Low Residual Risk Research Articles

The relationship between ceramide profile and residual inflammatory risk in patients with coronary artery disease: Insights from an prospective study

BackgroundAlthough progress has been made in managing cholesterol, targeting inflammation is essential for further reducing cardiovascular risk, as CVDs remain the leading cause of death globally. This study aimed to explore the association between plasma ceramide levels and residual inflammatory risk in patients with CAD. MethodsA cross-sectional observational design was adopted using data from a secondary analysis of a multicenter prospective cohort study in China. Patients were categorized into two groups based on a hs-CRP level of 2.0mg/L. Plasma ceramide levels were measured using the LC-MS/MS system. By collecting and statistically analyzing patient demographic and clinical characteristics, differences were compared between the low residual inflammatory risk group (Low RIR) and the high residual inflammatory risk group (High RIR). Multivariate logistic regression analysis was used to assess the interaction of plasma ceramides with high residual inflammation risk. ResultsA total of 778 patients with confirmed CAD were included in the study. Compared to the Low RIR, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/24:0), and Cer (d18:1/24:1), were significantly elevated in the High RIR group. Spearman correlation analysis indicated that Cer (d18:1/16:0) levels were positively correlated with hsCRP. Further multivariable logistic regression analysis revealed that Cer (d18:1/16:0) was a significant independent indicator of high RIR beyond conventional cardiovascular risk factors. ConclusionThis study found a significant association between specific plasma ceramide Cer (d18:1/16:0) and high residual inflammatory risk in CAD patients, suggesting it could be an important inflammatory biomarker in the management of cardiovascular diseases.

Hybrid therapy with ablation + subcutaneous ICD for secondary prevention of sudden cardiac death in ischemic heart disease

Abstract Background The aim of the prospective Ventricular Tachycardia Ablation- Subcutaneous ICD (VTAbl-SICD) Trial was to provide data on the efficacy and safety of a novel hybrid management strategy that combines VT ablation (VTAbl) with S-ICD implantation in patients who present with scar-related VT. The rate of appropriate therapy in patients with S-ICD may be a quite fairest surrogate of true residual sudden death (SD) risk compared to transvenous ICD (TV-ICD). More specific data on ischemic heart disease – the prominent cause of VT with the better results of VTAbl – may give arguments for questioning current practices in the future. Methods 32 patients with post ischemic scar-related sustained VT/VF were included. Patients underwent VTAbl with subsequent (or previous prophylactic n=8) S-ICD implant and were followed for 2-years. We evaluate the occurrence of appropriate and ICD therapies once ablated, as well as cardiovascular (CV) readmissions or death. We also compared to 64 propensity-score matched patients implanted with a secondary prevention TV-ICD (enrolled in the Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators (RAID) trial). Results Mean age was 57±12 years (28 males, 87%) (53% hypertension, 31% diabetes and 47% congestive heart failure with NYHA 1.6±1). Mean LVEF was 39±9%.There were no major complications associated with the ablation and implant procedures. Propensity-score matched patients implanted with a secondary prevention TV-ICD displayed similar clinical characteristics. At 16.5±8.6 months FU, appropriate ICD therapy occurred in 5 patients (15%) in the VTAbl-SICD group, significantly lower compared to the TV-ICD group (34 pts, 53%) (p<0.001). This corresponded to 2-year cumulative probability of 20% vs. 71% in the VTAbl-SICD vs. TV-ICD groups, respectively (log-rank p<0.001; Figure 1) and a significant 83% reduction in the risk of appropriate ICD therapy associated with VTAbl-SICD (HR= 0.17 [95% CI 0.07 - 0.39; p<0.001). Two of the patients who received appropriate ICD therapy in the VTAbl-SICD group may have had unrecognized transient causes of VT (torsades de pointes or unrecognized ischemia), letting 3 out of 32 (10%) with possible aborted SD caused by VT recurrences. There were no cases of untreated symptomatic VT. The rate of CV readmissions was similar in the VTAbl-SICD (41%) vs. TV-ICD group (44%) (p=0.7), whereas mortality was significantly lower in the VTAbl-SICD- vs.TV-ICD- group (0% vs. 17%, respectively; p<0.001) Conclusions Our findings suggest that VT ablation in ischemic heart disease patients allow reaching a low residual true risk for SD, which should now be evaluated in terms of cost-effectiveness compared to ablation + S-ICD implantation. Concommitant S-ICD implantation seems to be a safe alternative to TV-ICD without ablation.Appropriate ICD therapy-free KM

Prognostic significance of inflammation in patients with coronary artery disease at low residual inflammatory risk

