Development and validation of AI-based triage support algorithms for prevention of intradialytic hypotension.

BACKGROUND: Intradialytic hypotension remains one of the most recurrent complications of dialysis sessions. Inadequate management can lead to adverse outcomes, highlighting the need to develop personalized approaches for the prevention of intradialytic hypotension. Here, we sought to develop and validate two AI-based risk models predicting the occurrence of symptomatic intradialytic hypotension at different time points. METHODS: The models were built using the XGBoost algorithm and they predict the occurrence of intradialytic hypotension in the next dialysis session and in the next month. The initial dataset, obtained from routinely collected data in the EuCliD® Database, was split to perform model derivation, training and validation. Model performance was evaluated by concordance statistic and calibration charts; the importance of features was assessed with the Shapley Additive Explanation (SHAP) methodology. RESULTS: The final dataset included 1,249,813 dialysis sessions, and the incidence rate of intradialytic hypotension was 10.07% (95% CI 10.02-10.13). Our models retained good discrimination (AUC around 0.8) and a suitable calibration yielding to the selection of three classification thresholds identifying four distinct risk groups. Variables providing the most significant impact on risk estimates were blood pressure dynamics and other metrics mirroring hemodynamic instability over time. CONCLUSIONS: Recurrent symptomatic intradialytic hypotension could be reliably and accurately predicted using routinely collected data during dialysis treatment and standard clinical care. Clinical application of these prediction models would allow for personalized risk-based interventions for preventing and managing intradialytic hypotension.

Assessment of a serum calcification propensity test for the prediction of all-cause mortality among hemodialysis patients.

BACKGROUND: Vascular calcification is a major contributor to the high cardiac burden among hemodialysis patients. A novel in vitro T50-test, which determines calcification propensity of human serum, may identify patients at high risk for cardiovascular (CV) disease and mortality. We evaluated whether T50 predicts mortality and hospitalizations among an unselected cohort of hemodialysis patients. METHODS: This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 dialysis centers in Spain. T50 and fetuin-A were determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database. After their baseline T50 measurement, patients were followed for two years for the occurrence of all-cause mortality, CV-related mortality, all-cause and CV-related hospitalizations. Outcome assessment was performed with proportional subdistribution hazards regression modelling. RESULTS: Patients who died during follow-up had a significantly lower T50 at baseline as compared to those who survived (269.6 vs. 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI [0.9933;0.9981]). T50 remained significant after inclusion of known predictors. There was no evidence for prediction of CV-related outcomes, but for all-cause hospitalizations (mean c statistic: 0.5284). CONCLUSION: T50 was identified as an independent predictor of all-cause mortality among an unselected cohort of hemodialysis patients. However, the additional predictive value of T50 added to known mortality predictors was limited. Future studies are needed to assess the predictive value of T50 for CV-related events in unselected hemodialysis patients.

Global real-world data on hemodiafiltration: An opportunity to complement clinical trial evidence.

Hemodiafiltration (HDF) is a renal replacement therapy that utilizes both diffusive clearance and convective transport to achieve greater clearance of middle-molecular-weight solutes. Among other factors, important prerequisites for the implementation of HDF include access to high-flux dialyzers, achievement of high blood flow rates, and availability of high volumes of sterile substitution/replacement fluids. Online hemodiafiltration (OL-HDF) is an established kidney replacement therapy, frequently used in many countries. Although in the United States, some prerequisites (e.g., access to high-flux dialyzers and achievement of high blood flow rates) for OL-HDF treatment are readily available; however, a machine capable of generating the online solution for OL-HDF is currently not available. As the clinical experience with HDF accumulates globally, it is worth examining the evidence for this kidney replacement therapy as used in routine clinical care. Such real-world evidence is increasingly recognized as valuable by clinicians and may inform regulatory decisions. In this review, we will focus on emerging global real-world data derived from routine clinical practices and examine how these data may complement those derived from clinical trials.

Modifiable Risk Factors Are Important Predictors of COVID-19-Related Mortality in Patients on Hemodialysis.

