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Background Creatinine clearance (CrCl) is an independent determinant of mortality in predictive models of revascularisation outcomes for complex coronary artery disease. Aims This study aimed to investigate the impact of preprocedural biological markers on 10-year mortality following coronary revascularisation. Methods The SYNTAX Extended Survival (SYNTAXES) study evaluated the 10-year vital status follow-up of 1,800 patients with de novo three-vessel (3VD) and/or left main coronary artery disease (LMCAD) randomised to include percutaneous or surgical coronary revascularisation. The associations between mortality and preprocedural C-reactive protein (CRP), haemoglobin, HbA1c, CrCl, fasting triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were analysed. Results Out of 1,800 patients, 460 patients died before the 10-year follow-up. CRP, HbA1c and CrCl with threshold values of ≥2 mg/L, ≥6% (42 mmol/mol) and l60 ml/min, respectively, were associated with 10-year all-cause death (adjusted hazard ratio [95% confidence interval]: 1.35 [1.01-1.82], 1.51 [1.16-1.95], and 1.46 [1.07-2.00], respectively). There was no significant interaction between the biological markers on all-cause mortality and the type of revascularisation. Preprocedural lipid markers were not significantly associated with 10-year all-cause death, but the non-use of statins was a determinant factor of worse prognosis (adjusted confidence interval [95% confidence interval]: 1.68 [1.26-2.25]). Conclusions Preprocedural biomarkers, such as CRP and HbA1c, are associated with long-term mortality post revascularisation, regardless of the revascularisation technique. Conventional lipidic biomarkers associated with high-risk of cardiovascular events seem to be effectively mitigated by the long-term use of statins, whereas the non-use of statins was a factor of a worse prognosis, emphasising the importance of pharmacological treatment. Trial registration SYNTAXES ClinicalTrials.gov reference: NCT03417050. SYNTAX ClinicalTrials.gov reference: NCT00114972.

BACKGROUND The radial artery is recommended by international guidelines as the default vascular access in patients with acute coronary syndromes (ACS) managed invasively. However, crossover from radial to femoral access is required in 4-10% of cases and has been associated with worse outcomes. No standardised algorithm exists to predict the risk of radial crossover. AIMS We sought to derive and externally validate a risk score to predict radial crossover in patients with ACS managed invasively. METHODS The derivation cohort consisted of 4,197 patients with ACS undergoing invasive management via the randomly allocated radial access from the MATRIX trial. Using logistic regression, we selected predictors of radial crossover and developed a numerical risk score. External validation was accomplished among 3,451 and 491 ACS patients managed invasively and randomised to radial access from the RIVAL and RIFLE-STEACS trials, respectively. RESULTS The MATRIX score (age, height, smoking, renal failure, prior coronary artery bypass grafting, ST-segment elevation myocardial infarction, Killip class, radial expertise) showed a c-index for radial crossover of 0.71 (95% CI: 0.67-0.75) in the derivation cohort. Discrimination ability was modest in the RIVAL (c-index: 0.64; 95% CI: 0.59-0.67) and RIFLE-STEACS (c-index: 0.66; 95% CI: 0.57-0.75) cohorts. A cut-off of ≥41 points was selected to identify patients at high risk of radial crossover. CONCLUSIONS The MATRIX score is a simple eight-item risk score which provides a standardised tool for the prediction of radial crossover among patients with ACS managed invasively. This tool can assist operators in anticipating and better addressing difficulties related to transradial procedures, potentially improving outcomes.

Background: The goal of trauma systems is to match patient care needs to the capabilities of the receiving centre. Severely injured patients have shown better outcomes if treated in a major trauma centre (MTC). We aimed to evaluate patient distribution in the Dutch trauma system. Furthermore, we sought to identify factors associated with the undertriage and transport of severely injured patients (Injury Severity Score (ISS) >15) to the MTC by emergency medical services (EMS).Methods: Data on all acute trauma admissions in the Netherlands (2015-2016) were extracted from the Dutch national trauma registry. An ambulance driving time model was applied to calculate MTC transport times and transport times of ISS >15 patients to the closest MTC and non-MTC. A multivariable logistic regression analysis was performed to identify factors associated with ISS >15 patients' EMS undertriage to an MTC.Results: Of the annual average of 78,123 acute trauma admissions, 4.9% had an ISS >15. The nonseverely injured patients were predominantly treated at non-MTCs (79.2%), and 65.4% of patients with an ISS >15 received primary MTC care. This rate varied across the eleven Dutch trauma networks (36.8%-88.4%) and was correlated with the transport times to an MTC (Pearson correlation -0.753, p=0.007). The trauma networks also differed in the rates of secondary transfers of ISS >15 patients to MTC hospitals (7.8% 59.3%) and definitive MTC care (43.6% - 93.2%). Factors associated with EMS undertriage of ISS >15 patients to the MTC were female sex, older age, severe thoracic and abdominal injury, and longer additional EMS transport times.Conclusions: Approximately one-third of all severely injured patients in the Netherlands are not initially treated at an MTC. Special attention needs to be directed to identifying patient groups with a high risk of undertriage. Furthermore, resources to overcome longer transport times to an MTC, including the availability of ambulance and helicopter services, may improve direct MTC care and result in a decrease in the variation of the undertriage of severely injured patients to MTCs among the Dutch trauma networks. Furthermore, attention needs to be directed to improving primary triage guidelines and instituting uniform interfacility transfer agreements. (C) 2021 Elsevier Ltd. All rights reserved.

Rationale and research objective: As a result of neoadjuvant chemotherapy (NAC), approximately 1/3 of clinically node positive (cN+) breast cancer patients convert to a pathologic complete response (pCR) of the axilla. Targeted Axillary Dissection appears to be most accurate to evaluate axillary treatment-response, but evidence to support this is limited. The RISAS trial was set up to determine the accuracy of sentinel lymph node biopsy (SLNB) combined with excision of the pretreatment marked positive lymph node for axillary staging after NAC in cN+ patients. Methods: This prospective, multicenter trial included cT1-4N1,2,3b patients treated with NAC. Prior to NAC, an iodine seed was placed in the pathologically confirmed positive lymph node. After NAC, all patients underwent SLNB together with excision of the marked lymph node (RISAS-procedure) followed by axillary lymph node dissection (ALND). The identification rate and the accuracy (i.e. false negative rate (FNR) and negative predictive value (NPV)) were calculated for the RISAS procedure. Assuming an FNR of 2%, a prevalence of a positive ALND of 64% and a 10% drop-out rate, a sample size of 248 patients was needed to determine non-inferiority. The NULL hypothesis of inferiority would be rejected at a significance level of 5% if the upper bound of the two-sided 90% Clopper-Pearson confidence interval of the observed FNR would be below the non-inferiority margin of 6.25%. Secondary objectives included the accuracy of the SLNB and excision of the marked lymph node separately. Results: A total of 252 pathologically proven cN+ patients provided informed consent of whom 227 underwent the RISAS procedure/Targeted Axillary Dissection (SLNB combined with excision of the marked positive lymph node). The identification rate of the RISAS procedure is 98% (223/227). Preliminary analysis shows a false negative rate of approximately 5% and a negative predictive value of approximately 91%. Furthermore, by combining SLNB with excision of the marked lymph node, both the identification rate and the accuracy are improved compared to either the SLNB alone or the excision of the marked lymph node alone. Conclusion: This prospective multicenter validation trial shows that the RISAS procedure/Targeted Axillary Dissection is most suitable in terms of identification rate and accuracy to replace ALND for axillary staging after NAC in cN+ patients. The trial was funded by the Dutch Cancer Society (KWF, grant number 2015-8023). Citation Format: Janine Simons, Thiemo JA v Nijnatten, Linetta B Koppert, Carmen C van der Pol, Paul J v Diest, Agnes Jager, David v Klaveren, Boen LR Kam, Marc BI Lobbes, Maaike de Boer, Cees Verhoef, Paul RA Sars, Harold J Heijmans, Els RM van Haaren, Wouter J Vles, Caroline ME Contant, Marian BE Menke, Leonie HM Smit, Wendy Kelder, Marike Boskamp, Ingeborg Mares-Engelberts, Ernest JT Luiten, Marjolein L Smidt. Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: Results of the prospective multicenter RISAS trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-10.

