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In many clinical contexts, the event of interest could occur multiple times for the same patient. Considerable advancement has been made on developing recurrent event models based on or that use biomarker information. However, less attention has been given to evaluating the prognostic accuracy of a biomarker or a composite score obtained from a fitted recurrent event-rate model. In this manuscript, we propose novel measures to characterize the prognostic accuracy of a marker measured at baseline in the presence of recurrent events. The proposed estimators are based on a semiparametric frailty model that accounts for the informativeness of a marker and unobserved heterogeneity among patients with respect to the rate of event occurrence. We investigate the asymptotic properties of the proposed accuracy estimators and demonstrate these estimators' finite sample performance through simulation studies. The proposed estimators have minimal bias and appropriate coverage. The estimators are applied to evaluate the performance of a baseline forced expiratory volume, a measure of lung capacity, for repeated episodes of pulmonary exacerbations in patients with cystic fibrosis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Aortic root surgery is transitioning to aortic valve sparing (AVS), but little is known about the relative early outcomes of AVS versus composite graft-valve replacement (CVR). This study assessed mortality differences for AVS versus CVR to guide future practice decisions. METHODS: From January 2000 to June 2011, 31 747 patients had aortic root replacement with AVS (n = 3585; 11%) or CVR (n = 28 162; 89%). The cohort of Overall patients was divided into two subgroups: high-risk patients (n = 20 356; 6% AVS) having age >75 years, endocarditis, aortic stenosis, dialysis, multiple valves, reoperation or emergency/salvage status, and the remaining low-risk patients (n = 11 388; 21% AVS). Using logistic regression analysis, outcomes were presented as unadjusted operative mortality (UOM), risk-adjusted operative mortality (AOM) and adjusted odds ratio (AOR) for mortality. RESULTS: Baseline characteristics for the Overall group (AVS versus CVR) were: mean age (52 vs 57 years), endocarditis (1 vs 11%), aortic stenosis (4 vs 36%), dialysis (1 vs 2%), multiple valves (7 vs 10%), reoperation (6 vs 17%) and emergency status (14 vs 12%) (all P < 0.0001). In high- and low-risk groups, baseline differences narrowed, and lower mortality was generally observed with AVS: (AVS versus CVR) UOM group Overall (4.5 vs 8.9%)*, group High-risk (10.5 vs 11.7%), group Low-risk (1.4 vs 3.1%)*; AOM group Overall (6.2 vs 8.6%), group High-risk (10.1 vs 11.7%), group Low-risk (2.2 vs 2.8%); AOR group Overall (0.59)*, group High-risk (0.62)*, group Low-risk (0.69). *P < 0.05. CONCLUSIONS: Relative risk-adjusted mortality seemed comparable with AVS versus CVR in low- and high-risk subgroups. These data support judicious expansion of aortic valve repair in patients having aortic root replacement.

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual‐level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual‐level treatment response (ITR) score which represents individual‐level benefit of high‐dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating–Sum of Boxes (CDR‐SB;P = 0.034). The observed CDR‐SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. Highlights: Emerging trials have shown a population‐level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD).This work demonstrates significant heterogeneity of individual‐level treatment effect of aducanumab in early AD.The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process. [ABSTRACT FROM AUTHOR]

Evaluating the prognostic performance of candidate markers for future disease onset or progression is one of the major goals in medical research. A marker's prognostic performance refers to how well it separates patients at the high or low risk of a future disease state. Often the discriminative performance of a marker is affected by the patient characteristics (covariates). Time‐dependent receiver operating characteristic (ROC) curves that ignore the informativeness of the covariates will lead to biased estimates of the accuracy parameters. We propose a time‐dependent ROC curve that accounts for the informativeness of the covariates in the case of censored data. We propose inverse probability weighted (IPW) estimators for estimating the proposed accuracy parameters. We investigate the performance of the IPW estimators through simulation studies and real‐life data analysis. [ABSTRACT FROM AUTHOR]

