Measurable Residual FLT3 Internal Tandem Duplication Before Allogeneic Transplant for Acute Myeloid Leukemia.

Importance: Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown. Objective: To examine the association between pre-allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR. Design, Setting, and Participants: In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023. Exposure: Centralized DNA sequencing for FLT3-ITD in pre-allogeneic HCT first CR blood using a commercially available kit. Main Outcomes and Measures: The primary outcomes were overall survival and cumulative incidence of relapse, with non-relapse-associated mortality as a competing risk post-allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points. Results: Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning. Conclusions and Relevance: This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.

Similar Risk of Kidney Failure among Patients with Blinding Diseases Who Receive Ranibizumab, Aflibercept, and Bevacizumab: An Observational Health Data Sciences and Informatics Network Study.

PURPOSE: To characterize the incidence of kidney failure associated with intravitreal anti-VEGF exposure; and compare the risk of kidney failure in patients treated with ranibizumab, aflibercept, or bevacizumab. DESIGN: Retrospective cohort study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network. SUBJECTS: Subjects aged ≥ 18 years with ≥ 3 monthly intravitreal anti-VEGF medications for a blinding disease (diabetic retinopathy, diabetic macular edema, exudative age-related macular degeneration, or retinal vein occlusion). METHODS: The standardized incidence proportions and rates of kidney failure while on treatment with anti-VEGF were calculated. For each comparison (e.g., aflibercept versus ranibizumab), patients from each group were matched 1:1 using propensity scores. Cox proportional hazards models were used to estimate the risk of kidney failure while on treatment. A random effects meta-analysis was performed to combine each database's hazard ratio (HR) estimate into a single network-wide estimate. MAIN OUTCOME MEASURES: Incidence of kidney failure while on anti-VEGF treatment, and time from cohort entry to kidney failure. RESULTS: Of the 6.1 million patients with blinding diseases, 37 189 who received ranibizumab, 39 447 aflibercept, and 163 611 bevacizumab were included; the total treatment exposure time was 161 724 person-years. The average standardized incidence proportion of kidney failure was 678 per 100 000 persons (range, 0-2389), and incidence rate 742 per 100 000 person-years (range, 0-2661). The meta-analysis HR of kidney failure comparing aflibercept with ranibizumab was 1.01 (95% confidence interval [CI], 0.70-1.47; P = 0.45), ranibizumab with bevacizumab 0.95 (95% CI, 0.68-1.32; P = 0.62), and aflibercept with bevacizumab 0.95 (95% CI, 0.65-1.39; P = 0.60). CONCLUSIONS: There was no substantially different relative risk of kidney failure between those who received ranibizumab, bevacizumab, or aflibercept. Practicing ophthalmologists and nephrologists should be aware of the risk of kidney failure among patients receiving intravitreal anti-VEGF medications and that there is little empirical evidence to preferentially choose among the specific intravitreal anti-VEGF agents. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Measurable Residual IDH1 before Allogeneic Transplant for Acute Myeloid Leukemia.

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. The persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoetic cell transplant (alloHCT) has been established as associated with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remains incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR site between 2013-2019. No post-transplant differences were observed between those testing IDH1m positive (n=53, 36%) and negative pre-transplant (overall survival: p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD or increased post-transplant relapse risk.

DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant.

Importance: Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective: To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants: In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure: Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures: The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results: Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance: Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

Geographic variations in gender differences in cataract surgery volume among a national cohort of ophthalmologists.

PURPOSE: To assess factors associated with gender disparities in cataract surgery volume and evaluate how these differences have changed over time. SETTING: Cataract surgeons in the 2012 to 2018 Medicare database. DESIGN: Retrospective study. METHODS: The association of provider gender with the number of cataract surgeries per office visit billed was assessed with negative binomial regression models, controlling for calendar year, years in practice, hospital affiliation, geographic region, rurality, density of ophthalmologists, and the national percentile of Area Deprivation Index (ADI) score for the practice location. RESULTS: There were 8480 cataract surgeons, most of whom were male (78%). Male surgeons worked in more deprived areas with a higher ADI (median: 40 vs 33, P < .001). Female surgeons performed fewer cataracts per year (140 [95% CI, 126-154] vs 276 [95% CI, 263-288], P < .001) and billed fewer office visits (1038 [95% CI, 1008-1068] vs 1505 [95% CI, 1484-1526], P < .001). In multivariate analysis, the number of cataract surgeries per office visit was greater for males compared with females in all years in the South (average incidence rate ratio 1.80), Midwest (1.50), and West (1.53), but not in the Northeast (1.16). The relative rate of cataract surgeries between male and female surgeons in each region did not change significantly over time from 2012 to 2018 ( P > .05 in each region). CONCLUSIONS: Gender disparities in cataract volume among male and female surgeons have remained unchanged over time from 2012 to 2018. The higher cataract volume among male surgeons may be explained in part by provider practice location. Further studies are needed to better understand and address gender disparities.

