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Introduction: Missed and delayed diagnoses have received substantial attention as a quality and patient safety priority. To the extent that electronic health records, team-based care, and other mitigation strategies have been successful in improving diagnosis since the last large-scale study, we would expect that the contributing factors to diagnostic claims may have changed., Methods: This study sought to examine paid medical malpractice claims as a proxy to identify contributing factors that reflect a clear diagnostic error. Diagnostic error cases with indemnity payments (2009-2020) were identified using the Candello (formerly known as CRICO) proprietary taxonomy. Factors associated with indemnity payments were analyzed using a multivariable logistic regression model., Results: Of 5367 included claims, 2161 (40%) had indemnity payments. A majority of claims had multiple contributing factors on the diagnostic pathway. In multivariable analysis, factors independently associated with an indemnity payment included the insurer (odds ratio and 95% confidence interval, 2.8 [2.4-3.3]), high injury severity (1.9 [1.3-2.8]) or death (1.5 [0.99-2.1]), and case setting (inpatient (0.77 [0.65-0.91]) or emergency department (0.67 [0.49-0.92])). Importantly, cases with contributing factors outside of Candello's diagnostic pathway were more likely to lead to indemnity payment., Conclusions: The digital transformation and acceleration of team-based care in medicine have not mitigated the malpractice risks of complex cases with severe injuries and multiple missteps., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Environmental exposures account for a growing proportion of global mortality. Large cohort studies are needed to characterize the independent impact of environmental exposures on mortality in low-income settings., Methods: We collected data on individual and environmental risk factors for a multiethnic cohort of 50,045 individuals in a low-income region in Iran. Environmental risk factors included: ambient fine particular matter air pollution; household fuel use and ventilation; proximity to traffic; distance to percutaneous coronary intervention (PCI) center; socioeconomic environment; population density; local land use; and nighttime light exposure. We developed a spatial survival model to estimate the independent associations between these environmental exposures and all-cause and cardiovascular mortality., Findings: Several environmental factors demonstrated associations with mortality after adjusting for individual risk factors. Ambient fine particulate matter air pollution predicted all-cause mortality (per μg/m3, HR 1.20, 95% CI 1.07, 1.36) and cardiovascular mortality (HR 1.17, 95% CI 0.98, 1.39). Biomass fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.23, 95% CI 0.99, 1.53) and cardiovascular mortality (HR 1.36, 95% CI 0.99, 1.87). Kerosene fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.09, 95% CI 0.97, 1.23) and cardiovascular mortality (HR 1.19, 95% CI 1.01, 1.41). Distance to PCI center predicted all-cause mortality (per 10km, HR 1.01, 95% CI 1.004, 1.022) and cardiovascular mortality (HR 1.02, 95% CI 1.004, 1.031). Additionally, proximity to traffic predicted all-cause mortality (HR 1.13, 95% CI 1.01, 1.27). In a separate validation cohort, the multivariable model effectively predicted both all-cause mortality (AUC 0.76) and cardiovascular mortality (AUC 0.81). Population attributable fractions demonstrated a high mortality burden attributable to environmental exposures., Interpretation: Several environmental factors predicted cardiovascular and all-cause mortality, independent of each other and of individual risk factors. Mortality attributable to environmental factors represents a critical opportunity for targeted policies and programs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To identify individual-level factors associated with hospital readmission among individuals with SSc-associated pulmonary hypertension (SSc-PH)., Methods: Individuals enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry contributed clinical data related to SSc-PH disease severity and hospital admissions. Readmission was defined as a subsequent hospitalization within 12 months of any hospital discharge. Characteristics were compared between individuals with and without readmissions using Fisher's exact test, Wilcoxon rank-sum test, or Kruskal-Wallis test. Logistic regression was used to estimate associations between clinical predictors and likelihood of readmission., Results: Of 572 individuals with SSc-PH enrolled in PHAROS, 54% had ≥1 hospitalizations between 2005 and 2016. Among individuals ever-hospitalized, 34% had ≥1 readmission. Individuals with vs without readmissions had shorter median (IQR) time between index hospitalization date and next PHAROS visit [37 (3, 80) vs 81 (42, 136) days, P <0.001]. Index admissions related to PH or SSc (vs non-PH/SSc related) were associated with an increased odds of 12-month readmission [aOR 6.6 (95% CI 3.2, 13.6) and aOR 2.2 (95% CI 1.1, 4.5), respectively]. Readmission was less likely among home oxygen users (vs non-users) (aOR 0.44; 95% CI 0.22, 0.89). Race, age, sex, disease duration and disease subtype were not associated with readmission., Conclusion: The strongest predictor for 12-month readmission was an index hospitalization reason related to PH. Home oxygen use was associated with lower odds of readmission. Future studies should determine whether testing for the need for home oxygen mediates the risk of readmission in SSc-PH., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Primary care physicians (PCPs) are often gatekeepers to specialist care. This study assessed the relationship between PCP density and total knee (TKA) and total hip arthroplasty (THA) outcomes., Methods: We obtained patient-level data from an institutional registry on patients undergoing elective primary TKA and THA for osteoarthritis, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores at baseline and 2 years. Using geocoding, we identified the number of PCPs in the patient's census tract (communities). We used Augmented Inverse Probability Weighting and Cross-validated Targeted Minimum Loss-Based Estimation to compare provider density and outcomes adjusting for potential confounders., Results: Our sample included 3606 TKA and 4295 THA cases. The median number of PCPs in each community was similar for both procedures: TKA 2 (interquartile range 1, 6) and for THA 2 (interquartile range 1, 7). Baseline and 2-year follow-up WOMAC pain, function, and stiffness scores were not statistically significantly different comparing communities with more than median number of PCPs to those with less than median number of PCPs. In sensitivity analyses, adding 1 PCP to a community with zero PCPs would not have statistically significantly improved baseline or 2-year follow-up WOMAC pain, function, and stiffness scores., Conclusions: In this sample of patients who underwent elective TKA or THA for osteoarthritis, we found no statistically significant association between PCP density and pain, function, or stiffness outcomes at baseline or 2 years. Further studies should examine what other provider factors affect access and outcomes in THA and TKA., (© 2021 The Authors.)