Patients with coronary artery disease (CAD) at low residual inflammatory risk are often overlooked in research and practice. This study examined the associations between fourteen inflammatory indicators and all-cause mortality in 5,339 CAD patients with baseline high-sensitivity C-reactive protein (hsCRP) <2mg/L who received percutaneous coronary intervention and statin and aspirin therapy. The median follow-up time was 2.1 years. Neutrophil-derived systemic inflammatory response index (SIRI) yielded the strongest and most robust association with all-cause mortality among all indicators. Lower hsCRP remained to be associated with a lower risk of all-cause mortality. A newly developed comprehensive inflammation score (CIS) showed better predictive performance than other indicators, which was validated by an independent external cohort. In conclusion, neutrophil-derived indicators, particularly SIRI, strongly predicted all-cause mortality independent of hsCRP in CAD patients at low residual inflammatory risk. CIS may help identify individuals with inflammation burdens that cannot be explained by hsCRP alone.

There Is No Such Thing as Zero Risk of Sexual Offending

The public is justifiably concerned about the risk presented by individuals with a history of sexual crime. Given that recidivism risk varies across individuals and over time, what level is so low as to be indistinguishable from sexual recidivism risk in the general population (a desistance threshold)? This risk is not zero. Comparing census data with the number of males convicted of sexual offences in the province of British Columbia in two cohorts (2006, N = 362; 2011, N = 422), we found that approximately 1% of all adult males in British Columbia would be expected to be convicted of a sexual offence by age 50. Across the full lifespan (until 99), that proportion was estimated to be 1.38% for the 2006 cohort and 1.50% for the 2011 cohort. Other research has found that most individuals released from a sexual offence present a similarly low residual risk (&lt; 2%) after 10 years of being offence-free in the community. Consequently, applying long-term restrictions (e.g., lifetime registration; Criminal Code of Canada §161) to such individuals serves no public protection function.

Low risk of human T-lymphotropic virus infection in U.S. blood donors; Is it time to consider a one-time selective testing approach?

U.S. blood donors are tested at each donation for human T-lymphotropic virus (HTLV) antibodies. Depending on donor incidence and other mitigation/removal technologies, a strategy of one-time selective donor testing should be considered. Antibody seroprevalence was calculated for HTLV-confirmed-positive American Red Cross allogeneic blood donors from 2008 to 2021. Incidence was estimated for seven 2-year time periods using confirmed-positive repeat donors having seroconverted in 730 days. Leukoreduction failure rates were obtained from internal data from July 1, 2008-June 30, 2021. Residual risks were calculated using a 51-day window period. Between 2008 and 2021, >75 million donations (>18 million donors) yielded 1550 HTLV seropositives. HTLV seroprevalence was 2.05 antibody-positives per 100,000 donations (0.77 HTLV-1, 1.03 HTLV-2, 0.24 HTLV-1/2), and 10.32 per 100,000 among >13.9 million first-time donors. Seroprevalence differed significantly by virus type, sex, age, race/ethnicity, donor status, and U.S. census region. Over 14 years and 24.8 million person-years of observation, 57 incident donors were identified (25 HTLV-1, 23 HTLV-2, and 9 HTLV-1/2). Incidence decreased from 0.30 (13 cases) in 2008-2009 to 0.25 (7 cases) in 2020-2021. Female donors accounted for most incident cases (47 vs. 10 males). In the last 2-year reporting period, the residual risk was 1 per 2.8 million donations and 1 per 3.3 billion donations when coupled with successful leukoreduction (0.085% failure rate). HTLV donation seroprevalence for the years 2008-2021 varied by virus type and donor characteristics. Low HTLV residual risk and use of leukoreduction processes support the conclusion that a selective one-time donor testing strategy should be considered.

A Novel Biosignature Identifies Patients With DCIS With High Risk of Local Recurrence After Breast Conserving Surgery and Radiation Therapy

There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT. Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS >2.8 without RRt), and (3) Residual Risk (DS >2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment. In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P < .001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P < .001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive). The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches.

