Respiratory Syncytial Virus Prophylaxis in Infants With Congenital Diaphragmatic Hernia in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab, 2005-2017.

BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) are at an increased risk of respiratory morbidity from recurrent respiratory tract infections including those from respiratory syncytial virus (RSV). Prospective studies on RSV prophylaxis in CDH infants are limited. We determined the risk of respiratory illness- and RSV-related hospitalizations (RIH and RSVH, respectively) among infants prophylaxed for CDH, standard indications (SIs) and those without increased risk (NR). METHODS: The prospective Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab (CARESS) registry was searched for infants who received palivizumab during 12 RSV seasons (2005-2017) in Canada. Cox proportional hazards analyses were conducted to compare RIH and RSVH risks across the groups adjusted for potential confounders. RESULTS: In total, 21 107 infants (201 CDH, 389 NR, and 20 517 SI) were included. RIH incidences were 10.0% (CDH), 2.1% (NR), and 6.2% (SI). CDH patients had a significantly higher RIH hazard compared with NR (hazard ratio [HR], 3.6 [95% confidence interval {CI}, 1.5-8.8]; P = .005) but not SI (HR, 1.2 [95% CI, .8-2.0]; P = .379). RSVH incidences were 0.6%, 0.3%, and 1.5% for CDH, NR, and SI, respectively. RSVH risk was similar across groups (SI: HR, 0.0, P = .922; NR: HR, 0.0, P = .934). CONCLUSIONS: CDH infants had a 3-fold increased risk of RIH compared to NR but not SI infants. RSVH risk was similar with low RSVH incidences across all groups, implying that CDH infants may benefit from palivizumab during the RSV season, similar to other high-risk groups. CLINICAL TRIALS REGISTRATION: NCT00420966.

Association Between Endothelial Function and Cognitive Performance in Patients With Coronary Artery Disease During Cardiac Rehabilitation.

OBJECTIVE: Subtle cognitive deficits indicating early neural risk are common in the clinical presentation of coronary artery disease (CAD). Although deterioration may be mitigated by exercise, cognitive response to exercise is heterogeneous. Vasculopathy including endothelial dysfunction is a hallmark of CAD and may play an important role in impairing neural adaptation to exercise. This study aimed to assess peripheral measurements of endothelial function as predictors of cognitive performance in CAD participants undertaking cardiac rehabilitation (CR). METHODS: CAD patients (N = 64) undergoing CR were recruited for this prospective observational study. Neuropsychological and endothelial function assessments were performed at baseline and after 3 months of CR. Z-scores for overall cognitive performance and specific cognitive domains (verbal and visuospatial memory, processing speed, and executive function) were calculated. Endothelial function was measured by the reactive hyperemia index (RHI) using peripheral arterial tonometry. Cross-sectional and longitudinal associations between RHI and overall cognition were assessed using linear regressions and mixed models, respectively. Domain-specific associations were also explored. RESULTS: Although lower RHI was not associated with overall cognition at baseline (b = 0.26, p = .10), an increased RHI was significantly associated with an improvement in overall cognition (b = 0.55, p = .030) over 3 months. Lower RHI was associated with poorer verbal memory (ß = 0.28, p = .027) at baseline and an increased RHI over 3 months was associated with an improvement in processing speed (b = 0.42, p = .033). CONCLUSIONS: RHI may be a clinically useful predictor of cognitive change and might provide insight into the etiology of cognitive dysfunction in patients with CAD.

Respiratory illness and respiratory syncytial virus hospitalization in infants with a tracheostomy following prophylaxis with palivizumab.