Relationship Between Social Determinants of Health and Antihypertensive Medication Adherence in a Medicaid Cohort.

BACKGROUND: Little is known about the relationship between social determinants of health (SDH) and medication adherence among Medicaid beneficiaries with hypertension. METHODS: We conducted a posthoc subgroup analysis of 3044 adult Medicaid beneficiaries who enrolled in a parent prospective cohort study and had a diagnosis of hypertension based on their Medicaid claims during a 24-month period before study enrollment. We calculated the proportion of days covered by at least one antihypertensive medication during the first 12 months after study enrollment using the prescription claims data. We measured numerous SDH at the time of study enrollment and we categorized our hypertension cohort into 4 social risk groups based on their response profiles to the SDH variables. We compared the mean proportion of days covered by the different levels of the SDH factors. We modeled the odds of being covered by an antihypertensive medication daily throughout the follow-up period by social risk group, adjusted for age, sex, and disease severity using a generalized linear model. RESULTS: The nonrandom sample was predominately Black (93%), female (62%) and had completed high school (77%). The mean proportion of days covered varied significantly by different SDH, such as food insecurity (49%-56%), length of time living at present place (47%-57%), smoking status (50%-56%), etc. Social risk group was a significant predictor of medication adherence. Participants in the 2 groups with the most social risks were 36% (adjusted odds ratio=0.64 [95% CI, 0.53-0.78]) and 20% (adjusted odds ratio=0.80 [95% CI, 0.70-0.93]) less adherent to their hypertension therapy compared with participants in the group with the fewest social risks. CONCLUSIONS: Social risks are associated with lower antihypertensive medication adherence in the Medicaid population.

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19.

Importance: Clinical effectiveness data on remdesivir are urgently needed, especially among diverse populations and in combination with other therapies. Objective: To examine whether remdesivir administered with or without corticosteroids for treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population. Design, Setting, and Participants: This retrospective comparative effectiveness research study was conducted from March 4 to August 29, 2020, in a 5-hospital health system in the Baltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, and do-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheral blood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature, respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count, albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragment D [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatment was matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyond the matching day. Exposures: Remdesivir treatment with or without corticosteroid administration. Main Outcomes and Measures: The primary outcome was rate of clinical improvement (hospital discharge or decrease of 2 points on the World Health Organization severity score), and the secondary outcome, mortality at 28 days. An additional outcome was clinical improvement and time to death associated with combined remdesivir and corticosteroid treatment. Results: Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom also received corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, the median age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276 (80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time to clinical improvement than matched controls without remdesivir treatment (median, 5.0 days [interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazard ratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40 deaths) among matched controls, but this difference was not statistically significant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28 days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57). Conclusions and Relevance: In this comparative effectiveness research study of adults hospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.

Baseline and Dynamic Risk Predictors of Appropriate Implantable Cardioverter Defibrillator Therapy.