Background: Gold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau‐PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals. Method: Using the topographical information from [18F]MK6240 tau‐PET, we applied the Braak tau staging system to 324 living individuals. We used PET‐based Braak stage to model the trajectories of amyloid‐b, phosphorylated tau in cerebrospinal fluid (pTau181, pTau217, pTau231, pTau235) and plasma (pTau181, pTau231), neurodegeneration and cognitive symptoms. Result: PET‐based Braak stages were We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau‐PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III‐IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, while Braak stages V‐VI were incompatible with normal cognition. Follow up tau‐PET scans indicated sequential progression of in vivo Braak stages over time, with progression beyond Braak stage III requiring the presence of amyloid‐beta abnormality. Conclusion: Our results support PET‐based Braak staging as a framework to model the natural history of AD, as well as monitor AD severity from presymptomatic to clinical dementia phases. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive complaints (SCC) signal risk of objective cognitive decline. To better understand the bio‐behavioral factors that signal cognitive trajectories at‐risk for the earliest stages of Alzheimer' disease, there is a need for well‐phenotyped large‐scale population‐based cohorts with longitudinal assessments. Method: From the INTUITION decentralized observational brain health study (NCT0505895), using app‐collected self‐report data, we compared the demographic, clinical, and neuropsychological profiles of 2045 SCC versus 4090 age‐ and education‐matched cognitively normal (CN) participants. The SCC cohort was defined by age (> = 50 years) and presence of significant cognitive concerns based on total scores> = 4 on the 14‐item Cognitive Function Instrument (CFI‐14). Using customized assessments from Cambridge Cognition, Pattern Recognition Memory (PRM), Paired Associates Learning (PAL), Spatial Working Memory (SWM), and Match‐to‐Sample (MTS) tests were performed. SCC participants were stratified and compared by presence or absence of dementia risk factors (first‐degree family history of dementia (FH+/FH‐) or 2+ cardiovascular risk factors (CVRF2+/CVRF2‐)). Result: Cognitive and neuropsychiatric symptom‐burden were greater among the SCC cohort compared to CN participants (e.g., E‐Cog‐12: 1.8(0.5) vs 1.2(0.3), pathological PHQ2 (Total> = 3): 14% vs 2.7%, pathological GAD‐2(Total> = 3): 11.8% vs 1.9%, respectively p<0.001). Lifestyle factors differed, with SCC participants reporting lower level of physical activity, higher substance use and impaired sleep, relative to CN. Among SCC participants the prevalence of CVRF2+ and FH+ were 53.2% and 37.8%, respectively; and 43% (CVRF2+) and 33.5% (FH+) among CN. Among SCC, individuals with CVRF2+ were more likely to be older, male, and with higher rates of anxiety/depression symptoms. Mean total CFI‐14 scores were similar between FH+/FH‐ or CVRF2+/CVRF2‐, but item‐level CFI profiles differed (e.g., word‐finding complaints in FH+/CVRF2+). SCC scored lower on key CANTAB outcomes (e.g., PAL/PRM) evaluated compared to CN. Both CVRF2+ and FH+ participants with SCC performed worse on cognitive measures of learning (SWM) and attention (MTS) compared to CVRF2‐ and FH‐ respectively. Conclusion: In a large, decentralized cohort, SCC was associated with higher burden of modifiable and non‐modifiable risk factors. First‐degree family history of dementia and cardiovascular disease, when coupled with SCC, revealed more severe measurable objective cognitive deficits. Future work will assess individual longitudinal cognitive trajectories. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) was biologically defined by the 2018 NIA‐AA Research Framework (RF), which recommends dichotomously categorizing biomarker status as normal or abnormal using single cutpoints. Nevertheless, the RF also states a three‐range approach might be useful in AD research. However, this potentially relevant strategy remains mostly unexplored in the field. We hereby propose a three‐range cutpoint system to interpret CSF biomarker measurements. We hypothesized the intermediate group would have a different cognitive trajectory than negative/positive groups and that three‐range models would prognostically outperform binary models. Method: We included 1278 non‐demented individuals (CU: n=575; MCI: n=703) from the ADNI with baseline CSF Elecsys® biomarkers. 20% of these individuals (who had baseline [18F]AV45 Aβ‐PET) were randomly allocated to a "training set" to define three‐range cutpoints – which were later evaluated in a "test set" comprising the remainder 80% participants. Three‐range cutpoints were defined with two‐graph receiver operating characteristics (TGROC) for each CSF biomarker (Aβ1‐42, p‐tau, t‐tau, p‐tau/Aβ1‐42, t‐tau/Aβ1‐42). Cutpoints were generated with 100,000 bootstraps, combining conventional or earlier‐centiloid [18F]AV45 thresholds to cognition in five different schemes for each biomarker. Linear mixed‐effects models (LMM) were employed to choose the best three‐range scheme and also to main analyses. The primary outcome of LMMs was the mPACC composite and participants were followed for up to 6 years. Three‐range models were compared within themselves, to binary and to continuous models based on AIC, BIC, log‐likelihood and R2. Result: LMMs indicated all three‐range approaches outperformed models with binarized or linear‐continuous form of biomarkers and, interestingly, were closer in information metrics to more sophisticate spline‐continuous models, with p‐tau/Aβ1‐42 being the best three‐range predictor (Table 1). For the latter model (Figure 1), slope‐contrast analyses indicated the intermediate group had a faster rate of decline than the negative (β‐estimate: 2.04, t=4.88, p= 3.5x10‐6) but slower than the positive group (β‐estimate: 4.68, t=10.4, p=1x10‐14). Conclusion: Our findings demonstrate that the proposed three‐range system for interpreting CSF biomarkers in AD prognostically outperforms binary cutpoints for all evaluated biomarkers, supporting the existence of an intermediate zone beyond the current normal/abnormal paradigm. This approach has clear potential applications to clinical trial recruitment and to clinical practice. [ABSTRACT FROM AUTHOR]

