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Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model’s original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell’s adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model’s original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p

Background: The Leicester Cough Questionnaire (LCQ) is a validated tool for assessing cough that has three domains (physical, psychological, and social), with eight, seven, and four items, respectively. However, the assigned domain may not accurately reflect the characteristics of an item. This study aimed to reclassify the items in the Korean version of the LCQ (K-LCQ) to improve the coherence in each domain., Methods: Data of patients with chronic cough from 16 centers who completed the K-LCQ were retrospectively analyzed. Spearman's rank correlation analysis was used to assess the correlations between items and their domains. Principal component analysis was performed to recategorize the K-LCQ items., Results: The correlation analysis of the data from 255 patients demonstrated that certain items such as tiredness, embarrassment, and interference with daily work or overall life enjoyment showed strong or very strong correlations with all three domains. Cough bout frequency showed the weakest correlation with the physical domain, despite being included in that domain, and had stronger correlations with the psychological and social domain. The principal component analysis led to the reclassification of six items: one from the physical to psychological, two from the social to psychological, and three from the psychological to social domain. The within-domain correlation coherence was higher in the new classification than in the original. Validation using an independent cohort of 203 patients yielded similar results., Conclusions: The new classification of the K-LCQ items showed improved within-domain correlation coherence., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Genetic testing in the inherited arrhythmia clinic informs risk stratification, clinical management, and family screening. Periodic review of variant classification is recommended as supporting evidence accrues over time. However, there is limited reporting of real-world data on the frequency and impact of variant reclassification., Objective: The purpose of this study was to determine the burden of variant reclassification in our inherited arrhythmia clinic and the impact on clinical management., Methods: Genetic testing reports for patients referred to our clinic from 2004-2020 were reviewed. Reported variants were reinvestigated using ClinVar, VarSome, and a literature review. Classification was updated using the American College of Medical Genetics and Genomics (ACMG) criteria and tested for association with arrhythmic events and modification of medical management., Results: We identified 517 patients (median age 37 years) who underwent gene panel testing. A variant of uncertain significance (VUS) was reported for 94 patients (18.2%) and more commonly identified when using large gene panels (P <.001). A total of 28 of 87 unique VUSs (32.2%) were reclassified to pathogenic/likely pathogenic (n = 11) or benign/likely benign (n = 17). Of 138 originally reported pathogenic variants, 7 (5.1%) lacked support using ACMG criteria. Variant reclassification was not associated with arrhythmic events; however, it did impact genotype-specific counseling and future therapeutic options., Conclusion: In our large real-world patient cohort, we identify a clinically important proportion of both pathogenic variants and VUSs with evidence for reclassification. These findings highlight the need for informed pretest counseling, a regular structured review of variants reported in genetic testing, and the potential benefits to patients for supporting genotype-guided therapy., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

This dataset represents bridging matrices between two different data classification systems: consumption by purpose (COICOP) and products by activity (CPA). While the former classification is used in household budget and expenditure surveys, the latter represents the industry sector dimension that is typically adopted in national accounts and input–output tables. We collect input data from Eurostat on total household consumption for 35 COICOP and 63 CPA categories for the year 2015. Based on these data, we construct bridging or concordance tables for 30 European countries using recently developed matrix balancing techniques. The resulting tables enable data conversion between consumption- and production-based statistics, facilitating research that integrates macroeconomics, multi-sectoral international trade and heterogeneous agents in household-level expenditure micro-data. Although they are a necessary input in several types of research, they are often constructed on an ad hoc and region-specific basis and not shared publicly. As such, making this dataset available will be useful for computable general equilibrium and input–output models and for carbon footprint and life cycle analyses that incorporate rich consumption micro-data, for instance to shed light on distributional aspects of climate and energy policies. Furthermore, by eliminating a barrier raised by differences in statistical classifications, this dataset may foster collaboration between different research teams and may facilitate soft-linking between complementary analytical tools used for policy support.