Background: The poorer prognosis of coronary artery disease in females compared with males is related mainly to differences in baseline characteristics. In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, the effect of treatment with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting surgery (CABG) on mortality at 5 years differed significantly between females and males; however, the optimal revascularization beyond 5 years according to sex has not been evaluated. Objectives: The aim of this study was to investigate the impact of sex on mortality and sex-treatment interaction at 10 years. Methods: The SYNTAXES (SYNTAX Extended Survival) study evaluated vital status up to 10 years in 1,800 patients with de novo 3-vessel and/or left main coronary artery disease randomized to treatment with PCI or CABG in the SYNTAX trial. All-cause death at 10 years was separately evaluated in female and male patients with complex coronary artery disease. Results: Of 1,800 patients, 402 (22.3%) were female and 1,398 (77.7%) were males. Females had a higher 10-year mortality rate compared with males (32.8% vs. 24.7%; log-rank p = 0.002), but female sex was not an independent predictor of mortality (adjusted hazard ratio: 1.02; 95% confidence interval: 0.76 to 1.36). Mortality at 10 years tended to be lower after CABG than after PCI, with a similar treatment effect for female and male patients (adjusted hazard ratio for females: 0.90 [95% confidence interval: 0.54 to 1.51]; adjusted hazard ratio for males: 0.76 [95% confidence interval: 0.56 to 1.02]; p for interaction = 0.952). Conclusions: Female sex was not an independent predictor of mortality at 10 years in patients with complex coronary artery disease. The interaction between sex and treatment with PCI or CABG that was observed at 5 years was no longer present at 10 years. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES], NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX], NCT00114972)

Background This study was conducted to validate a pretreatment (i.e. prior to neoadjuvant chemoradiotherapy) pathological staging system in the resection specimen after neoadjuvant chemoradiotherapy for esophageal cancer. The study investigated the prognostic value of pretreatment pathological T and N categories (prepT and prepN categories) in both an independent and a combined patient cohort. Methods Patients with esophageal cancer treated with neoadjuvant chemotherapy and esophagectomy between 2012 and 2015 were included. PrepT and prepN categories were estimated based on the extent of tumor regression and regressional changes of lymph nodes in the resection specimen. The difference in Akaike’s information criterion (ΔAIC) was used to assess prognostic performance. PrepN and ypN categories were combined to determine the effect of nodal sterilization on prognosis. A multivariable Cox regression model was used to identify combined prepN and ypN categories as independent prognostic factors. Results The prognostic strength of the prepT category was better than the cT and ypT categories (ΔAIC 7.7 vs. 3.0 and 2.9, respectively), and the prognostic strength of the prepN category was better than the cN category and similar to the ypN category (ΔAIC 29.2 vs. − 1.0 and 27.9, respectively). PrepN + patients who became ypN0 had significantly worse survival than prepN0 patients (2-year overall survival 69% vs. 86% in 137 patients; p = 0.044). Similar results were found in a combined cohort of 317 patients (2-year overall survival 62% vs. 85%; p = 0.002). Combined prepN/ypN stage was independently associated with overall survival. Conclusions These results independently confirm the prognostic value of prepTNM staging. PrepTNM staging is of additional prognostic value to cTNM and ypTNM. PrepN0/ypN0 patients have a better survival than prepN +/ypN0 patients.

Quality of life research 31(2), 451-471 (2022). doi:10.1007/s11136-021-02932-z, Published by Springer Science + Business Media B.V, Dordrecht [u.a.]

The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.

Background Prehospital triage protocols typically try to select patients with Injury Severity Score (ISS) above 15 for direct transportation to a Level-1 trauma center. However, ISS does not necessarily discriminate between patients who benefit from immediate care at Level-1 trauma centers. The aim of this study was to assess which patients benefit from direct transportation to Level-1 trauma centers. Methods We used the American National Trauma Data Bank (NTDB), a retrospective observational cohort. All adult patients (ISS > 3) between 2015 and 2016 were included. Patients who were self-presenting or had isolated limb injury were excluded. We used logistic regression to assess the association of direct transportation to Level-1 trauma centers with in-hospital mortality adjusted for clinically relevant confounders. We used this model to define benefit as predicted probability of mortality associated with transportation to a non-Level-1 trauma center minus predicted probability associated with transportation to a Level-1 trauma center. We used a threshold of 1% as absolute benefit. Potential interaction terms with transportation to Level-1 trauma centers were included in a penalized logistic regression model to study which patients benefit. Results We included 388,845 trauma patients from 232 Level-1 centers and 429 Level-2/3 centers. A small beneficial effect was found for direct transportation to Level-1 trauma centers (adjusted Odds Ratio: 0.96, 95% Confidence Interval: 0.92–0.99) which disappeared when comparing Level-1 and 2 versus Level-3 trauma centers. In the risk approach, predicted benefit ranged between 0 and 1%. When allowing for interactions, 7% of the patients (n = 27,753) had more than 1% absolute benefit from direct transportation to Level-1 trauma centers. These patients had higher AIS Head and Thorax scores, lower GCS and lower SBP. A quarter of the patients with ISS > 15 were predicted to benefit from transportation to Level-1 centers (n = 26,522, 22%). Conclusions Benefit of transportation to a Level-1 trauma centers is quite heterogeneous across patients and the difference between Level-1 and Level-2 trauma centers is small. In particular, patients with head injury and signs of shock may benefit from care in a Level-1 trauma center. Future prehospital triage models should incorporate more complete risk profiles.

Background This study aimed to develop an easy to use prediction model to predict the risk of having a total of 1 to 2, >= 3, or >= 4 positive axillary lymph nodes (LNs), for patients with sentinel lymph node (SLN) positive breast cancer. Methods Data of 911 SLN positive breast cancer patients were used for model development. The model was validated externally in an independent population of 180 patients with SLN positive breast cancer. Results Final pathology after ALND showed additional positive LN for 259 (28%) of the patients. A total of 726 (81%) out of 911 patients had a total of 1 to 2 positive nodes, whereas 175 (19%) had >= 3 positive LNs. The model included three predictors: the tumor size (in mm), the presence of a negative SLN, and the size of the SLN metastases (in mm). At external validation, the model showed a good discriminative ability (area under the curve = 0.82; 95% confidence interval = 0.74-0.90) and good calibration over the full range of predicted probabilities. Conclusion This new and validated model predicts the extent of nodal involvement in node-positive breast cancer and will be useful for counseling patients regarding their personalized axillary treatment.

Aims To evaluate the impact of chronic obstructive pulmonary disease (COPD) on 10-year all-cause death and the treatment effect of CABG versus PCI on 10-year all-cause death in patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) and COPD. Methods Patients were stratified according to COPD status and compared with regard to clinical outcomes. Ten-year all-cause death was examined according to the presence of COPD and the revascularization strategy. Results COPD status was available for all randomized 1800 patients, of whom, 154 had COPD (8.6%) at the time of randomization. Regardless of the revascularization strategy, patients with COPD had a higher risk of 10-year all-cause death, compared with those without COPD (43.1% vs. 24.9%; hazard ratio [HR]: 2.03; 95% confidence interval [CI]: 1.56–2.64; p p = 0.858), whereas among those without COPD, CABG had a significantly lower risk of 10-year all-cause death (22.7% vs. 27.1%; HR: 0.81; 95% CI: 0.67–0.99, p = 0.041). There was no significant differential treatment effect of CABG versus PCI on 10-year all-cause death between patients with and without COPD (pinteraction = 0.544). Conclusions COPD was associated with a higher risk of 10-year all-cause death after revascularization for complex coronary artery disease. The presence of COPD did not significantly modify the beneficial effect of CABG versus PCI on 10-year all-cause death. Trial registration: SYNTAX: ClinicalTrials.gov reference: NCT00114972. SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050 Graphic abstract

