Search

Take Home Message In terms of clinically relevant outcomes, such as overall survival, prostate cancer–specific survival, metastasis-free survival, and treatment-free survival, a strict follow-up protocol does not provide benefit for men with low-risk prostate cancer on active surveillance., Background Active surveillance (AS) is the preferred option for initial management for low-risk prostate cancer (PC). Although many AS protocols exist, there is little evidence to support one over another. Objective To assess whether there is difference in overall (OS), prostate cancer–specific (CSS), metastasis-free (MFS), or treatment-free (TFS) survival between a strict (Prostate cancer Research International: Active Surveillance [PRIAS]) and a loose (European Randomized study of Screening for Prostate Cancer [ERSPC]) AS protocol. Design, setting, and participants This study included two cohorts of men (n = 518) with low-risk, localized, Gleason score ≤7 PC. The ERSPC cohort included 241 men followed for 9.5 yr (median) with a non–protocol-based follow-up. The PRIAS cohort included 277 men followed for 5 yr (median) with a strict protocol. Outcome measurements and statistical analysis OS, CSS, MFS, and TFS were compared by the Kaplan-Meier method, competing risk analysis, and Cox proportional hazard regression. Results and limitations As expected, due to the difference in median follow-up time between the cohorts, a difference in the absolute number of events was seen. However, no difference in any of the survival outcomes was evident in the Kaplan-Meier or competing risks analysis. Furthermore, in Cox proportional hazard regression analysis, cohort (ERSPC vs PRIAS) was not associated with any of the outcomes. Results are limited by the retrospective study design, limited statistical power, and inability to match the cohorts for predictive factors. Conclusions There was no difference in survival outcomes between a non–protocol-based follow-up and a protocol-based contemporary AS follow-up of patients with low-risk PC. However, a longer follow-up is needed. Patient summary We compared survival outcomes of two cohorts of patients with low-risk prostate cancer: a strict and a loose follow-up protocol. We found no differences in survival measures between the cohorts.

Purpose Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. Methods A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. Results After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. Conclusion In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only.

While genomic medicine is becoming an important part of patient care with an ever-increasing diagnostic yield, recontacting patients after reclassification of variants of uncertain clinical significance (VUSs) remains a major challenge. Although periodical reinterpretation of VUSs is highly desired, recontacting former patients with new classifications is commonly not fulfilled in practice. We draw on semi-structured interviews with 20 Israeli healthcare professionals and stakeholders involved in communicating the results of genome-wide sequencing to patients. Findings show agreement that an individual health care professional cannot address the task of recontacting patients after re-classification, and that responsibility should be shared among the medical specialties, laboratory scientists, as well as patients. In the absence of established guidelines, many respondents suggested that the patient should be informed about reclassification during a follow-up contact but they disagreed who should be responsible for informing the patient. HCPs agreed that the solution to this challenge involves a centralized automated database that is accessible, continuously updated, and facilitates retrospective as well as prospective flagging of reclassification for patients who can benefit from this information. National and international policies providing concrete guidelines on the optimal way to recontact patients with new valuable genomic information are needed.

Aims To validate the reported increased atherosclerotic cardiovascular disease (ASCVD) risk associated with very high lipoprotein(a) [Lp(a)] and to investigate the impact of routine Lp(a) assessment on risk reclassification. Methods and results We performed a cross-sectional case-control study in the Amsterdam UMC, a tertiary hospital in The Netherlands. All patients in whom a lipid blood test was ordered between October 2018 and October 2019 were included. Individuals with Lp(a) >99th percentile were age and sex matched to individuals with Lp(a) ≤20th percentile. We computed odds ratios (ORs) for myocardial infarction (MI) and ASCVD using multivariable logistic regression adjusted for age, sex, and systolic blood pressure. Furthermore, we assessed the additive value of Lp(a) to established ASCVD risk algorithms. Lipoprotein(a) levels were determined in 12 437 individuals, out of whom 119 cases [Lp(a) >99th percentile; >387.8 nmol/L] and 119 matched controls [Lp(a) ≤20th percentile; ≤7 nmol/L] were included. Mean age was 58 ± 15 years, 56.7% were female, and 30.7% had a history of ASCVD. Individuals with Lp(a) levels >99th percentile had an OR of 2.64 for ASCVD [95% confidence interval (CI) 1.45–4.89] and 3.39 for MI (95% CI 1.56–7.94). Addition of Lp(a) to ASCVD risk algorithms led to 31% and 63% being reclassified into a higher risk category for Systematic Coronary Risk Evaluation (SCORE) and Second Manifestations of ARTerial disease (SMART), respectively. Conclusion The prevalence of ASCVD is nearly three-fold higher in adults with Lp(a) >99th percentile compared with matched subjects with Lp(a) ≤20th percentile. In individuals with very high Lp(a), addition of Lp(a) resulted in one-third of patients being reclassified in primary prevention, and over half being reclassified in secondary prevention.

Background Non-prescription medicines are increasingly used in Germany, aided by prescription-to-non-prescription reclassification (or switch). This study aimed to examine the barriers and enablers to reclassification of medicines in Germany and provide recommendations for change. Methods Face-to-face conversational interviews with purposively selected key informants in Germany were conducted in 2017 by a researcher informed in the area. Interviews were transcribed, coded in NVIVO and systematically analysed using a framework approach. Results Twenty-four interviews were conducted with 32 participants including members of the committee considering reclassifications, and representatives from government, industry, health insurance, academia, and pharmacy, medical, and patients’ organisations. A range of enablers and barriers emerged that influence reclassification including effects on the committee and process, or the desire of pharmaceutical companies to pursue reclassifications. Enabling market factors included the large population and a culture of self-medication. Enabling health system factors include the pharmacy-only category. Some pharmacy factors appeared enabling (e.g. a positive experience after reclassifying emergency contraception) while others appeared to hinder reclassification (e.g. insufficient pharmacy practice research). Some medical factors were enabling (e.g. reported waiting times) and others limited reclassification (e.g. opposition to some reclassifications). Some committee and government openness to reclassification and self-medication reportedly enabled reclassification, while conservatism was considered a barrier, particularly for classifications with special conditions for supply such as initial doctor diagnosis or other complexities. Some improvements to the committee constitution and considerations were recommended. Some participants found the reclassification process after the committee recommendation opaque, with opportunity for delays and political interference. Industry factors included both enablers such as capability in reclassification, and barriers, such as a perceived low market potential of some reclassifications, and doubt that some candidates would be approved. A need for more data emerged strongly, both pre-reclassification in applications, and post-reclassification. Many participants saw merit with reclassification in non-traditional areas such as hypertension, diabetes and oral contraception. Conclusions Many factors influence reclassification in Germany. Recommended improvements included aspects of the process and committee consideration, and more data collection. Sufficient market exclusivity linked to data collection could aid the generation of evidence to aid committee considerations and encourage more applications of high quality.