Single-dose versus short-course prophylactic antibiotics for peroral endoscopic myotomy: a randomized controlled trial

Peroral endoscopic myotomy (POEM) has been recommended for achalasia treatment. To prevent the potential of infective risk, antibiotic prophylaxis is usually administered, whereas the additional need of antibiotic therapy after POEM is uncertain. The primary endpoint was to determine whether prophylaxis versus prophylaxis plus short therapy was needed after POEM. Consecutive patients scheduled for POEM were randomly assigned (1:1) to group A (prophylactic cefazolin 2 g IV) or group B (prophylaxis+ cefazolin 2 g IV× 3 followed by oral amoxicillin/clavulanate 3 g/day). Infective risk was assessed by means of host response, namely body temperature and serum levels of white blood cells and C-reactive protein; immune response (the cytokines interleukin [IL]-6, IL-1β, and tumor necrosis factor-α and microbial translocation mediators lipopolysaccharide binding protein and soluble CD14); and blood cultures at time points before (t0) and after (t1, t2) POEM. After POEM, none of the 124 enrolled patients (54.6 ± 12.6 years old; 64 men) developed any fever (body temperature: t0, 36.56± .49°C; t1, 36.53± .52°C; t2, 36.48± .41°C), without any differences between groups at any time point. Regarding systemic inflammation, no difference was reported between groups in serum levels of C-reactive protein and white blood cells. Considering microbial translocation mediated response, lipopolysaccharide binding protein (group A: t0, 1539 ± 168.6 pg/mL; t1, 1321 ± 149.1 pg/mL; t2, 2492 ± 283.2 pg/mL; group B: t0, 1318 ± 115.9 pg/mL; t1, 1492 ± 163.8 pg/mL; t2, 2600 ± 328.2 pg/mL) and soluble CD14 (group A: t0, 2.16 ± .15 μg/mL; t1, 1.89 ± .15 μg/mL; t2, 2.2 ± .15 μg/mL; group B: t0, 2.1 ± .13 μg/mL; t1, 2 ± .13 μg/mL; t2, 2.5 ± .2 μg/mL) were similar between the 2 groups; the immune response cytokines IL-6, IL-1β, and tumor necrosis factor-α also were similar in the 2 groups. In relation to blood cultures, at t1 the group B bacteremia rate was 3.2% (2/62) and group A was 1.6% (1/62) with no difference (P= .6). All subsequent blood cultures were negative at t2. According to our study, postprophylactic short-term antimicrobial therapy after POEM is not required because of a very low residual infective risk. (Clinical trial registration number: NCT03587337.).

Association between thromboembolic and bleeding risk with adverse outcomes in contemporary European atrial fibrillation patients: final analysis from the ESC-EHRA EORP AF general long-term registry

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The ESC-EHRA EORP AF General Long-Term Registry provides a contemporary snapshot of European atrial fibrillation (AF) patients’ characteristics and management. Aims: We present data about the final 2-years follow-up observation of AF patients enrolled in the ESC-EHRA EORP AF General Long-Term Registry. Methods A contemporary evaluation of residual risk of adverse outcomes in a cohort of largely anticoagulated AF patients according to the baseline thromboembolic and bleeding risk, defined according to CHA2DS2-VASc and HAS-BLED scores. We determined cardiovascular (CV) events, CV death and all-cause death as outcomes. Results Among the original 11069 patients enrolled, 8409 (76.0%) patients had available follow-up status at the end of the 2-years follow-up. Patients age, female sex and most comorbidities were progressively more prevalent across the spectrum of thromboembolic and bleeding risk. Data on adverse outcomes were available for 10087 (91.1%), over the 2-year observation period. Outcome rates were progressively higher across CHA2DS2-VASc and HAS-BLED scores (all p &amp;lt; 0.0001). A fully adjusted Cox multivariable regression analysis, adjusted for clinical covariates selected by a univariate procedure and not included in the scores, showed that increasing baseline CHA2DS2-VASc score was associated with an higher risk for CV events (hazard ratio [HR]: 1.25, 95% confidence interval [CI]: 1.21-1.30), CV death (HR: 1.31, 95%CI: 1.25-1.38) and all-cause death (HR: 1.30, 95%CI: 1.25-1.36). Similarly, increasing baseline HAS-BLED score was associated with an increased risk for all 3 outcomes (HR: 1.21, 95%CI: 1.13-1.28; HR: 1.24, 95%CI: 1.14-1.34; HR: 1.22, 95%CI: 1.14-1.31, respectively). An association with a progressively higher risk was found for all outcomes across the spectrum of thromboembolic and bleeding risk [Figure]. Both CHA2DS2-VASc and HAS-BLED scores showed a modest to good predictive ability for cardiovascular (CV) events, CV death and all-cause death, in terms of c-index and 95% CI[0.66 (0.64-0.68) and 0.62 (0.61-0.64), 0.70 (0.68-0.72) and 0.65 (0.63-0.67), 0.69 (0.68-0.71) and 0.64 (0.63-0.66) for CHA2DS2-VASc and HAS-BLED for each outcome respectively. Conclusions In this large contemporary European-wide cohort of AF patients, both baseline thromboembolic and bleeding risks were associated to an increased risk of major clinical outcomes. Both scores are reflective of high risk clinical states, and are predictive of major adverse outcomes even in a large cohort of largely anticoagulated patients with a lower residual risk of adverse outcomes. Abstract Figure.