Background/objective: The importance of patient-reported outcomes, like the Patient-Reported Outcomes Measurement Information System (PROMIS) measures, is increasingly recognized both in clinical care and in research. While "short forms" have been studied in juvenile idiopathic arthritis (JIA), study of PROMIS computer adaptive tests (CATs) in JIA is limited. This cross-sectional study evaluates whether PROMIS CATs correlate with disease activity in patients with JIA., Methods: A convenience sample of patients with JIA (N = 44) was recruited from a single center. Patients and parents completed pediatric and parent proxy PROMIS CATs. Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) and the Childhood Health Assessment Questionnaire (CHAQ). Correlation of the CAT T scores with disease activity was assessed using Spearman correlation coefficients., Results: Forty-four of 80 eligible subjects (29 patients and 15 parents) completed all or some PROMIS CATs. Pain interference and mobility CATs correlated moderately with JADAS-71. Nearly all correlations with the JADAS-71 were weakened when the patient global was removed. Pain interference, mobility, and fatigue were strongly correlated with the CHAQ. Among parent proxy CATs, only mobility and depressive symptoms correlated strongly with the CHAQ., Conclusions: Only pain interference and mobility PROMIS CATs showed strong correlation with standard disease activity measures in JIA, and nearly all correlations were weakened when the patient global was removed. Correlations of the CATs with the CHAQ were stronger than correlations with the JADAS-71, indicating that although the CHAQ is no longer routinely used it may be a better measure of health-related quality of life in routine clinical care., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background/objective: Patients with juvenile idiopathic arthritis (JIA) often present with signs and symptoms suggestive of serious bacterial infection (SBI). Procalcitonin (PCT) is a biomarker that is elevated in SBI. We conducted a comparative cohort study to test the hypothesis that PCT levels will differ between active JIA, quiescent JIA, and bacteremic patients and healthy controls., Methods: From October 2016 to May2018, consecutive children 6 months to 18 years of age with (a) active untreated JIA, (b) quiescent JIA, and (c) healthy elective presurgical candidates were recruited from clinics at a musculoskeletal specialty hospital. Juvenile idiopathic arthritis was defined according to the International League of Associations for Rheumatology criteria. Clinical data and serum samples meeting the same criteria were included from a prior study. Consecutive bacteremic patients were identified over the same period. Procalcitonin and other common measures of inflammation were measured. Descriptive statistics and univariate logistic analyses were performed., Results: Ninety-two study subjects were recruited. Erythrocyte sedimentation rate, C-reactive protein (CRP), and PCT levels were all elevated in bacteremic patients in comparison to the other groups. Erythrocyte sedimentation rate and CRP both had wide ranges that overlapped between groups; however, the PCT concentration was 0.15 μg/mL or greater in 1 of 59 patients with JIA, whereas it was 0.15 μg/mL or less in only 1 bacteremic patient., Conclusions: Our study indicates that serum erythrocyte sedimentation rate, CRP, and PCT levels are all biomarkers that can be used to distinguish SBI versus active JIA at presentation. However, PCT is the most accurate, with the least overlap between patients with infection and noninfectious inflammatory arthritis. This finding can help clinicians direct therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Electronic health records (EHRs) have become a common data source for clinical risk prediction, offering large sample sizes and frequently sampled metrics. There may be notable differences between hospital-based EHR and traditional cohort samples: EHR data often are not population-representative random samples, even for particular diseases, as they tend to be sicker with higher healthcare utilization, while cohort studies often sample healthier subjects who typically are more likely to participate. We investigate heterogeneities between EHR- and cohort-based inferences including incidence rates, risk factor identifications/quantifications, and absolute risks., Materials and Methods: This is a retrospective cohort study of older patients with type 2 diabetes using EHR from New York University Langone Health ambulatory care (NYULH-EHR, years 2009-2017) and from the Health and Retirement Survey (HRS, 1995-2014) to study subsequent cardiovascular disease (CVD) risks. We used the same eligibility criteria, outcome definitions, and demographic covariates/biomarkers in both datasets. We compared subsequent CVD incidence rates, hazard ratios (HRs) of risk factors, and discrimination/calibration performances of CVD risk scores., Results: The estimated subsequent total CVD incidence rate was 37.5 and 90.6 per 1000 person-years since T2DM onset in HRS and NYULH-EHR respectively. HR estimates were comparable between the datasets for most demographic covariates/biomarkers. Common CVD risk scores underestimated observed total CVD risks in NYULH-EHR., Discussion and Conclusion: EHR-estimated HRs of demographic and major clinical risk factors for CVD were mostly consistent with the estimates from a national cohort, despite high incidences and absolute risks of total CVD outcome in the EHR samples., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objective: Chinese Americans are a fast-growing immigrant group with worse rheumatic disease outcomes compared to white populations and frequently use traditional Chinese medicine (TCM). Whether TCM use is associated with lower adherence to Western rheumatic medications is unknown. The present study was undertaken to examine adherence to Western medications for systemic rheumatic diseases in the Chinese American immigrant population and its association with TCM use., Methods: Chinese Americans actively treated for a systemic rheumatic disease were recruited from 2 Chinatown clinics. Sociodemographic, TCM use, and clinical data were gathered. Self-reported health status was assessed using Patient-Reported Outcome Measurement Information System short forms. Adherence was stratified using the 8-item Morisky Medication Adherence Scale. Factors independently associated with high adherence were identified using multivariable logistic regression., Results: Of 230 subjects, the median age was 55 years (range 20-97 years), 65% were female, 71% had a high school education or less, 70% were enrolled in Medicaid, and 22% reported fluency in English. The most common rheumatic diagnoses were rheumatoid arthritis (41%), systemic lupus erythematosus (17%), and seronegative spondyloarthropathies (15%). One-half reported TCM use in the past year, and 28% reported high adherence to Western rheumatic medications. In multivariable analysis, high adherence was associated with TCM use (odds ratio [OR] 3.96, P < 0.001), being married (OR 3.69, P = 0.004), medication regimen complexity (OR 1.13, P = 0.004), and older age (OR 1.06, P < 0.001), and was negatively associated with anxiety (OR 0.94, P = 0.001)., Conclusion: While adherence to Western rheumatic medications was low in this cohort, interestingly, it was higher among TCM users compared to nonusers. TCM use appears to represent a complementary rather than an alternate approach to disease management for these patients. Future studies should evaluate whether TCM use is associated with better disease outcomes., (© 2019, American College of Rheumatology.)

Objective: To evaluate the longitudinal responsiveness (sensitivity to change) of the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: Outpatients with SLE who were receiving care at an academic medical center completed the PROMIS10 at 2 visits that were a minimum of 1 month apart. Responsiveness of the PROMIS10 global physical and mental health domains to Patient-Reported improvement or deterioration of health status was evaluated, as measured by standard validated instruments. Effect sizes of changes in PROMIS10 scores between visits were evaluated using Kruskal-Wallis testing., Results: A total of 223 SLE patients enrolled and completed baseline surveys, with 186 (83.4%) completing a second set of questionnaires. The PROMIS10 demonstrated mild-to-moderate responsiveness to Patient-Reported improvement (effect size 0.29) and worsening (effect sizes -0.27 and -0.54) of health status for both global physical health and global mental health. Changes in the PROMIS10 correlated poorly with changes in physician-reported measures of disease activity., Conclusion: The PROMIS10 showed responsiveness over time to Patient-Reported changes in SLE health status, but not physician-assessed changes. These data suggest that the PROMIS10 can be used to efficiently measure and monitor important aspects of the SLE patient experience that are not captured by standard physician-derived metrics. Further studies are needed to evaluate the role of the PROMIS10 in optimizing longitudinal disease management in SLE and to determine its responsiveness in other chronic health conditions., (© 2019, American College of Rheumatology.)