Aims: To assess rates of reclassification of severity and associated 5-year survival in patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) after application of a CT-derived correction factor (CF) to refine the measurement of aortic valve area (AVA) and stroke volume index (SVi) using Doppler echocardiography., Methods and Results: We enrolled 1450 patients with severe AS and preserved LVEF from a French registry. Multiplication of echocardiographic LV outflow tract diameter by a CT-derived CF of 1.13 to calculate the AVA and SVi using the continuity equation resulted in reclassification of 39% of patients from severe to moderate AS (AVA > 1 cm 2 ) and 77% from low flow (LF, SVi < 35 ml/m 2 ) to normal flow (NF, SVi ≥ 35 ml/m 2 ). After application of the CF, 5-year survival with conservative management was 50 ± 4% for severe AS compared to 62 ± 4% for moderate AS (p < 0.001). A strategy of medical management followed by intervention for severe AS was associated with higher risk of mortality over 5-year follow-up after adjustment for covariates and application of the CF (HR 1.35 [1.10-1.55], p = 0.015). Five-year survival was also poorer in patients remaining in the LF group after application of the CF, even after valve intervention (72%, 66% and 47% for NF to NF, LF to NF and LF to LF, respectively). After adjustment for covariates (including intervention), risk of mortality was higher in LF to LF patients compared to NF to NF (HR 1.78 [1.25-2.56]), but similar for NF to NF and LF to NF (HR 1.20 [0.90-1.60])., Conclusion: Refined accuracy of echocardiographic LV outflow tract diameter measurement using a CF of 1.13 before derivation of AVA and SVi in patients with severe AS and preserved LVEF allows improved grading of severity, and prediction of prognosis. We recommend implementation of the CF during routine echocardiography when using the continuity equation for Doppler haemodynamic measurements., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Genus Leuconostoc consists of a diverse range of lactic acid bacteria (LAB) from dairy, food and environmental ecology. Even though the species of Leuconostoc are commercially significant, their taxonomy is largely based on old, low-resolution classical methods. Several taxonomic reclassifications in the past were inadequate for microbiologist and food industry professionals to demarcate any new strain of genus Leuconostoc. The current taxonomy of the genus is largely based on classical approaches, which are in utmost need of reinvestigation by whole genome-based approaches. In the present study, the taxono-phylogenomic analysis depicted sixteen species, including three novel genomospecies and several reshufflings across the species, namely, L. mesenteroides, L. pseudomesenteroides, L. gelidum and L. lactis. Genus-wide T3PKS, CAZymes, and vector plasmids supports its biotechnological potential. However, detection of the antibiotic resistance genes in such an important LAB genus raises concern over their utility in industry. Present, large-scale in-depth genome-based study can shed light on the genome dynamics of the member species, help to obtain a more robust taxonomy and elucidate its biotechnology importance., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely., Methods: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification., Results: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score., Conclusion: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Detection of mismatched human leukocyte antigens by adaptive immune cells is considered as the main cause of transplant rejection, leading to either T-cell mediated rejection or antibody-mediated rejection. This canonical view guided the successful development of immunosuppressive therapies and shaped the diagnostic Banff classification for kidney transplant rejection that is used in clinics worldwide. However, several observations have recently emerged that question this dichotomization between T-cell mediated rejection and antibody-mediated rejection, related to heterogeneity in the serology, histology, and prognosis of the rejection phenotypes. In parallel, novel insights were obtained concerning the dynamics of donor-specific anti-human leukocyte antigen antibodies, the immunogenicity of donor-recipient non-human leukocyte antigen mismatches, and the autoreactivity against self-antigens. Moreover, the potential of innate allorecognition was uncovered, as exemplified by natural killer cell-mediated microvascular inflammation through missing self, and by the emerging evidence on monocyte-driven allorecognition. In this review, we highlight the gaps in the current classification of rejection, provide an overview of the expanding insights into the mechanisms of allorecognition, and critically appraise how these could improve our understanding and clinical approach to kidney transplant rejection. We argue that consideration of the complex interplay of various allorecognition mechanisms can foster a more integrated view of kidney transplant rejection and can lead to improved risk stratification, targeted therapies, and better outcome after kidney transplantation., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

There has been a growing number of infants identified as CRMS/CFSPID in countries applying genetic testing as part of cystic fibrosis (CF) newborn screening. Currently there are neither standardized protocols for follow up beyond infancy, nor established predictors to stratify this population as high or low risk of reclassification to CF or CFTR-related disorder. We report a series of 10 children who reclassified, including eight carrying CFTR variants of varying clinical consequence and seven with initial sweat chloride measurements <30 mmol/L. The overall increase in sweat chloride concentration was 5.8 mmol/L/year. Pseudomonas aeruginosa was isolated from respiratory cultures in five subjects, and reclassification was aided by human nasal epithelial cultures in two cases. In this center's experience, 6% of all CRMS/CFSPID referrals reclassified to CF over a 12-year period. The rate of sweat chloride increase, genotype, and CFTR functional assay can potentially be used as prognostic tools in the CRMS/CFSPID population., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: We aim to evaluate