Abstract Background Gastrointestinal bleeding (GIB) is a clinical challenge in kidney failure. INSPIRE group assessed if machine learning could determine a hemodialysis (HD) patient’s 180-day GIB hospitalization risk. Methods An eXtreme Gradient Boosting (XGBoost) and logistic regression model were developed using an HD dataset in United States (2017–2020). Patient data was randomly split (50% training, 30% validation, and 20% testing). HD treatments ≤ 180 days before GIB hospitalization were classified as positive observations; others were negative. Models considered 1,303 exposures/covariates. Performance was measured using unseen testing data. Results Incidence of 180-day GIB hospitalization was 1.18% in HD population (n = 451,579), and 1.12% in testing dataset (n = 38,853). XGBoost showed area under the receiver operating curve (AUROC) = 0.74 (95% confidence interval (CI) 0.72, 0.76) versus logistic regression showed AUROC = 0.68 (95% CI 0.66, 0.71). Sensitivity and specificity were 65.3% (60.9, 69.7) and 68.0% (67.6, 68.5) for XGBoost versus 68.9% (64.7, 73.0) and 57.0% (56.5, 57.5) for logistic regression, respectively. Associations in exposures were consistent for many factors. Both models showed GIB hospitalization risk was associated with older age, disturbances in anemia/iron indices, recent all-cause hospitalizations, and bone mineral metabolism markers. XGBoost showed high importance on outcome prediction for serum 25 hydroxy (25OH) vitamin D levels, while logistic regression showed high importance for parathyroid hormone (PTH) levels. Conclusions Machine learning can be considered for early detection of GIB event risk in HD. XGBoost outperforms logistic regression, yet both appear suitable. External and prospective validation of these models is needed. Association between bone mineral metabolism markers and GIB events was unexpected and warrants investigation. Trial registration This retrospective analysis of real-world data was not a prospective clinical trial and registration is not applicable. Graphical Abstract

Gastrointestinal bleeding (GIB) is a clinical challenge in kidney failure. The INSPIRE group assessed if machine learning could assist with determining a hemodialysis (HD) patient’s 180-day GIB hospitalization risk. Model was developed using adult HD patient data from United States (2017-2020). Patient data was randomly split (50% training, 30% validation, and 20% testing). HD treatments ≤ 180 days before GIB hospitalization were classified as positive observations, and others were negative observations. Datasets were randomly sampled to build an XGBoost model that considered 386 exposures initially and was refined to the top 50 exposures. Unseen testing dataset was used to determine final model performance. Incidence of 180-day GIB hospitalization was 1.18% in the HD population (n=451,579), and 1.16% among patients in the testing dataset (n=27,991). Model showed an area under the curve=0.69, sensitivity=57.9%, specificity=68.9%, accuracy=68.8% and balanced accuracy=63.4%. Exposures with largest effect size per Shapley values were older age (group mean GIB event=68.2 years vs no GIB event=63.4 years), shorter days since last all-cause hospital admission (group mean GIB event=203.2 days vs no GIB event=253.2 days), and higher serum 25-hydroxy (OH) vitamin D levels from most recent lab (group mean GIB event=33.4 ng/mL vs no GIB event=30.5 ng/mL). Other important predictors included lower hemoglobin and iron indices, longer dialysis vintage, and proton pump inhibitor use. Model appears suitable for early detection of GIB event risk in HD, yet prospective testing is needed. The association between higher 25OH vitamin D and GIB events was unexpected and warrants investigation.### Competing Interest StatementJ.W.L., S.L., S.C., J.W., A.C.W., Y.J., M.S.G., L.A.U., J.L.H., F.W.M. report being an employee of Fresenius Medical Care. J.W.L., S.C., M.S.G., L.A.U., J.L.H., F.W.M. report having share options/ownership in Fresenius Medical Care. J.W.L., S.C., L.A.U., J.L.H., F.W.M. report being an inventor on patent(s) in the field of dialysis. J.W.L. reports receipt of honorarium from The Lancet and being on the Editorial Board of Frontiers in Physiology and Frontiers in Medicine, Nephrology. L.A.U. reports being an advisory board member for Privacy Analytics Inc. F.W.M. reports directorships in Fresenius Medical Care Management Board and Vifor Fresenius Medical Care Renal Pharma. D.C.W. reports consultancy or honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Mundipharma, Napp, Mitsubishi, Ono Pharma, and Vifor Fresenius Medical Care Renal Pharma. P.S. reports serving on scientific advisory boards or speaker honoraria for AstraZeneca, REATA, Vifor, Baxter Healthcare, GSK, Pfizer, Invizius, Astellas, Novo Nordisk, and Fresenius Medical Care. J.F. reports consultancy or speaker honoraria from Astellas, AstraZeneca, Bayer, Boehringer, Fresenius Medical Care, and Vifor.### Funding StatementThere was no external funding for the work presented in this manuscript. Fresenius Medical Care internally supported the conduct of the analysis and manuscript composition, which included employee salaries and company infrastructure.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This project was reviewed and approved by New England Independent Review Board (Needham Heights, MA, United States; Work Oder# 1-1502098-1). It was determined by the Independent Review Board that this analysis was exempt due to deidentification of data and consent was not required per title 45 Code of Federal Regulations part 46.104(d)(4) in the United States. The analysis adhered to the Declaration of Helsinki.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe dataset used in the presented analyses is not publicly available. The dataset was captured from a private electronic medical record system that is restricted to use by only authorized employees of Fresenius Medical Care. The dataset can be made available upon reasonable request to access the dataset, which would require an agreement to be established between Fresenius Medical Care and an external institution of any applicable requestor.

