipid syndrome: a cross-sectional performance analysis of nine clinical risk prediction tools

Objectives This study aimed to assess the performance of cardiovascular risk (CVR) prediction models reported by European Alliance of Associations for Rheumatology and European Society of Cardiology recommendations to identify high-atherosclerotic CVR (ASCVR) patients with antiphospholipid syndrome (APS).Methods Six models predicting the risk of a first cardiovascular disease event (first-CVD) (Systematic Coronary Risk Evaluation (SCORE); modified-SCORE; Framingham risk score; Pooled Cohorts Risk Equation; Prospective Cardiovascular Münster calculator; Globorisk), three risk prediction models for patients with a history of prior arterial events (recurrent-CVD) (adjusted Global APS Score (aGAPSS); aGAPSSCVD; Secondary Manifestations of Arterial Disease (SMART)) and carotid/femoral artery vascular ultrasound (VUS) were used to assess ASCVR in 121 APS patients (mean age: 45.8±11.8 years; women: 68.6%). We cross-sectionally examined the calibration, discrimination and classification accuracy of all prediction models to identify high ASCVR due to VUS-detected atherosclerotic plaques, and risk reclassification of patients classified as non high-risk according to first-CVD/recurrent-CVD tools to actual high risk based on VUS.Results Spiegelhalter’s z-test p values 0.47–0.57, area under the receiver-operating characteristics curve (AUROC) 0.56–0.75 and Matthews correlation coefficient (MCC) 0.01–0.35 indicated moderate calibration, poor-to-acceptable discrimination and negligible-to-moderate classification accuracy, respectively, for all risk models. Among recurrent-CVD tools, SMART and aGAPSSCVD (for non-triple antiphospholipid antibody-positive patients) performed better (z/AUROC/MCC: 0.47/0.64/0.29 and 0.52/0.69/0.29, respectively) than aGAPSS. VUS reclassified 34.2%–47.9% and 40.5%–52.6% of patients classified as non-high-ASCVR by first-CVD and recurrent-CVD prediction models, respectively. In patients aged 40–54 years, >40% VUS-guided reclassification was observed for first-CVD risk tools and >50% for recurrent-CVD prediction models.Conclusion Clinical CVR prediction tools underestimate actual high ASCVR in APS. VUS may help to improve CVR assessment and optimal risk factor management

Application of EULAR and European Society of Cardiology recommendations with regard to blood pressure and lipid management in antiphospholipid syndrome

Background To examine blood pressure (BP) and lipid treatment eligibility in antiphospholipid syndrome (APS) according to European Alliance of Associations for Rheumatology (EULAR) and European Society of Cardiology (ESC) recommendations.Methods Systematic Coronary Risk Evaluation (SCORE), modified-SCORE, diabetes mellitus (DM)-equivalent risk classifiers (DIME) and disease-related classifiers –type of thrombotic events (APSevents), antiphospholipid-antibody profile (aPLprofile) and adjusted Global APS Score for cardiovascular disease– were used to calculate predicted low-moderate, high and very-high cardiovascular risk (CVR) in 111 patients with APS without prior atherosclerotic cardiovascular events or DM. Actual CVR (AR) was determined according to ESC guidelines, including carotid/femoral plaque presence. In low-moderate SCORE-predicted risk patients, classification ability and agreement for BP or lipid treatment was tested with Matthews’ correlation coefficient (MCC) and Cohen’s kappa, respectively, using the AR classes as reference qualifiers.Results SCORE underestimated high/very-high-AR in >50% of cases. SCORE-guided BP/lipid treatment eligibility was 4.2%/12.6% for high, 10.5%/16.8% for very-high AR patients, while 5.3% of low-moderate AR cases were eligible for lipid-lowering therapy. For BP treatment, MCC was higher using DIME for low-moderate and very-high-risk (0.33 and 0.32, respectively), and using modified-SCORE+APSevents (MCC=0.25) for high-risk patients. Eligibility agreement was better with DIME+APSevents or aPLprofile (kappa=0.51) for high-risk, and DIME (kappa=0.31) for very-high-risk patients. For lipid treatment, both classification ability and eligibility agreement were stronger with SCORE (or modified-SCORE)+APSevents in low-moderate (MCC/kappa=0.43/0.41) and very-high risk (MCC/kappa=0.30/0.30), and with DIME+aPLprofile (MCC/kappa=0.50/0.50) in high-risk patients, respectively.Conclusion Multimodal risk assessment including disease-related and cardiometabolic features used for high-risk diseases such as DM can improve CVR management in APS