the impact of multiparametric magnetic resonance imaging and fusion-target biopsy for early reclassification of patients with low-risk Prostate Cancer in a randomized trial., Materials and Methods: Between 2015 and 2018, patients diagnosed with Prostate Cancer after random biopsy fulfilling PRIAS criteria were enrolled and centrally randomized (1:1 ratio) to study group or control group. Patients randomized to study group underwent multiparametric magnetic resonance imaging at 3 months from enrollment: patients with positive findings (PIRADS-v2>2) underwent fusion-target biopsy; patients with negative multiparametric magnetic resonance imaging or confirmed ISUP - Grade Group 1 at fusion-target biopsy were managed according to PRIAS schedule and 12-core random biopsy was performed at 12 months. Patients in control group underwent PRIAS protocol, including a confirmatory 12-core random biopsy at 12 months. Primary endpoint was a reduction of reclassification rate at 12-month random biopsy in study group at least 20% less than controls. Reclassification was defined as biopsy ISUP Grade Group 1 in >2 biopsy cores or disease upgrading., Results: A total of 124 patients were randomized to study group (n = 62) or control group (n = 62). Around 21 of 62 patients (34%) in study group had a positive multiparametric magnetic resonance imaging, and underwent fusion-target biopsy, with 11 (17.7%) reclassifications. Considering the intention-to-treat population, reclassification rate at 12-month random biopsy was 6.5% for study group and 29% for control group, respectively (P < 0.001)., Conclusions: The early employment of multiparametric magnetic resonance imaging for active surveillance patients enrolled after random biopsy consents to significantly reduce reclassifications at 12-month random biopsy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine the long-term prognostic power of coronary computed tomography angiography (CTA) to predict cardiac death and nonfatal myocardial infarction., Background: Prognostic usefulness of coronary CTA has been confirmed for short- and intermediate-term follow-up. However, long-term data for prognostic usefulness is still lacking, but is paramount because of the slowly progressing nature of coronary artery disease (CAD)., Methods: A total of 2,011 patients with suspected but not previously diagnosed CAD were examined by coronary CTA. Mean follow-up was 10.0 years (interquartile range [IQR]: 8.1 to 11.2 years). Cox proportional hazards analysis was used for the composite endpoint of cardiac death and nonfatal myocardial infarction. Event-free survival, which was defined as the years it took to reach a cumulative 1% risk for the composite endpoint and reclassification from clinical risk, was calculated., Results: The study endpoint was reached in 58 patients (42 cardiac deaths, 16 nonfatal myocardial infarctions). Coronary CTA-assessed CAD severity (normal, nonobstructive, or obstructive) showed the best correlation with the endpoint, with an adjusted c-index of 0.704, compared with a univariate c-index of 0.622 for the clinical risk model (Morise score) alone. The annual event rate for patients with normal coronary arteries on baseline coronary CTA was 0.04%, which translated to an event-free survival period of 10 years. The highest annual event rate of 1.33% was found in patients with 3-vessel obstructive CAD. Reclassification from clinical risk (Morise score) was possible in approximately two-thirds of all patients (68%; p < 0.0001), which led to a substantial reduction of the intermediate-risk group (reduction from 74% to 15%) in favor of the low-risk group (increase from 20% to 83%)., Conclusions: Patients with normal coronary CTA results benefitted from an event-free survival period of 10 years against cardiac death and nonfatal myocardial infarction. Risk stratification according to coronary CTA results allowed for the delineation of clearly diverging prognostic groups and reclassified approximately two-thirds of all patients from clinical risk groups., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to compare the performance of history-based risk scores in predicting obstructive coronary artery disease (CAD) among patients with stable chest pain from the SCOT-HEART study., Background: Risk scores for estimating pre-test probability of CAD are derived from referral-based populations with a high prevalence of disease. The generalizability of these scores to lower prevalence populations in the initial patient encounter for chest pain is uncertain., Methods: We compared 3 scores among patients with suspected CAD in the coronary computed tomographic angiography (CTA) randomized arm of the SCOT-HEART study for the outcome of obstructive CAD by coronary CTA: the updated Diamond-Forrester score (UDF), CAD Consortium clinical score (CAD2), and CONFIRM risk score (CRS). We tested calibration with goodness-of-fit, discrimination with area under the receiver-operating curve (AUC), and reclassification with net reclassification improvement (NRI) to identify low-risk patients., Results: In 1,738 patients (age 58 ± 10 years and 44.0% women), overall calibration was best for UDF, with underestimation by CRS and CAD2. Discrimination by AUC was highest for CAD2 at 0.79 (95% confidence interval [CI]: 0.77 to 0.81) than for UDF (0.77 [95% CI: 0.74 to 0.79]) or CRS (0.75 [95% CI: 0.73 to 0.77]) (p < 0.001 for both comparisons). Reclassification of low-risk patients at the 10% probability threshold was best for CAD2 (NRI 0.31, 95% CI: 0.27 to 0.35) followed by CRS (NRI 0.21, 95% CI: 0.17 to 0.25) compared with UDF (p < 0.001 for all comparisons), with a consistent trend at the 15% threshold., Conclusions: In this multicenter clinic-based cohort of patients with suspected CAD and uniform CAD evaluation by coronary CTA, CAD2 provided the best discrimination and classification, despite overestimation of obstructive CAD as evaluated by coronary CTA. CRS exhibited intermediate performance followed by UDF for discrimination and reclassification., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge., Methods: We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes., Results: We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication., Conclusion: This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.

