Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

An Analytic Model for Negative Obstacle Detection with Lidar and Numerical Validation Using Physics-Based Simulation.

Negative obstacles have long been a challenging aspect of autonomous navigation for ground vehicles. However, as terrestrial lidar sensors have become lighter and less costly, they have increasingly been deployed on small, low-flying UAV, affording an opportunity to use these sensors to aid in autonomous navigation. In this work, we develop an analytical model for predicting the ability of UAV or UGV mounted lidar sensors to detect negative obstacles. This analytical model improves upon past work in this area because it takes the sensor rotation rate and vehicle speed into account, as well as being valid for both large and small view angles. This analytical model is used to predict the influence of velocity on detection range for a negative obstacle and determine a limiting speed when accounting for vehicle stopping distance. Finally, the analytical model is validated with a physics-based simulator in realistic terrain. The results indicate that the analytical model is valid for altitudes above 10 m and show that there are drastic improvements in negative obstacle detection when using a UAV-mounted lidar. It is shown that negative obstacle detection ranges for various UAV-mounted lidar are 60-110 m, depending on the speed of the UAV and the type of lidar used. In contrast, detection ranges for UGV mounted lidar are found to be less than 10 m.

Evaluation of an Internet-based intervention for ICD patients with elevated symptoms of posttraumatic stress disorder.

BACKGROUND: To date, treatment to reduce posttraumatic stress disorder (PTSD) symptoms in implantable cardioverter defibrillator (ICD) patients has been limited by lack of symptom recognition, lack of provider referrals, barriers to treatment access, and inadequate evidence base of treatment effectiveness in this population. METHODS: Participants were 46 patients with ICDs (17 paired) with elevated PTSD symptoms who were recruited in electrophysiology clinics at community and university hospitals as well as ICD support forums. Participants were provided the Web-based, brief psychosocial intervention, which was tailored to ICD patients and contained elements of evidence-based cognitive-behavioral protocols for PTSD. Pretest and posttest measurement assessed participants' trauma experiences, mental health, and device-specific distress (device acceptance and shock anxiety). RESULTS: Postintervention scores on the PTSD Checklist (PCL; M = 35.5, SD = 10.09) were significantly lower than preintervention scores (M = 46.31, SD = 9.88), t (16) = 3.51, P = 0.003, d = 1.08. CONCLUSIONS: Preliminary results indicate that future research with a more robust design is warranted. Given limitations in accessibility of mental health providers to manage cardiac-related psychological sequelae, brief, Web-based intervention may be an effective, supplemental, clinical modality to offer treatment to this population.

Five-year rehospitalization experience of a state-wide cohort of persons with schizophrenia.

PURPOSE: This study has the objective of assessing the psychiatric rehospitalization experience of a large cohort of persons with schizophrenia and modeling the effects of personal and systemic conditions on rehospitalization risk. METHODS: The study employs a secondary analysis of US data from Massachusetts' casemix database of all patients discharged from acute general hospital units. It focuses on 11,291 patients during 1994-2000 who were discharged from acute adult psychiatric units. Predictors used include basic demographics, length of stay, continuity of care with doctors and facilities, diagnoses, discharge referral, type of insurance, and distance to and selected socioeconomic characteristics of the patient's home zip code. Data are analyzed with descriptive statistics and modeled with the Cox proportional hazard model. The model was assessed through split-half reliability testing, the generalized R2, and Harrell's Concordance Index. RESULTS: Overall, 13.4% of patients were rehospitalized within 1 month; 38.9% within 1 year; and 64.1% within 5 years. Predictors that are most strongly associated with lower rehospitalization rates include continuity of care, discharge to a chronic hospital, and density of home zipcode, whereas discharge to another acute psychiatric unit had the greatest effect on increasing risk of rehospitalization. Overall the Cox model has generalized R2 of 0.343 and a Concordance Index of 0.734. CONCLUSIONS: The results highlight the need to enhance the continuity of the relationships with providers, whether these are with the assigned psychiatrists or other therapists and case managers, as well as workplace issues involving staff turnover and hospital assignment and admitting policies.

Transfusion Requirements in Cardiac Surgery III (TRICS III): Study Design of a Randomized Controlled Trial.

OBJECTIVES: To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN: Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING: Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS: Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS: Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION: By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass.

PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation.

BRAF inhibitors (BRAFi) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma, but can lead to paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway. This can result in the promotion of precancerous lesions and secondary neoplasms, mainly (but not exclusively) associated with pre-existing mutations in RAS genes. We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF wt /KRAS G12D-metastatic colorectal cancer (CRC), whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib (GSK2118436). We used tissue from the resected CRC metastasis to derive a cell line, LM-COL-1, which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment. Novel BRAF inhibitors (PLX8394 and PLX7904), dubbed as "paradox breakers", were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation. In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling.

Cerebral Oximetry Monitoring to Maintain Normal Cerebral Oxygen Saturation during High-risk Cardiac Surgery: A Randomized Controlled Feasibility Trial.