Well-Typed Programs Can Go Wrong: A Study of Typing-Related Bugs in JVM Compilers

Despite the substantial progress in compiler testing, research endeavors have mainly focused on detecting compiler crashes and subtle miscompilations caused by bugs in the implementation of compiler optimizations. Surprisingly, this growing body of work neglects other compiler components, most notably the front-end. In statically-typed programming languages with rich and expressive type systems and modern features, such as type inference or a mix of object-oriented with functional programming features, the process of static typing in compiler front-ends is complicated by a high-density of bugs. Such bugs can lead to the acceptance of incorrect programs (breaking code portability or the type system's soundness), the rejection of correct (e.g. well-typed) programs, and the reporting of misleading errors and warnings. We conduct, what is to the best of our knowledge, the first empirical study for understanding and characterizing typing-related compiler bugs. To do so, we manually study 320 typing-related bugs (along with their fixes and test cases) that are randomly sampled from four mainstream JVM languages, namely Java, Scala, Kotlin, and Groovy. We evaluate each bug in terms of several aspects, including their symptom, root cause, bug fix's size, and the characteristics of the bug-revealing test cases. Some representative observations indicate that: (1) more than half of the typing-related bugs manifest as unexpected compile-time errors: the buggy compiler wrongly rejects semantically correct programs, (2) the majority of typing-related bugs lie in the implementations of the underlying type systems and in other core components related to operations on types, (3) parametric polymorphism is the most pervasive feature in the corresponding test cases, (4) one third of typing-related bugs are triggered by non-compilable programs. We believe that our study opens up a new research direction by driving future researchers to build appropriate methods and techniques for a more holistic testing of compilers

Well-typed programs can go wrong: A study of typing-related bugs in JVM compilers

Despite the substantial progress in compiler testing, research endeavors have mainly focused on detecting compiler crashes and subtle miscompilations caused by bugs in the implementation of compiler optimizations. Surprisingly, this growing body of work neglects other compiler components, most notably the front-end. In statically-typed programming languages with rich and expressive type systems and modern features, such as type inference or a mix of object-oriented with functional programming features, the process of static typing in compiler front-ends is complicated by a high-density of bugs. Such bugs can lead to the acceptance of incorrect programs (breaking code portability or the type system's soundness), the rejection of correct (e.g. well-typed) programs, and the reporting of misleading errors and warnings. We conduct, what is to the best of our knowledge, the first empirical study for understanding and characterizing typing-related compiler bugs. To do so, we manually study 320 typing-related bugs (along with their fixes and test cases) that are randomly sampled from four mainstream JVM languages, namely Java, Scala, Kotlin, and Groovy. We evaluate each bug in terms of several aspects, including their symptom, root cause, bug fix's size, and the characteristics of the bug-revealing test cases. Some representative observations indicate that: (1) more than half of the typing-related bugs manifest as unexpected compile-time errors: the buggy compiler wrongly rejects semantically correct programs, (2) the majority of typing-related bugs lie in the implementations of the underlying type systems and in other core components related to operations on types, (3) parametric polymorphism is the most pervasive feature in the corresponding test cases, (4) one third of typing-related bugs are triggered by non-compilable programs. We believe that our study opens up a new research direction by driving future researchers to build appropriate methods and techniques for a more holistic testing of compilers. Software Engineerin

One-year outcome and adherence to pharmacological guidelines in first-episode schizophrenia: Results from a consecutive cohort study

Background Remission in schizophrenia is difficult to achieve. Antipsychotic drugs are critical in the treatment of schizophrenia. International guidelines for the pharmacological treatment of schizophrenia recommend a 3-step algorithm with clozapine being the third-line antipsychotic agent. This study investigated the 1-year outcome and the application of the guidelines for the pharmacological treatment of nonremitted first-episode schizophrenia (FES) patients during the first year of follow-up. Methods A sample of 78 FES patients from the Norwegian TIPS (Early Treatment and Intervention in Psychosis) 2 study was assessed at the end of the first year of follow-up. The symptom remission criteria were those defined by the Remission in Schizophrenia Working Group. The adherence to the pharmacological guidelines was assessed by reading the medical files and by a digital search of the words “clozapine,” “klozapin,” and “Leponex” in the hospital electronic data system. Results The majority (n = 53, 67.9%) of the patients included were nonremitted at the 1-year follow-up. The majority of the nonremitted patients received either none (7.5%), one (56.6%), or 2 types (15.1%) of antipsychotic drugs during the first year of follow-up. Only 2 (3.8%) received treatment with clozapine, and 3 (5.7%) in total were offered it. Conclusions For our FES sample, there was a low 1-year remission rate and a poor adherence to the pharmacological guidelines. Higher adherence to treatment guidelines with a more intensified antipsychotic treatment, which in some cases will include clozapine, will enhance the quality of treatment and may enhance the rates of remission for schizophrenia