AIMS We aimed to update the logistic clinical SYNTAX score to predict 2��year all-cause mortality after contemporary percutaneous coronary intervention (PCI). METHODS AND RESULTS We analyzed 15,883 patients in the GLOBAL LEADERS study who underwent PCI. The logistic clinical SYNTAX model was updated after imputing missing values by refitting the original model (refitted original model) and fitting an extended new model (new model, with, selection based on the Akaike Information Criterion). External validation was performed in 10,100 patients having PCI at Fu Wai hospital. Chronic obstructive pulmonary disease, prior stroke, current smoker, hemoglobin level, and white blood cell count were identified as additional independent predictors of 2��year all-cause mortality and included into the new model. The c-indexes of the original, refitted original and the new model in the derivation cohort were 0.74 (95% CI 0.72-0.76), 0.75 (95% CI 0.73-0.77), and 0.78 (95% CI 0.76-0.80), respectively. The c-index of the new model was lower in the validation cohort than in the derivation cohort, but still showed improved discriminative ability of the newly developed model (0.72; 95% CI 0.67-0.77) compared to the refitted original model (0.69; 95% CI 0.64-0.74). The models overestimated the observed 2��year all-cause mortality of 1.11% in the Chinese external validation cohort by 0.54 percentage points, indicating the need for calibration of the model to the Chinese patient population. CONCLUSIONS The new model of the logistic clinical SYNTAX score better predicts 2��year all-cause mortality after PCI than the original model. The new model could guide clinical decision making by risk stratifying patients undergoing PCI.

OBJECTIVE: Approximately 84 million people in the US have pre-diabetes, but only a fraction of them receive proven effective therapies to prevent type 2 diabetes. We estimated the value of prioritizing individuals at highest risk of progression to diabetes for treatment, compared to non-targeted treatment of individuals meeting inclusion criteria for the Diabetes Prevention Program (DPP). METHODS: Using microsimulation to project outcomes in the DPP trial population, we compared two interventions to usual care: (1) lifestyle modification and (2) metformin administration. For each intervention, we compared targeted and non-targeted strategies, assuming either limited or unlimited program capacity. We modeled the individualized risk of developing diabetes and projected diabetic outcomes to yield lifetime costs and quality-adjusted life expectancy, from which we estimated net monetary benefits (NMB) for both lifestyle and metformin versus usual care. RESULTS: Compared to usual care, lifestyle modification conferred positive benefits and reduced lifetime costs for all eligible individuals. Metformin’s NMB was negative for the lowest population risk quintile. By avoiding use when costs outweighed benefits, targeted administration of metformin conferred a benefit of $500 per person. If only 20% of the population could receive treatment, when prioritizing individuals based on diabetes risk, rather than treating a 20% random sample, the difference in NMB ranged from $14,000 to $20,000 per person. CONCLUSIONS: Targeting active diabetes prevention to patients at highest risk could improve health outcomes and reduce costs compared to providing the same intervention to a similar number of patients with pre-diabetes without targeted selection.

OBJECTIVE: To develop an electronic health record (EHR)-based risk tool that provides point-of-care estimates of diabetes risk to support targeting interventions to patients most likely to benefit.PATIENTS AND METHODS: A risk prediction model was developed and validated in a large observational database of patients with an index visit date between January 1, 2012, and December 31, 2016, with treatment effect estimates from risk-based reanalysis of clinical trial data. The risk model development cohort included 1.1 million patients with prediabetes from the OptumLabs Data Warehouse (OLDW); the validation cohort included a distinct sample of 1.1 million patients in OLDW. The randomly assigned clinical trial cohort included 3081 people from the Diabetes Prevention Program (DPP) study.RESULTS: Eleven variables reliably obtainable from the EHR were used to predict diabetes risk. This model validated well in the OLDW (C statistic = 0.76; observed 3-year diabetes rate was 1.8% (95% confidence interval [CI], 1.7 to 1.9) in the lowest-risk quarter and 19.6% (19.4 to 19.8) in the highest-risk quarter). In the DPP, the hazard ratio (HR) for lifestyle modification was constant across all levels of risk (HR, 0.43; 95% CI, 0.35 to 0.53), whereas the HR for metformin was highly risk dependent (HR, 1.1; 95% CI, 0.61 to 2.0 in the lowest-risk quarter vs HR, 0.45; 95% CI, 0.35 to 0.59 in the highest-risk quarter). Fifty-three percent of the benefits of population-wide dissemination of the DPP lifestyle modification and 73% of the benefits of population-wide metformin therapy can be obtained by targeting the highest-risk quarter of patients.CONCLUSION: The Tufts-Predictive Analytics and Comparative Effectiveness DPP Risk model is an EHR-compatible tool that might support targeted diabetes prevention to more efficiently realize the benefits of the DPP interventions.

BackgroundAn intensive lifestyle modification program or metformin pharmacotherapy reduced the risk of developing diabetes in patients at high risk, but are not widely used in the 88 million American adults with prediabetes.ObjectiveDevelop an electronic health record (EHR)-based risk tool that provides point-of-care estimates of diabetes risk to support targeting interventions to patients most likely to benefit.DesignCross-design synthesis: risk prediction model developed and validated in large observational database, treatment effect estimates from risk-based reanalysis of clinical trial data.SettingOutpatient clinics in US.PatientsRisk model development cohort: 1.1 million patients with prediabetes from the OptumLabs Data Warehouse (OLDW); validation cohort: distinct sample of 1.1 million patients in OLDW. Randomized clinical trial cohort: 3081 people from the Diabetes Prevention Program (DPP) study.InterventionsRandomization in the DPP: 1) an intensive program of lifestyle modification; 2) standard lifestyle recommendations plus 850 mg metformin twice daily; or 3) standard lifestyle recommendations plus placebo twice daily.ResultsEleven variables reliably obtainable from the EHR were used to predict diabetes risk. This model validated well in the OLDW (c-statistic = 0.76; observed 3-year diabetes rate was 1.8% in lowest-risk quarter and 19.6% in highest-risk quarter). In the DPP, the hazard ratio for lifestyle modification was constant across all levels of risk (HR = 0.43, 95% CI 0.35 – 0.53); while the HR for metformin was highly risk-dependent (HR HR = 1.1 [95% CI: 0.61 - 2.0] in the lowest-risk quarter vs. HR=0.45 [95% CI: 0.35 0.59] in the highest risk quarter). Fifty-three percent of the benefits of population-wide dissemination of the DPP lifestyle modification, and 76% of the benefits of population-wide metformin therapy can be obtained targeting the highest risk quarter of patients.LimitationsDifferences in variable definitions and in missingness across observational and trial settings may introduce estimation error in risk-based treatment effects.ConclusionAn EHR-compatible risk model might support targeted diabetes prevention to more efficiently realize the benefits of the DPP interventions.

Aims Adequate risk prediction can optimize the clinical management in adult congenital heart disease (ACHD). We aimed to update and subsequently validate a previously developed ACHD risk prediction model. Methods and results A prediction model was developed in a prospective cohort study including 602 moderately or severely complex ACHD patients, enrolled as outpatients at a tertiary centre in the Netherlands (2011–2013). Multivariable Cox regression was used to develop a model for predicting the 1-year risks of death, heart failure (HF), or arrhythmia (primary endpoint). The Boston ACHD Biobank study, a prospectively enrolled cohort (n = 749) of outpatients who visited a referral centre in Boston (2012–2017), was used for external validation. The primary endpoint occurred in 153 (26%) and 191 (28%) patients in the derivation and validation cohorts over median follow-up of 5.6 and 2.3 years, respectively. The final model included 5 out of 14 pre-specified predictors with the following hazard ratios; New York Heart Association class ≥II: 1.92 [95% confidence interval (CI) 1.28–2.90], cardiac medication 2.52 (95% CI 1.72–3.69), ≥1 reintervention after initial repair: 1.56 (95% CI 1.09–2.22), body mass index: 1.04 (95% CI 1.01–1.07), log2 N-terminal pro B-type natriuretic peptide (pmol/L): 1.48 (95% CI 1.32–1.65). At external validation, the model showed good discrimination (C-statistic 0.79, 95% CI 0.74–0.83) and excellent calibration (calibration-in-the-large = −0.002; calibration slope = 0.99). Conclusion These data support the validity and applicability of a parsimonious ACHD risk model based on five readily available clinical variables to accurately predict the 1-year risk of death, HF, or arrhythmia. This risk tool may help guide appropriate care for moderately or severely complex ACHD.