ContextFollowing total thyroidectomy and radioactive iodine (RAI) ablation, serum thyroglobulin levels should be undetectable to assure that patients are excellent responders and at very low risk of recurrence.ObjectiveTo assess the utility of stimulated (sTg) and non-stimulated (nsTg) thyroglobulin levels in prediction of patients outcomes with differentiated thyroid cancer (DTC) following total thyroidectomy and RAI ablation.MethodA prospective observational study conducted at a University Hospital in Saudi Arabia. Patients diagnosed with differentiated thyroid cancer and were post total thyroidectomy and RAI ablation. Thyroglobulin levels (nsTg and sTg) were estimated 3–6 months post-RAI. Patients with nsTg ResultsOf 196 patients, nsTg levels were 1 occurred in 26 (35%) of patients with nsTg 0.1–2.0 ng/ml, 11 (15%) had structural incomplete response. None of the patients with sTg levels ConclusionSuppressed thyroglobulin (nsTg < 0.1 ng/ml) indicates a very low risk of recurrence that does not require stimulation. Stimulated thyroglobulin is beneficial with nsTg 0.1–2 ng/ml for re-classifying patients and estimating their risk for incomplete responses over a 7 years follow-up period.

Aims: We aimed to reclassify a population-based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour classification. Moreover, we evaluated the feasibility of gene panel next-generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients. Methods: The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH-R132H, fluorescence in situ hybridization for 1p/19q-codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up-front. Results: The entire population-based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population-based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas, IDH-mutant astrocytomas and IDH-wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH-mutant astrocytoma. The survival of patients with IDH-wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH-wildtype glioblastoma patients. Conclusions: Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population-based cohort. Molecular features of glioblastoma in IDH-wildtype diffuse glioma were linked to poor survival corresponding to IDH-wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH-mutant diffuse astrocytic gliomas.

Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2–5 and 15–23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

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.

Objective To assess the influence of pressure recovery (PR)-corrected haemodynamic parameters on outcome in patients with aortic stenosis. Methods Aortic stenosis severity parameters were corrected for PR (increase in static pressure due to decreasing dynamic pressure), assessed using transthoracic echocardiography (TTE) or cardiac magnetic resonance imaging (CMR), in patients with aortic stenosis. PR, indexed PR (iPR) and energy loss index (ELI) were determined. Factors that predicted all-cause mortality, and 9-month or 10-year New York Heart Association classification ≥2 were assessed using Cox proportional hazards regression. Results A total of 25 patients, aged 68 ± 10 years, were included. PR was 17 ± 6 mmHg using CMR, and CMR correlated with TTE measurements. PR correction using CMR data reduced the AS-severity classification in 12–20% of patients, and correction using TTE data reduced the AS-severity classification in 16% of patients. Age (Wald 4.774) was a statistically significant predictor of all-cause mortality; effective orifice area (Wald 3.753) and ELI (Wald 3.772) almost reached significance. Conclusions PR determination may result in significant reclassification of aortic stenosis severity and may hold value in predicting all-cause mortality.

Aims: To examine whether electrocardiography (ECG) could provide additional values to the traditional risk factors for cardiovascular disease (CVD) risk prediction among different cardiovascular risk subgroups. Methods: A total of 7,872 community residents aged ≥40 years were followed up for a median of 4.5 years. A 12-lead resting ECG was examined for participants at baseline. CVD events including myocardial infarction, stroke and cardiovascular mortality were collected. Cox proportional hazards models were used and models of traditional risk factors with and without ECG were compared. Results: At baseline, 2,470 participants (31.3%) had ECG abnormalities. During follow-up, 464 participants developed CVD events. ECG abnormalities were associated with an increased risk of CVD after adjustment for the traditional risk factors in participants with a 10-year atherosclerotic CVD (ASCVD) risk ≥10% (hazard ratio, HR: 1.45; 95% confidence interval, CI: 1.11, 1.91). Adding ECG abnormalities to the traditional CVD risk factors improved reclassification for those who did not experience events [net reclassification index: 8.0% (95% CI: 2%, 19.5%)], discrimination (integrated discrimination improvement: 0.7% (95% CI: 0.1%, 1.9%), and calibration (goodness of fit P value from 0.600 to 0.873) in participants with a 10-year ASCVD risk ≥10%. However, no significant association and improvement were found in participants with a 10-year ASCVD risk

Objectives: To establish tailored preventive treatment, we studied the ability of coronary artery calcium scoring to reclassify patients with intermediate cardiovascular risk and its association with additional risk factors in our Mexican preventive care center. Materials and methods: In this retrospective cohort study, we analyzed 520 asymptomatic patients from a Mexican primary prevention population between 2014 and 2018. Coronary artery calcium scoring, laboratory results, and anthropometric measurements (abdominal circumference and body mass index) were assessed. The Framingham risk score and American Heart Association/American College of Cardiology (AHA/ACC) atherosclerotic cardiovascular disease risk algorithm were calculated. Correlations between coronary artery calcium scoring, anthropometric measurements, and clinical cardiovascular risk scores were assessed. We assessed the ability of coronary artery calcium scoring to reclassify patients recommended for statin therapy compared with the cardiovascular risk scores. Results: Patients had a mean age of 67.5 years ( SD ± 9.8) and 294 subjects (56.5%) were male. Coronary artery calcium scoring has a positive correlation with age, AHA/ACC atherosclerotic cardiovascular disease risk algorithm, and Framingham risk score ( p Conclusion: Coronary artery calcium scoring is prevalent in this Mexican primary prevention cohort and has the ability to reclassify a significant percentage of intermediate cardiovascular risk patients.