Background: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS)., Objective: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity., Methods: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria., Results: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant., Conclusion: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The two reclassifications of cannabis in England & Wales in 2004 and 2009 have been subjected to a series of academic analyses which have largely been centred on either the relationship to evidence, or in terms of the implications and realities of policing and health under the changes. However, despite the wealth of attention on this area, there have been relatively few attempts to understand these policy movements through broader criminological theoretical frameworks. One recent exception is Shiner's (2015) utilisation of Garland's (2001) concept of 'structured ambivalence'. This paper seeks to test this application through drawing upon an alternative source of evidence, namely, a series of 'elite' qualitative interviews, and using Kingdon's (1995) Multiple Streams model to make sense of the policy processes. In doing so, it largely corroborates Shiner's conclusions whilst also further illuminating particular agentic aspects and their intertwining with other structural and cultural forces which led to the reclassifications. These findings demonstrate the value of triangulating evidential sources and advances knowledge about the role of individuals in pursuing policy agendas within a broader shifting political climate. This provides greater scope to further test and understand how structured ambivalence manifests itself in other cultural contexts and policy domains., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Acute coronary syndrome (ACS) treatments increase bleeding complications that also impair prognosis. Bleeding risk scores reclassification of actual mortality risk estimated by the GRACE score might improve overall estimation., Methods: Observational and prospective study of all ACS patients admitted in two hospitals. Mortality risk was assessed by the GRACE score and bleeding risk by the CRUSADE score. We analyzed the net reclassification improvement (NRI) of adding the CRUSADE score to the GRACE score., Results: We included 6997 patients, mean age 67.4 (12.9), 38.0% ST-elevation ACS, mean GRACE score 145.2 (39.9). The percentage of patients with CRUSADE score >20 or >50 increased as the GRACE score was higher. Hospital mortality was 5.3% and the addition of the CRUSADE score reclassified a relevant percentage of patients with GRACE score >109; NRI was 3.80% (1.10-6.10). During follow-up, (median 53.0months) mortality rate was 22.6% and patients with CRUSADE score >50 had significantly higher mortality rates in all GRACE score categories; NRI was high (46.6%, 95% CI 41.0-53.1). The multivariate analysis outlined the independent predictive value of CRUSADE score >20 or >50 as well as GRACE scores 109-139 and >140., Conclusions: The addition of the CRUSADE score to the GRACE score improved mortality risk estimation. A CRUSADE score >50 identified patients with higher post-discharge mortality and higher hospital mortality if GRACE score was >109. The CRUSADE score improved hospital and long-term mortality prediction in patients with GRACE score >140. Individual mortality risk estimation should integrate the CRUSADE and GRACE scores., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although the incidence of prostate cancer is rising due to PSA screening and increased life expectancy, the metastatic potential of low-grade, organ-confined disease remains low. An increasing number of studies suggest that radical treatment in such cases confers little or no survival benefit at a significant cost to morbidity. Active surveillance is a promising management approach of such low-risk cancers: eligible patients are selected based on clinical and pathological findings at diagnosis and are regularly monitored with digital rectal examinations, PSA testing and biopsies. Treatment, however, is deferred until and unless there is evidence of disease progression. This is a key difference from watchful waiting, where treatment is avoided until and unless there are symptoms. The purpose of this work is to review the rationale and evidence behind active surveillance and to offer an overview of current active surveillance strategies and outcomes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Left ventricular hypertrophy is a strong causal risk factor of cardiovascular morbidity and death in end stage kidney failure, and its prognostic value is taken for granted in this population. However, the issue has never been formally tested by state-of-art prognostic analyses. Therefore, we determined the prognostic power of the left ventricular mass index (LVMI) for all-cause and cardiovascular death beyond and above that provided by well validated clinical risk scores, the annualized rate of occurrence cohort risk scores (ARO, all cause death risk and cardiovascular risk). Two large cohorts that measured LVMI in 207 hemodialysis patients in the South Italian CREED cohort and 287 patients in the French Hospital Manhes cohort were analyzed. Over a two year follow-up, 123 patients died (cardiovascular death 65%). In Cox