Background: Longitudinal bleeding risk scores have been validated in patients treated with dual antiplatelet therapy (DAPT) following percutaneous coronary intervention. How these scores apply to the population of patients with acute coronary syndrome (ACS) treated without revascularization remains unknown. The objective was to evaluate and compare the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) bleeding risk scores in the medically managed patients with ACS treated with DAPT. Methods and Results: TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a double-blind, placebo-controlled randomized trial conducted from 2008 to 2012 over a median follow-up of 17.0 months in 966 sites (52 countries). High-risk patients with unstable angina or non–ST-segment–elevation myocardial infarction who did not undergo revascularization were randomized to prasugrel or clopidogrel. The PRECISE-DAPT, PARIS, and DAPT (bleeding component) risk scores were applied in the TRILOGY ACS population to evaluate their performance to predict adjudicated non–coronary artery bypass grafting–related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe/life-threatening/moderate and TIMI (Thrombolysis in Myocardial Infarction) major/minor bleeding with time-dependent c-indices. Among the 9326 participants, median age was 66 years (interquartile range, 59–74 years), and 3650 were females (39.1%). A total of 158 (1.69%) GUSTO severe/life-threatening/moderate and 174 (1.87%) TIMI major/minor non–coronary artery bypass grafting bleeding events occurred. The c-indices (95% CI) of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores through 12 months were 0.716 (0.677–0.758), 0.693 (0.658–0.733), and 0.674 (0.637–0.713), respectively, for GUSTO bleeding and 0.624 (0.582–0.666), 0.612 (0.578–0.651), and 0.608 (0.571–0.649), respectively, for TIMI bleeding. There was no significant difference in the c-indices of each score based upon pairwise comparisons. Conclusions: Among medically managed patients with ACS treated with DAPT, the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores were reasonable and similar to their performances in the derivation percutaneous coronary intervention populations. Bleeding risk scores may be used to predict longitudinal bleeding risk in patients with ACS treated with DAPT without revascularization and help support shared decision making. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00699998.

PURPOSE: Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM).METHODS: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation.RESULTS: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of CONCLUSIONS: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.

Background Pneumonectomy in lung cancer treatment is associated with considerable morbidity and mortality. Its use is reserved only for patients in whom a complete oncological resection by (sleeve) lobectomy is not possible. It is unclear whether a patients’ risk of receiving a pneumonectomy is equally distributed. This study examined between-hospital variation of pneumonectomy use for primary lung cancer in the Netherlands. Methods Data from the Dutch Lung Cancer Audit for Surgery from 2012 to 2016 were used to study the use of pneumonectomy for primary lung cancer in the Netherlands. Using multivariable logistic regression, factors associated with pneumonectomy use were identified and the expected number of pneumonectomies per hospital was determined. Subsequently, the observed/expected ratio (O/E ratio) per hospital was calculated to study between-hospital differences. Results Of the 8446 included patients, 659 (7.8%) underwent a pneumonectomy with a mean postoperative mortality of 7.1% (n = 47). Factors associated with receiving a pneumonectomy were age, gender, cardiac and pulmonary comorbidities, tumor side, size and histopathology. The pneumonectomy use in the Netherlands varied considerably between hospitals (IQR 5.5–10.1%). Three hospitals out of 51 performed significantly less pneumonectomies than expected (O/E ratio O/E ratio > 1.7). In the latter group, severe complications were more frequent, taking other influencing factors into account (OR 1.51, 95% CI 1.05–2.19). Conclusions There is a considerable between-hospital variation in pneumonectomy use in lung cancer treatment. To further optimize surgical lung cancer care, we suggest center-specific feedback on pneumonectomy use and the development of a risk-adjusted pneumonectomy indicator.

Background: Time-to-first-event analysis considers only the first event irrespective of its severity. There are several methods to assess trial outcomes beyond time-to-first-event analysis, such as analyzing total events and ranking outcomes. In the GLOBAL LEADERS study, time-to-first-event analysis did not show superiority of ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention to conventional 12-month DAPT followed by aspirin monotherapy in the reduction of the primary composite end point of all-cause mortality or new Q-wave myocardial infarction. This study sought to explore various analytical approaches in assessing total ischemic and bleeding events after percutaneous coronary intervention in the GLOBAL LEADERS study. Methods and Results: Total ischemic and bleeding events were defined as all-cause mortality, any stroke, any myocardial infarction, any revascularization, or Bleeding Academic Research Consortium grade 2 or 3 bleeding. We used various analytical approaches to analyze the benefit of ticagrelor monotherapy over conventional DAPT. For ischemic and bleeding events at 2 years after percutaneous coronary intervention, ticagrelor monotherapy demonstrated a 6% risk reduction, compared with conventional 12-month DAPT in time-to-first-event analysis (hazard ratio, 0.94 [95% CI, 0.88–1.01]; log-rank P =0.10). In win ratio analysis, win ratio was 1.05 (95% CI, 0.97–1.13; P =0.20). Negative binomial regression and Andersen-Gill analyses which include repeated events showed statistically significant advantage for ticagrelor monotherapy (rate ratio, 0.92 [95% CI, 0.85–0.99; P =0.020] and hazard ratio, 0.92 [95% CI, 0.85–0.99; P =0.028], respectively), although in weighted composite end point analysis, the hazard ratio was 0.93 (95% CI, 0.84–1.04; log-rank P =0.22). Conclusions: Statistical analyses considering repeated events or event severity showed that ticagrelor monotherapy consistently reduced ischemic and bleeding events by 5% to 8%, compared with conventional 1-year DAPT. Applying multiple statistical methods could emphasize the multiple facets of a trial and result in accurate and more appropriate analyses. Considering the recurrence of ischemic and bleeding events, ticagrelor monotherapy appeared to be beneficial after percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01813435.

Background: In 1 of 3 patients with initial lymph node-positive (cN(+)) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB). Patients and Methods: In the present open single-arm multicenter validation study, 225 cN(+) (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported. Conclusion: The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN(+) patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure.

Background ACEF score has been shown to have predictive ability in the patients undergoing percutaneous coronary intervention (PCI). The ACEF II score has recently been developed to predict short-term mortality after cardiac surgery. We compared the predictive ability of the ACEF and ACEF II scores to predict mortality after PCI in the all-comers population. Methods The ACEF and ACEF II scores were calculated in 15,968 patients enrolled in the GLOBAL LEADERS study. Discrimination and calibration were assessed for outcomes after PCI. Recalibration of the regression model by updating the intercept and slope were performed to adjust the original ACEF model to the PCI setting. In a stratified approach, patients were divided into quintiles according to the score. Outcomes were compared between quintiles. Results The ACEF and ACEF II score were available in 14,941 and 14,355 patients respectively. Discrimination for 30-day all-cause mortality was acceptable for both scores (C-statistic ACEF 0.75 and ACEF II 0.77). For 2-year all-cause mortality, the discrimination of ACEF score was acceptable (C-statistic 0.72) while the discrimination of ACEF II score was moderate (C-statistic 0.69). Both scores identified patients at high risk of mortality but overestimated all-cause mortality at 30 days in all quintiles. After recalibration, agreement between predicted and observed 30-day all-cause mortality in both scores are close to the identity line. Conclusions The ACEF II model did not improve the predictive ability of the ACEF score. Recalibrated ACEF model can be used to estimated all-cause mortality rate at 30 days after PCI.

Background Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk (HBR) may be present, making it unclear whether short- or long-term DAPT should be prioritized. Objectives This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting. Methods Complex PCI was defined as ≥3 stents implanted and/or ≥3 lesions treated, bifurcation stenting and/or stent length >60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥25) or non-high ( Results Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: −3.86%; 95% confidence interval: −7.71 to +0.06) and noncomplex PCI strata (absolute risk difference: −1.14%; 95% confidence interval: −2.26 to −0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity. Conclusions Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT.