Background Little is known about the impact of reclassification on patients’ perception of medical uncertainty or trust in genetics‐based clinical care. Methods Semistructured telephone interviews were conducted with 20 patients who had received a reclassified genetic test result related to hereditary cancer. All participants had undergone genetic counseling and testing for cancer susceptibility at Vanderbilt‐Ingram Cancer Center Hereditary Cancer Clinic within the last six years. Results Most of the participants did not express distress related to the variant reclassification and only a minority expressed a decrease in trust in medical genetics. However, recall of the new interpretation was limited, even though all participants were recontacted by letter, phone, or clinic visit. Conclusion Reclassification of genetic tests is an important issue in modern healthcare because changes in interpretation have the potential to alter previously recommended management. Participants in this study did not express strong feelings of mistrust or doubt about their genetic evaluation. However, there was a low level of comprehension and information retention related to the updated report. Future research can build on this study to improve communication with patients about their reclassified results., Little is known about the impact of reclassification on patients’ perception of medical uncertainty or trust in genetics‐based clinical care. Participants in this study did not express strong feelings of mistrust or doubt about their genetic evaluation. However, there was a low level of comprehension and information retention related to the updated report.

International audience; This cross-sectional study evaluates the association of major adverse cardiac events (MACE) integrated with fractional flow reserve as the management strategy for diabetes with outcomes in patients with ambiguous lesions who undergo angiography.Key PointsQuestionWhat are the usefulness, rate of major adverse cardiovascular events (MACE), and clinical outcomes of routinely integrating fractional flow reserve in the management strategy for patients with diabetes who undergo coronary angiography? FindingsIn this cross-sectional study of 1983 patients, overall reclassification by fractional flow rate was high and similar in patients with diabetes (41.2%) and patients without diabetes (37.5%); however, reclassification from medical treatment to revascularization was more frequent among patients with diabetes. The rate of 1-year MACE was similar in reclassified (9.7%) and nonreclassified (12.0%) patients with diabetes, and the rate of MACE of patients deferred based on fractional flow reserve was similar among those with and without diabetes. MeaningThe findings suggest that management strategies guided by fractional flow reserve, including revascularization deferral, may be useful for patients with diabetes.ImportanceApproximately one-third of patients considered for coronary revascularization have diabetes, which is a major determinant of clinical outcomes, often influencing the choice of the revascularization strategy. The usefulness of fractional flow reserve (FFR) to guide treatment in this population is understudied and has been questioned. ObjectiveTo evaluate the usefulness and rate of major adverse cardiovascular events (MACE) of integrating FFR in management decisions for patients with diabetes who undergo coronary angiography. Design, Setting, and ParticipantsThis cross-sectional study used data from the PRIME-FFR study derived from the merger of the POST-IT study (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease [March 2012-November 2013]) and R3F study (French Study of FFR Integrated Multicenter Registries Implementation of FFR in Routine Practice [October 2008-June 2010]), 2 prospective multicenter registries that shared a common design. A population of all-comers for whom angiography disclosed ambiguous lesions was analyzed for rates, patterns, and outcomes associated with management reclassification, including revascularization deferral, in patients with vs without diabetes. Data analysis was performed from June to August 2018. Main Outcomes and MeasuresDeath from any cause, myocardial infarction, or unplanned revascularization (MACE) at 1 year. ResultsAmong 1983 patients (1503 [77%] male; mean [SD] age, 65 [10] years), 701 had diabetes, and FFR was performed for 1.4 lesions per patient (58.2% of lesions in the left anterior descending artery; mean [SD] stenosis, 56% [11%]; mean [SD] FFR, 0.81 [0.01]). Reclassification by FFR was high and similar in patients with and without diabetes (41.2% vs 37.5%, P=.13), but reclassification from medical treatment to revascularization was more frequent in the former (142 of 342 [41.5%] vs 230 of 730 [31.5%], P=.001). There was no statistical difference between the 1-year rates of MACE in reclassified (9.7%) and nonreclassified patients (12.0%) (P=.37). Among patients with diabetes, FFR-based deferral identified patients with a lower risk of MACE at 12 months (25 of 296 [8.4%]) compared with those undergoing revascularization (47 of 257 [13.1%]) (P=.04), and the rate was of the same magnitude of the observed rate among deferred patients without diabetes (7.9%, P=.87). Status of insulin treatment had no association with outcomes. Patients (6.6% of the population) in whom FFR was disregarded had the highest MACE rates regardless of diabetes status. Conclusions and RelevanceRoutine integration of FFR for the management of coronary artery disease in patients with diabetes may be associated with a high rate of treatment reclassification. Management strategies guided by FFR, including revascularization deferral, may be useful for patients with diabetes.

Despite the proven superiority of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) over the Cockcroft&ndash, Gault (CG) formula, current guidelines recommend the latter to assess renal function in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). To assess the relationship between the CG and the recommended CKD-EPI formulas, in a cohort of atrial fibrillation (AF) patients treated with NOACs, and the misclassifications introduced by the CG formula for renal function levels, we estimated renal function with three equations: CG, CKD-EPI with body surface adjustment (1.73 mL/m2, CKD-EPI) and without such adjustment (CKD-EPI_noBSA), in all consecutive AF patients discharged from NOACs from the Cardiology Division of a main city hospital between February 1st and May 31st 2018. We compared the different estimates of glomerular filtration rate and potential renal function class misclassifications. We reclassified 37/115 patients (32.1%) when switching from the CG to the CKD-EPI, and 24/115 (20.8%) switching from the CG to the CKD-EPI_noBSA formulas. Class reallocation was distributed across all levels of renal function, but mostly affected the &ldquo, hyper-normal&rdquo, function. In estimating consequences of such reallocation, a change in NOAC dosages would have occurred in 10/115 patients (8.7%) when switching from the CG to the CKD-EPI formula and in 10/115 patients when switching from the CG to the CKD-EPI_noBSA formula. Although the CG method has been traditionally used to calculate renal function in all NOAC studies, a renal dysfunction class reallocation occurs in a substantial fraction of hospital-admitted AF patients with the use of better estimates of renal function.

In August 2019, ESC published new guidelines on Chronic Coronary Syndromes including a new risk assessment paradigm for estimation of pre-test-probability. The CAD-score is an acoustic-based score for ruling-out of coronary artery disease (CAD). In the current letter to the editor we re-evaluate the re-classification potential the CAD-score in the view of the new guidelines.