models both the LVMI and the ARO risk scores were significantly related to all-cause and cardiovascular death. In prognostic analyses, LVMI per se showed an inferior discriminatory power (Harrell's C index) to that of the ARO risk scores (all-cause death: -10%; cardiovascular death: -5%). LVMI largely failed to improve model calibration based on the ARO risk scores, and added nonsignificant discriminatory power (Integrated Discrimination Index +2% and +3%) and quite limited reclassification ability (Net Reclassification Index +4.3%, and +8.8) to the ARO risk scores. Thus, while left ventricular hypertrophy remains a fundamental treatment target in end stage kidney failure, the measurement of LVMI solely for risk stratification is unwarranted in this condition., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Coronary CT angiography (CTA) is a reliable tool for the detection of coronary artery disease (CAD) that conveys significant prognostic information. It does not provide data on the hemodynamic significance of a given lesion, particularly in intermediate-grade stenosis. Fractional flow reserve by CT (FFR CT ) can accurately predict the hemodynamic significance of coronary lesions. The primary objective of this registry is to determine whether the integration of FFR CT as an adjunct to coronary CTA will lead to a significant change in the management of CAD in patients with stable angina., Methods: The ADVANCE Registry is a multi-center, prospective registry designed to evaluate utility, clinical outcomes and resource utilization following FFR CT -guided treatment in clinically stable, symptomatic patients diagnosed with CAD by coronary CTA. Approximately 5000 patients will be enrolled from up to 50 sites in Europe, USA, Canada and Asia. Requirement for enrollment is the presence of atherosclerosis on coronary CTA. For each enrolled patient, a clinical management review committee will use data from coronary CTA and FFR CT to determine the management plan using the following criteria: (a) optimal medical therapy, (b) percutaneous coronary intervention, (c) coronary artery bypass graft surgery, or (d) more information required. The primary endpoint of the registry is the reclassification rate between the management plan based on coronary CTA alone versus CTA plus FFR CT . The secondary endpoints of the registry include the evaluation of the rate of invasive coronary angiography (ICA), revascularization, major adverse coronary events, resource utilization, cumulative radiation dose exposure and the rate of ICA without obstructive CAD at 3-year follow-up., Conclusions: The ADVANCE registry is designed to assess the real-world impact of FFR CT on the clinical management of stable CAD when used along with coronary CTA., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the prognostic effect of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model reclassification after targeted therapy administration in metastatic renal cell carcinoma (mRCC)., Patients and Method: A total of 245 mRCC patients treated with targeted therapy are included. The IMDC model reclassification is performed at 1 month after treatment induction of both first-line and second-line targeted therapy., Results: Of the 245 patients, 74 (30.2%) are divided into different risk groups by the IMDC model reclassification after first-line targeted therapy, and patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.018). Of the 119 patients treated with subsequent second-line targeted therapy, 25 (21.0%) are divided into different risk groups by the IMDC model reclassification after second-line targeted therapy, and patients newly classified with poor risk tend to have increased all-cause mortality compared with those remaining in the primary intermediate-risk group (P = 0.007), whereas patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.034)., Conclusion: Approximately a quarter of the mRCC patients are classified into different risk groups of the IMDC model following targeted therapy administration in the first-line and second-line settings. There is a significant difference in overall survival of subgroups after the IMDC model reclassifications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Prior studies have demonstrated a decline in the predictive ability of conventional risk factors (RF) with advancing age, emphasizing the need for novel tools to improve risk stratification in the elderly. Coronary artery calcification (CAC) is a robust predictor of adverse cardiovascular events, but its long-term prognostic utility beyond RFs in elderly persons is unknown., Methods: A consecutive series of 9715 individuals underwent CAC scoring and were followed for a mean of 14.6 ± 1.1 years. Multivariable Cox proportional hazards regression (HR) with 95% confidence intervals (95% CI) was employed to assess the independent relationship of CAC and RFs with all-cause death. The incremental value of CAC, stratified by age, was examined by using an area under the receiver operator characteristic curve (AUC) and category-free net reclassification improvement (NRI)., Results: Of the overall study sample, 728 (7.5%) adults (mean age 74.2 ± 4.2 years; 55.6% female) were 70 years or older, of which 157 (21.6%) died. The presence of any CAC was associated with a >4-fold (95% CI = 