Background Current approaches fail to separate patients at high versus low risk for ventricular arrhythmias owing to overreliance on a snapshot left ventricular ejection fraction measure. We used statistical machine learning to identify important cardiac imaging and time-varying risk predictors. Methods and Results Three hundred eighty-two cardiomyopathy patients (left ventricular ejection fraction ≤35%) underwent cardiac magnetic resonance before primary prevention implantable cardioverter defibrillator insertion. The primary end point was appropriate implantable cardioverter defibrillator discharge or sudden death. Patient characteristics; serum biomarkers of inflammation, neurohormonal status, and injury; and cardiac magnetic resonance-measured left ventricle and left atrial indices and myocardial scar burden were assessed at baseline. Time-varying covariates comprised interval heart failure hospitalizations and left ventricular ejection fractions. A random forest statistical method for survival, longitudinal, and multivariable outcomes incorporating baseline and time-varying variables was compared with (1) Seattle Heart Failure model scores and (2) random forest survival and Cox regression models incorporating baseline characteristics with and without imaging variables. Age averaged 57±13 years with 28% women, 66% white, 51% ischemic, and follow-up time of 5.9±2.3 years. The primary end point (n=75) occurred at 3.3±2.4 years. Random forest statistical method for survival, longitudinal, and multivariable outcomes with baseline and time-varying predictors had the highest area under the receiver operating curve, median 0.88 (95% CI, 0.75-0.96). Top predictors comprised heart failure hospitalization, left ventricle scar, left ventricle and left atrial volumes, left atrial function, and interleukin-6 level; heart failure accounted for 67% of the variation explained by the prediction, imaging 27%, and interleukin-6 2%. Serial left ventricular ejection fraction was not a significant predictor. Conclusions Hospitalization for heart failure and baseline cardiac metrics substantially improve ventricular arrhythmic risk prediction.

Impact of Improved Biomass and Liquid Petroleum Gas Stoves on Birth Outcomes in Rural Nepal: Results of 2 Randomized Trials.

BACKGROUND: Few randomized trials have assessed the impact of reducing household air pollution from biomass stoves on adverse birth outcomes in low-income countries. METHODS: Two sequential trials were conducted in rural low-lying Nepal. Trial 1 was a cluster-randomized step-wedge trial comparing traditional biomass stoves and improved biomass stoves vented with a chimney. Trial 2 was a parallel household-randomized trial comparing vented biomass stoves and liquid petroleum gas (LPG) stoves with a year's supply of gas. Kitchen particulate matter of 2.5 µm or less (PM2.5) and carbon monoxide (CO) were assessed before and after stove installation. Prevalent and incident pregnancies were enrolled at baseline and throughout the trials. Birth anthropometry was compared across differing exposure times in pregnancy. RESULTS: In trial 1, the mean 20-hour kitchen PM2.5 concentration was reduced from 1380 µg/m3 to 936 µg/m3. Among infants born before the intervention, mean birth weight and gestational age were 2627 g (SD=443) and 38.8 weeks (SD=3.1), and 39% were low birth weight (LBW), 22% preterm, and 55% small for gestational age (SGA). Adverse birth outcomes were not significantly different with increasing exposure to improved stoves during pregnancy. In trial 2, the mean 20-hour PM2.5 concentration was 885 µg/m3 in households with vented biomass and 442 µg/m3 in those with LPG stoves. Mean birth weight was 2780 g (SD=427) and 2742 g (SD=431), among households with vented and LPG stoves, respectively. Respective percentages for LBW, SGA, and preterm were 23%, 13%, and 42% in the vented stove group and not statistically different from 31%, 17%, and 42% in the LPG group. CONCLUSIONS: Improved biomass or LPG stoves did not reduce adverse birth outcomes. PM2.5 and CO following improved stove installation remained well above the World Health Organization indoor air standard of 25 µg/m3 or intermediate air quality guideline of 37.5 µg/m3. Trials that lower indoor air pollution further are needed.

Frequency of Complicated Symptomatic Bone Metastasis Over a Breadth of Operational Definitions.