Background: Total hip replacement (THR)/total knee replacement (TKR) studies do not uniformly measure patient centered domains, pain, and function. We aim to validate existing measures of pain and function within subscales of standard instruments to facilitate measurement., Methods: We evaluated baseline and 2-year pain and function for THR and TKR using Hip disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS), with primary unilateral TKR (4796) and THR (4801). Construct validity was assessed by correlating HOOS/KOOS pain and activities of daily living (ADL), function quality of life (QOL), and satisfaction using Spearman correlation coefficients. Patient relevant thresholds for change in pain and function were anchored to improvement in QOL; minimally clinically important difference (MCID) corresponded to "a little improvement" and a really important difference (RID) to a "moderate improvement." Pain and ADL function scores were compared by quartiles using Kruskal-Wallis., Results: Two-year HOOS/KOOS pain and ADL function correlated with health-related QOL (KOOS pain and Short Form 12 Physical Component Scale ρ = 0.54; function ρ = 0.63). Comparing QOL by pain and function quartiles, the highest levels of pain relief and function were associated with the most improved QOL. MCID for pain was estimated at ≥20, and the RID ≥29; MCID for function ≥14, and the RID ≥23. The measures were responsive to change with large effect sizes (≥1.8)., Conclusion: We confirm that HOOS/KOOS pain and ADL function subscales are valid measures of critical patient centered domains after THR/TKR, and achievable thresholds anchored to improved QOL. Cost-free availability and brevity makes them feasible, to be used in a core measurement set in total joint replacement trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Up to 30% of selected heart failure patients do not benefit clinically from cardiac resynchronization therapy (CRT). Left ventricular (LV) wall thickness (WT) analysed using computed tomography (CT) has rarely been evaluated in response to CRT and mitral regurgitation (MR) improvement. We examined the association of LVWT and the ability to reverse LV remodelling and MR improvement after CRT., Methods and Results: Fifty-four patients scheduled for CRT underwent pre-procedural CT. Reduced LVWT was defined as WT <6 mm and quantified as a percentage of total LV area. Endpoints were 6-month clinical and echocardiographic response to CRT [New York Heart Association (NYHA) class, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV)], MR improvement and 2-year major adverse cardiac events (MACE). Patients were divided into three groups according to the percentage of LVWT <6 mm area: ≤20%, 20-50%, and ≥50%. At 6 months, 75%, 71%, and 42% of the patients experienced NYHA improvement in the ≤20%, 20-50%, and ≥50% group, respectively. Additionally, ≤20% group presented higher LVEF, LVEDV, and LVESV positive response rate (86%, 59%, and 83%, respectively). Both 20-50% and ≥50% groups exhibited a lower LVEF, LVEDV, and LVESV positive response rate (52% and 42%; 47% and 45%; and 53% and 45%, respectively). Additionally, ≥25% of LVWT <6 mm inclusive of at least one papillary muscle insertion was the only predictor of lack of MR improvement. Lastly, ≥50% group experienced significantly lower 2-year MACE survival free probability., Conclusion: WT evaluated using CT could help to stratify the response to CRT and predict MR improvement and outcomes., Clinical Trial Registration: NCT01097733., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The residual risk of ventricular arrhythmia (VA) after cardiac resynchronization therapy (CRT) implantation in patients with nonischemic cardiomyopathy (NICM) remains difficult to evaluate. The impact of left ventricular (LV) wall thickness (WT) measured using computed tomography (CT) on the occurrence of VA after CRT implantation has never been investigated. In this pilot study, we examined the association of LV WT and the occurrence of VA in NICM patients receiving CRT. Thirty three patients with NICM scheduled for CRT underwent preprocedural CT. Reduced LV WT was defined as WT <6 mm and quantified as a percentage of total LV area. The end point was the occurrence of VA episode during 2-years follow-up after CRT implantation. During the 2-years follow-up, a total of 37 VA episodes occurred in 6 (18.2%) patients. Patients with VA exhibited significantly higher NT-pro BNP level before CRT implantation. Additionally, CT analysis showed that patients with VA had a higher percentage of total LV with reduced WT compared with those free from VA (49.5% vs 25.8%, respectively; p = 0.005). In multivariable analysis, the total percentage of LV area with WT <6 mm was the only predictor of VA (odds ratio 1.07 [1.00 to 1.14]; p = 0.047). Receiver-operator curves analysis for total percentage of LVWT <6 mm demonstrated that an optimal cut-off value of 40% differentiated patients at risk of VA. In conclusion, LVWT evaluated using cardiac CT is an independent predictor of VA in NICM patients implanted with CRT. Patients with a total percentage of LVWT <6 mm ≥40% are especially at high risk of VA after CRT implantation., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Chinese Americans are a fast-growing immigrant group with more severe rheumatic disease manifestations than whites and often a strong cultural preference for traditional Chinese medicine (TCM). We aimed to examine TCM use patterns and association with patient-reported outcomes (PRO) among Chinese American rheumatology patients., Methods: Chinese Americans actively treated for systemic rheumatic diseases were recruited from urban Chinatown rheumatology clinics. Data on sociodemographics, acculturation, clinical factors, and TCM use (11 modalities) were gathered. Self-reported health status was assessed using Patient Reported Outcomes Measurement Information System (PROMIS) short forms. TCM users and nonusers were compared. Factors independently associated with TCM use were identified using multivariable logistic regression., Results: Among 230 participants, median age was 57 years (range 20-97), 65% were women, 71% had ≤ high school education, 70% were on Medicaid insurance, 47% lived in the United States for ≥ 20 years, and 22% spoke English fluently. Half used TCM in the past year; these participants had worse self-reported anxiety, depression, fatigue, and ability to participate in social roles and activities compared with nonusers. In multivariable analysis, TCM use was associated with belief in TCM, female sex, ≥ 20 years of US residency, reporting Western medicine as ineffective, and shorter rheumatic disease duration., Conclusion: Among these Chinese American rheumatology patients, TCM users had worse PRO in many physical and mental health domains. TCM use may be a proxy for unmet therapeutic needs. Asking about TCM use could help providers identify patients with suboptimal health-related quality of life who may benefit from targeted interventions.

Background: Pulmonary hypertension (PH) is an adverse prognostic marker in patients undergoing cardiac resynchronization therapy (CRT). We sought to determine the relation of biomarkers of fibrosis [soluble ST2 (sST2), galectin-3], wall stretch [amino terminal pro-brain natriuretic peptide (NT-proBNP)], and necrosis [high-sensitivity troponin-I (hsTnI)] to PH severity in CRT patients., Methods: Biomarkers and right ventricular systolic pressure (RVSP) were measured at CRT implant and 6-month later (n=111). PH was categorized into 3 groups based on RVSP: no (<35 mmHg), mild-moderate (35-60 mmHg), and severe (>60 mmHg). Patients were categorized as progressors (worsened PH), persistent PH (no change) and regressors (improved PH). Endpoints were 6-month CRT response and 2-year major adverse cardiac event (MACE)., Results: RVSP was associated with CRT nonresponse (P=0.02) and MACE (P=0.03). Severe PH patients had 5-fold increase risk for CRT nonresponse (OR 5.0, P=0.04) and MACE (HR 5.7, P=0.04) over non-PH patients. Progressors and persistent PH patients had >2-fold odds for CRT non-response (OR 2.8, P=0.45) and >11-fold increase in MACE compared to no PH patients or regressors (HR 11.6, P=0.02). Only NT-proBNP and sST2 were discernable between PH groups, with graded increase based on PH severity (both P≤0.02), and lower values in regressors versus non-regressors (both P≤0.01). Levels of sST2 decreased at 6 months in regressors (15 ng/mL, P=0.03) and increased slightly (3-8 ng/mL) in non-regressors, without difference for NT-proBNP (P=0.08)., Conclusions: sST2 levels are related with PH severity in CRT patients. Serial sST2 changes after CRT implant suggests potential role to monitor PH after CRT., Competing Interests: Conflicts of Interest: Dr. Januzzi is supported in part by the Hutter Family Professorship, receives grant support from Siemens, Singulex, Prevencio, and Roche, and has served as a consultant to Roche Diagnostics, Critical Diagnostics, Abbott, GE, Amgen, and Novartis. Dr. Singh receives grant support from St. Jude Medical, Medtronic Inc., Boston Scientific Corp., Sorin Group, Biotronik, BG Medicine and Siemens. Dr. Truong received grant support from Ziosoft, Inc. (formerly Qi Imaging LLC). The other authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Background: By virtue of its proximity to structures vital to cardiac conduction, aortomitral continuity calcification (AMCC) may help identify patients at highest risk for developing atrioventricular conduction disease requiring permanent pacemaker implantation (PPMI). We aim to determine the association of AMCC and need for PPMI after transcatheter aortic valve replacement., Methods: Of 614 patients who underwent transcatheter aortic valve replacement (11.8% PPMI rate), we included 136 patients (age 85±8 years, 47% male) without a preexisting intracardiac device or prior valve surgery who underwent preprocedural computed tomography. We analyzed for the presence of AMCC, aortic valve calcification, and mitral annular calcification as well as quantified AMCC and aortic valve calcification score using the Agatston method. We further stratified AMCC score into 3 categories: 0, 1 to 300, and >300. End point was PPMI at 1 month after transcatheter aortic valve replacement., Results: There were 51 (38%) new PPMIs (median time to PPMI, 5 days). Patients who underwent PPMI had a higher prevalence of AMCC than patients without PPMI (69% versus 32%; P <0.0001), as well as higher median AMCC score (263 versus 0; P <0.0001). There was no difference in aortic valve calcification and mitral annular calcification between patients with and without PPMI (all P ≥0.09). Patients with AMCC had a 4-fold increase in odds for PPMI compared with those without (adjusted odds ratio, 4.0; P =0.0026). Compared with patients with an AMCC score of 0, patients with an AMCC score >300 had greater than a 5-fold increased odds for PPMI (adjusted odds ratio, 5.7; P =0.0016)., Conclusions: Presence of AMCC, particularly with AMCC score >300, is associated with the need for PPMI after transcatheter aortic valve replacement.

Objective: To determine whether racial disparities in total knee replacement (TKR) failure are explained by poverty., Methods: Black and white New York state residents, enrolled in a prospective single-institution TKR registry January 1, 2008 to February 6, 2012, who underwent primary unilateral TKR (n = 4,062) were linked to the New York Statewide Planning and Research Cooperative System database (January 1, 2008 to December 31, 2014) to capture revisions performed at outside institutions. Patients were linked by geocoded addresses to residential census tracts. Multivariable Cox regression was used to assess predictors of TKR revision. Multivariable logistic regression was used to analyze predictors of TKR failure, defined as TKR revision in New York state ≤2 years after surgery, or as Hospital for Special Surgery (HSS) TKR quality of life score "not improved" or "worsened" 2 years after surgery., Results: The mean ± SD age was 68.4 ± 10 years, 64% of patients were female, 8% lived in census tracts with >20% of the population under the poverty line, and 9% were black. Median follow-up time was 5.3 years. A total of 3% of patients (122 of 4,062) required revision a median 454 days (interquartile range 215-829) after surgery. TKR revision risk was higher in blacks than whites, with a hazard ratio of 1.69 (95% confidence interval 1.01-2.81), but in multivariable analysis, only younger age, male sex, and constrained prosthesis were predictors of TKR revision. TKR failure occurred in 200 of 2,832 cases (7%) with 2-year surveys. Risk factors for TKR failure were non-osteoarthritis TKR indication, low surgeon volume, and low HSS Expectations Survey score, but not black race. Community poverty was not associated with TKR revision or failure., Conclusion: There was a trend toward higher TKR revision risk in blacks, but poverty did not modify the relationship between race and TKR revision or failure., (© 2019, American College of Rheumatology.)