Introduction: Patients with end-stage kidney disease face a higher risk of severe outcomes from SARS-CoV-2 infection. Moreover, it is not well known to what extent potentially modifiable risk factors contribute to mortality risk. In this historical cohort study, we investigated the incidence and risk factors for 30-day mortality among hemodialysis patients with SARS-CoV-2 infection treated in the European Fresenius Medical Care NephroCare network using conventional and machine learning techniques. Methods: We included adult hemodialysis patients with the first documented SARS-CoV-2 infection between February 1, 2020, and March 31, 2021, registered in the clinical database. The index date for the analysis was the first SARS-CoV-2 suspicion date. Patients were followed for up to 30 days until April 30, 2021. Demographics, comorbidities, and various modifiable risk factors, expressed as continuous parameters and as key performance indicators (KPIs), were considered to tap multiple dimensions including hemodynamic control, nutritional state, and mineral metabolism in the 6 months before the index date. We used logistic regression (LR) and XGBoost models to assess risk factors for 30-day mortality. Results: We included 9,211 patients (age 65.4 ± 13.7 years, dialysis vintage 4.2 ± 3.7 years) eligible for the study. The 30-day mortality rate was 20.8%. In LR models, several potentially modifiable factors were associated with higher mortality: body mass index (BMI) 30-40 kg/m2 (OR: 1.28, CI: 1.10-1.50), single-pool Kt/V (OR off-target vs on-target: 1.19, CI: 1.02-1.38), overhydration (OR: 1.15, CI: 1.01-1.32), and both low (<2.5 mg/dl) and high (≥5.5 mg/dl) serum phosphate levels (OR: 1.52, CI: 1.07-2.16 and OR: 1.17, CI: 1.01-1.35). On-line hemodiafiltration was protective in the model using KPIs (OR: 0.86, CI: 0.76-0.97). SHapley Additive exPlanations analysis in XGBoost models shows a high influence on prediction for several modifiable factors as well, including inflammatory parameters, high BMI, and fluid overload. In both LR and XGBoost models, age, gender, and comorbidities were strongly associated with mortality. Conclusion: Both conventional and machine learning techniques showed that KPIs and modifiable risk factors in different dimensions ascertained 6 months before the COVID-19 suspicion date were associated with 30-day COVID-19-related mortality. Our results suggest that adequate dialysis and achieving KPI targets remain of major importance during the COVID-19 pandemic as well.

Effectiveness of COVID-19 vaccines in a large European hemodialysis cohort.

Background: Hemodialysis patients have high-risk of severe SARS-CoV-2 infection but were unrepresented in randomized controlled trials evaluating the safety and efficacy of COVID-19 vaccines. We estimated the real-world effectiveness of COVID-19 vaccines in a large international cohort of hemodialysis patients. Methods: In this historical, 1:1 matched cohort study, we included adult hemodialysis patients receiving treatment from December 1, 2020, to May 31, 2021. For each vaccinated patient, an unvaccinated control was selected among patients registered in the same country and attending a dialysis session around the first vaccination date. Matching was based on demographics, clinical characteristics, past COVID-19 infections and a risk score representing the local background risk of infection at vaccination dates. We estimated the effectiveness of mRNA and viral-carrier COVID-19 vaccines in preventing infection and mortality rates from a time-dependent Cox regression stratified by country. Results: In the effectiveness analysis concerning mRNA vaccines, we observed 850 SARS-CoV-2 infections and 201 COVID-19 related deaths among the 28110 patients during a mean follow up of 44 ± 40 days. In the effectiveness analysis concerning viral-carrier vaccines, we observed 297 SARS-CoV-2 infections and 64 COVID-19 related deaths among 12888 patients during a mean follow up of 48 ± 32 days. We observed 18.5/100-patient-year and 8.5/100-patient-year fewer infections and 5.4/100-patient-year and 5.2/100-patient-year fewer COVID-19 related deaths among patients vaccinated with mRNA and viral-carrier vaccines respectively, compared to matched unvaccinated controls. Estimated vaccine effectiveness at days 15, 30, 60 and 90 after the first dose of a mRNA vaccine was: for infection, 41.3%, 54.5%, 72.6% and 83.5% and, for death, 33.1%, 55.4%, 80.1% and 91.2%. Estimated vaccine effectiveness after the first dose of a viral-carrier vaccine was: for infection, 38.3% without increasing over time and, for death, 56.6%, 75.3%, 92.0% and 97.4%. Conclusion: In this large, real-world cohort of hemodialyzed patients, mRNA and viral-carrier COVID-19 vaccines were associated with reduced COVID-19 related mortality. Additionally, we observed a strong reduction of SARS-CoV-2 infection in hemodialysis patients receiving mRNA vaccines.