Effectiveness of cardiac telerehabilitation with relapse prevention compared to centre-based cardiac rehabilitation: results from the SmartCare-CAD randomised controlled trial

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was part of the SmartCare project, which was partially funded under the ICT Policy Support Programme (ICT PSP), grant agreement number 325158. Background Most studies failed to show superiority of cardiac telerehabilitation (CTR) over traditional, centre-based cardiac rehabilitation (CR). Purpose To evaluate the effectiveness of a novel CTR intervention on the adherence to a physically active lifestyle in patients with coronary artery disease (CAD). Methods We randomised patients with CAD entering phase II outpatient CR to either CTR with relapse prevention by on-demand coaching (intervention group), or centre-based CR with supervised exercise training (control group). The primary outcome measure was objectively assessed physical activity level (PAL), secondary outcome measures included physical fitness and quality of life (QoL). Results A total of 300 patients (89% male, mean age 60.7 ± 9.5 years) participated in the trial. Both groups significantly improved their PAL at 12 months follow-up (p &amp;lt; 0.01), but without a significant between-group difference in the response over time (p = 0.73). Similarly, we observed sustained increases in physical fitness and QoL, but without significant between-group differences in responses over time. Conclusions In patients with CAD who had low residual cardiovascular risk, CTR with relapse prevention resulted in a sustained increase in PAL, physical fitness and QoL, but without differences in responses over time as compared to centre-based CR. For this reason, future CTR interventions should be directed specifically to patients who are at risk for relapse into unhealthy lifestyle behaviour. Main outcome measures Control (centre-based CR) Intervention (CTR) Baseline 3 months 12 months Within groups p-value 0-3 months Within groups p-value 0-12 months Baseline 3 months 12 months Within groups p-value 0-3 months Within groups p-value 0-12 months PAL † 1.40 (0.45) 1.53 (0.48) 1.55 (0.46) &amp;lt;0.001 0.001 1.44 (0.50) 1.67 (0.50) 1.61 (0.46) &amp;lt;0.001 &amp;lt;0.001 Workload (% of expected) * 92.1 ± 19.3 103.6 ± 19.5 104.8 ± 21.0 &amp;lt;0.001 &amp;lt;0.001 91.3 ± 18.6 101.2 ± 18.8 102.5 ± 19.6 &amp;lt;0.001 &amp;lt;0.001 KVL-H total † 5.3 (1.4) 6.1 (1.0) 6.3 (0.9) &amp;lt;0.001 &amp;lt;0.001 5.4 (1.8) 6.0 (1.0) 6.2 (1.0) &amp;lt;0.001 &amp;lt;0.001 CR cardiac rehabilitation; CTR: cardiac telerehabilitation; KVL-H: Kwaliteit van Leven bij Hartpatiënten (quality of life in cardiac patients); PAL: physical activity level. †Values reported as median (interquartile range). Within-groups differences assessed by Wilcoxon signed-rank test. *Values reported as mean ± standard deviation. Within-groups differences assessed by paired samples T-test.

Extremely low HDL and residual cardiovascular risk—a case report

Extremely low high-density lipoprotein cholesterol (HDL-C) is defined as levels below 20 mg/dL. Association between extremely low HDL-C levels may occur from artifactual, primary monogenic disorders or from secondary causes. We present a 55-year-old known diabetic male with extremely low HDL, in the absence of severe hypertriglyceridemia, with apolipoprotein A1 deficiency and presenting with acute myocardial infarction. Transradial angiography revealed triple vessel disease, for which the patient was medically managed and sent home in a stable condition and is presently on follow-up. Such cases are infrequent and pose a diagnostic challenge.

Hard or soft flood adaptation? Advantages of a hybrid strategy for Shanghai

Flood risk is expected to increase in coastal cities, particularly in Asian megacities such as Shanghai. This paper presents an integrated modeling framework to simulate changes in the flood risk in Shanghai and provide a cost-benefit analysis of multiple adaptation strategies used to reduce risk. The results show that the potential flood risk will increase dramatically as a result of sea level rise, land subsidence, and socioeconomic development. By 2100, the expected annual damage could reach 0.8% (uncertainty range: 0.4%–1.4%) of local GDP under an optimistic emission scenario (RCP4.5), compared to the current value of 0.03%. All of the adaptation strategies can effectively reduce the flood risk under the current conditions and those in 2050. In contrast to the ‘hard’ flood protection strategies (i.e., storm-surge barriers and floodwalls), the ‘soft’ strategies (i.e., building codes and nature-based measures) cannot substantially reduce the flood risk in 2100. However, the soft strategies can play a critical role in reducing the residual risk resulting from the hard strategies. A ‘hybrid’ strategy combining a storm-surge barrier, wet-proofing, and coastal wetland development outperforms both hard and soft strategies in terms of low residual risk and high benefit/cost ratio. Additionally, the hybrid strategy can also enable a larger reduction in casualties. These findings imply that managing flood risk is more than the use of single adaptation measures. The methodology developed in this paper can enlighten Shanghai and other coastal cities on an economically and socially feasible adaptation strategy in an uncertain future.