Purpose Ultrasound examinations of atherosclerotic carotid plaques can be used to calculate risk markers associated with plaque vulnerability. Recent studies demonstrate significant inter-frame variability in risk markers. Here, we investigate risk marker variability in symptomatic plaques and its impact on reclassification of plaque vulnerability, as well as its association with the shape of the temporal variation over the cardiac cycle. Methods 56 patients with symptomatic carotid stenosis were included in this study. 88 plaques were identified and the plaque risk markers size (area), echogenicity (gray scale median, GSM) and heterogeneity (coarseness) were measured in all frames of ultrasound B-mode image sequences. Inter-frame variability was quantified using the coefficient of variation (CV). Results Inter-frame variabilities of the risk markers were area CV 5–8%; GSM CV 4–7%; coarseness CV 8–15% and was in general significantly lower in large as compared to smaller plaques. The variability in GSM risk marker caused a reclassification of vulnerability in 30 to 38% of the plaques. Temporal variations in GSM with a heart rate periodic or drift/trending pattern were found in smaller plaques (2), whereas random pattern was found in larger plaques. In addition, hypoechoic plaques (GSM Conclusions Risk marker variability causes substantial reclassification of plaque vulnerability in symptomatic patients. Inter-frame variation and its temporal pattern should be considered in the design of future studies related to risk markers.

Background The urinary albumin/creatinine ratio (ACR) is an important indicator of albuminuria. We aimed to estimate ACR uncertainty and its impact on test results and proposed imprecision quality goals based on the estimated uncertainty. Methods The combined ACR uncertainty was calculated using the individual uncertainties of urinary albumin and creatinine. ACR confidence intervals (CIs) were estimated based on the expanded uncertainty. When the CI contained the ACR category boundary (30 or 300 mg/g), the cases were considered ambiguous. Quality goals for ACR were suggested using the number of ambiguous cases among actual patient results. Results The number of ambiguous cases resulting from the combined ACR uncertainty was higher than expected based on biological variation (BV) quality goals. When the ACR met BV quality specifications, we estimated that 4.8-15.5% of the results may have been misclassified. To minimize the number of ambiguous results, the minimum, desirable, and optimum quality goals were set at 34.0%, 18.0%, and 4.5%, respectively. Conclusions We expressed ACR uncertainty using the uncertainties of urinary albumin and creatinine and assessed the impact of this combined uncertainty on the test results. Subsequently, we proposed imprecision quality goals for ACR based on ambiguous results.

Background: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised. Objective: To develop consensus statements for all domains of DAT. Design, setting, and participants: A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed. Results and limitations: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion. Conclusions: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials. Patient summary: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology.

Background Many members of Streptococcus and Enterococcus genera are clinically relevant opportunistic pathogens warranting accurate and rapid identification for targeted therapy. Currently, the developed method based on next generation sequencing (NGS) of the 16S–23S rRNA region proved to be a rapid, reliable and precise approach for species identification directly from polymicrobial and challenging clinical samples. The introduction of this new method to routine diagnostics is hindered by a lack of the reference sequences for the 16S–23S rRNA region for many bacterial species. The aim of this study was to develop a careful assignment for streptococcal and enterococcal species based on NGS of the 16S–23S rRNA region. Methods Thirty two strains recovered from clinical samples and 19 reference strains representing 42 streptococcal species and nine enterococcal species were subjected to bacterial identification by four Sanger-based sequencing methods targeting the genes encoding (i) 16S rRNA, (ii) sodA, (iii) tuf and (iv) rpoB; and NGS of the 16S–23S rRNA region. Results This study allowed obtainment and deposition of reference sequences of the 16S–23S rRNA region for 15 streptococcal and 3 enterococcal species followed by enrichment for 27 and 6 species, respectively, for which reference sequences were available in the databases. For Streptococcus, NGS of the 16S–23S rRNA region was as discriminative as Sanger sequencing of the tuf and rpoB genes allowing for an unambiguous identification of 93% of analyzed species. For Enterococcus, sodA, tuf and rpoB genes sequencing allowed for identification of all species, while the NGS-based method did not allow for identification of only one enterococcal species. For both genera, the sequence analysis of the 16S rRNA gene was endowed with a low identification potential and was inferior to that of other tested identification methods. Moreover, in case of phylogenetically related species the sequence analysis of only the intergenic spacer region was not sufficient enough to precisely identify Streptococcus strains at the species level. Conclusions Based on the developed reference dataset, clinically relevant streptococcal and enterococcal species can now be reliably identified by 16S–23S rRNA sequences in samples. This study will be useful for introduction of a novel diagnostic tool, NGS of the 16S–23S rRNA region, which undoubtedly is an improvement for reliable culture-independent species identification directly from polymicrobially constituted clinical samples.

To determine the potential of a non-invasive acoustic device (CADScor®System) to reclassify patients with intermediate pre-test probability (PTP) and clinically suspected stable coronary artery disease (CAD) into a low probability group thereby ruling out significant CAD. Audio recordings and clinical data from three studies were collected in a single database. In all studies, patients with a coronary CT angiography indicating CAD were referred to coronary angiography. Audio recordings of heart sounds were processed to construct a CAD-score. PTP was calculated using the updated Diamond-Forrester score and patients were classified according to the current ESC guidelines for stable CAD: low 85% PTP. Intermediate PTP patients were re-classified to low probability if the CAD-score was ≤ 20. Of 2245 patients, 212 (9.4%) had significant CAD confirmed by coronary angiography ( ≥ 50% diameter stenosis). The average CAD-score was higher in patients with significant CAD (38.4 ± 13.9) compared to the remaining patients (25.1 ± 13.8; p

Background Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. Methods In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