Data on respiratory-related illness and respiratory syncytial virus (RSV) infection in children with a tracheostomy are sparse. We determined respiratory illness hospitalization (RIH) and RSV-related hospitalization (RSVH) hazard ratios in children with a tracheostomy following prophylaxis compared with infants' prophylaxed for standard indications (prematurity ≤ 35 weeks' gestational age, bronchopulmonary dysplasia, and significant congenital heart disease) and children with complex medical disorders. Children who received ≥ 1 injection of palivizumab were prospectively enrolled across 32 Canadian sites during the RSV season. Respiratory illness event data were collected monthly. Data were analyzed using t tests, chi-square tests, and Cox proportional hazards adjusted for confounders. A total of 23,597 infants were enrolled; 220 tracheostomy, 19,402 standard indications, 3975 complex medical disorders. Of the 220 tracheostomy infants, 30 had bronchopulmonary dysplasia, 18 were premature, 12 had congenital heart disease, and 160 had other medical complexities. RIH and RSVH incidences (tracheostomy, standard indications, complex medical disorders) were 24.5%, 6.2%, and 9.8% and 2.0%, 1.5%, and 1.8% respectively. RIH hazard was significantly higher in tracheostomy infants compared with standard indications (HR = 1.8, 95% CI 1.1-3.0, p = 0.02) but was similar between the tracheostomy and complex medical disorders groups (HR = 1.3, 95% CI 0.7-2.2, p = 0.37). RSVH hazard was also similar in tracheostomy infants relative to standard indications and complex medical disorders (both p > 0.75). Children with tracheostomies who received palivizumab had an increased RIH hazard compared with the standard indications group. Similar RSVH hazard between tracheostomy, standard indications, and complex medical disorders groups suggests that children with tracheostomies may benefit from palivizumab by reducing RSVH during the RSV season.

Respiratory syncytial virus prophylaxis in infants with congenital airway anomalies compared to standard indications and complex medical disorders.

An observational study was conducted of children < 2 years who received ≥ 1 dose of palivizumab in 32 Canadian institutions from 2005 to 2017. We compared respiratory illness (RIH) and respiratory syncytial virus-related hospitalization (RSVH) hazards in children with a congenital airway anomaly (CAA) versus those prophylaxed for standard indications (SI) and serious medical disorders (SMD). Data were assembled on neonatal course, demographics, palivizumab utilization and adherence, and respiratory illness events, and analyzed using ANOVA, chi-square tests and Cox proportional hazards. Twenty-five thousand three children (1219 CAA, 3538 SMD, and 20,246 SI) were enrolled. Palivizumab adherence was 74.8% overall and similar across groups. For 2054 respiratory-related events, 1724 children were hospitalized. RIH rates were 13.6% (CAA), 9.6% (SMD), and 6.0% (SI). RSVH rates were 2.4% (CAA), 1.6% (SMD), and 1.5% (SI). After adjustment for demographic and neonatal differences, children with a CAA had a significantly increased RIH and RSVH hazard relative to SI (RIH, HR = 1.6, 95% CI 1.2-2.2, p = 0.002; RSVH, HR = 2.1, 95% CI 1.0-4.4, p = 0.037) but similar to SMD (RIH, HR = 1.3, 95% CI 0.9-1.9, p = 0.190; RSVH, HR = 1.7, 95% CI 0.7-4.1, p = 0.277).Conclusion: Children with a CAA experience higher RIH risk. RSVH hazard was similar between CAA and SMD but higher for CAA compared to SI, implying that this population requires surveillance for RSV prophylaxis. What is Known: • Children with congenital airway anomalies (CAA) are at risk for respiratory tract illness and respiratory syncytial virus-related hospitalization (RSVH) with accompanying morbidity and mortality • RSV prophylaxis may be useful in children with a CAA, but is not routinely recommended What is New: • Children with a CAA had a 1.6-2.3 fold greater risk of respiratory-related hospitalization and RSVH compared to those prophylaxed for standard, approved indications and serious medical disorders. • RSVH risk in children aged < 2 years with either upper or lower airway anomalies is similar. Children with a CAA require careful surveillance during the RSV season and prophylaxis may be appropriate.

Validity of a novel screen for cognitive impairment and neuropsychiatric symptoms in cardiac rehabilitation.

BACKGROUND: Currently, there is no composite screening tool that can efficiently and effectively assess prevalent yet under-recognized cognitive and neuropsychiatric comorbidities in patients with cardiovascular disease. We aimed to determine the validity and feasibility of a novel screen assessing cognitive impairment, anxiety, apathy and depression (CAAD screen) in those attending cardiac rehabilitation (CR). METHODS: All patients diagnosed with cardiovascular disease or cardiovascular risk factors entering CR were screened as part of clinical care. A subset of those patients agreed to complete validation assessments (n = 127). Screen results were compared to widely accepted standards for cognition, anxiety, apathy, and depression using a modified receiver operating characteristic (ROC) and area under the curve analysis. RESULTS: The screen was completed by 97% of participants in 10 min or less with an average completion time of approximately 5 min. Screening scores adjusted for age, sex and years of education had acceptable or excellent validity compared to widely accepted standard diagnoses: CAAD-Cog (AUC = 0.80); CAAD-Anx (AUC = 0.81); CAAD-Apathy (AUC = 0.79) and CAAD-Dep (AUC = 0.85). CONCLUSIONS: The CAAD screen may be a valid and feasible tool for detecting cognitive impairment, anxiety, apathy and depression in CR settings.