Purpose: We sought to determine the performance of an automated computed tomography (CT) software that provides dynamic annular measurements of all available cardiac phases for transcatheter aortic valve replacement (TAVR) sizing as compared to the standard single manual measurement., Materials and Methods: In 60 TAVR patients (84±7 years, 60% male) who underwent pre-procedural CT scans, we measured the aortic annular diameters, perimeter, and area using (1) the dynamic automated CT measurements and (2) standard single manual measurement from the cardiac phase of maximum systolic opening by visual estimate., Results: The automated software was successful in providing annular measurements in 43/60 (72%) of cases, with the remainder requiring semi-automated contours. The maximum dynamic automated values were predominantly in systole (46/60[77%] for diameter, 44/60[73%] for perimeter, 48/60[80%] for area), and was a different phase from the standard manual phase in 46/60 (77%) cases. The maximum dynamic automated annular values were larger than the standard manual values measured (Δdiameter 0.35 mm, p=0.04; Δperimeter 1.71 mm, p<0.001; Δarea 15.6 mm 2 , p<0.001). When comparing standard manual to the same phase by automated measurements, while there was no difference in annular mean diameter (p=0.80), perimeter and area were larger with the automated measurements (Δperimeter 0.95 mm, p=0.002; Δarea 10.8 mm 2 , p=0.03). However, the maximum automated measurements were consistently larger than the same phase automated measurements (Δdiameter 0.13 mm, p<0.001; Δperimeter 0.42 mm, p<0.001; Δarea 4.4 mm 2 , p<0.001)., Conclusions: Automated maximum dynamic CT annular measurements provide larger values than standard manual and same phase automated measurements.

Objective: Patients with rheumatoid arthritis (RA) in clinical remission may have subclinical synovial inflammation. This study was undertaken to determine the proportion of patients with RA in remission or with low disease activity at the time of arthroplasty who had histologic or transcriptional evidence of synovitis, and to identify clinical features that distinguished patients as having subclinical synovitis., Methods: We compared Disease Activity Score in 28 joints (DAS28) to synovial histologic features in 135 patients with RA undergoing arthroplasty. We also compared DAS28 scores to RNA-Seq data in a subset of 35 patients., Results: Fourteen percent of patients met DAS28 criteria for clinical remission (DAS28 <2.6), and another 15% met criteria for low disease activity (DAS28 <3.2). Histologic analysis of synovium revealed synovitis in 27% and 31% of samples from patients in remission and patients with low disease activity, respectively. Patients with low disease activity and synovitis also exhibited increased C-reactive protein (CRP) (P = 0.0006) and increased anti-cyclic citrullinated peptide (anti-CCP) antibody levels (P = 0.03) compared to patients without synovitis. Compared to patients with a "low inflammatory synovium" subtype, 183 genes were differentially expressed in the synovium of patients with subclinical synovitis. The majority of these genes (86%) were also differentially expressed in the synovium of patients with clinically active disease (DAS28 ≥3.2)., Conclusion: Thirty-one percent of patients with low clinical disease activity exhibited histologic evidence of subclinical synovitis, which was associated with increased CRP and anti-CCP levels. Our findings suggest that synovial gene expression signatures of clinical synovitis are present in patients with subclinical synovitis., (© 2019, American College of Rheumatology.)

Background: Cardiorenal syndrome comprises a heterogeneous group of disorders characterized by acute or chronic cardiac and renal dysfunction., Objective: The purpose of this study was to determine the effect of cardiorenal status using a dual-marker strategy with amino-terminal pro-brain natriuretic peptide (NT-proBNP) and cystatin C on cardiac resynchronization therapy (CRT) outcomes., Methods: In 92 patients (age 66 ± 13 years; 80% male; left ventricular ejection fraction 26% ± 7%), NT-proBNP and cystatin C levels were measured at CRT implantation and at 1 month. NT-proBNP >1000 pg/mL and cystatin C >1 mg/L were considered high. Baseline cardiorenal patients were defined as having high NT-proBNP and cystatin C. At 1 month, CRT patients were categorized as (1) irreversible cardiorenal if cystatin C was persistently high; (2) progressive cardiorenal with transition from low to high cystatin C; (3) reversible cardiorenal with transition from high to low cystatin C; and (4) "normal" with stable low cystatin C. Outcomes were 6-month clinical and echocardiographic CRT response and 2 -year major adverse cardiovascular event (MACE)., Results: Compared to patients with low NT-proBNP and cystatin C, cardiorenal patients had >9-fold increase risk of CRT nonresponse (odds ratio uncompensated 9.0; compensated 36.4; both P ≤.004) and >6-fold risk of MACE (hazard ratio uncompensated 8.5; P = .005). Compared to "normal" and reversible patients (referent), irreversible patients had a 9-fold increase for CRT nonresponse (odds ratio 9.1; P <.001) and had >4-fold risk of MACE (adjusted hazard ratio 5.1; P <.001). Irreversible patients were most likely echocardiographic CRT nonresponders., Conclusion: Cardiorenal status by NT-proBNP and cystatin C can identify high-risk CRT patients, and those with both elevated concentrations have worse prognosis., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with inflammatory arthritis (IA) are at increased risk of prosthetic joint infections (PJI), yet differentiating between septic and aseptic failure is a challenge. The aim of our systematic review is to evaluate synovial biomarkers and their efficacy at diagnosing PJI in patients with IA., Methods: A comprehensive literature search was performed in the following databases from inception to January 2018: Ovid MEDLINE, Ovid EMBASE, and the Cochrane Library. Searches across the databases retrieved 367 results. Two of 5 reviewers independently screened a total of 298 citations. Discrepancies were resolved by a third reviewer. Twenty articles fit our criteria, but due to methodological differences findings could not be pooled for meta-analysis. For 5 studies, raw data were provided, pooled, and used to derive optimal diagnostic cut points., Results: Our final analysis included 1861 non-IA patients, including 426 patients with PJI, and 90 IA patients of whom 26 had PJI. There was a significant difference among the 4 groups for serum C-reactive protein (CRP), erythrocyte sedimentation rate, and synovial CRP, polymorphonuclear neutrophil percent, white blood cells, interleukin (IL)-6, IL-8, and IL-1b. Polymorphonuclear neutrophil percent had the highest sensitivity (95.2%) and specificity (85.0%) to detect infections with an optimum threshold of 78%., Conclusion: While levels of synovial white blood cells, IL-6, IL-8, and serum CRP appear higher in patients with IA, there is overlap with those who are not infected. Further studies are needed to explore diagnostic tests that will better detect PJI in patients with IA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP 1-108 , or C-type natriuretic peptide (CNP) is not well understood., Objectives: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays., Methods: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP 1-108 , and CNP were measured over 3 visits., Results: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP 1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change., Conclusions: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Community characteristics such as poverty affect total knee arthroplasty (TKA) outcomes. However, it is unknown whether other community factors such as immigrant proportion (IP) also affect outcomes. Our objective was to determine the association of neighborhood IP on preoperative (pre-op) and 2-year postoperative (post-op) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function after elective TKA., Methods: Patients in a high volume institutional TKA registry between May 2007 and February 2011 were retrospectively analyzed. Demographics, pre-op and 2-year post-op WOMAC pain and function scores, and geocodable addresses were obtained. Patient-level variables were linked to US Census Bureau census tract data. The effect of patient and neighborhood-level factors on WOMAC scores were analyzed using linear mixed effects models., Results: 3898 TKA patients were analyzed. Pre-op and 2-year post-op WOMAC pain and function scores were between 2.75-4.88 WOMAC points worse in neighborhoods with a high IP (≥ 40%) compared to low IP (< 10%). In multivariable analyses, these differences were not statistically significant. Women had worse pre-op and 2-year post-op WOMAC scores (all p ≤ 0.04), but this difference was not influenced by neighborhood IP (all p interaction NS)., Conclusions: Patients living in high (≥40%) IP neighborhoods do not have worse pre-op or 2-year post-op pain and function outcomes after TKA compared to those living in low (< 10%) IP neighborhoods. Although sex differences favoring males are notable, these differences are not associated with IP. High neighborhood IP do not appear to affect outcomes after TKA.