Objectives The study sought to validate the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score II mortality prediction model after percutaneous coronary intervention (PCI) or coronary artery bypass grafting in a large pooled population of patients with multivessel coronary disease (MVD) and/or unprotected left main disease (UPLMD) enrolled in the PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) and BEST (Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) randomized controlled trials. Background For patients with MVD and/or UPLMD, the choice of the best revascularization strategy remains challenging. Methods Pooled individual patient-level data from PRECOMBAT and BEST were used to assess calibration and discrimination of the SYNTAX score II prediction model for all-cause mortality after PCI and coronary artery bypass grafting at 4-year follow-up. The study population comprised 1,480 patients (600 with UPLMD, 880 with MVD). Results The overall incidence of all-cause mortality was 6.1% after a median follow-up period of 4.9 years. Validation plots showed good model calibration overall and across treatment groups but tended to overestimate all-cause mortality in the highest risk quintiles of patients in the whole population and the PCI arm. The SYNTAX score II showed moderate discrimination ability for the whole population (C index = 0.685) but better for patients receiving PCI than CABG (C index = 0.718 vs. 0.662 in patients with UPLMD, C index = 0.700 vs. 0.661 in those with MVD). Observed all-cause mortality was higher when the treatment received was at variance with that recommended by the model and similar when it was concordant. Conclusions The SYNTAX score II has good calibration but only moderate discrimination ability for long-term mortality prediction in this randomized population. This score provides an important tool to help guide the heart team’s decision-making process regarding the selection of the best revascularization strategy for patients with MVD and/or UPLMD. (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease, NCT00422968; Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease, NCT00997828)

The performance of previously developed models to predict non sentinel lymph node status for patients with sentinel lymph node-positive breast cancer was poor for our Dutch patient population. Therefore, a new model was developed that includes only 2 predictors, is easy to use, and can help clinicians and their patients in the clinical decision-making regarding axillary treatment. Background: Multiple predictive systems have previously been developed to identify the sentinel lymph node (SLN)-positive patients at low risk of additional axillary non-SLN involvement and for whom completion axillary lymph node dissection (ALND) could be avoided. However, previous studies showed that these tools had poor performance in Dutch patients with breast cancer, probably owing to variations in pathology settings and differences in population characteristics. The aim of the present study was to develop a predictive tool for the risk of non-SLN involvement in a Dutch population with SLN-positive breast cancer. Materials and Methods: The data from 513 patients with SLN-positive breast cancer at 10 participating hospitals, who had undergone ALND from January 2007 to December 2008 were studied. The uni- and multivariable associations of predictors for non-SLN metastases were analyzed, and a predictive model was developed. The discriminatory ability of the model was measured by the area under the receiver operating characteristic curve (AUC) and the agreement between predicted probabilities and observed frequencies was visualized by a calibration plot. Results: A predictive model was developed that included the 2 strongest predictors: the size of the SLN metastases in millimeters and the presence of a negative sentinel lymph node. The model showed good discriminative ability (AUC, 0.75) and good calibration over the complete range of predicted probabilities. Conclusion: We have developed a tool to predict additional non-SLN metastases in Dutch patients with SLN-positive breast cancer that is easy to use in daily clinical breast cancer practice. (C) 2016 Elsevier Inc. All rights reserved.

Objectives To develop prediction models for Chlamydia trachomatis (Ct) infection with different levels of detail in information, that is, from readily available data in registries and from additional questionnaires. Methods All inhabitants of Rotterdam and Amsterdam aged 16–29 were invited yearly from 2008 until 2011 for home-based testing. Their registry data included gender, age, ethnicity and neighbourhood-level socioeconomic status (SES). Participants were asked to fill in a questionnaire on education, sexually transmitted infection history, symptoms, partner information and sexual behaviour. We developed prediction models for Ct infection using first-time participant data—including registry variables only and with additional questionnaire variables—by multilevel logistic regression analysis to account for clustering within neighbourhoods. We assessed the discriminative ability by the area under the receiver operating characteristic curve (AUC). Results Four per cent (3540/80 385) of the participants was infected. The strongest registry predictors for Ct infection were young age (especially for women) and Surinamese, Antillean or sub-Saharan African ethnicity. Neighbourhood-level SES was of minor importance. Strong questionnaire predictors were low to intermediate education level, ethnicity of the partner (non-Dutch) and having sex with casual partners. When using a prediction model including questionnaire risk factors (AUC 0.74, 95% CI 0.736 to 0.752) for selective screening, 48% of the participating population needed to be screened to find 80% (95% CI 78.4% to 81.0%) of Ct infections. The model with registry risk factors only (AUC 0.67, 95% CI 0.656 to 0.675) required 60% to be screened to find 78% (95% CI 76.6% to 79.4%) of Ct infections. Conclusions A registry-based prediction model can facilitate selective Ct screening at population level, with further refinement at the individual level by including questionnaire risk factors.

Background: In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB).Methods: A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC).Results: In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived.Conclusions: Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences. (C) 2018 Elsevier Ltd. All rights reserved.

Objectives Clinical prediction models that support treatment decisions are usually evaluated for their ability to predict the risk of an outcome rather than treatment benefit–the difference between outcome risk with vs. without therapy. We aimed to define performance metrics for a model's ability to predict treatment benefit. Study Design and Setting We analyzed data of the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial and of three recombinant tissue plasminogen activator trials. We assessed alternative prediction models with a conventional risk concordance-statistic (c-statistic) and a novel c-statistic for benefit. We defined observed treatment benefit by the outcomes in pairs of patients matched on predicted benefit but discordant for treatment assignment. The ‘c-for-benefit’ represents the probability that from two randomly chosen matched patient pairs with unequal observed benefit, the pair with greater observed benefit also has a higher predicted benefit. Results Compared to a model without treatment interactions, the SYNTAX score II had improved ability to discriminate treatment benefit (c-for-benefit 0.590 vs. 0.552), despite having similar risk discrimination (c-statistic 0.725 vs. 0.719). However, for the simplified stroke–thrombolytic predictive instrument (TPI) vs. the original stroke-TPI, the c-for-benefit (0.584 vs. 0.578) was similar. Conclusion The proposed methodology has the potential to measure a model's ability to predict treatment benefit not captured with conventional performance metrics.

OBJECTIVES/SPECIFIC AIMS: Objective: Approximately 86 million people in the US have prediabetes, but only a fraction of them receive proven effective therapies to prevent diabetes. Further, the effectiveness of these therapies varies with individual risk of progression to diabetes. We estimated the value of targeting those individuals at highest diabetes risk for treatment, compared to treating all individuals meeting inclusion criteria for the Diabetes Prevention Program (DPP). METHODS/STUDY POPULATION: METHODS: Using a micro-simulation model, we estimated total lifetime costs and quality-adjusted life expectancy (QALE) for individuals receiving: (1) lifestyle intervention involving an intensive program focused on healthy diet and exercise, (2) metformin administration, or (3) no intervention. The model combines several components. First a Cox proportional hazards model predicted onset of diabetes from baseline characteristics for each pre-diabetic individual and yielded a probability distribution for each alternative. We derived this risk model from the Diabetes Prevention Program (DPP) clinical trial data and the follow-up study DPP-OS. The Michigan Diabetes Research Center Model for Diabetes then estimated costs and outcomes for individuals after diabetes diagnosis using standard of care diabetes treatment. Based on individual costs and QALE, we evaluated NMB of the two interventions at population and individual levels, stratified by risk quintiles for diabetes onset at 3 years. RESULTS/ANTICIPATED RESULTS: Results: Compared to usual care, lifestyle modification conferred positive benefits for all eligible individuals. Metformin’s NMB was negative for the lowest population risk quintile. By avoiding use among individuals who would not benefit, targeted administration of metformin conferred a benefit of $500-$800 per person, depending on duration of treatment effect. When treating only 20% of the population (e.g., due to capacity constraints), targeting conferred a NMB of $14,000-$18,000 per person for lifestyle modification and $16,000-$20,000 for metformin. DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusions: Metformin confers value only among higher risk individuals, so targeting its use is worthwhile. While lifestyle modification confers value for all eligible individuals, prioritizing the intervention to high risk patients when capacity is constrained substantially increases societal benefits.