Subcortical hyperintensities in the cholinergic system are associated with improvements in executive function in older adults with coronary artery disease undergoing cardiac rehabilitation.

OBJECTIVE: Coronary artery disease (CAD) is frequently accompanied by white matter hyperintensities and executive dysfunction. Because acetylcholine is important in executive function, these symptoms may be exacerbated by subcortical hyperintensities (SH) located in cholinergic (CH) tracts. This study investigated the effects of SH on cognitive changes in CAD patients undergoing a 48-week cardiac rehabilitation program. METHODS: Fifty patients (age 66.5 ± 7.1 years, 84% male) underwent the National Institute of Neurological Disorders and Stroke - Canadian Stroke Network neurocognitive battery at baseline and 48 weeks. Patients underwent a 48-week cardiac program and completed neuroimaging at baseline. Subcortical hyperintensities in CH tracts were measured using Lesion Explorer. Repeated measures general linear models were used to examine interactions between SH and longitudinal cognitive outcomes, controlling for age, education, and max VO2 change as a measure of fitness. RESULTS: In patients with SH in CH tracts, there was a significant interaction with the Trail Making Test (TMT) part A and part B over time. Patients without SH improved on average 16.6 and 15.0% on the TMT-A and TMT-B, respectively. Patients with SH on average showed no improvements in either TMT-A or TMT-B over time. There were no significant differences in other cognitive measures. CONCLUSION: These results suggest that CAD patients with SH in CH tracts improve less than those without SH in CH tracts, over 48 weeks of cardiac rehabilitation. Thus, SH in CH tracts may contribute to longitudinal cognitive decline following a cardiac event and may represent a vascular risk factor of cognitive decline. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

White Matter Microstructural Integrity Is Associated with Executive Function and Processing Speed in Older Adults with Coronary Artery Disease.

OBJECTIVE: Coronary artery disease (CAD) is associated with an increased risk of cognitive decline. Although cerebral white matter (WM) damage predicts cognitive function in CAD, conventional neuroimaging measures only partially explain the effect of CAD on cognition. The purpose of this study was to determine if WM microstructural integrity and CAD using diffusion tensor imaging (DTI) correlates with cognitive function in older adults with CAD. METHODS: Forty-nine CAD patients (66 ± 7 years old, 86% male) underwent neurocognitive assessments using the cognitive battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network for the study of vascular cognitive impairment. Composite scores for each cognitive domain were calculated. Microstructural integrity in normal-appearing WM was quantified as fractional anisotropy (FA) using DTI in nine bilateral and two interhemispheric WM tracts from the Johns Hopkins University WM Tractography Atlas. Linear regression models examined associations between FA and cognitive performance, controlling for age, sex, and education, with correction for multiple comparisons using a false discovery rate of 5%. RESULTS: Executive function was most significantly associated with FA in the left parahippocampal cingulum (ß = 0.471, t = 3.381, df = 44, p = 0.002) and left inferior fronto-occipital fasciculus (ß = 0.430, t = 2.984, df = 44, p = 0.005). FA was not associated with memory in any of the WM tracts examined. CONCLUSION: These results suggest that WM microstructural integrity may be an important neural correlate of executive function even in cognitively intact CAD patients. This study suggests WM damage may be relevant to subtle cognitive decline in a population that may have early neural risk for dementia.

Assessing cognitive effects of anticholinergic medications in patients with coronary artery disease.