Trajectories of clinical and laboratory characteristics associated with COVID-19 in hemodialysis patients by survival.

INTRODUCTION: The clinical impact of COVID-19 has not been established in the dialysis population. We evaluated the trajectories of clinical and laboratory parameters in hemodialysis (HD) patients. METHODS: We used data from adult HD patients treated at an integrated kidney disease company who received a reverse transcription polymerase chain reaction (RT-PCR) test to investigate suspicion of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection between May 1 and September 1, 2020. Nonparametric smoothing splines were used to fit data for individual trajectories and estimate the mean change over time in patients testing positive or negative for SARS-CoV-2 and those who survived or died within 30 days of first suspicion or positive test date. For each clinical parameter of interest, the difference in average daily changes between COVID-19 positive versus negative group and COVID-19 survivor versus nonsurvivor group was estimated by fitting a linear mixed effects model based on measurements in the 14 days before (i.e., Day -14 to Day 0) Day 0. RESULTS: There were 12,836 HD patients with a suspicion of COVID-19 who received RT-PCR testing (8895 SARS-CoV-2 positive). We observed significantly different trends (p < 0.05) in pre-HD systolic blood pressure (SBP), pre-HD pulse rate, body temperature, ferritin, neutrophils, lymphocytes, albumin, and interdialytic weight gain (IDWG) between COVID-19 positive and negative patients. For COVID-19 positive group, we observed significantly different clinical trends (p < 0.05) in pre-HD pulse rate, lymphocytes, neutrophils, and albumin between survivors and nonsurvivors. We also observed that, in the group of survivors, most clinical parameters returned to pre-COVID-19 levels within 60-90 days. CONCLUSION: We observed unique temporal trends in various clinical and laboratory parameters among HD patients who tested positive versus negative for SARS-CoV-2 infection and those who survived the infection versus those who died. These trends can help to define the physiological disturbances that characterize the onset and course of COVID-19 in HD patients.

Evolution of body composition and wasting indicators by time of day of haemodialysis.

BACKGROUND: It has been a long-standing clinical concern that haemodialysis (HD) patients on afternoon shifts (ASs) are more prone to protein-energy wasting (PEW) than those on morning shifts (MSs), as their dialysis scheme and post-dialysis symptoms may interfere with meal intake. We evaluated the effect of time of day of HD on the evolution of body composition changes and PEW surrogates. METHODS: We conducted a retrospective study among 9.963 incident HD patients treated in NephroCare centres (2011-16); data were routinely collected in the European Clinical Database. The course of multi-frequency bioimpedance determined lean and fat tissue indices (LTI and FTI) between patients in MSs/ASs over 2 years were compared with linear mixed models. Secondary PEW indicators were body mass index, albumin, creatinine index and normalized protein catabolic rate. Models included fixed (age, sex, vascular access and diabetes mellitus) and random effects (country and patient). RESULTS: Mean baseline LTI and FTI were comparable between MSs (LTI: 12.5 ± 2.9 kg/m2 and FTI: 13.7 ± 6.0 kg/m2) and ASs (LTI: 12.4 ± 2.9 kg/m2 and FTI: 13.2 ± 6.1 kg/m2). During follow-up, LTI decreased and FTI increased similarly, with a mean absolute change (baseline to 24 months) of -0.3 kg/m2 for LTI and +1.0 kg/m2 for FTI. The course of these malnutrition indicators did not differ between dialysis shifts (P for interaction ≥0.10). We also did not observe differences between groups for secondary PEW indicators. CONCLUSIONS: This study suggests that a dialysis shift in the morning or in the afternoon does not impact the long-term nutritional status of HD patients. Regardless of time of day of HD, patients progressively lose muscle mass and increase body fat.