2.84-6.59) adjusted risk of death for those over the age of 70, which was higher compared with younger study counterparts, or other measured RFs. For individuals 70 years or older, the discriminatory ability of CAC improved upon that of RFs alone (C statistics 0.764 vs. 0.675, P < 0.001). CAC also enabled improved reclassification (category-free NRI = 84%, P < 0.001) when added to RFs., Conclusion: In a large-scale observational cohort registry, CAC improves prediction, discrimination, and reclassification of elderly individuals at risk for future death., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD., Methods: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively., Results: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]., Conclusion: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Little is known about the vitamin D3 epimer [3-epi-25(OH)D3], particularly in adults. We describe characteristics of the D3 epimer within the community-based ARIC cohort., Methods: The vitamin D3 epimer, 25(OH)D3, and 25(OH)D2 were measured using LC-MS/MS in stored serum collected in 1990-1992 from 9,887 white and 3,221 black ARIC study participants, aged 46-70years. Cross-sectional characteristics were explored., Results: Concentrations of the epimer were quantifiable (≥1.41ng/ml) in 33.4% of whites and 15.0% of blacks and made up on average 3.23% and 2.25% of total D3 [epimer+25(OH)D3] concentrations, respectively. Epimer levels were positively correlated with 25(OH)D3 in both whites (r=0.54) and blacks (r=0.36) and were unrelated to 25(OH)D2 concentrations. Overall, epimer levels were associated with participant characteristics in a manner similar to that typically observed for 25(OH)D3. Including the epimer in the calculation of total 25(OH)D resulted in approximately 2% of participants being reclassified from being clinically 25(OH)D deficient to having suboptimal levels., Conclusions: Low concentrations of the D3 epimer were present in adult serum and overall the epimer concentration is moderately correlated with the 25(OH)D3 concentration. The reclassification of participant's clinical 25(OH)D status upon inclusion of the epimer was minimal., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort., Materials and Methods: We performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4)., Results: The final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤ 10 ng/ml, PSAD ≤ 0.15 ng/ml/g, T1c, and ≤ 2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers., Conclusions: Approximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Neutrophil lymphocyte ratio (NLR) has been shown to predict cardiovascular events in several studies. We sought to study if NLR predicts coronary heart disease (CHD) in a healthy US cohort and if it reclassifies the traditional Framingham risk score (FRS) model., Methods: We performed post hoc analysis of National Health and Nutrition Examination Survey-III (1998-94) including subjects aged 30-79 years free from CHD or CHD equivalent at baseline. Primary endpoint was death from ischemic heart disease. NLR was divided into four categories: <1.5, ≥1.5 to <3.0, 3.0-4.5 and >4.5. Statistical analyses involved multivariate Cox proportional hazards models as well as discrimination, calibration and reclassification., Results: We included 7363 subjects with a mean follow up of 14.1 years. There were 231 (3.1%) CHD deaths, more in those with NLR>4.5 (11%) compared to NLR<1.5 (2.4%), p<0.001. Adjusted hazard ratio of NLR>4.5 was 2.68 (95% CI 1.07-6.72, p=0.035). There was no significant improvement in C-index (0.8709 to 0.8713) or area under curve (0.8520 to 0.8531) with addition of NLR to FRS model. Model with NLR was well calibrated with Hosmer-Lemeshow chi-square of 8.57 (p=0.38). Overall net reclassification index (NRI) was 6.6% (p=0.003) with intermediate NRI of 10.1% (p<0.001) and net upward reclassification of 5.6%. Absolute integrated discrimination index (IDI) was 0.003 (p=0.039) with relative IDI of 4.3%., Conclusions: NLR can independently predict CHD mortality in an asymptomatic general population cohort. It reclassifies intermediate risk category of FRS, with significant upward reclassification. NLR should be considered as an inflammatory biomarker of CHD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: In the UK, over 90 medicines that were previously available only through prescription have been reclassified to allow over-the-counter (OTC) availability via pharmacies. Pharmacists are personally responsible for undertaking or supervising the sales and supplies of these OTC 'pharmacy only' (P) medicines. Reclassification facilitates pharmacy management of a wide range of conditions., Objective: This research aimed to evaluate Scottish community pharmacists' perspectives of newly reclassified 'P' medicines from diverse therapeutic areas and to identify factors associated with their adoption into practice of these medicines., Methods: A cross-sectional postal survey of all community pharmacies in Scotland (N = 1138) was undertaken. The questionnaire was mailed to the pharmacist responsible for OTC medicines. Four newly reclassified 'P' medicines: omeprazole, naproxen, simvastatin and chloramphenicol eye drops were evaluated. Outcomes of interests included pharmacist support for the reclassified