PURPOSE: Numerous randomized trials have demonstrated noninferiority of single- versus multiple-fraction palliative radiation therapy (RT) in the management of uncomplicated bone metastases; yet there is neither a clear definition of what constitutes a complicated lesion, nor substantial data regarding the prevalence of such complicating features in clinical practice. Thus, we identify a range of evidence-based operational definitions of complicated symptomatic bone metastases and characterize the frequency of such complicating features at a high-volume, tertiary care center. METHODS AND MATERIALS: A retrospective review of patients seen in consultation for symptomatic bone metastases between March 1, 2007, and July 31, 2013, at Johns Hopkins Hospital identified patient and disease characteristics. Descriptive statistics characterized the frequency of the following complicating features: prior RT, prior surgery, neuraxis compromise, pathologic fracture, and soft tissue component at the symptomatic site. A range of definitions for complicated bone metastases was evaluated based on combinations of these features. Uni- and multivariable logistic regressions evaluated the odds of complicated bone metastases as a function of site of primary cancer and of the symptomatic target lesion. RESULTS: A total of 686 symptomatic bone metastases in 401 patients were evaluated. Percent of target sites complicated by prior RT was 4.4%, prior surgery was 8.9%, pathologic fracture was 20.6%, neuraxis compromise was 52.0% among spine and medial pelvis sites, and soft tissue component was 38.6%. More than 96 possible definitions of complicated bone metastases were identified. The presence of such complicated lesions ranged from 2.3% to 67.3%, depending on the operational definition used. Odds of a complicated lesion were significantly higher for spine sites and select nonbreast histologies. CONCLUSIONS: In this retrospective study, we found complicated symptomatic bone metastases may be present in up to two-thirds of patients. Literature review also demonstrates no clear standard definition of complicated bone metastases, potentially explaining underutilization of single-fraction palliative RT in this setting.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

BACKGROUND.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. METHODS.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. RESULTS.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. CONCLUSIONS.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

Prediction of the Pathologic Gleason Score to Inform a Personalized Management Program for Prostate Cancer.

BACKGROUND: Active surveillance (AS) is an alternative to curative intervention, but overtreatment persists. Imperfect alignment of prostate biopsy and Gleason score after radical prostatectomy (RP) may be a contributing factor. OBJECTIVE: To develop a statistical model that predicts the post-RP Gleason score (pathologic Gleason score [PGS]) using clinical observations made in the course of AS. DESIGN, SETTING, AND PARTICIPANTS: Repeated prostate-specific antigen measurements and biopsy Gleason scores from 964 very low-risk patients in the Johns Hopkins Active Surveillance cohort were used in the analysis. PGS observations from 191 patients who underwent RP were also included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Bayesian joint model based on accumulated clinical data was used to predict PGS in these categories: 6 (grade group 1), 3+4 (grade group 2), 4+3 (grade group 3), and 8-10 (grade groups 4 and 5). The area under the receiver operating characteristic curve (AUC) and calibration of predictions was assessed in patients with post-RP Gleason score observations. RESULTS AND LIMITATIONS: The estimated probability of harboring a PGS >6 was <20% for most patients who had not experienced grade reclassification or elected surgery. Among patients with post-RP Gleason score observations, the AUC for predictions of PGS >6 was 0.74 (95% confidence interval, 0.66-0.81), and the mean absolute error was 0.022. CONCLUSIONS: Although the model requires external validation prior to adoption, PGS predictions can be used in AS to inform decisions regarding follow-up biopsies and remaining on AS. Predictions can be updated as additional data are observed. The joint modeling framework also accommodates novel biomarkers as they are identified and measured on AS patients. PATIENT SUMMARY: Measurements taken in the course of active surveillance can be used to accurately predict patients' underlying prostate cancer status. Predictions can be communicated to patients via a decision support tool and used to guide clinical decision making and reduce patient anxiety.

A Bayesian hierarchical model for prediction of latent health states from multiple data sources with application to active surveillance of prostate cancer.

In this article, we present a Bayesian hierarchical model for predicting a latent health state from longitudinal clinical measurements. Model development is motivated by the need to integrate multiple sources of data to improve clinical decisions about whether to remove or irradiate a patient's prostate cancer. Existing modeling approaches are extended to accommodate measurement error in cancer state determinations based on biopsied tissue, clinical measurements possibly not missing at random, and informative partial observation of the true state. The proposed model enables estimation of whether an individual's underlying prostate cancer is aggressive, requiring surgery and/or radiation, or indolent, permitting continued surveillance. These individualized predictions can then be communicated to clinicians and patients to inform decision-making. We demonstrate the model with data from a cohort of low-risk prostate cancer patients at Johns Hopkins University and assess predictive accuracy among a subset for whom true cancer state is observed. Simulation studies confirm model performance and explore the impact of adjusting for informative missingness on true state predictions. R code is provided in an online supplement and at http://github.com/rycoley/prediction-prostate-surveillance.