Serum Uric Acid and Mortality Risk Among Hemodialysis Patients.

INTRODUCTION: Although high serum uric acid (SUA) has been consistently associated with an increased risk of death in the general population and in persons with nondialysis chronic kidney disease (CKD), studies in patients undergoing dialysis are conflicting. It has been postulated that low SUA simply reflects poor nutritional status in dialysis patients. We here characterize the association between SUA and the risk of death in a large dialysis cohort and explore effect modification by underlying nutritional status as reflected by body composition. METHODS: In this retrospective cohort study, we included 16,057 hemodialysis (HD) patients treated during 2007 to 2016 in NephroCare centers as recorded in the European Clinical Database (EuCliD). The association between SUA, all-cause, and cardiovascular (CV)-related mortality was evaluated with competing risk models and characterized with splines. Effect modification was explored by lean tissue index (LTI) and fat tissue index (FTI). RESULTS: During a mean of 1.8 years of follow-up, 2791 patients (17.4%) died. We found a multivariable-adjusted U-shaped pattern between SUA and all-cause mortality. Patients with SUA levels of 6.5 mg/dl (387 µmol/l) were at the lowest risk of death (subdistribution hazard ratio = 0.94 [confidence interval {CI} 0.91; 0.96]). The form of association was not meaningfully affected by underlying LTI and FTI. CONCLUSION: We found a U-shaped pattern between SUA levels and all-cause mortality among HD patients, which was independent of the patients' body composition.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Multimorbidity in randomized controlled trials of behavioral interventions: A systematic review.

OBJECTIVE: As the population with multiple chronic conditions (MCC) increases, it is essential that randomized controlled trials (RCTs) consider MCC. Behavioral interventions have the potential to positively impact MCC patient outcomes; however, a comprehensive review of consideration of MCC in these trials has not been conducted. The purpose of this systematic review is to determine the frequency with which participants with MCC are represented in behavioral intervention RCTs targeting chronic illness published 2000-2014. METHOD: MEDLINE and EMBASE were searched from 2000 to 2014 to identify RCTs testing behavioral interventions among adults with chronic illness. A random sampling selection process was performed to identify 600 eligible studies representative of the literature. Two reviewers independently extracted information on consideration of MCC in eligibility criteria and evaluated the reporting and consideration of MCC in trial analyses. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias Tool. RESULTS: In 600 behavioral intervention RCTs, targeting MCC was rare (4.3%). Exclusion of MCC was common (68.3%) and was done through general, specific, or vague exclusion criteria. 218 (36.3%) trials reported presence of MCCs through general or condition-specific measures. Comorbidities were only considered in 4.8% of all trial analyses. CONCLUSIONS: In this comprehensive systematic review of 600 studies published from 2000-2014, RCTs testing behavioral interventions rarely consider individuals with MCC, limiting generalizability. Given the public health relevance and limited evidence base, this work highlights the urgent need to improve the consideration of MCC in clinical trial research. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of high-volume online mixed-hemodiafiltration on anemia management in dialysis patients.

BACKGROUND: Anemia is a major comorbidity of patients with end-stage renal disease and poses an enormous economic burden to health-care systems. High dose erythropoiesis-stimulating agents (ESAs) have been associated with unfavorable clinical outcomes. We explored whether mixed-dilution hemodiafiltration (Mixed-HDF), based on its innovative substitution modality, may improve anemia outcomes compared to the traditional post-dilution hemodiafiltration (Post-HDF). METHODS: We included 174 adult prevalent dialysis patients (87 on Mixed-HDF, 87 on Post-HDF) treated in 24 NephroCare dialysis centers between January 2010 and August 2016 into this retrospective cohort study. All patients were dialyzed three times per week and had fistula/graft as vascular access. Patients were matched at baseline and followed over a one-year period. The courses of hemoglobin levels (Hb) and monthly ESA consumption were compared between the two groups with linear mixed models. RESULTS: Mean baseline Hb was 11.9±1.3 and 11.8±1.1g/dl in patients on Mixed- and Post-HDF, respectively. While Hb remained stable in patients on Mixed-HDF, it decreased slightly in patients on Post-HDF (at month 12: 11.8±1.2 vs 11.1±1.2g/dl). This tendency was confirmed by our linear mixed model (p = 0.0514 for treatment x time interaction). Baseline median ESA consumption was 6000 [Q1:0;Q3:16000] IU/4 weeks in both groups. Throughout the observation period ESA doses tended to be lower in the Mixed-HDF group (4000 [Q1:0;Q3:16000] vs 8000 [Q1:0;Q3:20000] IU/4 weeks at month 12; p = 0.0791 for treatment x time interaction). Sensitivity analyses, adjusting for differences not covered by matching at baseline, strengthened our results (Hb: p = 0.0124; ESA: p = 0.0687). CONCLUSIONS: Results of our explorative study suggest that patients on Mixed-HDF may have clinical benefits in terms of anemia management. This may also have a beneficial economic impact. Future studies are needed to confirm our hypothesis-generating results and to provide additional evidence on the potential beneficial effects of Mixed-HDF.