status, perceived adoption into practice of these medicines (i.e., how often they supplied each of these medicines) and factors associated with decision-making. Analyses included descriptive, bivariate correlation, principal component factor and binary regression., Results: Five hundred sixty-three pharmacists responded (response rate: 49.5%). Newly reclassified medicines studied had been adopted into practice by the respondent pharmacists to varying degrees. A high majority of the respondents expressed support for the reclassified status (82.4%) and perceived that the level of adoption into practice of OTC chloramphenicol was high (92.1%). In contrast, over 80% of respondents had not yet made a supply of OTC simvastatin to patients, mainly owing to pharmacists' perceptions of lack of evidence of efficacy of the OTC dose and patient demand. Decision-making was influenced by factors such as perceived benefits to patients and pharmacy practice; e.g., respondents who agreed that reclassified naproxen was a good opportunity to develop their professional role were significantly more likely to rate their support for the reclassified status highly than those who were unsure or disagreed (odds ratio = 3.7 (95% confidence interval: 2.1-6.7); P value <0.001)., Conclusions: Key factors informing decisions to adopt the reclassified medicines into pharmacists' practice relate to perceptions regarding the benefits of reclassification to patient care and their professional roles. The results have relevance to future reclassification decisions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The UK Misuse of Drugs Act (1971) divided controlled drugs into three groups A, B and C, with descending criminal sanctions attached to each class. Cannabis was originally assigned by the Act to Group B but in 2004, it was transferred to the lowest risk group, Group C. Then in 2009, on the basis of increasing concerns about a link between high strength cannabis and schizophrenia, it was moved back to Group B. The aim of this study is to test the assumption that changes in classification lead to changes in levels of psychosis. In particular, it explores whether the two changes in 2004 and 2009 were associated with changes in the numbers of people admitted for cannabis psychosis., Method: An interrupted time series was used to investigate the relationship between the two changes in cannabis classification and their impact on hospital admissions for cannabis psychosis. Reflecting the two policy changes, two interruptions to the time series were made. Hospital Episode Statistics admissions data was analysed covering the period 1999 through to 2010., Results: There was a significantly increasing trend in cannabis psychosis admissions from 1999 to 2004. However, following the reclassification of cannabis from B to C in 2004, there was a significant change in the trend such that cannabis psychosis admissions declined to 2009. Following the second reclassification of cannabis back to class B in 2009, there was a significant change to increasing admissions., Conclusion: This study shows a statistical association between the reclassification of cannabis and hospital admissions for cannabis psychosis in the opposite direction to that predicted by the presumed relationship between the two. However, the reasons for this statistical association are unclear. It is unlikely to be due to changes in cannabis use over this period. Other possible explanations include changes in policing and systemic changes in mental health services unrelated to classification decisions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aims: This study was conducted to determine whether galectin-3 (Gal3), a β-galactoside-binding lectin, has usefulness to predict outcomes in patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF)., Methods and Results: We measured Gal3, urea, creatinine and natriuretic peptides on admission in 419 selected patients with HF and LVEF over 45%. The primary endpoint was all-cause mortality and/or readmission at one-year follow-up. Multivariable Cox proportional hazards models were generated for Gal3 and classical risk factors. We also evaluated the reclassification of patients on the basis of the different score category after adding Gal3 levels. A total of 219 patients had combined adverse events, and 129 patients died during the follow-up. Kaplan-Meir survival curve showed significantly increased primary endpoint and all-cause mortality according to quartiles of Gal3 (log rank, P<0.001). Serum Gal3 levels above median (13.8 ng/ml) was a significant predictor of primary endpoint risk after adjustment for age, estimated glomerular filtration rate, anemia, diabetes, serum sodium, brain natriuretic peptide levels, NYHA class and urea, respectively (hazard ratio 1.43, 95% CI 1.07-1.91 P=0.015). The reclassification index increased significantly after addition of Gal3 (9.5%, P<0.001) and the integrated discrimination index was 0.022, (P=0.001). The clinical prediction model with Gal3 increased the c-statistic from 0.711 to 0.731 (difference of 0.020, P=0.001)., Conclusions: Serum Gal3 is a strong and independent predictor of unfavorable outcomes in patients with HF and preserved LVEF. We also demonstrated the improvement of adding the new biomarker to the model., (© 2013.)