Background--Bleeding is associated with poor outcomes after percutaneous coronary intervention (PCI). Although arterial closure devices (ACDs) are widely used in clinical practice, whether they are effective in reducing bleeding complications during transfemoral PCI is uncertain. The objective of this study was to evaluate the effectiveness of ACDs for the prevention of vascular access site complications in patients undergoing transfemoral PCI using an instrumental variable approach. Methods and Results--We performed a retrospective analysis of the CathPCI Registry from 2009 to 2013 at 1470 sites across the United States. Variation in the proportion of ACDs used by each individual physician operator was used as an instrumental variable to address potential confounding. A 2-stage instrumental variable analysis was used as the primary approach. The main outcome measure was vascular access site complications, and nonaccess site bleeding was used as a falsification end point (negative control) to evaluate for potential confounding. A total of 1053155 ACDs were used during 2056585 PCIs during the study period. The vascular access site complication rate was 1.5%. In the instrumental variable analysis, the use of ACDs was associated with a 0.40% absolute risk reduction in vascular access site complications (95% confidence interval, 0.31-0.42; number needed to treat=250). Absolute differences in nonaccess site bleeding were negligible (risk difference, 0.04%; 95% confidence interval, 0.01-0.07), suggesting acceptable control of confounding in the comparison. Conclusions--ACDs are associated with a modest reduction in major bleeding after PCI. The number needed to treat with ACDs to prevent 1 major bleeding event is high. [ABSTRACT FROM AUTHOR]