The Use of Nerve Transfers to Restore Upper Extremity Function in Cervical Spinal Cord Injury.

BACKGROUND: Nerve transfer surgery to restore upper extremity function in cervical spinal cord injury (SCI) is novel and may transform treatment. Determining candidacy even years post-SCI is ill defined and deserves investigation. OBJECTIVE: To develop a diagnostic algorithm, focusing on electrodiagnostic (EDX) studies, to determine eligibility for nerve transfer surgery. DESIGN: Retrospective descriptive case series. SETTING: Tertiary university-based institution. PATIENTS: Individuals with cervical SCI (n = 45). METHODS: The electronic medical records of people referred to the Plastic Surgery Multidisciplinary Upper Extremity Surgery in SCI clinic from 2010-2015 were reviewed. People were considered for nerve transfers to restore elbow extension or finger flexion and/or extension. Data including demographic, clinical evaluation, EDX results, surgery, and outcomes were collected and analyzed. MAIN OUTCOME MEASUREMENTS: EDX data, including nerve conduction studies and electromyography, for bilateral upper extremities of each patient examined was used to assess for the presence of lower motor neuron injury, which would preclude late nerve transfer. RESULTS: Based on our criteria and the results of EDX testing, a substantial number of patients presenting even years post-SCI were candidates for nerve transfers. Clinical outcome results are heterogeneous but promising and suggest that further refinement of eligibility, long-term follow-up, and standardized assessment will improve our understanding of the role of nerve transfer surgery to restore function in people with midcervical SCI. CONCLUSIONS: Many patients living with SCI are candidates for nerve transfer surgery to restore upper extremity function. Although the ultimate efficacy of these surgeries is not yet determined, this study attempts to report the criteria we are using and may ultimately determine the timing for intervention and which transfers are most useful for this heterogeneous population. LEVEL OF EVIDENCE: IV.

Migraine and the risk of incident hypertension among women.

Background Few studies have examined whether migraine is associated with an increased risk of incident hypertension. Methods We performed a prospective cohort study among 29,040 women without hypertension at baseline. Women were classified as having active migraine with aura, active migraine without aura, a past history of migraine, or no history of migraine. Incident hypertension was defined as new physician diagnosis or newly self-reported systolic or diastolic blood pressure ≥140 mmHg or ≥90 mmHg respectively. Cox proportional hazards models were used to evaluate the association between migraine and incident hypertension. Results During a mean follow-up of 12.2 years, 15,176 incident hypertension cases occurred. Compared to those with no history of migraine, women who experience migraine with aura had a 9% increase in their risk of developing hypertension (95% CI: 1.02, 1.18); women who experience migraine without aura had a 21% increase in their risk of developing hypertension (95% CI: 1.14, 1.28); and women with a past history of migraine had a 15% increase in their risk of developing hypertension (95% CI: 1.07, 1.23). Conclusions Women with migraine have a higher relative risk of developing hypertension compared to women without migraine.

Migraine and invasive epithelial ovarian cancer risk in the Nurses' Health Study II and the Women's Health Study.