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII- deficient mice ( F8 -/- mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-α levels in the affected joint of F8 -/- mice. Moreover, inactivation of TNF-α or iRhom2 in F8 -/- mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients., (© 2018 by The American Society of Hematology.)

Background: Dual-source computed tomography (CT) can evaluate left ventricular (LV) dyssynchrony, myocardial scar, and coronary venous anatomy in patients undergoing cardiac resynchronization therapy (CRT)., Objective: We aimed to determine whether dual-source CT predicts clinical CRT outcomes and reduces intraprocedural time., Methods: In this prospective study, 54 patients scheduled for CRT (mean age 63 ± 11 years; 74% men) underwent preprocedural CT to assess their venous anatomy as well as CT-derived dyssynchrony metrics and myocardial scar. Based on 1:1 randomization, the implanting physician had preimplant knowledge of the venous anatomy in half the patients. In blinded analyses, we measured time to maximal wall thickness and inward wall motion to determine (1) CT global and segmental dyssynchrony and (2) concordance of lead location to regional LV mechanical contraction. End points were 6-month CRT response measured using heart failure clinical composite score and 2-year major adverse cardiac events (MACE)., Results: There were 72% CRT responders and 17% with MACE. Two wall motion dyssynchrony indices-global wall motion and opposing anteroseptal-inferolateral wall motion-predicted MACE (P < .01). Lead location concordant to regions of maximal wall thickness was associated with less MACE (P < .01). No CT dyssynchrony metrics predicted 6-month CRT response (P = NS for all). Myocardial scar (43%), posterolateral wall scar (28%), and total scar burden did not predict outcomes (P = NS for all). Preknowledge of coronary venous anatomy by CT did not reduce implant or fluoroscopy time (P = NS for both)., Conclusion: Two CT dyssynchrony metrics predicted 2-year MACE, and LV lead location concordant to regions of maximal wall thickness was associated with less MACE. Other CT factors had little utility in CRT., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: Total knee arthroplasty (TKA) outcomes are worse for patients from poor neighborhoods, but whether education mitigates the effect of poverty is not known. We assessed the interaction between education and poverty on 2-year Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function., Methods: Patient-level variables from an institutional registry were linked to US Census Bureau data (census tract [CT] level). Statistical models including patient and CT-level variables were constructed within multilevel frameworks. Linear mixed-effects models with separate random intercepts for each CT were used to assess the interaction between education and poverty at the individual and community level on WOMAC scores., Results: Of 3,970 TKA patients, 2,438 (61%) had some college or more. Having no college was associated with worse pain and function at baseline and 2 years (P = 0.0001). Living in a poor neighborhood (>20% below poverty line) was associated with worse 2-year pain (P = 0.02) and function (P = 0.006). There was a strong interaction between individual education and community poverty with WOMAC scores at 2 years. Patients without college living in poor communities had pain scores that were ~10 points worse than those with some college (83.4% versus 75.7%; P < 0.0001); in wealthy communities, college was associated with a 1-point difference in pain. Function was similar., Conclusion: In poor communities, those without college attain 2-year WOMAC scores that are 10 points worse than those with some college; education has no impact on TKA outcomes in wealthy communities. How education protects those in impoverished communities warrants further study., (© 2017, American College of Rheumatology.)

Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF., Methods and Results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ∼three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P < 0.0001), while the trans-pulmonary gradient was neutral (n = 5, P = 1.0)., Conclusion: The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.

Objective: Rates of total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain high for patients with rheumatoid arthritis (RA), who are at risk of flaring after surgery. We aimed to describe rates, characteristics, and risk factors of RA flare within 6 weeks of THA and TKA., Methods: Patients with RA were recruited prior to elective THA and TKA surgery and prospectively followed. Clinicians evaluated RA clinical characteristics 0-2 weeks before and 6 weeks after surgery. Patients answered questions regarding disease activity including self-reported joint counts and flare status weekly for 6 weeks. Per standard of care, biologics were stopped before surgery, while glucocorticoids and methotrexate (MTX) were typically continued. Multivariable logistic regression was used to identify baseline characteristics associated with postsurgical RA flares., Results: Of 120 patients, the mean age was 62 years and the median RA duration 14.8 years. Ninety-eight (82%) met 2010/1987 American College of Rheumatology/European League Against Rheumatism criteria, 53 (44%) underwent THA (and the rest TKA), and 61 (51%) were taking biologics. By 6 weeks, 75 (63%) had flared. At baseline, flarers had significantly higher disease activity (as measured by the 28-joint Disease Activity Score), erythrocyte sedimentation rate, C-reactive protein, and pain. Numerically more flarers used biologics, but stopping biologics did not predict flares, and continuing MTX was not protective. A higher baseline disease activity predicted flaring by 6 weeks (OR 2.12, p = 0.02)., Conclusion: Flares are frequent in patients with RA undergoing arthroplasty. Higher baseline disease activity significantly increases the risk. Although more patients stopping biologics flared, this did not independently predict flaring. The effect of early postsurgery flares requires further study.

Objective: In this study, we sought to refine histologic scoring of rheumatoid arthritis (RA) synovial tissue by training with gene expression data and machine learning., Methods: Twenty histologic features were assessed in 129 synovial tissue samples (n = 123 RA patients and n = 6 osteoarthritis [OA] patients). Consensus clustering was performed on gene expression data from a subset of 45 synovial samples. Support vector machine learning was used to predict gene expression subtypes, using histologic data as the input. Corresponding clinical data were compared across subtypes., Results: Consensus clustering of gene expression data revealed 3 distinct synovial subtypes, including a high inflammatory subtype characterized by extensive infiltration of leukocytes, a low inflammatory subtype characterized by enrichment in pathways including transforming growth factor β, glycoproteins, and neuronal genes, and a mixed subtype. Machine learning applied to histologic features, with gene expression subtypes serving as labels, generated an algorithm for the scoring of histologic features. Patients with the high inflammatory synovial subtype exhibited higher levels of markers of systemic inflammation and autoantibodies. C-reactive protein (CRP) levels were significantly correlated with the severity of pain in the high inflammatory subgroup but not in the others., Conclusion: Gene expression analysis of RA and OA synovial tissue revealed 3 distinct synovial subtypes. These labels were used to generate a histologic scoring algorithm in which the histologic scores were found to be associated with parameters of systemic inflammation, including the erythrocyte sedimentation rate, CRP level, and autoantibody levels. Comparison of gene expression patterns to clinical features revealed a potentially clinically important distinction: mechanisms of pain may differ in patients with different synovial subtypes., (© 2018, American College of Rheumatology.)