AIM To evaluate the role of small bowel capsule endoscopy (SBCE) on the reclassification of colonic inflammatory bowel disease type unclassified (IBDU). METHODS We performed a multicenter, retrospective study including patients with IBDU undergoing SBCE, between 2002 and 2014. SBCE studies were reviewed and the inflammatory activity was evaluated by determining the Lewis score (LS). Inflammatory activity was considered significant and consistent with Crohn's disease (CD) when the LS >= 135. The definitive diagnosis during follow-up (minimum 12 mo following SBCE) was based on the combination of clinical, analytical, imaging, endoscopic and histological elements. RESULTS Thirty-six patients were included, 21 females (58%) with mean age at diagnosis of 33 +/- 13 (15-64) years. The mean follow-up time after the SBCE was 52 +/- 41 (12-156) mo. The SBCE revealed findings consistent with significant inflammatory activity in the small bowel (LS >= 135) in 9 patients (25%); in all of them the diagnosis of CD was confirmed during follow-up. In 27 patients (75%), the SBCE revealed no significant inflammatory activity (LS < 135); among these patients, the diagnosis of Ulcerative Colitis (UC) was established in 16 cases (59.3%), CD in 1 case (3.7%) and 10 patients (37%) maintained a diagnosis of IBDU during follow-up. A LS >= 135 at SBCE had a sensitivity = 90%, specificity = 100%, positive predictive value = 100% and negative predictive value = 94% for the diagnosis of CD. CONCLUSION SBCE proved to be fundamental in the reclassification of patients with IBDU. Absence of significant inflammatory activity in the small intestine allowed exclusion of CD in 94% of cases., info:eu-repo/semantics/publishedVersion

As a result of amendments in existing financial reporting standards, certain items have been transferred (or recycled) from other comprehensive income to income statement since 2013. Based on a sample of Turkish listed firms over 2013-2018, we document the following outcomes for accounting quality, measured by value relevance and predictive power, of recycling. First, recycling is not value relevant, and net income with recycling and net income are equally value relevant. In other words, recycling does not provide useful information for valuation purposes. Second, net income with recycling and net income have statistically indifferent predictive powers

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis This work was supported by Obra Social “La Caixa Foundation” (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), La Marató de TV3 (400/U/2015) and Sociedad Española Cardiología, Proyecto Investigación Básica Cardiología 2020

Background National mortality statistics should be comparable between countries that use the World Health Organization’s International Classification of Diseases. Distinguishing between manners of death, especially suicides and accidents, is a challenge. Knowledge about accidents is important in prevention of both accidents and suicides. The aim of the present study was to assess the reliability of classifying deaths as accidents and undetermined manner of deaths in the three Scandinavian countries and to compare cross-national differences. Methods The cause of death registers in Norway, Sweden and Denmark provided data from 2008 for samples of 600 deaths from each country, of which 200 were registered as suicides, 200 as accidents or undetermined manner of deaths and 200 as natural deaths. The information given to the eight experts was identical to the information used by the Cause of Death Register. This included death certificates, and if available external post-mortem examinations, forensic autopsy reports and police reports. Results In total, 69 % (Sweden and Norway) and 78 % (Denmark) of deaths registered in the official mortality statistics as accidents were confirmed by the experts. In the majority of the cases where disagreement was seen, the experts reclassified accidents to undetermined manner of death, in 26, 25 and 19 % of cases, respectively. Few cases were reclassified as suicides or natural deaths. Among the extracted accidents, the experts agreed least with the official mortality statistics concerning drowning and poisoning accidents. They also reported most uncertainty in these categories of accidents. In a second re-evaluation, where more information was made available, the Norwegian psychiatrist and forensic pathologist increased their agreement with the official mortality statistics from 76 to 87 %, and from 85 to 88 %, respectively, regarding the Norwegian and Swedish datasets. Among the extracted undetermined deaths in the Swedish dataset, the two experts reclassified 22 and 51 %, respectively, to accidents. Conclusion There was moderate agreement in reclassification of accidents between the official mortality statistics and the experts. In the majority of cases where there was disagreement, accidents were reclassified as undetermined manner of death, and only a small proportion as suicides.

OBJECTIVES The study sought to investigate the association between soluble growth stimulation expressed gene 2 (sST2) Level and adverse outcomes in acute heart failure (HF).BACKGROUND Several studies have demonstrated the prognostic utility of sST2 Levels in HF.METHODS sST2 levels were measured in sequential baseline and follow-up (48 to 72 h and 30 days) plasma samples from 858 acute HF subjects enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial biomarker substudy and were related to in-hospital and post-discharge clinical outcomes.RESULTS Higher sST2 levels were associated with increased death risk at 180 days (baseline hazard ratio [FIR]: 2.21; follow-up HR: 2.64; both p 60 ng/ml) sST2 Levels at follow-up had higher 180-day death rates than those with lower follow-up sST2 Levels (adjusted HR: 2.91, p = 0.004). Neither baseline nor follow-up sST2 levels were associated with dyspnea improvement. Changes in sST2 from baseline were less in the nesiritide versus placebo group at follow-up, but were similar at 30 days.CONCLUSIONS Elevated levels of sST2 were associated with an increased risk of adverse clinical events in acute HF, but prognostic value of baseline sST2 diminished after adjusting for clinical covariates and aminoterminal pro-B-type natriuretic peptide. In those with elevated baseline sST2 Levels, persistently elevated sST2 levels at follow-up were associated with increased mortality risk. In addition, nesiritide did not demonstrate an incremental impact on sST2 Levels over standard therapy. (C) 2016 by the American College of Cardiology Foundation.

Background: Disease severity may change in the first week after acute respiratory distress syndrome (ARDS) onset. The aim of this study was to evaluate whether the reclassification of disease severity after 48 h (i.e. day 3) of ARDS onset could help in predicting mortality and determine factors associated with ARDS persistence and mortality. Methods: We performed a secondary analysis of a 3-year prospective, observational cohort study of ARDS in a tertiary care referral center. Disease severity was reclassified after 48 h of enrollment, and cases that still fulfilled the Berlin criteria were regarded as nonresolving ARDS. Results: A total of 1034 ARDS patients were analyzed. Overall hospital mortality was 57.7% (56.7%, 57.5%, and 58.6% for patients with initial mild, moderate, and severe ARDS, respectively, p = 0.189). On day 3 reclassification, the hospital mortality rates were as follows: resolved (42.1%), mild (47.9%), moderate (62.4%), and severe ARDS (76.1%) ( p 2/FiO2, or higher positive end-expiratory pressure on day 1 were significantly associated with nonresolving ARDS on day 3. A Cox regression model with ARDS severity as a time-dependent covariate and competing risk analysis demonstrated that ARDS severity was independently associated with hospital mortality, and nonresolving ARDS had significantly increased hazard of death than resolved ARDS ( p Conclusions: Reclassification of disease severity after 48 h of ARDS onset could help to divide patients into subgroups with greater separation in terms of mortality. The reviews of this paper are available via the supplemental material section.