1029: Low residual risk NIPT: does 1st trimester biochemistry add clinical value?

PAPP-A and beta-hCG are used in aneuploidy risk assessment and abnormal levels are associated with adverse OB outcomes. In those with normal NIPT, there is no known benefit to obtaining biochemistry. Our objective was to determine the impact of biochemistry in those with normal NIPT on rates of invasive genetic testing, fetal assessment, or OB outcomes. Women with normal NIPT referred for ultrasound at 11-14 weeks from 7/1/2018 - 9/30/2018 were included. Those with biochemistry were compared to those referred for NT only. Women with invasive testing for conditions other than aneuploidy were excluded. Rates of invasive testing (CVS or amnio), rates of third trimester fetal assessment, and OB outcomes were compared in the two groups. Fisher’s exact test and Mann-Whitney U were used for comparison. 622 patients were included: 490 (79%) with biochemistry and 132 (21%) with NT only. 47% were ≥35-years, and were less likely to have biochemistry vs. women < 35 (66% vs. 90%; p< .001). Invasive testing rates were similar with and without biochemistry (5.9% vs. 7.6%; p=.54), with a trend towards higher rates in women < 35 who had biochemistry (9.4% vs. 2.4%; p=.06). Women categorized as “increased risk” based on NT/biochemistry had higher rates (35.3% vs. 4.9%; p< .001). Invasive testing identified only one abnormal karyotype (mosaic T21) in a woman at low adjusted risk based on NT/biochemistry. There were no differences in rates of third-trimester fetal assessment (ultrasound EFW or NST/BPP). Gestational age at birth, Apgar scores, and rates of prematurity and IUGR were similar between the two groups adjusted for age. Obtaining biochemistry with NT in those at low risk based on normal NIPT was not associated with different rates of invasive testing and did not lead to any diagnoses of aneuploidy. In younger women, false-positive results were associated with a trend towards higher rates of invasive testing. Rates of fetal assessment and OB outcomes were similar. Our data do not support any clinical role for first-trimester biochemistry in those with normal NIPT.

88. Public Health Service (PHS) Increased-Risk Factors in Organ Donors: A Review of the OPTN Ad hoc Disease Transmission Advisory Committee (DTAC)

BackgroundIn the United States, all deceased donors (DD) are evaluated for behavioral risk factors for human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) infection during the past 12 months. DD with behavioral risk factors or hemodilution are designated as PHS increased risk donors (IRD). Since 2013, the number of IRD has increased from 13.4% of DD to 27% in 2018. Despite a low residual risk of disease transmission after a negative nucleic acid test for HIV/HBV/HCV, the considerable underutilization of IRD has driven an interest in revising the PHS IRD 2013 guidelines. The objective of this study was to describe the epidemiology of IRD with the goal of guiding policy change and maximize organ use.MethodsThis is a retrospective cohort study of DD during 2018. Characteristics of IRD were compared with non-IRD. A random 10% sample of IRD was selected for manual review of text narratives and donor questionnaires submitted by organ procurement organizations to determine specific PHS IRD factors. Categorical variables were compared using the χ 2 test and continuous variables were compared using a 2-sample t-test for independent samples.ResultsAmong 10,721 DD in 2018, 2,904 were designated IRD (27.1%) with regional variability noted (Figure). Compared with non-IRD, IRD were younger (median age 35 vs. 45 years, P < 0.001) and more often died from drug intoxication (33.2 vs. 5.6%, P < 0.001). Hemodilution was found in 6.8% of all IRD and was the only factor for IRD designation in 60% of pediatric donors <12 years old. The random sample of IRD (N = 288) was similar to IRD population for age, gender, ethnicity, cause of death, and region of recovery (table). Descriptive analysis of the random sample showed that intravenous drug use was the most common behavioral risk factor (N = 124, 43.1%), followed by incarceration (N = 108, 37.5%). Most DD met only 1 criterion (N = 179, 62%); 21% met 2 criteria; and 17% had >3 criteria.ConclusionThis study represents the most detailed description of PHS IRD factors since the adoption of the new guidelines in 2013. Understanding the prevalence of factors that lead to IRD designation will help inform future policy development, optimize safe DD use, and increase the number of transplants. Disclosures All Authors: No reported Disclosures.