BACKGROUNDIt 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.METHODSWe 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).RESULTSMean 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.CONCLUSIONSThis 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.

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 mmol/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.

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.

OBJECTIVEAs 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.METHODMEDLINE 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.RESULTSIn 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.CONCLUSIONSIn 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).

IMPORTANCE Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. OBJECTIVE To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitment was from January 2015 to May 2018, with follow-up until July 2018. INTERVENTIONS Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). MAIN OUTCOMES AND MEASURES The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. RESULTS Of the 1232 randomized patients (median age, 69 years [range, 60 to 95]; 563 women [45.7%]), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0%[95% CI, -2.0% to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, -0.11 [95% CI, -0.13 to -0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, -6.0[95% CI, -9.9 to -2.1]). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mmHg (7 vs 7 minutes; difference, 0.0[95% CI, -1.7 to 1.7]). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. CONCLUSIONS AND RELEVANCE Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication.

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.

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.

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.

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.

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.

To evaluate the association between migraine, including migraine subtypes, and risk of developing hypertension.

INTRODUCTION:Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life.METHODS AND ANALYSIS:This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05.ETHICS AND DISSEMINATION:Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media.TRIAL REGISTRATION NUMBER:NCT02241655; Pre-results.

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.

Objective: To determine the association between Parkinson's disease (PD) and mortality among women. Introduction: PD has been linked with an increased risk of overall mortality compared to the general population. Among men, PD is associated with a two-fold increase in the risk of mortality. It has been hypothesized that women may have lower mortality rates from PD than men. However, many prior studies which estimated mortality risks among females with PD have been small and substantial between study heterogeneity has impeded the pooling of effect estimates. Additionally, these studies may not have adequately controlled for confounding by comorbidities. Design/Methods: We conducted a matched cohort study among participants in the Women's Health Study. Six hundred and two 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 PD onset, smoking, alcohol consumption, exercise, and body mass index were used to determine the association between PD and mortality. Results: During a median of 6.6 years of follow-up, 85 women died (55 PD cases and 30 comparators). The multivariable-adjusted hazard ratio for mortality was 2.34 (95[percnt] CI: 1.48, 3.71). An exploratory analysis observed that the hazard ratio was higher among those who were non-smokers (HR=3.45; 95[percnt] CI: 1.73-6.89) than smokers (HR=1.53; 95[percnt] CI: 0.82, 2.86); however the interaction between smoking and PD did not reach statistical significance (p-value=0.08). Conclusion: In this age- and comorbidity-matched cohort study among women, PD was associated with more than a two-fold increased risk of all-cause mortality. Results are similar to men. Study Supported by: CA047988, HL043851, HL080467, HL099355, UM1 CA182913

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.