Aim: This study aims to evaluate the incremental value of plasma biomarkers to traditional clinical variables for risk stratification of 30-day and one-year mortality in acutely decompensated heart failure (ADHF)., Methods and Results: Through an international collaborative network, individual patient data on 5306 patients hospitalized for ADHF were collected. The all-cause mortality rate was 11.7% at 30 days and 32.9% at one year. The clinical prediction model (age, gender, blood pressure on admission, estimated glomerular filtration rate <60 mL/min/1.73 m(2), sodium and hemoglobin levels, and heart rate) had a c-statistic of 0.74 for 30-day mortality and 0.73 for one-year mortality. Several biomarkers measured at presentation improved risk stratification when added to the clinical model. At 30 days, the net reclassification improvement (NRI) was 28.7% for mid-regional adrenomedullin (MR-proADM; p<0.001) and 25.5% for soluble (s)ST2 (p<0.001). At one year, sST2 (NRI 10.3%), MR-proADM (NRI 9.1%), amino-terminal pro-B-type natriuretic peptide (NT-proBNP; NRI 9.1%), mid-regional proatrial natriuretic peptide (MR-proANP; NRI 7.4%), B-type natriuretic peptide (NRI 5.5%) and C-reactive protein (CRP; NRI 5.3%) reclassified patients with ADHF (p<0.05 for all). CRP also markedly improved risk stratification of patients with ADHF as a dual biomarker combination with MR-proADM (NRI 36.8% [p<0.001] for death at 30 days) or with sST2 (NRI 20.3%; [p<0.001] for one-year mortality)., Conclusion: In this study, biomarkers provided incremental value for risk stratification of ADHF patients. Biomarkers such as sST2, MR-proADM, natriuretic peptides and CRP, reflecting different pathophysiologic pathways, add prognostic value to clinical risk factors for predicting both short-term and one-year mortality in ADHF., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Conventional factors do not fully explain the distribution of cardiovascular outcomes. Biomarkers are known to participate in well-established pathways associated with cardiovascular disease, and may therefore provide further information over and above conventional risk factors. This study sought to determine whether individual and/or combined assessment of 9 biomarkers improved discrimination, calibration and reclassification of cardiovascular mortality., Methods: 3267 patients (2283 men), aged 18-95 years, at intermediate-to-high-risk of cardiovascular disease were followed in this prospective cohort study. Conventional risk factors and biomarkers were included based on forward and backward Cox proportional stepwise selection models., Results: During 10-years of follow-up, 546 fatal cardiovascular events occurred. Four biomarkers (interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D) were retained during stepwise selection procedures for subsequent analyses. Simultaneous inclusion of these biomarkers significantly improved discrimination as measured by the C-index (0.78, P = 0.0001), and integrated discrimination improvement (0.0219, P<0.0001). Collectively, these biomarkers improved net reclassification for cardiovascular death by 10.6% (P<0.0001) when added to the conventional risk model., Conclusions: In terms of adverse cardiovascular prognosis, a biomarker panel consisting of interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D offered significant incremental value beyond that conveyed by simple conventional risk factors., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the impact of detailed biopsy characteristics such as positive cores location or multifocality on the risk of initial reclassification in prostate cancer (CaP) patients eligible for active surveillance (AS)., Materials and Methods: We reviewed data from 300 consecutive men eligible for AS (PSA ≤ 10 ng/ml, clinical stage T1c, Gleason score ≤ 6, <3 positive cores, extent of cancer in any core < 50%) who have undergone a radical prostatectomy (RP). Reclassification was defined as upstaged disease and/or upgraded disease in RP specimens., Results: Biopsy features showed 36% of CaP involving 2 cores and a mean total tumor length of 2.63 mm. The 2 most frequently positive sites were base and apex. Mean total tumor length was significantly associated with upgraded disease (P = 0.025). In a multivariate model taking into account PSA, PSAD, number of positive cores and total tumor length, a total tumor length > 5 mm were independently predictor for a upgraded disease (OR 1.93, P = 0.046). The number, the multifocality and the bilaterality of positive cores were not associated with reclassification. Upgraded disease was significantly less reported in case of positivity at midline zone compared with positivity at base, apex, or transition zone (P = 0.013)., Conclusions: Detailed biopsy data provide additional information on the initial risk of reclassification in AS patients. Patients having a total tumor length < 5 mm and positive cores at midline zone are more likely to have favorable pathologic characteristics at diagnosis. These variables can be used for selection and monitoring improvement in AS programs., (Copyright © 2013 Elsevier Inc. All rights reserved.)