Objectives: The current meta-analysis aimed to evaluate the diagnostic performance of hybrid cardiac imaging techniques compared with stand-alone coronary computed tomography angiography (CTA) for assessment of obstructive coronary artery disease (CAD)., Background: The usefulness of coronary CTA for detecting obstructive CAD remains suboptimal at present. Myocardial perfusion imaging encompasses positron emission tomography, single-photon emission computed tomography, and cardiac magnetic resonance, which permit the identification of myocardial perfusion defects to detect significant CAD. A hybrid approach comprising myocardial perfusion imaging and coronary CTA may improve diagnostic performance for detecting obstructive CAD., Methods: PubMed and Web of Knowledge were searched for relevant publications between January 1, 2000 and December 31, 2015. Studies using coronary CTA and hybrid imaging for diagnosis of obstructive CAD (a luminal diameter reduction of >50% or >70% by invasive coronary angiography) were included. In total, 12 articles comprising 951 patients and 1,973 vessels were identified, and a meta-analysis was performed to determine pooled sensitivity, specificity, and summary receiver-operating characteristic curves., Results: On a per-patient basis, the pooled sensitivity of hybrid imaging was comparable to that of coronary CTA (91% vs. 90%; p = 0.28). However, specificity was higher for hybrid imaging versus coronary CTA (93% vs. 66%; p < 0.001). On a per-vessel basis, sensitivity for hybrid imaging against coronary CTA was comparable (84% vs. 89%; p = 0.29). Notably, hybrid imaging yielded a specificity of 95% versus 83% for coronary CTA (p < 0.001). Summary receiver-operating characteristic curves displayed improved discrimination for hybrid imaging beyond coronary CTA alone, on a per-vessel basis (area under the curve: 0.97 vs. 0.93; p = 0.047), although not on a per-patient level (area under the curve: 0.97 vs. 0.93; p = 0.132)., Conclusions: Hybrid cardiac imaging demonstrated improved diagnostic specificity for detection of obstructive CAD compared with stand-alone coronary CTA, yet improvement in overall diagnostic performance was relatively limited., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The diagnosis of venous thromboembolism is difficult in the postoperative setting because signs such as hypoxemia, leg pain, and swelling are so common. CTPA can also detect subsegmental PE (SSPE), of which the clinical significance has been widely debated. Clinical decision rules (CDR), such as the Wells and PISA 2, have been developed to identify symptomatic patients at low risk for PE who could forgo imaging. We performed this study in order to (1) compare the performance of the Wells and PISA 2 CDR in orthopedic patients; (2) compare CDR scores in patients with subsegmental PE (SSPE) versus larger clots; and (3) identify variables that improve performance of the Wells in orthopedic patients. This retrospective cohort study included all orthopedic surgery patients that underwent computerized tomographic pulmonary angiography at a single institution from 1/1/13 to 12/31/14 and had data to calculate both Wells and PISA 2 scores. CDR sensitivity, specificity and c-statistics were calculated. Multivariable logistic regression was used to identify variables that improved CDR performance. 402 patients were included in the study. The Wells rule (cutoff > 4) had sensitivity 74% and specificity 45%. PISA 2 (cutoff 0.6) had sensitivity 90% and specificity 11%. The Wells performed better than PISA 2: c-statistic 0.60 vs. 0.50; p = 0.007. The mean Wells score was 5.20 ± 1.68 for patients with SSPE and 5.41 ± 1.86 for patients with larger clots. Adding the variables prior smoking and varicose veins improved the performance of the Wells rule (c-statistic 0.66 vs. 0.60, p = 0.008). The Wells rule (cutoff > 4) performs better than PISA 2 in orthopedic patients. Neither can distinguish patients with SSPE from those with larger clots. Although adding past smoking and varicose veins to the Wells improves its performance, this requires validation in other populations.

Objectives: The purpose of this study was to develop and validate a simple-to-use nomogram for prediction of 5-, 10-, and 15-year survival among asymptomatic adults., Background: Simple-to-use prognostication tools that incorporate robust methods such as coronary artery calcium scoring (CACS) for predicting near-, intermediate- and long-term mortality are warranted., Methods: In a consecutive series of 9,715 persons (mean age: 53.4 ± 10.5 years; 59.3% male) undergoing CACS, we developed a nomogram using Cox proportional hazards regression modeling that included: age, sex, smoking, hypertension, dyslipidemia, diabetes, family history of coronary artery disease, and CACS. We developed a prognostic index (PI) summing the number of risk points corresponding to weighted covariates, which was used to configure the nomogram. Validation of the nomogram was assessed by discrimination and calibration applied to a separate cohort of 7,824 adults who also underwent CACS., Results: A total of 936 and 294 deaths occurred in the derivation and validation sets at a median follow-up of 14.6 years (interquartile range: 13.7 to 15.5 years) and 9.4 years (interquartile range: 6.8 to 11.5 years), respectively. The developed model effectively predicted 5-, 10-, and 15-year probability of survival. The PI displayed high discrimination in the derivation and validation sets (C-index 0.74 and 0.76, respectively), indicating suitable external performance of our nomogram model. The predicted and actual estimates of survival in each dataset according to PI quartiles were similar (though not identical), demonstrating improved model calibration., Conclusions: A simple-to-use nomogram effectively predicts 5-, 10- and 15-year survival for asymptomatic adults undergoing screening for cardiac risk factors. This nomogram may be considered for use in clinical care., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test-retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC)., Results: A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations ≥ 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC ≥ 0.85). PROMIS10 required < 2 minutes to complete., Conclusion: PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives.

Background: Orthopedic patients are at risk for adverse postoperative cardiovascular outcomes., Questions/purposes: This pilot randomized controlled trial (RCT) of atorvastatin vs. placebo in orthopedic surgery patients was performed in order to assess: (1) the prevalence of perioperative myocardial injury; (2) the effect of atorvastatin on perioperative inflammation; and (3) the feasibility of performing a large RCT of statin therapy in orthopedic patients., Methods: Hip fracture (hip Fx) and total hip and knee replacement (THR and TKR) patients were randomized 1:1 to atorvastatin 40 mg daily vs. placebo, starting preoperatively and continuing until postoperative day (POD) 45. High-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) were measured preoperatively and on POD 2. Patients were monitored for adverse events until POD 90., Results: Five hundred fifty-six patients were screened, 22 were recruited (4 hip Fx, 11 THR, 7 TKR), and 2 withdrew. Most (80%) had detectable hs-cTnI (> 1.1 pg/mL) preoperatively. Twenty percent had a perioperative rise in hs-cTnI (≥ 10 pg/mL), which was not blunted by atorvastatin. Hs-CRP rose in 19/20 patients, and IL-6 rose in all patients. However, atorvastatin did not blunt the rise in these inflammatory biomarkers. On POD 2, IL-6 and hs-cTnI levels correlated ( ρ  = 0.59, p  = 0.02). Recruitment was limited by the high prevalence of statin use in the screened population and a high prevalence of exclusions among hip fracture patients., Conclusion: Perioperative myocardial injury and inflammation are common in orthopedic patients and do not appear to be reduced in those randomized to atorvastatin., Trial Registration: NCT02197065., Competing Interests: Compliance with Ethical StandardsJaclyn D. Szymonifka, MA; Matthew T. Rondina, MD, MS; Margaret Bogardus, BA; Scott C. Woller, MD; Scott M. Stevens, MD; Kerri Merritt; Gerard Moskowitz, PhD; Alejandro Gonzalez Della Valle, MD; and Eva Flores, MD, have declared that they have no conflict of interest. Mitchell G. Scott, PhD, reports a grant from Abbott Diagnostics during the conduct of the study. He also reports grants from Instrumentation Laboratory and Siemens Healthcare; other from Becton, Dickinson and Roche Diagnostics, outside the work. Anne R. Bass, MD, reports grants from Weill Cornell Clinical and Translational Science Center (UL1TR000457-06) and other from Pfizer and Abbott Labs during the conduct of the study. Charles Eby, MD, reports grants from Siemens Healthcare Diagnostics and personal fess from Boehringer Ingelheim and Bayer Pharmaceuticals, outside the work. Brian F. Gage, MD, MSc, reports ownership of stock in at least 1 pharmaceutical company that markets or manufactures statins.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).Informed consent was obtained from all patients for being included in the study. Disclosure forms provided by the authors are available with the online version of this article.

Objective: To assess the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF)., Methods: In this 52-week, investigator-initiated, single-center, double-blind, placebo-controlled, pilot study, 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo. We assessed safety, efficacy, and differential gene expression., Results: In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) (P = 0.039). In the placebo group, the median MRSS decreased from 28 (IQR 22, 28) to 21 (IQR 14, 25) (P = 0.023). The median change in MRSS was -10 (IQR -13, -9) in the belimumab group and -3.0 (IQR -15, -1) in the placebo group (P = 0.411). There were no significant differences between the groups in the number of adverse events (AEs). A significant decrease in expression of B cell signaling and profibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group., Conclusion: Patients in both treatment groups experienced significant improvements in MRSS. The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study. AEs were similar between the groups. Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab is associated with a significant decrease in profibrotic genes and pathways. Additional studies are needed to determine the role of belimumab in the treatment of dcSSc., (© 2017, American College of Rheumatology.)