BACKGROUND: Cognitive function is a significant determinant of overall quality of life in patients with coronary artery disease. Medications prescribed to control vascular risk factors often have anticholinergic effects, which can cause central side effects and affect cognitive function. OBJECTIVE: This cross-sectional study aimed to identify cognitive deficits associated with the use of anticholinergic medications in patients with coronary artery disease. METHODS: Demographics, medications, and vascular risk factors were assessed for each patient by interview and chart review. Anticholinergic burden was estimated using the anticholinergic cognitive burden scale. Cognition was assessed objectively using a battery of neuropsychologic tests, including the California Verbal Learning Test second edition, Revised Brief Visuospatial Memory Test, Stroop test, Trail-Making Test Parts A and B, Digit-Symbol Coding, FAS test, and animal naming. RESULTS: Patients with coronary artery disease (mean ± standard deviation age 64.2 ± 9.1, 15.3% female) presented with 2.6 ± 1.4 vascular risk factors and were using 5.1 ± 1.8 medications. Scores on the anticholinergic cognitive burden scale were associated with poorer performance on the Trail-Making Test Part A (ß = 0.280, p = 0.002), Trail-Making Test Part B (ß = 0.256, p = 0.004), and animal naming (ß = -0.212; p = 0.015) tasks in models controlling for age, gender, years of education, number of vascular risk factors and total medications. Beta-blockers frequently prescribed in this population (i.e., metoprolol and atenolol) accounted for a large proportion of the total anticholinergic cognitive burden score, and their use was independently associated with poorer cognitive performance in a post hoc model including the anticholinergic estimate. CONCLUSIONS: Anticholinergic exposure was associated with poorer performance on tests of attention, speed, and executive function in patients with coronary artery disease.

Ceramides predict verbal memory performance in coronary artery disease patients undertaking exercise: a prospective cohort pilot study.

BACKGROUND: Coronary artery disease (CAD) is associated with verbal memory decline, although deterioration may be mitigated in individuals undertaking exercise interventions. Ceramide sphingolipids, suggested to play a role in pathological neurodegeneration, have been associated with the development and progression of CAD but their relationship with cognitive response to exercise has not been assessed. In this study, concentrations of very long chain ceramides (C22:0 and C24:0) were assessed as predictors of changes in verbal memory performance over 1 year in subjects with CAD undertaking cardiac rehabilitation (CR). METHODS: Verbal memory was measured using the California Verbal Learning Test 2nd Ed. (CVLT-II), from which Z-scores were calculated based on age, gender and education matched norms. Baseline plasma C22:0 and C24:0 ceramide concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Repeated measures general linear models were used to determine the association between baseline plasma ceramides and the change in verbal memory performance over 1 year of CR controlling for age and body mass index (BMI). RESULTS: In patients with CAD (n = 33, mean age = 62 ± 9 years, 84.8% male, years of education = 17 ± 3 years), higher baseline plasma C22:0 (F1, 29 = 5.30, p = 0.03) and C24:0 (F1, 29 = 4.04, p = 0.05) concentrations significantly predicted less improvement in verbal memory performance over 1 year of CR controlling for age and BMI. CONCLUSIONS: Plasma ceramide concentrations should be further examined as potential predictors of cognitive response to exercise and worse cognitive outcomes in patients with CAD.

Verbal memory performance and completion of cardiac rehabilitation in patients with coronary artery disease.

OBJECTIVE: To assess cognitive performance as a predictor of noncompletion of cardiac rehabilitation (CR) using a standardized verbal memory test. METHODS: This was a prospective cohort study of consecutive patients with coronary artery disease (n = 131) entering 1-year outpatient CR between April 2007 and May 2009. Verbal memory performance was assessed using the California Verbal Learning Test, Second Edition. Attendance at weekly CR sessions was recorded, and completion or noncompletion was determined according to comprehensive CR criteria. Depression was diagnosed according to DSM-IV criteria as a possible confounder. RESULTS: Verbal memory performance at entry into CR differed significantly (F(1,130) = 7.80, p = .006) between noncompleters and completers (mean [SD] cumulative California Verbal Learning Test, Second Edition, score, -1.15 [2.59] versus 0.47 [3.12]) in analysis of covariance controlling for pertinent clinical confounders. Better verbal memory performance predicted a reduced risk of noncompletion (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.77-0.96, p = .009) in time-to-event analysis adjusted for depression (HR = 2.62, 95% CI = 1.33-5.17, p = .006) and smoking history (HR = 2.03, 95% CI = 0.98-4.22, p = .06). A post hoc analysis suggested that better verbal memory performance predicted a reduced risk of noncompletion for medical reasons (HR = 0.83, 95% CI = 0.70-0.99, p = .03). CONCLUSIONS: Poorer verbal memory performance was associated with an increased risk of noncompletion of CR among participants with coronary artery disease. Further studies exploring practical methods for screening and targeted support might improve rehabilitation outcomes.

Glutathione Peroxidase Activity Is Altered in Vascular Cognitive Impairment-No Dementia and Is a Potential Marker for Verbal Memory Performance.