Well-typed programs can go wrong: a study of typing-related bugs in JVM compilers

Summarization: Despite the substantial progress in compiler testing, research endeavors have mainly focused on detecting compiler crashes and subtle miscompilations caused by bugs in the implementation of compiler optimizations. Surprisingly, this growing body of work neglects other compiler components, most notably the front-end. In statically-typed programming languages with rich and expressive type systems and modern features, such as type inference or a mix of object-oriented with functional programming features, the process of static typing in compiler front-ends is complicated by a high-density of bugs. Such bugs can lead to the acceptance of incorrect programs (breaking code portability or the type system's soundness), the rejection of correct (e.g. well-typed) programs, and the reporting of misleading errors and warnings. We conduct, what is to the best of our knowledge, the first empirical study for understanding and characterizing typing-related compiler bugs. To do so, we manually study 320 typing-related bugs (along with their fixes and test cases) that are randomly sampled from four mainstream JVM languages, namely Java, Scala, Kotlin, and Groovy. We evaluate each bug in terms of several aspects, including their symptom, root cause, bug fix's size, and the characteristics of the bug-revealing test cases. Some representative observations indicate that: (1) more than half of the typing-related bugs manifest as unexpected compile-time errors: the buggy compiler wrongly rejects semantically correct programs, (2) the majority of typing-related bugs lie in the implementations of the underlying type systems and in other core components related to operations on types, (3) parametric polymorphism is the most pervasive feature in the corresponding test cases, (4) one third of typing-related bugs are triggered by non-compilable programs. We believe that our study opens up a new research direction by driving future researchers to build appropriate methods and techniques for a more holistic testing of compilers.Presented on: Proceedings of the ACM on Programming Language

Prevalence of comorbidities in systemic sclerosis versus rheumatoid arthritis: a comparative, multicenter, matched-cohort study

Abstract Background Comorbidities are common in chronic systemic connective tissue diseases and are associated with adverse outcomes, increased morbidity and mortality. Although the prevalence of comorbidities has been well-studied in isolated diseases, comparative studies between different autoimmune diseases are limited. In this study, we compared the prevalence of common comorbidities between patients with systemic sclerosis (SSc) and patients with rheumatoid arthritis (RA). Methods Between 2016 and 2017, 408 consecutive patients with SSc, aged 59 ± 13 years (87% women), were matched 1:1 for age and gender with 408 patients with RA; mean disease duration was 10 ± 8 and 9 ± 8 years, respectively. Rates of cardiovascular risk factors, coronary artery disease, stroke, chronic obstructive pulmonary disease (COPD), osteoporosis, neoplasms and depression were compared between the two cohorts. Results The prevalence of dyslipidemia (18.4% vs 30.1%, p = 0.001) and diabetes mellitus (5.6% vs 11.8%, p = 0.007) and body mass index (p = 0.001) were lower in SSc compared to RA, while there was no difference in arterial hypertension or smoking. While there was a trend for lower prevalence of ischemic stroke in SSc than in RA (1.1% vs 3.2%, p = 0.085), coronary artery disease was comparable (2.7% vs 3.7%). No differences were found between patients with SSc and patients with RA in the prevalence of COPD (5.2% vs 3.7%), osteoporosis (24% vs 22%) or neoplasms overall (1.1% vs 1.7%); however lung cancer was the most prevalent cancer in SSc (7/17, 41%), whereas hematologic malignancies (7/19, 36%) and breast cancer (7/19, 36%) predominated in RA. Depression was more prevalent in SSc (22% vs 12%, p = 0.001), especially in diffuse SSc. Conclusions Despite the prevalence of dyslipidemia and diabetes mellitus in SSc being almost half that in RA, the cardiovascular comorbidity burden appears to be similar in both. The overall prevalence of neoplasms is no higher in SSc than in RA, but SSc has a more negative impact on quality of life, as clearly, more SSc patients develop depression compared to patients with RA