Empagliflozin (EMPA) Reduces Mortality and Hospitalization for Heart Failure (HHF) Irrespective of Cardiovascular (CV) Risk Score at Baseline

In the EMPA-REG OUTCOME trial, EMPA added to standard of care reduced CV death vs. placebo (PBO) by 38% (HR 0.62 [95% CI 0.49, 0.77]), all-cause death by 32% (HR 0.68 [95% CI 0.57, 0.82]) and HHF by 35% (HR 0.65 [95% CI 0.50, 0.85]) in patients with type 2 diabetes and established CV disease. We investigated CV death, all-cause death, HHF and the composite of HHF or CV death by degree of baseline CV risk using the 10-point TIMI Risk Score for Secondary Prevention (TRS 2°P). P-values for treatment-by-subgroup interaction were obtained from tests of homogeneity of treatment group differences among subgroups with no adjustment for multiple testing. Based on the TRS 2°P risk score, of 7020 patients who received study drug in the EMPA-REG OUTCOME trial, 12%, 40%, 30% and 18% were at low, intermediate, high and highest residual CV risk, respectively, at baseline. In the placebo group, from low to highest predicted risk, the proportion of patients with CV death increased from 2.2% to 11.2% and the proportion of patients with HHF increased from 1.1% to 10.0%. Effects of EMPA on CV death, all-cause death, HHF and HHF or CV death were consistent across subgroups by baseline CV risk score (Figure). In conclusion, the benefits of EMPA on key clinical outcomes in the EMPA-REG OUTCOME trial occurred irrespective of the degree of baseline CV risk. Disclosure D.H. Fitchett: Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Amgen Inc., Sanofi. B.M. Scirica: Research Support; Self; AstraZeneca, Eisai Inc., Novartis Pharmaceuticals Corporation, Merck &amp; Co., Inc., Poxel SA. Consultant; Self; AstraZeneca, Biogen, Boehringer Ingelheim Pharmaceuticals, Inc., Covance Inc., Elsevier, GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, St. Jude Medical, LLC., Dr Reddy's Laboratory. Other Relationship; Self; Health[at] Scale. S. Inzucchi: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Sanofi, Lexicon Pharmaceuticals, Inc.. Consultant; Self; VTV Therapeutics. Other Relationship; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc., Alere Inc. C.P. Cannon: Research Support; Self; Amgen Inc., Arisaph Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Takeda Pharmaceuticals U.S.A., Inc.. Consultant; Self; Alnylam, Amarin Corporation, Amgen Inc., Arisaph Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Regeneron Pharmaceuticals, Inc., Sanofi, Eisai Inc., GlaxoSmithKline plc., Kowa Pharmaceuticals America, Inc., Lipimedix, Merck &amp; Co., Inc., Pfizer Inc., Takeda Pharmaceuticals U.S.A., Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. O. Johansen: Employee; Self; Boehringer Ingelheim GmbH. S. Sambevski: Employee; Self; Boehringer Ingelheim GmbH. U. Hehnke: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck &amp; Co., Inc., Abbott.

Comparison of Residual Risk–Based Eligibility vs Tumor Size and Nodal Status for Power Estimates in Adjuvant Trials of Breast Cancer Therapies

Many large adjuvant clinical trials end up underpowered because of fewer than expected events in the control arm. Ensuring a minimum number of events would result in more informative trials. To calculate individualized residual risk estimates using residual risk prediction software and assess whether defining eligibility based on a minimum residual risk threshold could increase the reliability of clinical trial power calculations compared with eligibility criteria based on tumor size and nodal status. We estimated residual risk in 443 consecutive patients with early-stage breast cancer and assessed clinical trial power as a function of residual risk distribution among the accrued patients. We defined residual risk as the risk of recurrence that remains despite receipt of standard-of-care therapy; this risk is determined by baseline prognostic risk and by the improvement from adjuvant therapy. We performed trial simulations to examine how the power of a 2-arm, 1:1 randomized clinical trial would change as the residual risk distribution of the trial population that met eligibility criteria based on tumor size and nodal status changes. We also simulated trials that use a minimum residual risk value as eligibility criterion. Residual risk; clinical trial power as a function of residual risk distribution among the patients. In the 443 patients (mean [SD] age, 56.1 [12.3] years; range, 23-89 years), baseline prognostic and residual risks differed substantially: 328 (74%) patients had more than 20% baseline risk of recurrence; however, after adjustment for treatment effect only 12 (27%) had more than 20% residual risk. We assessed residual risk distribution in patient cohorts that met tumor size- and nodal status-based eligibility criteria for 3 currently accruing randomized adjuvant trials; the median residual risks were 28% (interquartile range [IQR], 25%-31%), 22% (IQR, 15%-28%), and 22% (IQR, 15%-28%), respectively, indicating that the power of these trials could vary unpredictably. Simulations showed that trials that use anatomical risk-based eligibility criteria can become underpowered if they accrue patients with low residual risk despite all participants meeting eligibility requirements. Using a minimum required residual risk threshold as eligibility criterion produced more reliable power calculations. When tumor size and nodal status are used to determine trial eligibility, the residual risk of recurrence can vary broadly, leading to unstable power estimates. The success of future adjuvant trials could be improved by defining patient eligibility based on a minimal residual risk of recurrence, and these trials can achieve a prespecified power with smaller sample sizes.