Background Patients undergoing coronary artery bypass grafting (CABG) are at risk for a variety of infections. Investigators have focused on predictors of these adverse sequelae, but less attention has been focused on characterizing hospital-level variability in these outcomes. Methods Between July 2011 and December 2013, The Society of Thoracic Surgeons Adult Cardiac Surgery Database shows 365,686 patients underwent isolated CABG in 1,084 hospitals. Hospital-acquired infections (HAIs) were defined as pneumonia, sepsis/septicemia, deep sternal wound infection/mediastinitis, vein harvest/cannulation site infection, or thoracotomy infection. Hospitals were ranked by their HAI rate as low (≤10th percentile), medium (10th to 90th percentile), and high (>90th percentile). Differences in perioperative factors and composite morbidity and mortality end points across these groups were determined using the Wilcoxon rank sum and χ 2 tests. Results HAIs occurred among 3.97% of patients overall, but rates varied across hospital groups (low: <0.84%, medium: 0.84% to 8.41%, high: >8.41%). Pneumonia (2.98%) was the most common HAI, followed by sepsis/septicemia (0.84%). Patients at high-rate hospitals more often smoked, had diabetes, chronic lung disease, New York Heart Association Functional Classification III to IV, and received blood products ( p < 0.001); however, they less often were prescribed the appropriate antibiotics ( p < 0.001). Major morbidity and mortality occurred among 12.3% of patients, although this varied by hospital group (low: 8.6%, medium: 12.3%, high: 17.9%; p < 0.001). Conclusions Substantial hospital-level variation exists in postoperative HAIs among patients undergoing CABG, driven predominantly by pneumonia. Given the relatively small absolute differences in comorbidities across hospital groups, our findings suggest factors other than case mix may explain the observed variation in HAI rates. [ABSTRACT FROM AUTHOR]

Background Risk-adjusted mortality (RAM) models are increasingly used to evaluate hospital performance, but the validity of the RAM method has been questioned. Providers are concerned that these methods might not adequately account for the highest levels of risk and that treating high-risk cases will have a negative impact on RAM rankings. Methods Using cases of isolated coronary artery bypass grafting (CABG) performed at 1002 sites in the United States participating in The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database from 2008 to 2010 (N = 494,955), the STS CABG RAM model performance in high-risk patients was assessed. The ratios of observed to expected (O/E) perioperative mortality were compared among groups of hospitals with varying expected risks. Finally, RAM rates during the overall study period for each site were compared with its performance in a simulated “nightmare year” in which the site’s highest risk cases over a 3-year period were concentrated into a 1-year period of exceptional risk. Results The average predicted mortality for center risk groups ranged from 1.46% for the lowest risk quintile to 2.87% for the highest. The O/E ratios for center risk quintiles 1 to 5 during the overall period were 1.01 (95% confidence interval, 0.96% to 1.06%), 1.00 (0.95% to 1.04%), 0.98 (0.94% to 1.03%), 0.97 (0.93% to 1.01%), and 0.80 (0.77% to 0.84%), respectively. The sites’ risk-adjusted mortality rates were not increased when the centers’ highest risk cases were concentrated into a single “nightmare year.” Conclusions Our results show that the current risk-adjusted models accurately estimate CABG mortality and that hospitals accepting more high-risk CABG patients have equal or better outcomes than do those with predominately lower-risk patients. [ABSTRACT FROM AUTHOR]

Background We studied the association between components of chronic lung disease (CLD) assessment and operative outcomes in patients undergoing aortic valve replacement (AVR) for aortic stenosis. Methods From 2011 to 2012, 9,177 patients included in The Society of Thoracic Surgeons (STS) Cardiac Surgery Database underwent AVR for aortic stenosis with complete pulmonary function tests (PFT) and CLD data (31% of AVRs). We evaluated markers of CLD and their association with operative mortality, pulmonary morbidity, and length of hospital stay using multivariable logistic regression analysis. Results In a selected population of AVR patients with PFTs, CLD was prevalent in 50% (mild, 25.6%; moderate, 13.2%; severe, 11.2%). Predicted forced expiratory volume in 1 second (FEV 1 ) was obtained in all patients and diffusion capacity of the lung for carbon monoxide (DLCO), arterial oxygen tension (PaO 2 ), and arterial carbon dioxide tension (PaCO 2 ) in 31%. The STS predicted risk of operative mortality, mortality, pulmonary morbidity, and hospital stay increased with severity of CLD and with low FEV 1 , DLCO, and PaO 2 . Moderate and severe CLD were independently associated with operative mortality (odds ratio [OR] 2.88, 95% confidence interval [CI]: 2.0–4.5), pulmonary morbidity (OR 2.33, 95% CI: 1.93–2.8), and prolonged hospital stay (OR 2.73, 95% CI: 2.17–3.45). Low FEV 1 was independently associated with pulmonary morbidity and prolonged hospital stay. Low PaO 2 and DLCO were independently associated with a combined mortality and pulmonary morbidity endpoint. Conclusions CLD is associated with adverse operative outcomes in selected patients with aortic stenosis undergoing AVR. FEV 1 , DLCO, and PaO 2 may add important information to current risk adjustment models beyond the broad CLD classification. [ABSTRACT FROM AUTHOR]