Aim: To test the efficacy of achieving target SBP less than 120 mmHg, or less than 140 mmHg, for lowering the risk of major adverse cardiovascular events (MACE) in persons with diabetes mellitus., Method: The study comprised 4732 [mean ± SD age: 63 ± 7 years; 2258 (48%) women] persons with advanced diabetes mellitus. Participants randomly assigned to achieve intensive (<120 mmHg) or standard (<140 mmHg) SBP control were grouped according to whether or not they achieved their respective SBP goal. MACE consisted of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes., Results: During a median 5.0 (interquartile range: 4.2-5.7) years, 1939 (82%) and 2038 (86%) persons achieved SBP targets less than 120 and less than 140 mmHg in each treatment arm, respectively. Overall, 208 (9%) and 237 (10%) persons in the intensive and standard treatment arms experienced MACE. In the intensive treatment arm, multivariable Cox regression revealed no significant reduction in risk of MACE for those who achieved a target SBP less than 120 mmHg. In the standard treatment arm, those who achieved a target SBP less than 140 mmHg displayed a substantial reduction in risk of MACE (hazard ratio = 0.65, P = 0.005), all-cause death (hazard ratio = 0.64, P = 0.02), and nonfatal stroke (hazard ratio = 0.47, P = 0.02) as compared with those whose achieved SBP was 140 mmHg or higher., Conclusion: Achieving a standard SBP goal between 120 and 140 mmHg may prove useful for lowering cardiovascular risk in persons with diabetes mellitus. Achieving a target SBP less than 120 mmHg does not appear to mitigate risk., Clinical Trial Registration: ClinicalTrials.gov # NCT00000620 (https://clinicaltrials.gov/ct2/results?term=NCT00000620&Search=Search).

Background: We aimed to develop a severity classification system of the main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans., Methods: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n = 114), we determined cutpoints for a four-tier severity grading system that would maximize sensitivity and specificity, and validated it in a separate cohort (n = 114). Cutpoints for mPA were defined with ≤27 mm(F) and ≤29 mm(M) as the normal reference range; mild as >27 to <31 mm(F) and >29 to <31 mm(M); moderate≥31-34 mm; and severe>34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1., Results: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34 mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p < 0.001). Moderate-severe mPA values of ≥31 mm and ratio PA>1.1 had worse survival than normal values (all p ≤ 0.01)., Conclusion: A CT-based four-tier severity classification system of PA diameter and its ratio to the aortic diameter has high accuracy for PH diagnosis with increased mortality in patients with moderate-severe severity grades. These results may support clinical utilization on chest and cardiac CT reports., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Aims: Cardiac resynchronization therapy (CRT) induces reverse cardiac remodelling in heart failure (HF), but many patients receiving CRT remain non-responders. This study assessed the role of amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide (MR-proANP), and mid-regional-pro-adrenomedullin (MR-proADM) at the time of device implantation to predict favourable clinical course (CRT response and/or risk of MACE) in HF patients receiving CRT., Methods and Results: A total of 137 HF patients were prospectively included. Blood was drawn from the coronary sinus (CS) at CRT implantation, and from a peripheral vein (PV) simultaneously and after 6 months. Clinical CRT response at 6 months and major adverse cardiovascular events (MACE) at 2 years were assessed. Baseline PV-levels of MR-proANP (202 vs. 318 pmol/L, P = 0.009) and MR-proADM (843 vs. 1112 pmol/L, P = 0.02) were lower in CRT responders compared with non-responders. At 6 months, CRT responders showed a decrease in MR-proANP levels, compared with an increase in non-responders (-32 vs. +7 pmol/L, P = 0.02). During the same period, NT-proBNP decreased by a similar way in responders and non-responders, while MR-proADM was unchanged in both groups. High baseline MR-proANP, either in PV (OR 0.41, 95% CI 0.24-0.71, P = 0.002) or CS (OR 0.32, 95% CI 0.15-0.70, P = 0.005) was associated with reduced likelihood of CRT response. Furthermore, PV and CS levels of NT-proBNP, MR-proANP, and MR-proADM were all associated with increased risk of 2-year MACE (all P < 0.01)., Conclusion: Mid-regional-pro-atrial natriuretic peptide may assist prediction of clinical course in HF patients undergoing CRT implantation. Low circulating MR-proANP at the time of device implantation is associated with CRT response and more favourable outcome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Objective: The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SLE)., Methods: Adults with SLE completed the Medical Outcomes Study Short Form-36, LupusQoL-US version ("legacy instruments"), and 14 selected PROMIS CAT. Using Spearman correlations, PROMIS CAT were compared with similar domains measured with legacy instruments. CAT were also correlated with the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) disease activity and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores. Test-retest reliability was evaluated using ICC., Results: There were 204 outpatients with SLE enrolled in the study and 162 completed a retest. PROMIS CAT showed good performance characteristics and moderate to strong correlations with similar domains in the 2 legacy instruments (r = -0.49 to 0.86, p < 0.001). However, correlations between PROMIS CAT and the SELENA-SLEDAI disease activity and SDI were generally weak and statistically insignificant. PROMIS CAT test-retest ICC were good to excellent, ranging from 0.72 to 0.88., Conclusion: To our knowledge, these data are the first to show that PROMIS CAT are valid and reliable for many SLE-relevant domains. Importantly, PROMIS scores did not correlate well with physician-derived measures. This disconnect between objective signs and symptoms and the subjective patient disease experience underscores the crucial need to integrate patient-reported outcomes into clinical care to ensure optimal disease management.

Aims: The aim of this study was to determine the diagnostic performance of single-photon emission computed tomography (SPECT), stress echocardiography (SE), invasive coronary angiography (ICA), coronary computed tomography angiography (CCTA), fractional flow reserve (FFR) derived from CCTA (FFRCT), and cardiac magnetic resonance (MRI) imaging when directly compared with an FFR reference standard., Method and Results: PubMed and Web of Knowledge were searched for investigations published between 1 January 2002 and 28 February 2015. Studies performing FFR in at least 75% of coronary vessels for the diagnosis of ischaemic coronary artery disease (CAD) were included. Twenty-three articles reporting on 3788 patients and 5323 vessels were identified. Meta-analysis was performed for pooled sensitivity, specificity, likelihood ratios (LR), diagnostic odds ratio, and summary receiver operating characteristic curves. In contrast to ICA, CCTA, and FFRCT reports, studies evaluating SPECT, SE, and MRI were largely retrospective, single-centre and with generally smaller study samples. On a per-patient basis, the sensitivity of CCTA (90%, 95% CI: 86-93), FFRCT (90%, 95% CI: 85-93), and MRI (90%, 95% CI: 75-97) were higher than for SPECT (70%, 95% CI: 59-80), SE (77%, 95% CI: 61-88), and ICA (69%, 95% CI: 65-75). The highest and lowest per-patient specificity was observed for MRI (94%, 95% CI: 79-99) and for CCTA (39%, 95% CI: 34-44), respectively. Similar specificities were noted for SPECT (78%, 95% CI: 68-87), SE (75%, 95% CI: 63-85), FFRCT (71%, 95% CI: 65-75%), and ICA (67%, 95% CI: 63-71). On a per-vessel basis, the highest sensitivity was for CCTA (pooled sensitivity, 91%: 88-93), MRI (91%: 84-95), and FFRCT (83%, 78-87), with lower sensitivities for ICA (71%, 69-74), and SPECT (57%: 49-64). Per-vessel specificity was highest for MRI (85%, 79-89), FFRCT (78%: 78-81), and SPECT (75%: 69-80), whereas ICA (66%: 64-68) and CCTA (58%: 55-61) yielded a lower specificity., Conclusions: In this meta-analysis comparing cardiac imaging methods directly to FFR, MRI had the highest performance for diagnosis of ischaemia-causing CAD, with lower performance for SPECT and SE. Anatomic methods of CCTA and ICA yielded lower specificity, with functional assessment of coronary atherosclerosis by SE, SPECT, and FFRCT improving accuracy., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology)

Background and Aims: Coronary computed tomography angiography (CCTA) permits effective identification of diffuse CAD and atherosclerotic plaque characteristics (APCs). We sought to examine the usefulness of diffuse CAD beyond luminal narrowing and APCs by CCTA to detect vessel-specific ischemia., Methods: 407 vessels (n = 252 patients) from the DeFACTO diagnostic accuracy study were retrospectively analyzed for percent plaque diffuseness (PD). Percent plaque diffuseness (PD) was obtained on per-vessel level by summation of all contiguous lesion lengths and divided by total vessel length, and was logarithmically transformed (log percent PD). Additional CCTA measures of stenosis severity including minimal lumen diameter (MLD), and APCs, such as positive remodeling (PR) and low attenuation plaque (LAP), were also included. Vessel-specific ischemia was defined as fractional flow reserve (FFR) ≤0.80. Multivariable regression, discrimination by area under the receiver operating characteristic curve (AUC), and category-free net reclassification improvement (cNRI) were assessed., Results: Backward stepwise logistic regression revealed that for every unit increase in log percent PD, there was a 58% (95% CI: 1.01-2.48, p = 0.048) rise in the odds of having an abnormal FFR, independent of stenosis severity and APCs. The AUC indicated no further improvement in discriminatory ability after adding log percent PD to the final parsimonious model of MLD, PR, and LAP (AUC difference: 0.003, 95% CI: -0.003-0.010, p = 0.33). Conversely, adding log percent PD to the base model of MLD, PR, and LAP improved cNRI by 0.21 (95% CI: 0.01-0.41, p < 0.001)., Conclusions: Accounting for diffuse CAD may help improve the accuracy of CCTA for detecting vessel-specific ischemia., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF., Methods: In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years., Results: The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 μg/L) compared to the control arm (+16 μg/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years., Conclusions: Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients., (© 2016 American Association for Clinical Chemistry.)