Low hepatitis E virus RNA prevalence in a large-scale survey of United States source plasma donors.

Hepatitis E virus (HEV) is a small, nonenveloped, single-stranded, RNA virus of emerging concern in industrialized countries. HEV transmission through transfusion of blood components has been reported, but not via plasma-derived medicinal products (PDMPs) manufactured with virus inactivation and/or removal steps. This study aimed to determine the prevalence of HEV among US source plasma donors. Samples were collected from US source plasma donors at centers across the United States and were initially screened for HEV RNA in 96-sample minipools using the Roche cobas HEV test on the cobas 8800 system. Assuming a sensitivity of 18.6IU/mL, the minipool screening strategy allowed for reliable detection of individual donations with HEV RNA titers of more than 2×103 IU/mL. Reactive minipools were resolved to individual donations, which were further analyzed to quantify viral RNA concentration, determine HEV genotype, and immunoglobulin (Ig)G and IgM HEV antibody status. A total of 128,020 samples were collected from 96 CSL Plasma centers in the United States, representing 27 states. The prevalence of HEV RNA-positive samples was 0.002% with three unique HEV-positive donors identified, all HEV Subgenotype 3a. Virus titers of HEV-positive samples were relatively low (103 -104 IU HEV RNA/mL). One positive donation was HEV IgG seropositive. Routine screening of US source plasma donations for HEV would not substantially improve the safety of most PDMPs. The low prevalence and potential viral load of HEV, together with effective virus reduction steps in manufacturing processes, results in a low residual risk and acceptable safety margins for PDMPs derived from US plasma donors.

Portfolio optimization of safety measures for reducing risks in nuclear systems

In the framework of Probabilistic Risk Assessment (PRA), we develop a method to support the selection of cost-effective portfolios of safety measures. This method provides a systemic approach to determining the optimal portfolio of safety measures that minimizes the risk of the system and thus provides an alternative to using risk importance measures for guiding the selection of safety measures. We represent combinations of events leading to system failure with Bayesian Belief Networks (BBNs) which can be derived from traditional Fault Trees (FTs) and are capable of encoding event dependencies and multi-state failure behaviours. We also develop a computationally efficient enumeration algorithm to identify which combinations (portfolios) of safety measures minimize the risk of failure at different costs of implementing the safety measures. The method is illustrated by revisiting an earlier case study concerning the airlock system of a CANDU Nuclear Power Plant (NPP). The comparison of results with those of choosing safety measures based on risk importance measures shows that our approach leads to considerably lower residual risk at different cost levels.

Abstract P4-11-03: Androgen receptor expression is an independent marker of lower residual risk in the TACT2 trial (CRUK/05/019)