Background Wedge resection is often used instead of anatomic resection in an attempt to mitigate perioperative risk. In propensity-matched populations, we sought to compare the perioperative outcomes of patients undergoing wedge resection with those undergoing anatomic resection. Methods The Society of Thoracic Surgery database was reviewed for stage I and II non-small cell lung cancer patients undergoing wedge resection and anatomic resection to analyze postoperative morbidity and mortality. Propensity scores were estimated using a logistic model adjusted for a variety of risk factors. Patients were then matched by propensity score using a greedy 5- to 1-digit matching algorithm, and compared using McNemar’s test. Results Between 2009 and 2011, 3,733 wedge resection and 3,733 anatomic resection patients were matched. The operative mortality was 1.21% for wedge resection versus 1.93% for anatomic resection ( p = 0.0118). Major morbidity occurred in 4.53% of wedge resection patients versus 8.97% of anatomic resection patients ( p < 0.0001). A reduction was noted in the incidence of pulmonary complications, but not cardiovascular or neurologic complications. There was a consistent reduction in major morbidity regardless of age, lung function, or type of incision. Mortality was reduced in patients with preoperative forced expiratory volume in 1 second less than 85% predicted. Conclusions Wedge resection has a 37% lower mortality and 50% lower major morbidity rate than anatomic resection in these propensity-matched populations. The mortality benefit is most apparent in patients with forced expiratory volume in 1 second less than 85% predicted. These perioperative benefits must be carefully weighed against the increase in locoregional recurrence and possible decrease in long-term survival associated with the use of wedge resection for primary lung cancers. [ABSTRACT FROM AUTHOR]

Background National prosthesis use in active aortic valve infective endocarditis (IE) is unreported. Prosthesis usage and outcomes in patients undergoing an aortic valve operation with active IE was evaluated. Methods The Society of Thoracic Surgeons Adult Cardiac Surgery Database was used to identify patients with active IE who underwent an aortic valve operation from January 1, 2005, to June 30, 2011. All patients with active IE were included. Demographics, procedures, outcomes, and trends were analyzed. Results Of 11,560 patients who were identified as having active IE, 8,421 (73%) had no prior operations (primary) and 3,139 (27%) had a history of any prior cardiac operation (reoperative). Operations for primary vs reoperative patients included isolated replacement in 88.5% vs 58.7% and root replacement in 7.2% vs 29.9%. Major morbidity was 60.8% vs 68%, and the unadjusted mortality rate was 9.8% vs 21.1%. Over time, for primary operations, biologic valve use increased (57% to 67%), and mechanical and homograft valve use decreased (30% to 24% and 9% to 6%; p < 0.001). For reoperations, biologic valve use increased (38% to 52%), and mechanical and homograft use decreased (20% to 17% and 38% to 28%; p < 0.001). Homografts were used more often in reoperations (32% vs 7%). Conclusions Morbidity and mortality rates death are high for operations for active IE. Biologic valves were increasingly used vs mechanical and homograft valves. Homograft valves were used more often in reoperative patients after any prior cardiac operation. The mortality rate varied among prosthesis groups but may be related to the severity of infection and type of procedure performed. [ABSTRACT FROM AUTHOR]