Delirium after coronary artery bypass graft surgery and late mortality.

OBJECTIVE: Delirium is common after cardiac surgery, although under-recognized, and its long-term consequences are likely underestimated. The primary goal of this study was to determine whether patients with delirium after coronary artery bypass graft (CABG) surgery have higher long-term out-of-hospital mortality when compared with CABG patients without delirium. METHODS: We studied 5,034 consecutive patients undergoing CABG surgery at a single institution from 1997 to 2007. Presence or absence of neurologic complications, including delirium, was assessed prospectively. Survival analysis was performed to determine the role of delirium in the hazard of death, including a propensity score to adjust for potential confounders. These analyses were repeated to determine the association between postoperative stroke and long-term mortality. RESULTS: Individuals with delirium had an increased hazard of death (adjusted hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.38-1.97) up to 10 years postoperatively, after adjustment for perioperative and vascular risk factors. Patients with postoperative stroke had a HR of 2.34 (95% CI, 1.87-2.92). The effect of delirium on subsequent mortality was the strongest among those without a prior stroke (HR 1.83 vs HR 1.11 [with a prior stroke] [p-interaction = 0.02]) or who were younger (HR 2.42 [<65 years old] vs HR 1.49 [>/=65 years old] [p-interaction = 0.04]). INTERPRETATION: Delirium after cardiac surgery is a strong independent predictor of mortality up to 10 years postoperatively, especially in younger individuals and in those without prior stroke. Future studies are needed to determine the impact of delirium prevention and/or treatment in long-term patient mortality.

A systematic review of anterior cruciate ligament reconstruction with autograft compared with allograft.

BACKGROUND: Anterior cruciate ligament reconstruction can be performed with use of either autograft or allograft tissue. It is currently unclear if the outcomes of these two methods differ significantly. This systematic review and meta-analysis investigated whether the short-term clinical outcomes of anterior cruciate reconstruction with allograft were significantly different from those with autograft. METHODS: A computerized search of the electronic databases MEDLINE and EMBASE was conducted. Only therapeutic studies with a prospective or retrospective comparative design were considered for inclusion in the present investigation. Two reviewers independently assessed the methodological quality and extracted relevant data from each included study. If a study failed the qualitative assessment and statistical tests of homogeneity, it was excluded from the meta-analysis. Furthermore, a study was withdrawn from the meta-analysis of a particular outcome if that outcome was not studied or was not reported adequately. A Mantel-Haenszel analysis utilizing a random-effects model allowed for pooling of results according to graft source while accounting for the number of subjects in individual studies. RESULTS: Nine studies were determined to be appropriate for the systematic review. Eight studies compared bone-patellar tendon-bone grafts, and one study compared quadruple-stranded hamstring grafts. Five studies were prospective comparative studies, and four were retrospective comparative studies. One study, which investigated allografts that underwent a unique sterilization process, demonstrated an allograft failure rate of 45% (thirty-eight of eighty-five). That study failed the qualitative assessment and statistical tests of homogeneity and consequently was excluded from the meta-analysis. When the outcomes from the remaining studies were pooled according to graft source, the meta-analyses of the Lysholm score, instrumented laxity measurements, and the clinical failure rate estimated mean differences and odds ratios that were not significant. These findings were robust during the sensitivity analysis, which varied the included studies or variables on the basis of graft type, instrumented laxity cut-off value, secondary sterilization technique, duration of follow-up, mean patient age, and study methodology. CONCLUSIONS: In general, the short-term clinical outcomes of anterior cruciate reconstruction with allograft were not significantly different from those with autograft. However, it is important to note that none of these nonrandomized studies stratified outcomes according to age or utilized multivariable modeling to mathematically control for age (or any other possible confounder, such as activity level, that is not equally distributed in the two treatment groups). Understanding these limitations of the best available evidence, the surgeon may incorporate the results of the present systematic review into the informed-consent and shared-decision-making process in order to individualize optimum patient care.

Do management strategies for coronary artery disease influence 6-year cognitive outcomes?