The aim of this paper was to explore pharmacists&rsquo, views on reclassifications from pharmacy-only to general sales and their experiences with the supply of these medicines, in addition to pharmacists&rsquo, views on the reclassification of the shingles vaccine and sildenafil to be available through &lsquo, accredited&rsquo, pharmacists. New Zealand community pharmacists were surveyed in 2013 with a written questionnaire of six Likert-style or open-ended questions sent to Pharmacy Guild member pharmacies. The analysis involved descriptive statistics. Responses were received from 246 pharmacies. Two thirds of pharmacists supported the reclassification of the shingles vaccine and sildenafil, although 14% disagreed with the sildenafil reclassification. Over 90% of pharmacists disagreed with the reclassification of paracetamol and ibuprofen liquids, omeprazole, naproxen, and oxymetazoline from pharmacy-only medicine to general sales. This opinion was strongest for omeprazole. With liquid paracetamol and ibuprofen, pharmacists described consumer confusion with dosing, and particularly potentially doubling-up on liquid analgesics/antipyretics including using both prescription and non-prescription variants. Many reported giving safety advice frequently. Anti-inflammatories and omeprazole were also subject to potential double-dosing, as well as requests by consumers with contraindications, precautions, and drug interactions, and for inappropriate indications. Pharmacists described various interventions, including some that were potentially life-saving. Pharmacy availability of medicines provides the potential for intervention that would not happen in a general sales environment.

WOS: 000436479200017, PubMed ID: 29758173, 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., National Health and Medical Research Council Early Career FellowshipNational Health and Medical Research Council of Australia [1122330]; National Heart Foundation of Australia Future Leader FellowshipNational Heart Foundation of Australia [100833]; National Health and Medical Research Council Practitioner FellowshipNational Health and Medical Research Council of Australia [1059156]; Robert Lancaster Memorial Fund - McColl's Retail Group Ltd., Dr Gray is the recipient of a National Health and Medical Research Council Early Career Fellowship (Fellowship no # 1122330). Dr Ingles is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (Fellowship no # 100833). Dr Semsarian is the recipient of a National Health and Medical Research Council Practitioner Fellowship (Fellowship no # 1059156). Dr Behr receives research funding from the Robert Lancaster Memorial Fund sponsored by McColl's Retail Group Ltd.

// Angel Borque-Fernando 1, * , Jose Rubio-Briones 2, * , Luis Mariano Esteban 3 , Argimiro Collado-Serra 2 , Yoni Pallas-Costa 4 , Pedro Angel Lopez-Gonzalez 5 , Jorge Huguet-Perez 6 , Jose Ignacio Sanz-Velez 7 , Jesus Manuel Gil-Fabra 1 , Enrique Gomez-Gomez 8 , Cristina Quicios-Dorado 9 , Lluis Fumado 10 , Sara Martinez-Breijo 11 and Juan Soto-Villalba 12 , on behalf of the PIEM Active Surveillance Study Group 1 Department of Urology, Hospital Universitario Miguel Servet, IIS-Aragon, Zaragoza, Spain 2 Department of Urology, Instituto Valenciano de Oncologia, Valencia, Spain 3 Escuela Universitaria Politecnica de La Almunia, Universidad de Zaragoza, Zaragoza, Spain 4 Department of Urology, Hospital de Manises, Valencia, Spain 5 Department of Urology, Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain 6 Department of Urology, Hospital Clinic de Barcelona, Barcelona, Spain 7 Department of Urology, Hospital General San Jorge, Huesca, Spain 8 Department of Urology, Hospital Universitario Reina Sofia, IMIBIC, Cordoba, Spain 9 Department of Urology, Fundacion Jimenez Diaz, Madrid, Spain 10 Department of Urology, Hospital del Mar, Barcelona, Spain 11 Department of Urology, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain 12 Department of Urology, Hospital Universitario Puerta del Mar, Cadiz, Spain * These authors have contributed equally to this work Correspondence to: Luis Mariano Esteban, email: lmeste@unizar.es Keywords: active surveillance; prostate cancer; reclassification; risk calculator; external validation Received: August 10, 2017 Accepted: October 03, 2017 Published: October 24, 2017 ABSTRACT The follow up of patients on active surveillance requires to repeat prostate biopsies. Predictive models that identify patients at low risk of progression or reclassification are essential to reduce the number of unnecessary biopsies. The aim of this study is to validate the Prostate Active Surveillance Study risk calculator (PASS-RC) in the multicentric Spanish Urological Association Registry of patients on active surveillance (AS), from common clinical practice. Results: We find significant differences in age, PSA and clinical stage between our validation cohort and the PASS-RC generation cohort ( p < .0001), with a reclassification rate of 10–22% on the follow-up Bx, no cancer was found in 43% of the first follow-up Bx. The calibration curve shows underestimation of real appearance of reclassification. The AUC is 0.65 (C.I.95%: 0.60–0.71). PDF and CUC do not suggest a specific cut-off point of clinical use. Methods: We select 498 patients on AS with a minimum of one follow-up biopsy (Bx) from the 1,024 males registered by 36 Spanish centers recruiting patients on the Spanish Urological Association Registry on AS. PASS-RC external validation is carried by means of calibration curve and area under de ROC-curve (AUC), identifying cut-offs of clinical utility by probability density functions (PDF) and clinical utility curves (CUC). Conclusions: In our first external validation of the PASS-RC we have obtained a moderate discrimination ability, although we cannot recommend cut-off points of clinical use. We suggest the exploration of new biomarkers and/or morpho-functional parameters from multiparametric magnetic resonance image, to improve those necessary tools on AS.