BACKGROUND: Cerebral oxygen desaturation during cardiac surgery has been associated with adverse perioperative outcomes. Before a large multicenter randomized controlled trial (RCT) on the impact of preventing desaturations on perioperative outcomes, the authors undertook a randomized prospective, parallel-arm, multicenter feasibility RCT to determine whether an intervention algorithm could prevent desaturations. METHODS: Eight Canadian sites randomized 201 patients between April 2012 and October 2013. The primary outcome was the success rate of reversing cerebral desaturations below 10% relative to baseline in the intervention group. Anesthesiologists were blinded to the cerebral saturation values in the control group. Intensive care unit personnel were blinded to cerebral saturation values for both groups. Secondary outcomes included the area under the curve of cerebral desaturation load, enrolment rates, and a 30-day follow-up for adverse events. RESULTS: Cerebral desaturations occurred in 71 (70%) of the 102 intervention group patients and 56 (57%) of the 99 control group patients (P = 0.04). Reversal was successful in 69 (97%) of the intervention group patients. The mean cerebral desaturation load (SD) in the operating room was smaller for intervention group patients compared with control group patients (104 [217] %.min vs. 398 [869] %.min, mean difference, -294; 95% CI, -562 to -26; P = 0.03). This was also true in the intensive care unit (P = 0.02). There were no differences in adverse events between the groups. CONCLUSIONS: Study sites were successful in reversal of desaturation, patient recruitment, randomization, and follow-up in cardiac surgery, supporting the feasibility of conducting a large multicenter RCT.

Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia.

Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus-specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. © 2016 Wiley Periodicals, Inc.

Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study.

OBJECTIVE: Clinical handover is a critical moment in patient care. The authors tested the hypothesis that handover of anesthesia care is associated with increased mortality and morbidity in patients undergoing cardiac surgery. DESIGN: This was a single-center, retrospective cohort study of prospectively collected data. SETTING: The study was conducted in a quaternary care cardiac surgery center and university research hospital. PARTICIPANTS: All patients undergoing cardiac surgical procedures between April 1, 1999 and October 31, 2009 were included in the study. INTERVENTIONS: Propensity-score matching was used to adjust for differences between patients who received intraoperative handover of anesthesia care and those who did not, and in-hospital mortality and morbidity were compared using multivariate logistic modeling. MEASUREMENTS AND MAIN RESULTS: 14,421 patients met the inclusion criteria for this study; handover occurred in 966 cases (6.7%). After propensity-score matching, 7,137 patients were included for analysis. In-hospital mortality was 5.4% in the handover group and 4.0% in the non-handover group (match-adjusted odds ratio, 1.425; 95% confidence interval, 1.013-2.006; p = 0.0422); the incidence of major morbidity was 18.5% in the handover group and 15.6% in the non-handover group (match-adjusted odds ratio, 1.274; 95% confidence interval, 1.037-1.564; p = 0.0212). CONCLUSIONS: Handover of anesthetic care during cardiac surgery is associated with a 43% greater risk of in-hospital mortality and 27% greater risk of major morbidity. Further studies are required to explore this relationship and to systematically evaluate and improve the process of handover.

Impact of subglottic suctioning on the incidence of pneumonia after cardiac surgery: a retrospective observational study.

OBJECTIVE: Continuous aspiration of subglottic secretions (CASS) has been found to decrease the incidence of pneumonia in the general intensive care unit (ICU) population, but its benefit in cardiac surgery patients is unclear. The present study aimed to determine whether the routine use of CASS in cardiac surgical patients was associated with decreased pneumonia. DESIGN: A retrospective, single-center observational study. SETTING: The study was conducted in a quaternary care cardiac surgery center and university research hospital. PARTICIPANTS: 4,880 patients undergoing cardiac surgery were studied. INTERVENTIONS: The control group (no CASS) received a standard endotracheal tube and underwent surgery between April 1, 2007 and March 31, 2009. The intervention group (CASS) received a subglottic suctioning endotracheal tube and underwent surgery between June 1, 2009 and May 31, 2011. The primary outcome was the development of pneumonia, and the secondary outcomes were 30-day in-hospital mortality, ventilation time, need for tracheostomy, ICU length of stay (LOS), and hospital LOS. MEASUREMENTS AND MAIN RESULTS: The unadjusted incidence of pneumonia was 1.9% in the CASS group and 5.6% in the control group (p<0.0001). The CASS group also had lower 30-day in-hospital mortality (2.1% v 3.3%; p = 0.007), median ventilation time (8.42 v 7.3 hours; p<0.0001), and shorter median ICU LOS (1.77 v 1.17 days; p<0.0004) compared with the control group. Tracheostomy rates and median hospital LOS did not differ between groups. After adjusting using multivariable modeling, CASS remained an independent risk predictor for pneumonia (odds ratio [OR] 0.342, 95% confidence interval [CI] 0.239-0.490) and ICU LOS (OR 0.817, 95% CI 0.718-0.931). CONCLUSIONS: The universal implementation of CASS in a quaternary care cardiac surgical population was associated with a decreased incidence of pneumonia.