Background. Cardiovascular complications occur in 10% to 15% of patients after major lung resection. We evaluated the utility of a revised scoring system (thoracic revised cardiac risk index; ThRCRI) in identifying patients at increased risk for major cardiovascular complications. Methods. We analyzed outcomes from the Society of Thoracic Surgeons General Thoracic Database for the period 2003 to 2011 for elective major lung resection. The ThRCRI risk score was based on weighted values for serum creatinine, coronary artery disease, cerebrovascular disease, and extent of lung resection, and was stratified into the following 4 risk categories: 0 (A); 1 to 1.5 (B); 2 to 2.5 (C); and >2.5 (D). Major cardiovascular complications included myocardial infarction, adult respiratory distress syndrome, ventricular arrhythmia requiring treatment, and all-cause death. Results. A total of 26,085 patients (mean age 65.4 ± 11.4 years; 51.3% men) underwent lobectomy (21,679; 83.2%), bilobectomy (1,446; 5.5%) or pneumonectomy (1,697; 6.5%). Major cardiovascular complications occurred in 1,125 patients (4.3%). ThRCRI scores in patients without and with major cardiovascular complications were 0.6 ± 0.9 and 1.1 ± 1.1 (p < 0.0001). Score categories yielded incremental risks of major cardiovascular complications (A: 2.9%; B: 5.8%; C: 11.9%; D: 11.1%; p < 0.0001). Conclusions. The ThRCRI score stratified risk moderately well for major postoperative cardiovascular events after major lung resection. Use of this scoring system might help in identifying patients who would benefit from additional preoperative evaluation and from closer perioperative monitoring. [ABSTRACT FROM AUTHOR]

Background: This study evaluated trends and outcomes of tricuspid valve surgery (TVS) in North America over the past decade. Methods: Adults undergoing TVS between 2000 and 2010 were identified in The Society of Thoracic Surgeons (STS) National Database. Trends were evaluated using linear regression. Multivariable logistic regression analysis was conducted using covariates from the STS valve risk model to identify significant predictors of operative mortality. Results: A total of 54,375 patients underwent TVS during the study period. The majority of cases were repairs (89%; n = 48,322) and were performed concomitant with another major procedure (86%; n = 46,593). The proportion of TVS that were repairs increased from 84.6% in 2000 to 89.8% in 2010 (p = 0.01). Trend analysis revealed significant changes in patient characteristics with time, including increasing age, a higher comorbidity burden, and a higher proportion of emergency cases. Despite worsening risk factors, unadjusted operative mortality for TVS declined from 10.6% in 2000 to 8.2% in 2010 (p < 0.001), and this trend persisted after risk adjustment. In the multivariable model, concomitant procedures involving multiple valves or coronary artery bypass grafting were associated with an increased risk of mortality compared with isolated TVS, although other factors including renal failure, congestive heart failure, nonelective presentation, reoperation, and tricuspid valve replacement exerted equal or stronger effects. Conclusions: During the past decade, repair rates for TVS have increased significantly. Although patients undergoing TVS have demonstrated worsening risk factors, unadjusted and adjusted operative mortalities have declined. Finally, the data suggest that tricuspid valve repair when technically feasible, together with early elective surgical intervention, should be emphasized as potential candidates for continued outcome improvement. [Copyright &y& Elsevier]

Exposure assessment using biologic specimens is important for epidemiology but may become impracticable if assays are expensive, specimen volumes are marginally adequate, or analyte levels fall below the limit of detection. Pooled exposure assessment can provide an effective remedy for these problems in unmatched case-control studies. We extend pooled exposure strategies to handle specimens collected in a matched case-control study. We show that if a logistic model applies to individuals, then a logistic model also applies to an analysis using pooled exposures. Consequently, the individual-level odds ratio can be estimated while conserving both cost and specimen. We discuss appropriate pooling strategies for a single exposure, with adjustment for multiple, possibly continuous, covariates (confounders) and assessment of effect modification by a categorical variable. We assess the performance of the approach via simulations and conclude that pooled strategies can markedly improve efficiency for matched as well as unmatched case-control studies. [ABSTRACT FROM AUTHOR]