Background: The use of the Coronary Artery Calcium Score (CACS) for risk categorization instead of the Framingham Risk Score (FRS) or European Heart SCORE (EHS) to improve classification of individuals is well documented. However, the impact of reclassifying individuals using CACS on initiating lipid lowering therapy is not well understood. We aimed to determine the percentage of individuals not requiring lipid lowering therapy as per the FRS and EHS models but are found to require it using CACS and vice versa; and to determine the level of agreement between CACS, FRS and EHS based models. Methods: Data was collected for 500 consecutive patients who had already undergone CACS. However, only 242 patients met the inclusion criteria and were included in the analysis. Risk stratification comparisons were conducted according to CACS, FRS, and EHS, and the agreement (Kappa) between them was calculated. Results: In accordance with the models, 79.7% to 81.5% of high-risk individuals were down-classified by CACS, while 6.8% to 7.6% of individuals at intermediate risk were up-classified to high risk by CACS, with slight to moderate agreement. Moreover, CACS recommended treatment to 5.7% and 5.8% of subjects untreated according to European and Canadian guidelines, respectively; whereas 75.2% to 81.2% of those treated in line with the guidelines would not be treated based on CACS. Conclusion: In this simulation, using CACS for risk categorization warrants lipid lowering treatment for 5–6% and spares 70–80% from treatment in accordance with the guidelines. Current strong evidence from double randomized clinical trials is in support of guideline recommendations. Our results call for a prospective trial to explore the benefits/risks of a CACS-based approach before any recommendations can be made.

Diabetic kidney disease is diagnosed and staged by albuminuria and estimated glomerular filtration rate. Although albuminuria has strong predictive power for renal function decline, there is still variability in the rate of renal disease progression across individuals that are not fully captured by the level of albuminuria. Therefore, research focuses on discovering and validating additional biomarkers that improve risk stratification for future renal function decline and end-stage renal disease in patients with diabetes, on top of established biomarkers. Most studies address the value of single biomarkers to predict progressive renal disease and aim to understand the mechanisms that underlie accelerated renal function decline. Since diabetic kidney disease is a disease encompassing several pathophysiological processes, a combination of biomarkers may be more likely to improve risk prediction than a single biomarker. In this review, we provide an overview of studies on the use of multiple biomarkers and biomarker panels, appraise their study design, discuss methodological pitfalls and make recommendations for future biomarker panel studies.

Aims The low lymphocyte counts and high neutrophil leucocyte fractions have been associated with poor prognosis in chronic heart failure. We hypothesized that the baseline ratio of the neutrophil leucocytes to the lymphocytes (NL ratio) would predict the outcome of chronic heart failure patients undergoing cardiac resynchronization therapy (CRT). Methods and results The qualitative blood counts and the serum levels of N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) of 122 chronic heart failure patients and 122 healthy controls were analysed prospectively in this observational study. The 2-year mortality was considered as primary endpoint and the 6-month reverse remodelling (≥15% decrease in the end-systolic volume) as secondary endpoint. Multivariable regression analyses were applied and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. The NL ratio was elevated in chronic heart failure patients when compared with the healthy controls [2.93 (2.12–4.05) vs. 2.21 (1.64–2.81), P < 0.0001]. The baseline NL ratio exceeding 2.95 predicted the lack of the 6-month reverse remodelling [n = 63, odds ratio = 0.38 (0.17–0.85), P = 0.01; NRI = 0.49 (0.14–0.83), P = 0.005; IDI = 0.04 (0.00–0.07), P = 0.02] and the 2-year mortality [n = 29, hazard ratio = 2.44 (1.04–5.71), P = 0.03; NRI = 0.63 (0.24–1.01), P = 0.001; IDI = 0.04 (0.00–0.08), P = 0.02] independently of the NT-proBNP levels or other factors. Conclusion The NL ratio is elevated in chronic heart failure and predicts outcome after CRT. According to the reclassification analysis, 4% of the patients would have been better categorized in the prediction models by combining the NT-proBNP with the NL ratio. Thus, a single blood count measurement could facilitate the optimal patient selection for the CRT.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

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.

Purpose: The objective of the present study was to validate an existing prediction rule (including age, education, depressive/anxiety symptoms, and recovery expectations) for predictions of the duration of sickness absence due to common mental disorders (CMDs) and investigate the added value of work-related factors. Methods: A prospective cohort study including 596 employees who reported sick with CMDs in the period from September 2013 to April 2014. Work-related factors were measured at baseline with the Questionnaire on the Experience and Evaluation of Work. During 1-year follow-up, sickness absence data were retrieved from an occupational health register. The outcome variables of the study were sickness absence (no = 0, yes = 1) at 3 and 6 months after reporting sick with CMDs. Discrimination between workers with and without sickness absence was investigated at 3 and 6 months with the area under the receiver operating characteristic curve (AUC). Results: A total of 220 (37 %) employees agreed to participate and 211 (35 %) had complete data for analysis. Discrimination was poor with AUC = 0.69 and AUC = 0.55 at 3 and 6 months, respectively. When ‘variety in work’ was added as predictor variable, discrimination between employees with and without CMD sickness absence improved to AUC = 0.74 (at 3 months) and AUC = 0.62 (at 6 months). Conclusions: The original prediction rule poorly predicted CMD sickness absence duration. After adding ‘variety in work’, the prediction rule discriminated between employees with and without CMD sickness absence 3 months after reporting sick. This new prediction rule remains to be validated in other populations.

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 53.0 months) 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. (C) 2017 Elsevier B.V. All rights reserved.

INTRODUCTION: CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to

SFAS No. 115 requires firms to recognize available-for-sale (AFS) securities at fair value with accumulated unrealized gains and losses (AUGL) recorded in accumulated other comprehensive income. Firms reclassify AUGL to net income when they realize gains and losses. We refer to the amount reclassified each period by ''RECLASS.'' As of 1998, SFAS No. 130 requires firms to present RECLASS prominently in their financial statements. We investigate the incremental explanatory power of RECLASS for banks' market values and market-adjusted returns. In the market value analysis, we control for AUGL, other components of book value of equity, net income before extraordinary items and RECLASS (NIBEXother), and other components of comprehensive income. In the returns analysis, we control for DAUGL, DNIBEXother, and extraordinary items. We find high positive coefficients on RECLASS in both analyses, consistent with investors pricing RECLASS as a relatively permanent component of net income. Exploring possible explanations for these pricing implications, we find no evidence that they are attributable to RECLASS remedying unreliable fair value measurement of AUGL. We provide three distinct analyses indicating that RECLASS's pricing implications are explained in significant part by it helping investors predict banks' future performance. Our results illustrate that an important type of amortized cost accounting information, realized gains and losses, remains highly useful to investors despite the overall fair-value-accounting framework for AFS securities.