Background: Cardiac resynchronization therapy (CRT) improves mitral regurgitation (MR) in a subset of patients. We hypothesized that biomarkers (amino-terminal pro-B type natriuretic peptide, high-sensitivity troponin I, galectin-3 [gal-3], and soluble ST2) might predict MR response after CRT., Methods: We measured levels of biomarkers during CRT implantation in 132 patients with a subsequent 2-year follow-up. MR was graded as no-trace, mild, moderate, or severe at baseline and at 6 months., Results: In patients with baseline at least mild MR, 56% had improvement at 6 months, with lower 2-year mortality vs patients without improvement (0% vs 18%; P = 0.002). At baseline, patients with MR improvement had lower high-sensitivity troponin I and gal-3 levels compared with those without improvement (19 vs 40 pg/L; P = 0.01; 14 vs 18 ng/mL; P = 0.007). In multivariable analyses, higher log-transformed gal-3 (odds ratio, 0.15; 95% confidence interval, 0.04-0.65; P = 0.01) remained an independent predictor for MR nonimprovement. Levels of pro-B type natriuretic peptide and soluble ST2 were lower at follow-up in patients with MR improvement (potentially reflecting reduced myocardial stretch and stress) without reaching statistical significance., Conclusions: Higher galectin levels at the time of CRT implantation are associated with MR nonresponse., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Recent developments in computed tomography (CT) technology have fulfilled the prerequisites for the clinical application of myocardial CT perfusion (CTP) imaging. The evaluation of myocardial perfusion by CT can be achieved by static or dynamic scan acquisitions. Although both approaches have proved clinically feasible, substantial barriers need to be overcome before its routine clinical application. The current review provides an outline of the current status of CTP imaging and also focuses on disparities between static and dynamic CTPs for the evaluation of myocardial blood flow., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Patients with locally advanced esophageal cancer who are treated with trimodality therapy have a high recurrence rate. Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk. This trial tested the safety and efficacy of combining a COX2 inhibitor, celecoxib, with neoadjuvant irinotecan/cisplatin chemoradiation., Methods: This single arm phase 2 trial combined irinotecan, cisplatin, and celecoxib with concurrent radiation therapy. Patients with stage IIA-IVA esophageal cancer received weekly cisplatin 30 mg/m(2) plus irinotecan 65 mg/m(2) on weeks 1, 2, 4, and 5 concurrently with 5040 cGy of radiation therapy. Celecoxib 400 mg was taken orally twice daily during chemoradiation, up to 1 week before surgery, and for 6 months following surgery., Results: Forty patients were enrolled with stage IIa (30 %), stage IIb (20 %), stage III (22.5 %), and stage IVA (27.5 %) esophageal or gastroesophageal junction cancer (AJCC, 5th Edition). During chemoradiation, grade 3-4 treatment-related toxicity included dysphagia (20 %), anorexia (17.5 %), dehydration (17.5 %), nausea (15 %), neutropenia (12.5 %), diarrhea (10 %), fatigue (7.5 %), and febrile neutropenia (7.5 %). The pathological complete response rate was 32.5 %. The median progression free survival was 15.7 months and the median overall survival was 34.7 months. 15 % (n = 6) of patients treated on this study developed brain metastases., Conclusions: The addition of celecoxib to neoadjuvant cisplatin-irinotecan chemoradiation was tolerable; however, overall survival appeared comparable to prior studies using neoadjuvant cisplatin-irinotecan chemoradiation alone. Further studies adding celecoxib to neoadjuvant chemoradiation in esophageal cancer are not warranted., Trial Registration: Clinicaltrials.gov: NCT00137852 , registered August 29, 2005.

Background: Despite the benefit of CRT in select patients with heart failure (HF), there remains significant need for predicting those at risk for adverse outcomes for this effective but costly therapy. CysC, an emerging marker of renal function, is predictive of worsening symptoms and mortality in patients with HF. This study assessed the utility of baseline and serial measures of cystatin C (CysC), compared to conventional creatinine-based measures of renal function (estimated glomerular filtration rate, eGFR), in predicting clinical outcomes following cardiac resynchronization therapy (CRT)., Methods: In 133 patients, we measured peripheral venous (PV) and coronary sinus (CS) CysC concentrations and peripheral creatinine levels at the time of CRT implant. Study endpoints included clinical response to CRT at 6 months and major adverse cardiac events (MACE) at 2 years., Results: While all 3 renal metrics were predictive of MACE (all adjusted p ≤ 0.02), only CysC was associated with CRT non-response at 6 months (adjusted odds ratio 3.6, p = 0.02). CysC improved prediction of CRT non-response (p ≤ 0.003) in net reclassification index analysis compared to models utilizing standard renal metrics. Serial CysC > 1mg/L was associated with 6-month CRT non-response and reduced 6-minute walk distance as well as 2-year MACE (all p ≤ 0.04)., Conclusion: In patients undergoing CRT, CysC demonstrated incremental benefit in the prediction of CRT non-response when compared to standard metrics of renal function. Baseline and serial measures of elevated CysC were predictive of CRT non-response and functional status at 6 months as well as long-term clinical outcomes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Object: Spinal chordomas can have high local recurrence rates after surgery with or without conventional dose radiation therapy (RT). Treatment outcomes and prognostic factors after high-dose proton-based RT with or without surgery were assessed., Methods: The authors conducted a retrospective review of 126 treated patients (127 lesions) categorized according to disease status (primary vs recurrent), resection (en bloc vs intralesional), margin status, and RT timing., Results: Seventy-one sacrococcygeal, 40 lumbar, and 16 thoracic chordomas were analyzed. Mean RT dose was 72.4 GyRBE (relative biological effectiveness). With median follow-up of 41 months, the 5-year overall survival (OS), local control (LC), locoregional control (LRC), and distant control (DC) for the entire cohort were 81%, 62%, 60%, and 77%, respectively. LC for primary chordoma was 68% versus 49% for recurrent lesions (p = 0.058). LC if treated with a component of preoperative RT was 72% versus 54% without this treatment (p = 0.113). Among primary tumors, LC and LRC were higher with preoperative RT, 85% (p = 0.019) and 79% (0.034), respectively, versus 56% and 56% if no preoperative RT was provided. Overall LC was significantly improved with en bloc versus intralesional resection (72% vs 55%, p = 0.016), as was LRC (70% vs 53%, p = 0.035). A trend was noted toward improved LC and LRC for R0/R1 margins and the absence of intralesional procedures., Conclusions: High-dose proton-based RT in the management of spinal chordomas can be effective treatment. In patients undergoing surgery, those with primary chordomas undergoing preoperative RT, en bloc resection, and postoperative RT boost have the highest rate of local tumor control; among 28 patients with primary chordomas who underwent preoperative RT and en bloc resection, no local recurrences were seen. Intralesional and incomplete resections are associated with higher local failure rates and are to be avoided.

Outcome-based sampling is an efficient study design for rare conditions, such as glioblastoma. It is often used in conjunction with matching, for increased efficiency and to potentially avoid bias due to confounding. A study was conducted at the Massachusetts General Hospital that involved retrospective sampling of glioblastoma patients with respect to multiple-ordered disease states, as defined by three categories of overall survival time. To analyze such studies, we posit an adjacent categories logit model and exploit its allowance for prospective analysis of a retrospectively sampled study and its advantageous removal of set and level specific nuisance parameters through conditioning on sufficient statistics. This framework allows for any sampling design and is not limited to one level of disease within each set, such as in previous publications. We describe how this ordinal conditional model can be fit using standard conditional logistic regression procedures. We consider an alternative pseudo-likelihood approach that potentially offers robustness under partial model misspecification at the expense of slight loss of efficiency under correct model specification for small sample sizes. We apply our methods to the Massachusetts General Hospital glioblastoma study., (Copyright © 2015 John Wiley & Sons, Ltd.)