Objective Failure to rescue is defined as death after an acute inpatient event and has been observed among hospitals that perform general, vascular, and cardiac surgery. This study aims to evaluate variation in complication and failure to rescue rates among hospitals that perform pulmonary resection for lung cancer. Methods By using the Society of Thoracic Surgeons General Thoracic Surgery Database, a retrospective, multicenter cohort study was performed of adult patients with lung cancer who underwent pulmonary resection. Hospitals participating in the Society of Thoracic Surgeons General Thoracic Surgery Database were ranked by their risk-adjusted, standardized mortality ratio (using random effects logistic regression) and grouped into quintiles. Complication and failure to rescue rates were evaluated across 5 groups (very low, low, medium, high, and very high mortality hospitals). Results Between 2009 and 2012, there were 30,000 patients cared for at 208 institutions participating in the Society of Thoracic Surgeons General Thoracic Surgery Database (median age, 68 years; 53% were women, 87% were white, 71% underwent lobectomy, 65% had stage I). Mortality rates varied over 4-fold across hospitals (3.2% vs 0.7%). Complication rates occurred more frequently at hospitals with higher mortality (42% vs 34%, P < .001). However, the magnitude of variation (22%) in complication rates dwarfed the 4-fold magnitude of variation in failure to rescue rates (6.8% vs 1.7%, P < .001) across hospitals. Conclusions Variation in hospital mortality seems to be more strongly related to rescuing patients from complications than to the occurrence of complications. This observation is significant because it redirects quality improvement and health policy initiatives to more closely examine and support system-level changes in care delivery that facilitate early detection and treatment of complications. [ABSTRACT FROM AUTHOR]

Objective: To examine the likelihood of mitral valve repair among dialysis patients and the influence of mitral procedure selection on surgical outcomes in this cohort. Methods: Among patients undergoing isolated primary mitral valve surgery in the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2002-2010), we used logistic regression models to evaluate the following: (1) the likelihood of attempted and successful mitral repair among dialysis patients (2008-2010), and (2) the impact of mitral procedural selection on surgical mortality and composite mortality/major morbidity experienced by dialysis patients (2002-2010). Patients with endocarditis and those undergoing emergent or major concomitant surgeries were excluded. Results: The study cohort consisted of 86,563 patients, of whom 1480 (1.7%) required preoperative dialysis. Dialysis patients had a high comorbid burden, including a high prevalence of congestive heart failure, stroke, diabetes, peripheral vascular disease, chronic obstructive pulmonary disease, and prior myocardial infarction. Dialysis-dependent patients had a lower propensity for mitral repair (44.6% vs 61.5%; P = .0010; adjusted odds ratio [OR], 0.69; 95% confidence interval [CI], 0.61-0.78); although the odds of successful repair (when attempted) were similar for dialysis versus nondialysis patients (OR, 0.87; 95% CI, 0.65-1.17). Compared with nondialysis patients, dialysis patients experienced a higher mortality rate (9.3% vs 2.3%; P < .0001; adjusted OR, 3.91; 95% CI, 3.17-4.81) and composite mortality or major morbidity (40.9% vs 15.9%; P < .0001; adjusted OR, 2.72; 95% CI, 2.41-3.07); however, adjustment for procedure selection did not substantially attenuate this effect (2.3% and 2.1% change-in-estimate for mortality and composite mortality/major morbidity, respectively). Conclusions: Dialysis patients undergo mitral repair less frequently, although repair success is equally likely when attempted among dialysis versus nondialysis patients. Dialysis-dependent renal failure is associated strongly with early mortality and major morbidity. However, procedure selection (repair vs replacement) does not appear to have a clinically meaningful impact on these short-term outcomes. [Copyright &y& Elsevier]

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-β-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software., Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA., Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023., Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification., Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC)., Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types., Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-β-directed monoclonal antibody therapies.