BACKGROUND: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. OBJECTIVE: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. METHODS: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks. RESULTS: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (ß= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005). CONCLUSION: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness.

The association between placebo arm inclusion and adverse event rates in antidepressant randomized controlled trials: An examination of the Nocebo Effect.

BACKGROUND: Antidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo. METHODS: RCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo. RESULTS: Among the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p<0.001 and B=17.8, p<0.001, respectively). AE rates in patients receiving placebo were not different between study designs. LIMITATIONS: The present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials. CONCLUSIONS: The inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.

Respiratory Syncytial Virus Prophylaxis in Immunocompromised Children: Outcomes From the Canadian RSV Evaluation Study of Palivizumab Registry Over Twelve Seasons (2005-2017).

BACKGROUND: Immunocompromised children are at increased risk for respiratory syncytial virus (RSV) infection with associated morbidity and mortality. Prophylaxis is usually provided to these children on a case-by-case basis. METHODS: Immunocompromised children who received ≥1 injection of palivizumab were prospectively enrolled across 32 Canadian sites, between 2005 and 2017, during the RSV season. We assessed respiratory illness hospitalization (RIH) and RSV-related hospitalization (RSVH) hazard ratios (HRs) in immunocompromised children versus infants' prophylaxed for standard indications (SI: prematurity ≤35 weeks' gestation, bronchopulmonary dysplasia, and congenital heart disease) and complex medical disorders (CMD). Data were analyzed using t-tests, χ and Cox proportional hazards adjusted for confounders. RESULTS: A total of 25,003 infants were recruited; 214 immunocompromised, 4283 CMD, 20,506 SI. On average, children received 4.4 ± 1.3 injections. A total of 16,231 children were perfectly adherent (58.4% immunodeficiency, 68.9% CMD, 64.2% SI; P < 0.0005). A higher proportion of immunocompromised children were aboriginal and exposed to smoking compared with CMD and SI. Immunocompromised children also had a higher median; gestational and enrollment age and birth weight compared with CMD and SI. Immunodeficient children had a higher RIH risk compared with SI (HR = 2.4, 95% confidence interval, 1.3-4.7, P = 0.009) but were similar to CMD (HR = 1.7, 95% confidence interval, 0.9-3.4, P = 0.118). RSVH in prophylaxed, immunocompromised children was similar to CMD (HR < 0.005, P = 0.955) and SI (HR < 0.005, P = 0.953). CONCLUSIONS: Immunocompromised children who received palivizumab had an increased RIH hazard compared with the SI group. Similar RSVH hazard between the 3 groups suggests that immunocompromised children may benefit from palivizumab during the RSV season.

Cost-analysis of Withdrawing Immunoprophylaxis for Respiratory Syncytial Virus in Infants Born at 33-35 Weeks Gestational Age in Quebec: A Multicenter Retrospective Study.

BACKGROUND: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA. METHODS: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator). RESULTS: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient). CONCLUSIONS: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

Association Between Sphingolipids and Cardiopulmonary Fitness in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation.

The long-term benefits conferred by cardiac rehabilitation (CR) in those with coronary artery disease (CAD) are strongly linked with an improvement in cardiopulmonary fitness. This study aimed to determine the association between peripheral sphingolipids and cardiopulmonary fitness in CAD subjects undertaking CR. Patients with CAD (n = 100, mean age = 64 ± 6 years, 85% male, mean years of education = 17 ± 3 years) underwent 6 months of CR with blood collected at baseline, 3 and 6 months. Cardiopulmonary fitness was assessed by measuring peak oxygen uptake (VO2peak) at all time points. High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to quantify plasma sphingolipid concentrations. Cross-sectional and longitudinal associations between sphingolipids and VO2peak were assessed using linear regressions and mixed models, respectively. Higher concentrations of sphingomyelin C18:1 (ß = -0.26, p = .01), ceramides C16:0 (ß = -0.24, p = .02), C18:0 (ß = -0.29, p = .002), C20:0 (ß = -0.24, p = .02) and C24:1 (ß = -0.24, p = .01) and monohexylceramide C18:0 (ß = -0.23, p = .02) were associated with poorer VO2peak at baseline. An improvement in VO2peak was associated with a decrease in sphingomyelin C18:1 (b = -10.09, p = .006), ceramides C16:0 (b = -9.25, p = .0003), C18:0 (b = -5.44, p = .0003) and C24:1 (b = -2.46, p = .006) and monohexylceramide C18:0 (b = -5.37, p = .005). Specific long chain sphingolipids may be useful markers of fitness and response to exercise in CAD.

Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review.

BACKGROUND: Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. METHODS: This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A "nocebo index" was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). RESULTS: Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13-1.99) but had a nocebo index of 0.67. LIMITATIONS: This study relied on multiple RCTs with subtle design differences. CONCLUSIONS: This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

Endostatin as a Mediator Between Endothelial Function and Cognitive Performance in Those at Risk for Vascular Cognitive Impairment.

BACKGROUND: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. OBJECTIVE: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. METHODS: In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. RESULTS: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. CONCLUSION: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

Respiratory Syncytial Virus Prophylaxis in Neurologic and Muscular Disorders in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab.

BACKGROUND: This study aimed to examine the risk of respiratory-related hospitalization in children with neurologic and muscular disorders (NMDs) who received respiratory syncytial virus (RSV) prophylaxis in the Canadian RSV Evaluation Study of Palivizumab. METHODS: Canadian RSV Evaluation Study of Palivizumab is a prospective registry of children who received ≥1 palivizumab injection among 32 Canadian sites. Demographic data were collected at enrollment, and respiratory events were documented monthly. Cox proportional hazard analyses were conducted to compare respiratory illness-related hospitalization (RIH) and RSV-related hospitalization (RSVH) among children with NMD and those prophylaxed for standard indications (SI) and complex medical disorders. RESULTS: Group differences were found in enrollment age and weight, birth weight, household crowding, neonatal stay and supplemental oxygen requirement (all P < 0.05). RIH and RSVH incidences were 19.2%, 3.3% (NMD, n = 605); 6.0%, 1.5% (SI, n = 20,335), 9.4%, 1.6% (complex medical disorders, n = 4063), respectively. Children with NMD had a higher risk of RIH (hazard ratio [HR]: 1.90; 95% confidence interval (CI): 1.41-2.56; P < 0.0005) than those with SI. RSVH risk was greater in children with NMD compared with both the SI (HR: 2.26; 95% CI: 1.38-3.72; P = 0.001) and complex medical disorders groups (HR: 2.74; 95% CI: 1.55-4.84; P = 0.001). Children with more severe infantile onset NMD had a higher risk of RIH than those with general hypotonic disorders (HR: 1.69; 95% CI: 1.06-2.68; P = 0.027) but not RSVH. CONCLUSIONS: Children with NMD who received palivizumab had a higher risk of both RIH and RSVH. Our results imply that all children with NMD, regardless of disease severity, are at risk for respiratory-related illness and RSV infection.

Plasma Sphingolipids Mediate a Relationship Between Type 2 Diabetes and Memory Outcomes in Patients with Coronary Artery Disease Undertaking Exercise.

BACKGROUND: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. OBJECTIVE: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. METHODS: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. RESULTS: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [-2.32, -0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [-1.17, -0.05]). CONCLUSIONS: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.

Longitudinal associations between 4-hydroxynonenal and depression in coronary artery disease patients.

Depressive symptoms in patients with coronary artery disease (CAD) attenuate the cardiovascular benefits of cardiac rehabilitation (CR). Given that oxidative stress may be an important mechanism underlying depression, this study aimed to understand the longitudinal relationship between lipid peroxidation markers and depression in CAD. Serum levels of early (lipid hydroperoxides, LPH) and late (4­hydroxy­2-nonenal, 4-HNE; 8-isoprotane, 8-ISO) lipid peroxidation markers were measured in 120 CAD patients undergoing CR. The Structured Clinical Interview for DSM Axis I Disorders - Depression Module (SCID) was used to diagnose depression at baseline and the Center for Epidemiological Studies Depression Scale (CES-D) was used to measure depressive symptom severity. Multivariate mixed models compared the trajectories of serum LPH, 4-HNE, and 8-ISO between depressed and non-depressed CAD patients undergoing 6 months of CR. Similar models evaluated the associations between serum LPH, 4-HNE, and 8-ISO and CES-D score over the course of CR. Serum 4-HNE decreased less in CAD patients with depression compared to those without. In addition, a decrease in 4-HNE concentrations was significantly associated with a decrease in CES-D scores over 6 months. These findings suggest that 4-HNE may be an important marker of depressive symptoms in CAD and may be involved in its progression.