M. Kaste on työryhmän VISTA-Acute Collaboration jäsen. Background: There is increasing interest in the use of administrative data (incorporating comorbidity index) and stroke severity score to predict ischemic stroke mortality. The aim of this study was to determine the optimal timing for the collection of stroke severity data and the minimum clinical dataset to be included in models of stroke mortality. To address these issues, we chose the Virtual International Stroke Trials Archive (VISTA), which contains National Institutes of Health Stroke Scale (NIHSS) on admission and at 24 hours, as well as outcome at 90 days. Methods: VISTA was searched for patients who had baseline and 24-hour NIHSS. Improvement in regression models was performed by the net reclassification improvement (NRI) method. Results: The clinical data among 5206 patients were mean age, 69 +/- 13; comorbidity index, 3.3 +/- .9; median NIHSS at baseline, 12 (interquartile range [IQR] 8-17); NIHSS at 24 hours, 9 (IQR 8-15); and death at 90 days in 15%. The baseline model consists of age, gender, and comorbidity index. Adding the baseline NIHSS to model 1 improved the NRI by 0.671 (95% confidence interval [CI] 0.595-0.747) [or 67.1% correct reclassification between model 1 and model 2]. Adding the 24 hour NIHSS term to model 1 (model 3) improved the NRI by 0.929 (95% CI 0.857-1.000) for model 3 versus model 1. Adding the variable thrombolysis to model 3 (model 4) improve NRI by 0.1 (95% CI 0.023-0.178) [model 4 versus model 3]. Conclusion: The optimal model for the prediction of mortality was achieved by adding the 24-hour NIHSS and thrombolysis to the baseline model.

OBJECTIVE Development of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth-differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF-15 potential in nondiabetic subjects with hypertension (HT). RESEARCH DESIGN AND METHODS Case and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition. RESULTS Prior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885–1,546] vs. 948 pg/mL [660–1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1–7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1–3.5], P = 0.02) and improved prediction significantly. CONCLUSIONS We identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects.

Many promising biomarkers for stratifying individuals at risk of developing a chronic disease or subsequent complications have been identified. Research into the potential cost-effectiveness of applying these biomarkers in actual clinical settings has however been lacking. Investors and analysts may improve their venture decision making should they have indicative estimates of the potential costs and effects associated with a new biomarker technology already at the early stages of its development. To assist in obtaining such estimates, this paper presents a general method for the early health technology assessment of a novel biomarker technology. The setting considered is that of primary prevention programs where initial screening to select high-risk individuals eligible for a subsequent intervention occurs, for example, prevention of type 2 diabetes. The method is based on quantifying the health outcomes and downstream healthcare consumption of all individuals who get reclassified as a result of moving from a screening variant based on traditional risk factors to a screening variant based on traditional risk factors plus a novel biomarker. As these individuals form well-defined subpopulations, a combination of disease progression modeling and sensitivity analysis can be used to perform an initial assessment of the maximum increase in screening cost for which the use of the new biomarker technology is still likely to be cost effective. Copyright (C) 2012 John Wiley & Sons, Ltd.

The act of classifying information created by accounting practices is ubiquitous in the accounting process; from recording to reporting, it has almost become second nature. The classification has to correspond to the requirements and demands of the changing environment in which it is practised. Evidence suggests that the current classification of items in financial statements is not keeping pace with the needs of users and the new financial constructs generated by the industry. This study addresses the issue of classification in two ways: by means of a critical analysis of classification theory and practices and by means of a questionnaire that was developed and sent to compilers and users of financial statements. A new classification framework for accounting information in the balance sheet and income statement is proposed.

Aims: To re-estimate the SCORE risk function using individual data on risk factors and coronary heart disease (CHD) incidence from the Dutch Cardiovascular Registry Maastricht (CAREMA) population-based cohort study; to evaluate changes that may improve risk prediction after re-estimation; and to compare the performance of the resulting CAREMA risk function with that of existing risk scores. Methods and results: The cohort consisted of 21,148 participants, born in 1927–1977 and randomly sampled from the Maastricht region in 1987–1997. After follow-up (median 10.9 years), 783 incident CHD cases occurred. Model performance was assessed by discrimination and calibration. The additional value of including other risk factors or current risk factors in a different manner was evaluated using the net reclassification index (NRI). The c statistic of the re-estimated SCORE model was 0.799 (95% CI 0.782–0.816). Separating the total/high-density lipoprotein (HDL) cholesterol ratio into total and HDL cholesterol levels did not improve the c statistic ( p = 0.22), but reclassified 6.0% of the participants into a more appropriate risk category ( p Conclusion: In this Dutch population, a re-estimated SCORE function with total and HDL cholesterol levels instead of the cholesterol ratio can be used for the risk prediction of CHD incidence.

Background: A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b ( 10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. Objective: Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. Design, setting, and participants: Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. Intervention: Patients underwent either radical or partial nephrectomy. Measurements: Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. Results and limitations: In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend < 0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. Conclusions: The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Background Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure. Methods and Results We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals ( PTI ) of the aortic pressure waveform, independently predicts incident heart failure ( HF ) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ E SPTI ) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ E SPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI =1.15 to 1.29; P HF ( HR =1.23; 95% CI =1.14 to 1.32: P HF , L/ E SPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ E SPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF , the HR associated with hypertension was 1.39 (95% CI =0.86 to 2.23; P =0.18), whereas the HR associated with a high L/E was 2.31 (95% CI =1.52 to 3.49; P Conclusions Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.

The Net Reclassification Improvement (NRI) has become a popular metric for evaluating improvement in disease prediction models through the past years. The concept is relatively straightforward but usage and interpretation has been different across studies. While no thresholds exist for evaluating the degree of improvement, many studies have relied solely on the significance of the NRI estimate. However, recent studies recommend that statistical testing with the NRI should be avoided. We propose using confidence ellipses around the estimated values of event and non-event NRIs which might provide the best measure of variability around the point estimates. Our developments are illustrated using practical examples from EPIC-Potsdam study.

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).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 rate60 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; p0.001) and 25.5% for soluble (s)ST2 (p0.001). 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 (p0.05 for all). CRP also markedly improved risk stratification of patients with ADHF as a dual biomarker combination with MR-proADM (NRI 36.8% [p0.001] for death at 30 days) or with sST2 (NRI 20.3%; [p0.001] for one-year mortality).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.