Background Cigarette smoking is a well-known risk factor for development of coronary artery disease (CAD). However, some studies have suggested a "smoker's paradox," meaning neutral or favorable outcomes in smokers who have developed CAD, especially myocardial infarction (MI). Objectives The study aimed to examine the association of smoking status with clinical outcomes in the randomized controlled SYNTAX (SYNergy Between PCI With TAXUS and Cardiac Surgery) trial at 5-year follow-up. Methods Detailed smoking history was collected at baseline, 6-month, 1-year, 3-year, and 5-year follow-up. The composite endpoints included death/MI/stroke (primary endpoint) plus major adverse cardiac and cerebrovascular events (MACCE) (combination of death/MI/stroke and target lesion revascularization) according to patient smoking status. The comparison of 5-year clinical outcomes between the groups according to smoking status was performed with Cox regression using smoking status at baseline or smoking as a time-dependent covariate. Results A sizeable proportion (n = 322, 17.9%) of patients had changing smoking status during 5-year follow-up. One in 5 patients with complex CAD was smoking at baseline. However, 60% stopped after revascularization while others continued to smoke. Smokers had worse clinical outcomes due to a higher incidence of recurrent MI in both revascularization arms. Smoking was an independent predictor of the composite endpoint of death/MI/stroke (hazard ratio [HR]: 1.8; 95% confidence interval [CI]: 1.3 to 2.5; p = 0.001) and MACCE (HR: 1.4; 95% CI: 1.1 to 1.7; p = 0.02). Conclusions Smoking is associated with poor clinical outcomes after revascularization in patients with complex CAD. This places further emphasis on efforts at smoking cessation to improve revascularization benefits. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries; NCT00114972)

Objectives: We aimed to compare modeling approaches to estimate the individual survival benefit of treatment with either coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) for patients with complex coronary artery disease. Study Design and Setting: We estimated survival with Cox regression models that included the treatment variable (CABG/PCI) interacting with either an internally developed overall prognostic index (PI) or with individual prognostic factors. We analyzed data of patients who were randomized in the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery trial (1,800 patients, 178 deaths). Results: A negligible interaction with the PI (P = 0.51) led to 4-year survival estimates in favor of CABG for all patients. In contrast, individual interactions indicated substantial relative treatment effect heterogeneity (overall interaction P = 0.004), and estimates of 4-year survival were numerically in favor of CABG for 1,275 of 1,800 patients (71%; 519 with 95% confidence). To test the more complex model with individual interactions, we first used penalized regression, resulting in smaller but largely Consistent individual estimates of the survival difference between CABG and PCI. Second, strong treatment interactions were confirmed at external validation in 2,891 patients from a multinational registry. Conclusion: Modeling strategies that omit interactions may result in misleading estimates of absolute treatment benefit for individual patients with the potential hazard of suboptimal decision making. (C) 2015 Elsevier Inc. All rights reserved.

Knowledge about lower leg chronic exertional compartment syndrome (CECS) is largely obtained from highly selected populations. Patient characteristics may therefore not be appropriate for the general population. Our purpose was to describe a heterogeneous population of individuals suspected of lower leg CECS and to identify predictors of CECS. Charts of individuals who were analyzed for exercise-induced lower leg pain in a referral center between 2001 and 2013 were retrospectively studied. Patients were included if history and physical examination were suggestive of CECS and if they had undergone a dynamic intracompartmental pressure measurement. Six hundred ninety-eight of 1411 individuals were diagnosed with CECS in one or more of three lower leg muscle compartments (anterior tibial, deep flexor, lateral). Prevalence of CECS peaked around the age of 20–25 years and decreased thereafter, although a plateau around 50 years was found. Age, gender, bilateral symptoms, previous lower leg pathology, sports (running and skating) and tender muscle compartments were identified as independent predictors of lower leg CECS. The proposed predictive model has moderate discriminative ability (AUC 0.66) and good calibration over the complete range of predicted probabilities. The predictive model, displayed as a nomogram, may aid in selecting individuals requiring an invasive dynamic intracompartmental muscle pressure measurement.

Recurrence of bladder cancer can occur repeatedly in the same patient after treatment of the primary tumor. Models predicting the risk of a next recurrence may inform individualized decision-making on surveillance frequency. We aimed to assess the usefulness of extensions of the Cox proportional hazards model for repeated events in this context. We analyzed 531 Dutch patients with bladder cancer (1990-2012) with information on 7 prespecified predictors at the time of diagnosis of the primary and recurrent tumors. We considered 3 aspects of model variants: how to model time to the repeated events (calendar time, gap time, elapsed time); the number of preceding events (predictor, stratum variable); and the within-subject correlation (ignored in a simple Cox model, robust standard errors in a variance-correction model, random effect in a frailty model). First to fourth recurrences of bladder cancer occurred in 313, 174, 103, and 66 patients, respectively, with median calendar follow-up times of 1.1, 2.5, 3.8, and 4.5 years, respectively. We focused on gap time in the detailed analyses, allowing for clinically meaningful predictions. Variance-correction models may be useful if predictor selection is part of the model development. Frailty models may be useful when within-subject correlation is strong.

Summary Background Incisional hernia is a frequent long-term complication after abdominal surgery, with a prevalence greater than 30% in high-risk groups. The aim of the PRIMA trial was to evaluate the effectiveness of mesh reinforcement in high-risk patients, to prevent incisional hernia. Methods We did a multicentre, double-blind, randomised controlled trial at 11 hospitals in Austria, Germany, and the Netherlands. We included patients aged 18 years or older who were undergoing elective midline laparotomy and had either an abdominal aortic aneurysm or a body-mass index (BMI) of 27 kg/m 2 or higher. We randomly assigned participants using a computer-generated randomisation sequence to one of three treatment groups: primary suture; onlay mesh reinforcement; or sublay mesh reinforcement. The primary endpoint was incidence of incisional hernia during 2 years of follow-up, analysed by intention to treat. Adjusted odds ratios (ORs) were estimated by logistic regression. This trial is registered at ClinicalTrials.gov, number NCT00761475. Findings Between March, 2009, and December, 2012, 498 patients were enrolled to the study, of whom 18 were excluded before randomisation. Therefore, we included 480 patients in the primary analysis: 107 were assigned primary suture only, 188 were allocated onlay mesh reinforcement, and 185 were assigned sublay mesh reinforcement. 92 patients were identified with an incisional hernia, 33 (30%) who were allocated primary suture only, 25 (13%) who were assigned onlay mesh reinforcement, and 34 (18%) who were assigned sublay mesh reinforcement (onlay mesh reinforcement vs primary suture, OR 0·37, 95% CI 0·20–0·69; p=0·0016; sublay mesh reinforcement vs primary suture, 0·55, 0·30–1·00; p=0·05). Seromas were more frequent in patients allocated onlay mesh reinforcement (34 of 188) than in those assigned primary suture (five of 107; p=0·002) or sublay mesh reinforcement (13 of 185; p=0·002). The incidence of wound infection did not differ between treatment groups (14 of 107 primary suture; 25 of 188 onlay mesh reinforcement; and 19 of 185 sublay mesh reinforcement). Interpretation A significant reduction in incidence of incisional hernia was achieved with onlay mesh reinforcement compared with sublay mesh reinforcement and primary suture only. Onlay mesh reinforcement has the potential to become the standard treatment for high-risk patients undergoing midline laparotomy. Funding Baxter; B Braun Surgical SA.