Abstract Introduction: TACT2 (CRUK/05/019), a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control tested two hypotheses in a 2x2 factorial design, with previously presented results showing: i) no evidence of a benefit from accelerated 2-weekly epirubicin (aE) compared to standard 3-weekly epirubicin (E) (Cameron 2012); and ii) capecitabine (X) gives equivalent efficacy but preferential side-effect profile to CMF (Canney 2014). Studies suggest that Androgen receptor (AR) expression may be associated with improved outcome in early breast cancer. We performed an analysis of AR expression in TACT2 patients to test the hypothesis that AR would represent an independent predictor of residual risk following adjuvant therapy. Methods: Tumour samples were collected prospectively from 3803/4391 TACT2 patients, Tissue micro-arrays were constructed as per published guidelines and central AR, ER, PgR, HER2, Ki67, CK5/6, EGFr and BCL2 staining performed and quantified by imaged analysis for ER, PgR, HER2, Ki67 and BCL2. EGFr and CK5/6 were dichotomised by light microscopy evaluation of cores. After planned biomarker analyses had been performed, a subset of TACT2 cases for whom remaining tissue was available were analysed for AR expression. Data for 1878 cases was available for this analysis (49% of those consenting to tissue collection). AR expression was dichotomised as AR-ve (&amp;lt;10%) vs AR+ve (&amp;gt;10%). Log-rank tests were used to explore the prognostic value of AR on time to recurrence (TTR). Cox-regression models were used to test the independent prognostic value of AR in the presence of tumour size, grade, nodal status, and biological subtypes. Marker by treatment interaction terms were included in models to test the predictive value of AR for both randomised treatment comparisons. Results: 1398/1878 (74%) patients were classed as AR+ve and 480/1878 (26%) as AR-ve. The proportion of AR+ve patients differed significantly between biological subtypes (Luminal A 269/293 (92%); Luminal B 784/928 (84%); HER+ve 86/111 (77%); Basal-like 37/216 (17%); 5-marker-ve 37/93 (40%); χ2 p&amp;lt;0.001) 117/480 (24%) AR-ve patients had a TTR event compared with 183/1398 (13%) AR+ve patients (HR for AR-ve compared to AR+ve =2.05 95%CI 1.63-2.59; p&amp;lt;0.001). AR expression remained independently prognostic following adjustment for nodal status, grade, tumour size and biological subtype (HR1.68, 95%CI 1.26-2.25; p&amp;lt;0.001). Exploratory analysis suggested the prognostic impact of AR might be predominantly in luminal B and 5-marker-ve breast cancers; however the interaction between subtype and AR was not statistically significant. No differential treatment effect between AR subtypes was observed for either randomised treatment comparison (E/aE or CMF/X). Conclusion: AR is an independent prognostic marker for residual risk following chemotherapy in this large study which included patients with both luminal and non-luminal cancers. AR expression patterns differ between molecular subtypes of early breast cancer, with evidence suggesting the impact of AR on residual risk may also differ between subtypes. AR is currently being explored as another potential target for therapy so these data could have future clinical relevance. Citation Format: Jane Bayani, James Morden, Sunil Skaria, Peter Bliss, Robert Grieve, Adrian Harnett, Chris Bradley, Diana Ritchie, Peter Barrett-Lee, Peter Canney, David Cameron, Judith Bliss, John Bartlett. Androgen receptor expression is an independent marker of lower residual risk in the TACT2 trial (CRUK/05/019) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-03.

Estimating the residual risk for HIV, HCV and HBV in different types of platelet concentrates in Germany

We estimated and compared the residual risks due to window-period donations for pooled and apheresis platelets in Germany using a modification of a previously described statistical model. This model directly utilizes the reported interdonation intervals before a positive donation and reflects in this aspect the look-back procedures used in haemovigilance. Data from the German National Blood Donor Surveillance System for the years 2006-2012, including reports about donations from repeat donors with confirmed positive test results for HIV, HCV and HBV, were used to estimate the risk of undetected infectious units for both pooled and apheresis platelets. Demographics of whole-blood and apheresis donors differed in age, gender, catchment area and interdonation interval. These differences impact on the prevalence and incidence of transfusion relevant infections and consequently the residual risk. The estimates for the residual risks for pooled and apheresis platelets were comparable. For HIV, there was no significant difference, for HCV apheresis platelets had a lower residual risk, whereas pooled platelets had a lower risk for undetected HBV infections. These findings do not support calls for a shift to an apheresis platelets-only policy in Germany.

Risk Assessment of Core Banking System Replacement based on ISACA Framework

Many banks are looking for a better core banking system to support their business growth with a more efficient and flexible core banking system to improve their sales and services in the competitive market and to fulfill regulatory requirements. The decision of replacing the legacy core banking system is difficult due to the high IT investment cost required for banks because they are also trying to cut costs. But maintaining the legacy system is costly in terms of upgrade. Changing the core banking system is also a difficult process and increases risks. To have a successful Core Banking System implementation, risk assessment is required to be performed prior to starting any activities. The assessment can help project teams to identify the risks and then to mitigate the risks as part of the plan. In this research the Core Banking System replacement risks were assessed based on ISACA Framework for IT Risk. Fourteen risk scenarios related to Core Banking System Replacement were identified. The high and medium rated inherent risks can become medium and low residual risk after assessment by putting the relevant control in place. The result proves that by adding mitigation plan it will help to mitigate the Residual Risk to become low risk. There are still three residual risk which categorized as medium risk and should be further mitigated they are Software Implementation, Project Delivery and Selection/Performance of Third Party Suppliers. It is also found that COBIT 5 has considered some specific process capabilities that can be used to improve the processes to mitigate the medium risks.