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.

BACKGROUND:Patient memories of the operating room (OR) may serve as the informational basis for assessing satisfaction with individual anesthesiologists. Furthermore, the provision of clinically important information may assume that perioperative memories are retained. Studies assessing the extent of perioperative amnesia and factors associated with perioperative amnesia are sparse. Therefore, we assessed patient amnesia of the OR and of the preoperative holding area in hospitals where midazolam is typically administered in the preoperative holding area and evaluated whether midazolam dose administered in the preoperative holding area and patient age were associated with amnesia of the OR before induction of anesthesia. METHODS:This was a retrospective study among 7750 adult patients who had general anesthesia and participated in the B-Unaware and Bispectral Index or Anesthetic Gas to Reduce Explicit Recall (BAG-RECALL) clinical trials. The last location the patient remembered before induction of anesthesia and the first location they remembered after induction of anesthesia were determined through a modified Brice questionnaire administered over the phone 30 days postoperatively. Regarding the preoperative period, patients were excluded if their last memory was unclear with respect to location before induction of anesthesia or if they were recruited at Winnipeg, where midazolam was typically first administered in the OR. Midazolam dose (mg/kg) administered in the preoperative holding area was divided into quartiles. Poisson regression models were used to calculate age- and multivariable-adjusted odds ratios (95% confidence intervals [CIs]) for the association between midazolam dose and amnesia of the OR before induction of anesthesia. RESULTS:Of the 5339 patients included, 59.5% (95% CI, 58.2–60.9) of patients had amnesia of the OR before induction of anesthesia. In addition, 44.1% (95% CI, 42.8–45.7) last remembered the preoperative holding area, and 15.4% (95% CI, 14.4–16.4) only had preoperative memories before the holding area. The percentages of patients with amnesia of the OR before induction of anesthesia differed according to age groups: 50.7% (95% CI, 47.7%–53.7%) in patients aged 18 to 47 years versus 70.0% (95% CI, 67.0%–72.9%) in patients aged 73 to 99 years. Patients in the highest midazolam quartile had an adjusted prevalence ratio of 1.31 (95% CI, 1.22–1.42) for amnesia of the OR compared with those who did not receive midazolam. CONCLUSIONS:In hospitals where patients typically receive midazolam in the preoperative holding area, the majority of patients do not remember the OR, and a clinically relevant number of patients does not remember the preoperative holding area. If additional studies produce results indicating that a substantial proportion of patients has amnesia of the anesthesiologist, these findings would argue against the validity of assessing patient satisfaction with individual anesthesiologists providing exclusively OR care in such hospitals. Furthermore, if additional studies yield findings suggesting patient amnesia of the preoperative holding area, these results would suggest reconsideration of providing clinically important information only in the preoperative holding area. Older age and midazolam-induced anterograde amnesia are probably associated with impaired perioperative memories.

Background: Restless legs syndrome (RLS) is increasingly being reported as a comorbidity of migraine.Methods: We conducted a systematic review and meta-analysis of studies investigating RLS in headache/migraine and vice versa. We calculated the prevalence and 95% confidence intervals (CI) of RLS in headache/migraine, of headache/migraine in RLS and controls, and odds ratios (ORs) of the association between the conditions. We then determined pooled effect estimates for the associations.Results: We identified 24 studies. RLS prevalence in migraine ranged from 8.7% to 39.0% with no apparent differences based on gender and aura status. Prevalence among controls was compatible with the literature. Migraine prevalence in RLS ranged from 15.1% to 62.6%. We did not pool prevalence data because of high unexplained heterogeneity. High heterogeneity with respect to the association between any migraine and RLS could be explained by study design. Pooled analyses showed substantially higher effect estimates in case-control studies (pooled OR = 4.19, 95% CI 3.07-5.71; I-2 = 0.0%) than in cohort studies (pooled OR = 1.22, 95% CI 1.14-1.30; I-2 = 0.0%).Conclusion: Our results support the concept of RLS as an important comorbidity of migraine. However, the degree of association appears to be strongly determined by study design. Potential effects by gender and aura status and the role of RLS in other headache disorders remain unclear.