Objective: We aimed to determine pretreatment pathological tumor extent in the resection specimen after neoadjuvant chemoradiotherapy (nCRT) and to assess its prognostic value in patients with esophageal cancer. Methods: Patients with esophageal cancer, treated with nCRT plus surgery were included (2003-2011). Pretreatment pathological T-stage (prepT-stage) and N-stage (prepN-stage) were estimated based on the extent of regressional changes and residual tumor cells in the resection specimen. Interobserver agreement was determined between 3 pathologists. The prognostic performance of prepT-stage and prepN-stage was scored using the difference in Akaike information criterion (AAIC). PrepN-stage and posttreatment pathological N-stage (ypN-stage) were combined to determine the effect of nodal sterilization on prognosis. Results: Overall concordance for prepT-stage and prepN-stage was 0.69 and 0.84, respectively. Prognostic strength of prepT-stage was similar to clinical T-stage and worse compared with ypT-stage (AAIC 1.3 versus 2.0 and 8.9, respectively). In contrast, prognostic strength of prepN-stage was better than cN-stage and similar to ypN-stage (AAIC 17.9 versus 6.2 and 17.2, respectively). PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients, with a five year overall survival of 51% versus 68%, P = 0.019, respectively. Conclusions: PrepT-stage and prepN-stage can be estimated reproducibly. Prognostic strength of prepT-stage is comparable with clinical T-stage, whereas prepN-stage is better than cN-stage. PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients. Pretreatment pathological staging should be considered useful as a new staging parameter for esophageal cancer and could also be of interest for other tumor types.

Objective B-mode ultrasound measurement of the carotid intima-media thickness (CIMT) is a widely used marker for atherosclerosis and is associated with future cardiovascular events. This article provides a review and meta-analysis of the published evidence on the association of CIMT with future cardiovascular events and its additional value to traditional cardiovascular risk prediction models. Methods A systematic review and meta-analysis of the evidence on the association of CIMT with future cardiovascular events and the additional value of CIMT to traditional cardiovascular risk prediction models was conducted. The association of CIMT with future cardiovascular events and the additional value of CIMT were calculated using random effects analysis. Results The literature search yielded 1196 articles of which 15 articles provided sufficient data for the meta-analysis. A 1 SD increase in CIMT was predictive for myocardial infarction (HR 1.26, 95% CI 1.20–1.31) and for stroke (HR 1.31, 95% CI 1.26–1.36). A 0.1 mm increase in CIMT was predictive for myocardial infarction (HR 1.15, 95% CI 1.12–1.18) and for stroke (HR 1.17, 95% CI 1.15–1.21). The overall performance of risk prediction models did not significantly increase after addition of CIMT data. The areas under the curve increased from 0.726 to 0.729 ( p = 0.8). Conclusions CIMT as measured by B-mode ultrasound is associated with future cardiovascular events. However, the addition of CIMT to traditional cardiovascular risk prediction models does not lead to a statistical significantly increase in performance of those models.

Summary Background The anatomical SYNTAX score is advocated in European and US guidelines as an instrument to help clinicians decide the optimum revascularisation method in patients with complex coronary artery disease. The absence of an individualised approach and of clinical variables to guide decision making between coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) are limitations of the SYNTAX score. SYNTAX score II aimed to overcome these limitations. Methods SYNTAX score II was developed by applying a Cox proportional hazards model to results of the randomised all comers SYNTAX trial (n=1800). Baseline features with strong associations to 4-year mortality in either the CABG or the PCI settings (interactions), or in both (predictive accuracy), were added to the anatomical SYNTAX score. Comparisons of 4-year mortality predictions between CABG and PCI were made for each patient. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling. External validation was done in the multinational all comers DELTA registry (n=2891), a heterogeneous population that included patients with three-vessel disease (26%) or complex coronary artery disease (anatomical SYNTAX score ≥33, 30%) who underwent CABG or PCI. The SYNTAX trial is registered with ClinicalTrials.gov, number NCT00114972. Findings SYNTAX score II contained eight predictors: anatomical SYNTAX score, age, creatinine clearance, left ventricular ejection fraction (LVEF), presence of unprotected left main coronary artery (ULMCA) disease, peripheral vascular disease, female sex, and chronic obstructive pulmonary disease (COPD). SYNTAX score II significantly predicted a difference in 4-year mortality between patients undergoing CABG and those undergoing PCI (p interaction 0·0037). To achieve similar 4-year mortality after CABG or PCI, younger patients, women, and patients with reduced LVEF required lower anatomical SYNTAX scores, whereas older patients, patients with ULMCA disease, and those with COPD, required higher anatomical SYNTAX scores. Presence of diabetes was not important for decision making between CABG and PCI (p interaction 0·67). SYNTAX score II discriminated well in all patients who underwent CABG or PCI, with concordance indices for internal (SYNTAX trial) validation of 0·725 and for external (DELTA registry) validation of 0·716, which were substantially higher than for the anatomical SYNTAX score alone (concordance indices of 0·567 and 0·612, respectively). A nomogram was constructed that allowed for an accurate individualised prediction of 4-year mortality in patients proposing to undergo CABG or PCI. Interpretation Long-term (4-year) mortality in patients with complex coronary artery disease can be well predicted by a combination of anatomical and clinical factors in SYNTAX score II. SYNTAX score II can better guide decision making between CABG and PCI than the original anatomical SYNTAX score. Funding Boston Scientific Corporation.

Background— Outpatients with heart failure (HF) who are at high risk for HF hospitalization and death may benefit from early identification. We sought to develop and externally validate a model to predict both HF hospitalization and mortality that accounts for the semicompeting nature of the 2 outcomes and captures the risk associated with the transition from the stable outpatient state to the post-HF hospitalization state. Methods and Results— A multistate model to predict HF hospitalization and all-cause mortality was derived using data (n=3834) from the HEAAL study (Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan), a multinational randomized trial in symptomatic patients with reduced left ventricular ejection fraction. Twelve easily and reliably obtainable demographic and clinical predictors were prespecified for model inclusion. Model performance was assessed in the SCD-HeFT cohort (Sudden Cardiac Death in Heart Failure Trial; n=2521). At 1 year, the probability of being alive without HF hospitalization was 94% for a typical patient in the lowest risk quintile and 77% for a typical patient in the highest risk quintile and this variability in risk continued through 7 years of follow-up. The model c-index was 0.72 in the derivation cohort, 0.66 in the validation cohort, and 0.69 in the implantable cardiac defibrillator arm of the validation cohort. There was excellent calibration across quintiles of predicted risk. Conclusions— Our findings illustrate the advantages of a multistate modeling approach, providing estimates of HF hospitalization and death in the same model, comparison of predictors for the different outcomes and demonstrating the different trajectories of patients based on baseline characteristics and intermediary events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00000609 and NCT00090259.

Background Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization. Methods and Results We conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction ≤45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest-risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality ( P = .94). Conclusions Participants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization.

Background Targeting low-dose computed tomography (LDCT) for lung cancer screening to persons at highest risk for lung cancer mortality has been suggested to improve screening efficiency. Objective To quantify the value of risk-targeted selection for lung cancer screening compared with National Lung Screening Trial (NLST) eligibility criteria. Design Cost-effectiveness analysis using a multistate prediction model. Data sources NLST. Target population Current and former smokers eligible for lung cancer screening. Time horizon Lifetime. Perspective Health care sector. Intervention Risk-targeted versus NLST-based screening. Outcome measures Incremental 7-year mortality, life expectancy, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of screening with LDCT versus chest radiography at each decile of lung cancer mortality risk. Results of base-case analysis Participants at greater risk for lung cancer mortality were older and had more comorbid conditions and higher screening-related costs. The incremental lung cancer mortality benefits during the first 7 years ranged from 1.2 to 9.5 lung cancer deaths prevented per 10 000 person-years for the lowest to highest risk deciles, respectively (extreme decile ratio, 7.9). The gradient of benefits across risk groups, however, was attenuated in terms of life-years (extreme decile ratio, 3.6) and QALYs (extreme decile ratio, 2.4). The incremental cost-effectiveness ratios (ICERs) were similar across risk deciles ($75 000 per QALY in the lowest risk decile to $53 000 per QALY in the highest risk decile). Payers willing to pay $100 000 per QALY would pay for LDCT screening for all decile groups. Results of sensitivity analysis Alternative assumptions did not substantially alter our findings. Limitation Our model did not account for all correlated differences between lung cancer mortality risk and quality of life. Conclusions Although risk targeting may improve screening efficiency in terms of early lung cancer mortality per person screened, the gains in efficiency are attenuated and modest in terms of life-years, QALYs, and cost-effectiveness. Primary funding source National Institutes of Health (U01NS086294).