Migraine is a common primary headache disorder, which predominantly impacts women. Recently, migraine has been hypothesized to be associated with hormonally related cancers; however, the potential association between migraine and ovarian cancer has not been studied. Therefore, we evaluated the association between migraine and invasive epithelial ovarian cancer risk in two prospective cohorts, the Nurses' Health Study II (NHSII) and the Women's Health Study (WHS). Our prospective analysis included 113,124 NHSII participants aged 25-42 at study baseline as well as 33,490 participants in the WHS who were 45 years or older at study entry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for the association between migraine and ovarian cancer risk in each cohort. In secondary analyses, we stratified by age and menopausal status. After adjusting for potential covariates, there was no statistically significant association between migraine and ovarian cancer risk in either the NHSII (HR = 1.29, 95%CI: 0.96, 1.74) or the WHS (HR = 0.60, 95%CI: 0.34, 1.06). In stratified analysis in the NHSII, there was a statistically significant positive association between migraine and ovarian cancer risk among women <45 years of age (HR = 1.76, 95%CI: 1.01, 3.07). We did not observe a clear association between migraine and ovarian cancer risk in two large prospective cohort studies.

Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial.

BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae. METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat). RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age-adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P < .001] and increase in median proportion of zero EEG suppression time from 87% to 94% [P < .01]). Nearly all patients (115 of 117, 98.3%) were assessed for delirium using the Confusion Assessment Method, and the delirium incidence was similar (28.1%; 95% CI, 20%-37%) to the estimate (25%) used for the sample size calculation. Good interrater reliability of delirium assessment was demonstrated (κ = 0.94 [95% CI, 0.86-1]). Finally, 1-month follow-up vital status data were obtained for 96.9% of patients, with 85.7% of patients completing at least 1 survey. CONCLUSIONS: With the ENGAGES trial, we demonstrated that key milestones can be identified and progressively assessed during a pilot phase. Success in attaining appropriate milestones hypothetically predicts meaningful completion of a study, and can provide justification for proceeding beyond a pilot phase. The impact of this phased approach on return on investment and scientific yield requires additional study.

Trichomonas vaginalis infection and risk of prostate cancer: associations by disease aggressiveness and race/ethnicity in the PLCO Trial.

PURPOSE: Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African-American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. METHODS: We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n = 438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (≥Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. RESULTS: No associations were observed for risk of Gleason 7 (odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.55-1.37) or more advanced (OR = 0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR = 1.06, 95% CI 0.67-1.68) in African-American men. CONCLUSIONS: Our findings do not support an association between T. vaginalis infection and PCa.

Insight into infection-mediated prostate damage: Contrasting patterns of C-reactive protein and prostate-specific antigen levels during infection.

BACKGROUND: To investigate mechanisms underlying our previous observation of a large rise in serum prostate-specific antigen, a marker of prostate pathology, during both sexually transmitted and systemic infections, we measured serum high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, in our previous case-control study of young, male US military members and compared our findings to those for PSA. METHODS: We measured hsCRP before and during infection for 299 chlamydia, 112 gonorrhea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases; before and after infection for 55 infectious mononucleosis (IM) and 90 other systemic/non-genitourinary cases; and for 220-256 controls. RESULTS: Only gonorrhea cases were significantly more likely to have a large hsCRP rise (≥1.40 mg/L or ≥239%) during infection than controls (P < 0.01). However, gonorrhea, IM, and other systemic/non-genitourinary cases were more likely to have a rise of any magnitude up to one year post-diagnosis than controls (p = 0.038-0.077). CONCLUSIONS: These findings, which differ from those for PSA, suggest distinct mechanisms of elevation for hsCRP and PSA, and support both direct (eg, prostate infection) and indirect (eg, systemic inflammation-mediated prostate cell damage) mechanisms for PSA elevation. Future studies should explore our PSA findings further for their relevance to both prostate cancer screening and risk.

Prospective comorbidity-matched study of Parkinson's disease and risk of mortality among women.