BACKGROUND: Previous uncontrolled studies have suggested that there is late cognitive decline after coronary artery bypass grafting that may be attributable to use of the cardiopulmonary bypass pump. METHODS: In this prospective, nonrandomized, longitudinal study, we compared cognitive outcomes after on-pump coronary artery bypass surgery (n = 152) with off-pump bypass surgery patients (n = 75); nonsurgical cardiac comparison subjects (n = 99); and 69 heart-healthy comparison (HHC) subjects. The primary outcome measure was change from baseline to 72 months in the following cognitive domains: verbal memory, visual memory, visuoconstruction, language, motor speed, psychomotor speed, attention, executive function, and a composite global score. RESULTS: There were no consistent differences in 72-month cognitive outcomes among the three groups with coronary artery disease (CAD). The CAD groups had lower baseline performance, and a greater degree of decline compared with HHC. The degree of change was small, with none of the groups having more than 0.5 SD decline. None of the groups was substantially worse at 72 months compared with baseline. CONCLUSIONS: Compared with subjects with no vascular disease risk factors, the CAD patients had lower baseline cognitive performance and greater degrees of decline over 72 months, suggesting that in these patients, vascular disease may have an impact on cognitive performance. We found no significant differences in the long-term cognitive outcomes among patients with various CAD therapies, indicating that management strategy for CAD is not an important determinant of long-term cognitive outcomes.

Subjective memory symptoms in surgical and nonsurgical coronary artery patients: 6-year follow-up.

BACKGROUND: Self-reported cognitive and memory complaints after coronary artery bypass graft (CABG) operations are common. Several studies have attempted to quantify the incidence of such complaints and to examine the relationship between subjective and objective cognitive functioning, but the etiology and longitudinal course of these self-reports remain unclear. METHODS: Measures of subjective memory complaints were compared in two groups: 220 CABG patients and 92 nonsurgical cardiac patients at 3 months, and 1, 3, and 6 years. At 6 years, additional measures were used to quantify memory self-assessment. The frequency of subjective complaints at each time point was determined, and associations with objective cognitive performance as well as depression were examined. RESULTS: At early (3-month or 1-year) follow-up, subjective memory complaints were reported more often by the CABG than the nonsurgical group (45.5% vs 17.0%, p < 0.0001). By 6 years, the frequency of complaints was similar (52%) in both groups. Subjective memory ratings were significantly correlated with performance on several memory tests at 6 years. This relationship was not confounded by depression. CONCLUSIONS: Subjective memory complaints are more frequent early in follow-up in patients undergoing CABG than in controls, but are similar by 6 years. The increase in subjective complaints over time may be related to progression of underlying cerebrovascular disease. Unlike previous studies, we found that subjective memory assessments were correlated with objective performance on several memory tests. Although subjective memory complaints are more common in patients with depression, they cannot be explained by depression alone.

Mortality in the Medicare population and chronic exposure to fine particulate air pollution in urban centers (2000-2005).

BACKGROUND: Prospective cohort studies constitute the major source of evidence about the mortality effects of chronic exposure to particulate air pollution. Additional studies are needed to provide evidence on the health effects of chronic exposure to particulate matter < or = 2.5 microm in aerodynamic diameter (PM(2.5)) because few studies have been carried out and the cohorts have not been representative. OBJECTIVES: This study was designed to estimate the relative risk of death associated with long-term exposure to PM(2.5) by region and age groups in a U.S. population of elderly, for the period 2000-2005. METHODS: By linking PM(2.5) monitoring data to the Medicare billing claims by ZIP code of residence of the enrollees, we have developed a new retrospective cohort study, the Medicare Cohort Air Pollution Study. The study population comprises 13.2 million participants living in 4,568 ZIP codes having centroids within 6 miles of a PM(2.5) monitor. We estimated relative risks adjusted by socioeconomic status and smoking by fitting log-linear regression models. RESULTS: In the eastern and central regions, a 10-microg/m(3) increase in 6-year average of PM(2.5) is associated with 6.8% [95% confidence interval (CI), 4.9-8.7%] and 13.2% (95% CI, 9.5-16.9) increases in mortality, respectively. We found no evidence of an association in the western region or for persons > or = 85 years of age. CONCLUSIONS: We established a cohort of Medicare participants for investigating air pollution and mortality on longer-term time frames. Chronic exposure to PM(2.5) was associated with mortality in the eastern and central regions, but not in the western United States.