Aims Recent cost-effectiveness analyses of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) have been limited by a short time horizon or were restricted to the US healthcare perspective. We, therefore, used individual patient-level data from the SYNTAX trial to evaluate the cost-effectiveness of PCI versus CABG from a European (Dutch) perspective. Methods and results Between 2005 and 2007, 1800 patients with three-vessel or left main coronary artery disease were randomised to either CABG (n=897) or PCI with drug-eluting stents (DES; n=903). Costs were estimated for all patients based on observed healthcare resource usage over 5 years of follow-up. Health state utilities were evaluated with the EuroQOL questionnaire. A patient-level microsimulation model based on Dutch life-tables was used to extrapolate the 5-year in-trial data to a lifetime horizon. Although initial procedural costs were lower for CABG, total initial hospitalisation costs per patient were higher (.17 506 vs .14 037, p >0.001). PCI was more costly during the next 5 years of follow-up, due to more frequent hospitalisations, repeat revascularisation procedures and higher medication costs. Nevertheless, total 5-year costs remained .2465/patient higher with CABG. When the in-trial results were extrapolated to a lifetime horizon, CABG was projected to be economically attractive relative to DES-PCI, with gains in both life expectancy and quality-adjusted life expectancy. The incremental cost-effectiveness ratio (ICER) (.5390/quality-adjusted life year (QALY) gained) was favourable and remained >.80 000/QALY in

Measurement of health-related quality of life (HRQL) is essential to quantify the subjective burden of traumatic brain injury (TBI) in survivors. We performed a systematic review of HRQL studies in TBI to evaluate study design, instruments used, methodological quality, and outcome. Fifty-eight studies were included, showing large variation in HRQL instruments and assessment time points used. The Short Form-36 (SF-36) was most frequently used. A high prevalence of health problems during and after the first year of TBI was a common finding of the studies included. In the long term, patients with a TBI still showed large deficits from full recovery compared to population norms. Positive results for internal consistency and interpretability of the SF-36 were reported in validity studies. The Quality of Life after Brain Injury instrument (QOLIBRI), European Brain Injury Questionnaire (EBIQ), Child Health Questionnaire (CHQ), and the World Health Organization Quality of Life short version (WHOQOL-BREF) showed positive results, but evidence was limited. Meta-analysis of SF-36 showed that TBI outcome is heterogeneous, encompassing a broad spectrum of HRQL, with most problems reported in the physical, emotional, and social functioning domain. The use of SF-36 in combination with a TBI-specific instrument, i.e., QOLIBRI, seems promising. Consensus on preferred methodologies of HRQL measurement in TBI would facilitate comparability across studies, resulting in improved insights in recovery patterns and better estimates of the burden of TBI. Electronic supplementary material The online version of this article (doi:10.1186/s12963-015-0037-1) contains supplementary material, which is available to authorized users.

Background:SYNTAX score II (SSII) provides individualized estimates of 4-year mortality after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in order to facilitate decision-making between these revascularization methods. The purpose of the present study was to assess SSII in a real-world multicenter registry with distinct regional and epidemiological characteristics.Methods and Results:Long-term mortality was analyzed in 3,896 patients undergoing PCI (n=2,190) or CABG (n=1,796) from the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG registry cohort-2. SSII discriminated well in both CABG and PCI patient groups (concordance index [c-index], 0.70; 95% CI: 0.68–0.72; and 0.75, 95% CI: 0.72–0.78) surpassing anatomical SYNTAX score (SS; c-index, 0.50; 95% CI: 0.47–0.53; and 0.59, 95% CI: 0.57–0.61). SSII had the best discriminative ability to separate low-, medium- and high-risk tertiles, and calibration plots showed good predictive performance for CABG and PCI groups. Use of anatomical SS as a reference improved the overall reclassification provided by SSII, with a net reclassification index of 0.5 (P

Objectives This study aimed to update the Logistic Clinical SYNTAX score to predict 3-year survival after percutaneous coronary intervention (PCI) and compare the performance with the SYNTAX score alone. Background The SYNTAX score is a well-established angiographic tool to predict long-term outcomes after PCI. The Logistic Clinical SYNTAX score, developed by combining clinical variables with the anatomic SYNTAX score, has been shown to perform better than the SYNTAX score alone in predicting 1-year outcomes after PCI. However, the ability of this score to predict long-term survival is unknown. Methods Patient-level data (N = 6,304, 399 deaths within 3 years) from 7 contemporary PCI trials were analyzed. We revised the overall risk and the predictor effects in the core model (SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction) using Cox regression analysis to predict mortality at 3 years. We also updated the extended model by combining the core model with additional independent predictors of 3-year mortality (i.e., diabetes mellitus, peripheral vascular disease, and body mass index). Results The revised Logistic Clinical SYNTAX models showed better discriminative ability than the anatomic SYNTAX score for the prediction of 3-year mortality after PCI (c-index: SYNTAX score, 0.61; core model, 0.71; and extended model, 0.73 in a cross-validation procedure). The extended model in particular performed better in differentiating low-and intermediate-risk groups. Conclusions Risk scores combining clinical characteristics with the anatomic SYNTAX score substantially better predict 3-year mortality than the SYNTAX score alone and should be used for long-term risk stratification of patients undergoing PCI. (C) 2014 by the American College of Cardiology Foundation

BACKGROUND: Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with postoperative mortality ranging from 5% to 18%. The aim of this study was to develop a preoperative risk score for postoperative mortality after liver resection for PHC, and to assess the effect of biliary drainage of the future liver remnant (FLR). STUDY DESIGN: A consecutive series of 287 patients submitted to major liver resection for presumed PHC between 1997 and 2014 at 2 Western centers was analyzed; 228 patients (79%) underwent preoperative drainage for jaundice. Future liver remnant volumes were calculated with CT volumetry and completeness of FLR drainage was assessed on imaging. Logistic regression was used to develop a mortality risk score. RESULTS: Postoperative mortality at 90 days was 14% and was independently predicted by age (odds ratio [OR] per 10 years = 2.1), preoperative cholangitis (OR = 4.1), FLR volume 50%, including 10 jaundiced patients (median bilirubin level 11 mg/dL). CONCLUSIONS: The mortality risk score for patients with resectable PHC can be used for patient counseling and identification of modifiable risk factors, which include FLR volume, FLR drainage status, and preoperative cholangitis. We found no evidence to support preoperative biliary drainage in patients with an FLR volume >50%. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.

BACKGROUND: In poor settings, where many births and neonatal deaths occur at home, prediction models of neonatal mortality in the general population can aid public-health policy-making. No such models are available in the international literature. We developed and validated a prediction model for neonatal mortality in the general population in India, Nepal and Bangladesh. METHODS: Using data (49 632 live births, 1742 neonatal deaths) from rural and urban surveillance sites in South Asia, we developed regression models to predict the risk of neonatal death with characteristics known at (i) the start of pregnancy, (ii) start of delivery and (iii) 5 minutes post partum. We assessed the models' discriminative ability by the area under the receiver operating characteristic curve (AUC), using cross-validation between sites. RESULTS: At the start of pregnancy, predictive ability was moderate {AUC 0.59 [95% confidence interval (CI) 0.58-0.61]} and predictors of neonatal death were low maternal education and economic status, short birth interval, primigravida, and young and advanced maternal age. At the start of delivery, predictive ability was considerably better [AUC 0.73 (95% CI 0.70-0.76)] and prematurity and multiple pregnancy were strong predictors of death. At 5 minutes post partum, predictive ability was good [AUC: 0.85 (95% CI 0.80-0.89)]; very strong predictors were multiple birth, prematurity and a poor condition of the infant at 5 minutes. CONCLUSIONS: We developed good performing prediction models for neonatal mortality. Neonatal deaths are highly concentrated in a small group of high-risk infants, even in poor settings in South Asia. Risk assessment, as supported by our models, can be used as a basis for improving community- and facility-based newborn care and prevention strategies in poor settings.