BACKGROUND: Individuals with Parkinson's disease (PD) may have an increased risk of overall mortality compared to the general population. Women may have lower mortality rates from PD than men; however, studies among women on the effect of PD on mortality have been limited and may not have adequately controlled for confounding by comorbidities. METHODS: We conducted a matched cohort study among participants in the Women's Health Study. 396 incident PD cases were identified through self-report. Each PD case was matched by age to a comparator who was alive and had the same modified Charlson comorbidity score as the PD case. The PD cases and matched comparators were followed for all-cause mortality. Cox proportional hazards models adjusted for age at the index date, smoking, alcohol consumption, exercise and body mass index were used to determine the association between PD and mortality. RESULTS: During a median of 6.2 years of follow-up, 72 women died (47 PD cases and 25 comparators). The multivariable-adjusted HR for mortality was 2.60 (95% CI 1.56 to 4.32). CONCLUSIONS: PD was associated with more than a twofold increased risk of all-cause mortality among women. Results are similar to those observed among men.

Methodologic Considerations for Collecting Patient-reported Outcomes from Unselected Surgical Patients.

BACKGROUND: The impact of surgery on health is only appreciated long after hospital discharge. Furthermore, patients' perceptions of postoperative health are not routinely ascertained. The authors instituted the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) registry to evaluate patients' postoperative health based on patient-reported outcomes (PROs). METHODS: This article describes the methods of establishing the SATISFY-SOS registry from an unselected surgical population, combining perioperative PROs with information from electronic medical records. Patients enrolled during their preoperative visit were surveyed at enrollment, 30 days, and 1-yr postoperatively. Information on PROs, including quality of life, return to work, pain, functional status, medical complications, and cognition, was obtained from online, mail, or telephone surveys. RESULTS: Using structured query language, 44,081 patients were identified in the electronic medical records as having visited the Center for Preoperative Assessment and Planning for preoperative assessment between July 16, 2012, and June 15, 2014, and 20,719 patients (47%) consented to participate in SATISFY-SOS. Baseline characteristics and health status were similar between enrolled and not enrolled patients. The response rate for the 30-day survey was 62% (8% e-mail, 73% mail, and 19% telephone) and for the 1-yr survey was 71% (13% e-mail, 78% mail, and 8% telephone). CONCLUSIONS: SATISFY-SOS demonstrates the feasibility of establishing a PRO registry reflective of a busy preoperative assessment center population, without disrupting clinical workflow. Our experience suggests that patient engagement, including informed consent and multiple survey modalities, enhances PROs collection from a large cohort of unselected surgical patients. Initiatives like SATISFY-SOS could promote quality improvement, enable efficient perioperative research, and facilitate outcomes that matter to surgical patients.

Migraine and risk of cardiovascular disease in women: prospective cohort study.

OBJECTIVE:  To evaluate the association between migraine and incident cardiovascular disease and cardiovascular mortality in women. DESIGN:  Prospective cohort study among Nurses' Health Study II participants, with follow-up from 1989 and through June 2011. SETTING:  Cohort of female nurses in United States. PARTICIPANTS:  115 541 women aged 25-42 years at baseline and free of angina and cardiovascular disease. Cumulative follow-up rates were more than 90%. MAIN OUTCOME MEASURES:  The primary outcome of the study was major cardiovascular disease, a combined endpoint of myocardial infarction, stroke, or fatal cardiovascular disease. Secondary outcome measures included individual endpoints of myocardial infarction, stroke, angina/coronary revascularization procedures, and cardiovascular mortality. RESULTS:  17 531 (15.2%) women reported a physician's diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased risk for major cardiovascular disease (hazard ratio 1.50, 95% confidence interval 1.33 to 1.69), myocardial infarction (1.39, 1.18 to 1.64), stroke (1.62, 1.37 to 1.92), and angina/coronary revascularization procedures (1.73, 1.29 to 2.32), compared with women without migraine. Furthermore, migraine was associated with a significantly increased risk for cardiovascular disease mortality (hazard ratio 1.37, 1.02 to 1.83). Associations were similar across subgroups of women, including by age (<50/≥50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current). CONCLUSIONS:  Results of this large, prospective cohort study in women with more than 20 years of follow-up indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality. Women with migraine should be evaluated for their vascular risk. Future targeted research is warranted to identify preventive strategies to reduce the risk of future cardiovascular disease among patients with migraine.