Introduction: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy., Methods: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE)., Results: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline., Discussion: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development., Highlights: Emerging trials have shown a population-level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Analyses of distributed data networks of rare diseases are constrained by legitimate privacy and ethical concerns. Analytical centers (e.g. research institutions) are thus confronted with the challenging task of obtaining data from recruiting sites that are often unable or unwilling to share personal records of participants. For time-to-event data, recently popularized disclosure techniques with privacy guarantees (e.g., Differentially Private Generative Adversarial Networks) are generally computationally expensive or inaccessible to applied researchers. To perform the widely used Cox proportional hazards regression, we propose an easy-to-implement privacy-preserving data analysis technique by pooling (i.e. aggregating) individual records of covariates at recruiting sites under the nested case-control sampling framework before sharing the pooled nested case-control subcohort. We show that the pooled hazard ratio estimators, under the pooled nested case-control subsamples from the contributing sites, are maximum likelihood estimators and provide consistent estimates of the individual level full cohort HRs. Furthermore, a sampling technique for generating pseudo-event times for individual subjects that constitute the pooled nested case-control subsamples is proposed. Our method is demonstrated using extensive simulations and analysis of the National Lung Screening Trial data. The utility of our proposed approach is compared to the gold standard (full cohort) and synthetic data generated using classification and regression trees. The proposed pooling technique performs to near-optimal levels comparable to full cohort analysis or synthetic data; the efficiency improves in rare event settings when more controls are matched on during nested case-control subcohort sampling., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Introduction: [18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694., Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups., Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex., Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies., Competing Interests: No conflicts of interest relevant to this article exist., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well-described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three-range approach and its prognostic impact remains under-explored for cerebrospinal fluid (CSF) biomarkers ., Methods: With two-graph receiver-operating characteristics based on different reference schemes, we derived three-range cut-points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid-beta (Aβ) positron emission tomography (PET) accumulation in non-demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein-derived three-range CSF cut-points to previously described binary ones., Results: In our main longitudinal analyses, we highlight CSF p-tau 181 /Aβ 1-42 three-range cut-points derived based on the cognitively normal Aβ-PET negative versus dementia Aβ-PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate-range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group., Discussion: The proposed approach can refine clinico-biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker-related cognitive decline in comparison to binary cut-points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications., Competing Interests: HZ has served on scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx; and has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen. KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Siemens Healthineers, and Roche Diagnostics. HZ and KB are co‐founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures‐based platform company at the University of Gothenburg. The other authors declare no competing interests., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Prostate cancer is the most common cancer diagnosis among men. Family caregivers (often female spouses) play a key role in ensuring patients' needs are met, frequently assuming their role with no formal training, which can contribute to a high burden. The purpose of this study was to pilot TEMPO -the first dyadic, Tailored, wEb-based, psychosocial and physical activity self-Management PrOgram for men with prostate cancer and their caregivers., Methods: 49 men with prostate cancer and their caregivers were randomized to TEMPO or usual care. Baseline and follow-up questionnaires were completed to assess feasibility, acceptability, and clinical significance. A priori benchmarks for these outcomes were set. Thirteen exit interviews were conducted to further explore acceptability., Results: Feasibility benchmarks were met with the exception for recruitment with on average 6.1 dyads recruited/month (benchmark: 8 dyads/month). Benchmarks of acceptability focused on attrition (<25%) and system usability, which were met. Using the strict criteria for adherence of 100% of the module viewed and participants spending at least 15 min on the module, 45% of participants were adherent. The clinical significance on anxiety and quality of life was supported for caregivers, and mostly supported for the men with prostate cancer., Conclusion: This pilot trial was successful, with minor modifications needed prior to a large trial.